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Genetics for Pediatricians The Molecular Genetic Basis
of Pediatric Disorders 1st Edition Mohnish Suri Digital
Instant Download
Author(s): Mohnish Suri, Ian Young
ISBN(s): 9781901346633, 1901346633
Edition: 1
File Details: PDF, 1.43 MB
Year: 2005
Language: english
P481_GenForPed_Cov2.qxd 24/8/04 10:13 Page 1

Genetics for Pediatricians

Remedica genetics series

Genetic testing plays an important role in the investigation of almost

every child who presents with one of the many common inherited
disorders. It can be difficult for even the most conscientious
practitioner to keep abreast of developments and to appreciate
both the significance and the relevance of some of the major
discoveries of recent years. So, it is with the busy general
pediatrician in mind that this contemporary account of the
molecular aspects of pediatric disorders has been prepared.

“This text is designed to be readily accessible, and effectively

blends clinical features with molecular and clinical genetics.
It will provide a valuable bridge between standard pediatric
sources and Internet-provided databases. Suri and Young are
highly respected clinical geneticists with vast experience in
the pediatric applications of their speciality. They are also
accomplished communicators – they recognize the challenges
of clinical syndrome identification, and the necessity to balance
diagnostic enthusiasm with restraint when it comes to selecting
from an ever-expanding repertoire of investigations, many
Genetics for
Pediatricians
Mohnish Suri, Ian D Young
of which generate both personal and financial pressures.”
Derek Johnston
Children’s Department, University Hospital, Queen’s Medical
Centre, Nottingham, UK

“Pediatricians will find this easy-to-read book a major step forward

in their clinical practice. It should be of interest to working
pediatricians who need help in diagnosing syndromes and in
understanding the molecular tests that are needed for diagnosis.
It wisely does not attempt to discuss every single genetic condition
that exists, but confines itself to the important conditions.”
Jo Sibert Mohnish Suri
Head of Department and Professor of Child Health, Department of Ian D Young
Child Health, University of Wales School of Medicine, Cardiff, UK

Series Editor
ISBN 1-901346-63-3 Eli Hatchwell
Remedica

9 781901 346633
P481_GenForPed_Complete.qxd 7/9/04 16:03 Page a

Genetics for Pediatricians

P481_GenForPed_Complete.qxd 7/9/04 16:03 Page b

The Remedica Genetics for… Series

Genetics for Cardiologists
Genetics for Dermatologists
Genetics for Endocrinologists
Genetics for Hematologists
Genetics for Oncologists
Genetics for Ophthalmologists
Genetics for Orthopedic Surgeons
Genetics for Pediatricians
Genetics for Pulmonologists
Genetics for Rheumatologists

Published by Remedica Publishing

32–38 Osnaburgh Street, London, NW1 3ND, UK
20 N Wacker Drive, Suite 1642, Chicago, IL 60606, USA
E-mail: [email protected]
www.remedica.com

Publisher: Andrew Ward

In-house editors: Thomas Moberly and James Griffin

© 2004 Remedica Publishing

While every effort is made by the publishers and authors to see that no inaccurate or misleading data, opinions, or
statements appear in this book, they wish to make it clear that the material contained in the publication represents
a summary of the independent evaluations and opinions of the authors and contributors. As a consequence, the authors,
publishers, and any sponsoring company accept no responsibility for the consequences of any such inaccurate or
misleading data, opinions, or statements. Neither do they endorse the content of the publication or the use of any
drug or device in a way that lies outside its current licensed application in any territory.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or
by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher.

ISBN 1 901346 63 3
ISSN 1472 4618
British Library Cataloguing-in Publication Data
A catalogue record for this book is available from the British Library.
P481_GenForPed_Complete.qxd 7/9/04 16:03 Page c

Genetics for Pediatricians

Mohnish Suri
Department of Clinical Genetics
City Hospital
Nottingham
UK

Ian D Young
Department of Clinical Genetics
Leicester Royal Infirmary
Leicester
UK

Series Editor
Eli Hatchwell
Investigator
Cold Spring Harbor Laboratory
USA
P481_GenForPed_Complete.qxd 7/9/04 16:03 Page d

To our wives and parents.

P481_GenForPed_Complete.qxd 7/9/04 16:03 Page e

Introduction to the Genetics for… series

Medicine is changing. The revolution in molecular genetics has
fundamentally altered our notions of disease etiology and classification,
and promises novel therapeutic interventions. Standard diagnostic
approaches to disease focused entirely on clinical features and relatively
crude clinical diagnostic tests. Little account was traditionally taken
of possible familial influences in disease.

The rapidity of the genetics revolution has left many physicians behind,
particularly those whose medical education largely preceded its birth.
Even for those who might have been aware of molecular genetics and
its possible impact, the field was often viewed as highly specialist and
not necessarily relevant to everyday clinical practice. Furthermore, while
genetic disorders were viewed as representing a small minority of the
total clinical load, it is now becoming clear that the opposite is true:
few clinical conditions are totally without some genetic influence.

The physician will soon need to be as familiar with genetic testing as

he/she is with routine hematology and biochemistry analysis. While
rapid and routine testing in molecular genetics is still an evolving field,
in many situations such tests are already routine and represent essential
adjuncts to clinical diagnosis (a good example is cystic fibrosis).

This series of monographs is intended to bring specialists up to date in

molecular genetics, both generally and also in very specific ways that
are relevant to the given specialty. The aims are generally two-fold:

(i) to set the relevant specialty in the context of the new

genetics in general and more specifically

(ii) to allow the specialist, with little experience of genetics

or its nomenclature, an entry into the world of genetic
testing as it pertains to his/her specialty

These monographs are not intended as comprehensive accounts of

each specialty — such reference texts are already available. Emphasis
has been placed on those disorders with a strong genetic etiology
and, in particular, those for which diagnostic testing is available.

Genetics for Pediatricians

P481_GenForPed_Complete.qxd 7/9/04 16:03 Page f

The glossary is designed as a general introduction to molecular genetics

and its language.

The revolution in genetics has been paralleled in recent years by

the information revolution. The two complement each other, and the
World Wide Web is a rich source of information about genetics. The
following sites are highly recommended as sources of information:

1. PubMed. Free on-line database of medical literature.

http://www.ncbi.nlm.nih.gov/PubMed/

2. NCBI. Main entry to genome databases and other

information about the human genome project.
http://www.ncbi.nlm.nih.gov/

3. OMIM. Online Mendelian Inheritance in Man. The Online

version of McKusick’s catalogue of Mendelian disorders.
Excellent links to PubMed and other databases.
http://www.ncbi.nlm.nih.gov/omim/

4. Mutation database, Cardiff.

http://www.uwcm.ac.uk/uwcm/mg/hgmd0.html

5. National Coalition for Health Professional Education in Genetics.

An organization designed to prepare health professionals for the
genomics revolution. http://www.nchpeg.org/

Finally, a series of articles from the New England Journal of Medicine,

entitled Genomic Medicine, has been made available free of charge at
http://www.nejm.org.

Eli Hatchwell
Cold Spring Harbor Laboratory

Introduction
P481_GenForPed_Complete.qxd 7/9/04 16:03 Page g

Preface
There can be very few areas of medicine in which progress has been
achieved at such a rapid pace as molecular genetics. Almost every
common single-gene disorder has succumbed to the march of scientific
progress to the extent that genetic testing now plays an important role in
the investigation of almost every child who presents with one of the many
common inherited disorders which make a major contribution to pediatric
morbidity and mortality throughout the world. The rate of progress is
such that it can be difficult for even the most conscientious practitioner
to keep abreast of developments and to appreciate both the significance
and the relevance of some of the major discoveries of recent years.

It is with the busy general pediatrician in mind that this contemporary

account of the molecular aspects of pediatric disorders has been
prepared. The number of conditions which have been mapped or in
which the causative gene has been isolated is vast. Thus in order to
ensure that this text is of manageable proportions, coverage has been
restricted to the more common single-gene disorders which are likely to
be encountered in general pediatric practice. “Small print” obscurities
and the many inborn errors for which comprehensive biochemical
testing is available have generally been omitted. Instead attention
has been focused on the more common conditions in which molecular
analysis can play an important role in diagnosis or in the management
of a child and his or her family. In some instances, notably with eye
and skin disorders, we have also omitted rare disorders which fall
within the remit of other specialties, particularly when these have
received detailed coverage in other books in this series.

In addition to providing a unique insight into the cause of so many

previously unexplained disorders, recent advances in molecular
genetics have also demonstrated that, far from being straightforward,
Mendelian inheritance and its contribution to genetic disease can be
remarkably complex. Thus a “simple” disorder such as cystic fibrosis
has proved to be extremely heterogeneous both clinically and at the
molecular level, with over 1,000 different mutations reported at the
main disease locus. Indeed, for many conditions such as cystic fibrosis
and β-thalassemia, mutational heterogeneity has proved to be the
norm. Entities such as nonsyndromal sensorineural hearing loss illustrate

Genetics for Pediatricians

P481_GenForPed_Complete.qxd 7/9/04 16:03 Page h

that locus heterogeneity can also be extremely important. Further

examples of etiologic complexity are provided by the Bardet–Biedl
syndrome, which shows not only locus heterogeneity but also the
curious phenomenon of triallelic inheritance, and by Hirschsprung
disease, for which the concept of synergistic heterozygosity has started
to shed light on how genes at several loci can interact to contribute to
what is commonly referred to as oligogenic or polygenic inheritance.
And if this was not enough, research on pediatric disorders such as
the fragile X syndrome and the Angelman/Prader–Willi syndromes has
identified “new” genetic mechanisms such as triplet repeat instability
with anticipation, and imprinting/uniparental disomy, respectively.
So as well as providing a useful up-to-date account of molecular
pathogenesis, we hope that this text will also help readers become
better acquainted with some of the new and exciting developments that
have characterized molecular genetic research over the last few years.

In writing this book we would like to offer our thanks to colleagues who
have provided photographs, and to Mrs Diane Castledine for secretarial
assistance. Above all we would like to express our gratitude to, and
admiration for, the many children and families who, over the years,
have taught us so much more than they could possibly have learned
from us.

Mohnish Suri
Ian D Young

Preface
P481_GenForPed_Complete.qxd 7/9/04 16:03 Page i

Contents
1. Progressive Ataxias and Neurologic Disorders 1
Ataxia–Telangiectasia 2
Duchenne Muscular Dystrophy 4
Facioscapulohumeral Muscular Dystrophy 7
Friedreich Ataxia 8
Hereditary Motor and Sensory Neuropathy 10
Limb-girdle Muscular Dystrophy 18
Myotonic Dystrophy 23
Spinal Muscular Atrophy 27

2. Cerebral Malformations and Mental Retardation Syndromes 29

Angelman Syndrome 30
Fragile X Syndrome 34
Holoprosencephaly 36
Hunter Syndrome 40
Huntington Disease 41
Lesch–Nyhan Syndrome 43
Lissencephaly 45
Lowe Syndrome 52
Neuronal Ceroid Lipofuscinosis 53
Pelizaeus–Merzbacher Syndrome 57
Prader–Willi Syndrome 59
Rett Syndrome 61
X-linked Adrenoleukodystrophy 62
X-linked α-Thalassemia and Mental Retardation Syndrome 64
X-linked Hydrocephalus 66

3. Disorders of Vision 69
Aniridia 70
Bardet–Biedl Syndrome 72
Juvenile Retinoschisis 74
Leber Congenital Amaurosis 75
Norrie Disease 79
Rieger Syndrome 80

Genetics for Pediatricians

P481_GenForPed_Complete.qxd 7/9/04 16:03 Page j

4. Hearing Disorders 83
Nonsyndromal Hearing Loss 84
Hearing Loss due to Connexin 26 Gene Defect 85
Pendred Syndrome 86
Usher Syndrome 87
Waardenburg Syndrome 90

5. Neurocutaneous Disorders and Childhood Cancer 93

Multiple Endocrine Neoplasia Type 2 94
Neurofibromatosis Type 1 96
Retinoblastoma 98
Tuberous Sclerosis 101
von Hippel–Lindau Disease 103

6. Connective Tissue and Skeletal Disorders 107

Achondroplasia 108
Ehlers–Danlos Syndrome 110
Hereditary Multiple Exostoses 115
Marfan Syndrome 117
Osteogenesis Imperfecta 119
Pseudoachondroplasia 124
Stickler Syndrome 125

7. Cardio-respiratory Disorders 129

Barth Syndrome 130
Cystic Fibrosis 131
DiGeorge/Shprintzen Syndrome 133
Holt–Oram Syndrome 135
Laterality Defects 137
Noonan Syndrome 138
Primary Ciliary Dyskinesia 139
Williams Syndrome 141

Contents
P481_GenForPed_Complete.qxd 7/9/04 16:03 Page k

8. Craniofacial Disorders 143

Apert Syndrome 144
Crouzon Syndrome 146
Greig Syndrome 148
Pfeiffer Syndrome 149
Rubinstein–Taybi Syndrome 151
Saethre–Chotzen Syndrome 152
Sotos Syndrome 153
Treacher Collins Syndrome 154
Van der Woude Syndrome 155

9. Endocrine Disorders 157

Androgen Insensitivity Syndrome 158
Congenital Adrenal Hyperplasia 160
Diabetes Insipidus 163
Growth Hormone Deficiency 164
Growth Hormone Receptor Defects 166
Panhypopituitarism 167
Pseudohypoparathyroidism 169

10. Gastrointestinal and Hepatic Diseases 173

Alagille Syndrome 174
α1-Antitrypsin Deficiency 175
Hirschsprung Disease 177

11. Hematologic Disorders 181

Fanconi Anemia 182
Glucose-6-Phosphate Dehydrogenase Deficiency 183
Hemophilia A 185
Hemophilia B 187
Hereditary Elliptocytosis 189
Hereditary Spherocytosis 190
Sickle Cell Anemia 193
α-Thalassemia 194
β-Thalassemia 197
von Willebrand Disease 198

Genetics for Pediatricians

P481_GenForPed_Complete.qxd 7/9/04 16:03 Page l

12. Immunologic Disorders 201

Bruton Agammaglobulinemia 202
Chronic Granulomatous Disease 203
Severe Combined Immunodeficiency 205
Wiskott–Aldrich Syndrome 207

13. Metabolic Disorders 209

Medium Chain Acyl-CoA Dehydrogenase Deficiency 210
Menkes Disease 211
Ornithine Transcarbamylase Deficiency 212
Phenylketonuria 214
Wilson Disease 215

14. Renal Disorders 217

Alport Syndrome 218
Beckwith–Wiedemann Syndrome 220
Cystinosis 224
Orofaciodigital Syndrome Type I 225
Polycystic Kidney Disease 226

15. Abbreviations 229

16. Glossary 235

17. Index 285

Contents
P481_GenForPed_Complete.qxd 7/9/04 16:03 Page 1

1
1. Progressive Ataxias and Neurologic Disorders

Ataxia–Telangiectasia 2
Duchenne Muscular Dystrophy 4
Facioscapulohumeral Muscular Dystrophy 7
Friedreich Ataxia 8
Hereditary Motor and Sensory Neuropathy 10
Limb-girdle Muscular Dystrophy 18
Myotonic Dystrophy 23
Spinal Muscular Atrophy 27
P481_GenForPed_Complete.qxd 7/9/04 16:03 Page 2

Ataxia–Telangiectasia
(also known as: AT; Louis-Bar syndrome)

MIM 208900

Clinical features AT is a neurocutaneous syndrome. Patients present with progressive

truncal and gait ataxia, unusual head movements, choreoathetosis, and
oculomotor apraxia in both horizontal and vertical gaze. Other features
include motor developmental delay, dysarthria, and mask-like facies.
Telangiectasia appears over the bulbar conjunctiva, face, and ears from
the age of 3–4 years (see Figure 1). Many children have a history of
recurrent respiratory infections, and 30%–40% of patients develop
a malignancy. These include T-cell leukemias and B-cell lymphomas
in children and epithelial tumors (such as breast and ovarian cancer)
in adults. Patients with AT usually survive into their twenties, although
longer survival periods have been documented. Investigations show
elevated levels of α-fetoprotein and carcinoembryonic antigen
and reduced levels of immunoglobulin (Ig)G2, IgA, and IgE.
Chromosome analysis can show reciprocal balanced translocations
involving the short arm of chromosome 7 and the long arm of
chromosome 14, or the short arm of chromosome 2 and the
long arm of chromosome 22.

Age of onset Most children present with ataxia between the ages of 1 and 3 years.

Epidemiology The population incidence is estimated to be about 1 in 40,000 to

1 in 100,000 live births. About 1% of the general population are
believed to be carriers (heterozygotes).

Inheritance Autosomal recessive

Chromosomal 11q22.3
location

Gene ATM (ataxia–telangiectasia mutated)

Mutational Over 400 mutations have been described. These include small and large
spectrum deletions and insertions, as well as nonsense, missense, and splice-site
mutations. About 65%–70% of mutations result in protein truncation,
and these mutations produce no detectable protein. The remaining

2 Ataxia–Telangiectasia
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 3

Figure 1. Telangiectasia over the

bulbar conjunctiva in a child with
ataxia–telangiectasia.

mutations result in the production of a normal-sized protein that is

nonfunctional. Almost all nonconsanguineous patients are compound
heterozygotes, ie, they have different mutations in their two ATM alleles.

Molecular ATM has 66 exons and encodes a protein with 3,056 amino acids.
pathogenesis The ATM protein is ubiquitously expressed and has homology to yeast
and mammalian phosphatidylinositol-3 kinases, which are involved in
signal transduction, cell cycle control, and DNA repair. It is believed that
the ATM protein phosphorylates several other proteins, including p53,
ABL, BRCA1, TERF1, RAD9, and nibrin (the protein product of the gene
for Nijmegen breakage syndrome, MIM 251260), after cell exposure to
ionizing radiation. This delays the progression of the cell through the cell
cycle at the G1/S checkpoint, allowing the cell to repair DNA damage
before entering the S phase. Without ATM protein the cell would be able
to progress to the S phase without repairing the DNA damage sustained
by radiation exposure, which could predispose to the development of
cancer. The molecular pathogenesis of the neurocutaneous phenotype
of AT is unknown.

Genetic diagnosis The diagnosis can be confirmed by demonstrating increased

and counseling chromosomal breakage in cultured lymphocytes after X-irradiation
and reduced or absent expression of ATM protein in lymphocytes.
Genetic testing is only available on a research basis.

Progressive Ataxias and Neurologic Disorders 3

P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 4

Counseling is on the basis of autosomal recessive inheritance.

Carrier females (particularly those who carry a missense mutation)
are at increased risk of developing breast cancer. Missense mutations
in ATM are believed to be associated with an increased cancer risk
as a result of a dominant-negative effect.
Prenatal diagnosis is possible by linkage analysis or by ATM mutation
analysis if mutations have been identified previously in an affected
child from the family. Prenatal diagnosis has been attempted by
amniocentesis followed by X-irradiation of cultured amniocytes
to look for chromosomal breakage, but this method of prenatal
diagnosis is unreliable.

Duchenne Muscular Dystrophy

(also known as: DMD)

MIM 310200

Clinical features This condition mainly affects males, who present with delayed
motor-developmental milestones, proximal muscle weakness with
pseudohypertrophy of some muscles, particularly the calves (see
Figure 2), and cardiomyopathy. The muscle weakness is progressive.
In classical cases, loss of ambulation occurs before the age of 12 years
and death occurs in the twenties. Intermediate forms of DMD exist
in which progression is slower, with loss of ambulation occurring
between 11 and 16 years of age. Learning difficulties are seen in
approximately 60% of patients. Death is usually due to respiratory
infection or cardiomyopathy. About 2.5% of female carriers are
symptomatic (manifesting carriers).

Figure 2. Calf hypertrophy in a boy with Duchenne muscular dystrophy.

4 Duchenne Muscular Dystrophy

P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 5

Age of onset Usually in the first year of life, although diagnosis is often delayed.

Epidemiology This is the most common form of muscular dystrophy, affecting

1 in 3,500 live-born males. The prevalence of symptomatic carriers
in the female population is estimated to be 1 in 100,000.

Inheritance X-linked recessive

Chromosomal Xp21.2
location

Gene DMD (dystrophin)

Mutational An intragenic deletion that involves one or more exons is present in

spectrum 65%–70% of patients. There are two deletion hotspots, one between
exons 2 and 20 and the other between exons 44 and 53. Intragenic
duplications are seen in 5%–6% of cases. The remainder of cases
involve point mutations (nonsense, missense, and splice-site
mutations), which are distributed across the whole gene.

Molecular DMD is the largest known gene in the human genome. It is 2.4 Mb
pathogenesis in size and composed of 79 exons. It encodes a large, rod-shaped
cytoskeletal protein made up of 3,685 amino acids. The dystrophin
protein has an actin-binding domain, two calpain-homology domains,
22 spectrin repeats, one WW domain (a short domain of about 40 amino
acids that contains two tryptophan residues that are spaced 20–23 amino
acids apart – the term WW derives from the two tryptophan residues,
as the single letter code for tryptophan is W) and one ZZ-type zinc finger
domain. The gene is subject to alternative splicing, and there are at
least four isoforms of dystrophin. These include a muscle (M) isoform,
a brain (B) isoform, and a cerebellar Purkinje (CP) isoform.
Dystrophin is expressed in several tissues and plays an important role
in anchoring the cytoskeleton to the plasma membrane. In muscle,
dystrophin links the sarcolemmal cytoskeleton to the extracellular matrix.
It is thought to protect the sarcolemma during muscular contractions.
Mutations that result in the DMD phenotype are associated with protein
truncation or loss of the translational reading frame. These mutations
result in the absence of dystrophin.
Mutations that maintain the translational reading frame result in the
phenotype of Becker muscular dystrophy (MIM 300376). These

Progressive Ataxias and Neurologic Disorders 5

P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 6

mutations result in the production of a shortened and only partially

functional protein. Patients with Becker muscular dystrophy have
clinical features similar to those of DMD, but the condition is milder,
progression is slower, and survival is prolonged.

Mutations in the 5´ end of DMD and in-frame deletions in exons 48

and 49 can also cause X-linked dilated cardiomyopathy (MIM 302045).
Mutations in the 5´ end of DMD result in failure to transcribe the M
isoform in skeletal and cardiac muscle. However, the absence of this
isoform in skeletal muscle can be compensated for by up-regulation of
the B and CP isoforms. This does not appear to be the case in cardiac
muscle, where the lack of dystrophin expression results in cardiomyopathy.
The mechanism by which in-frame deletions in exons 48 and 49
cause X-linked dilated cardiomyopathy is not understood, but it
has been suggested that intron 48 might contain sequences that
are necessary for the expression of dystrophin in cardiac muscle.

Genetic diagnosis The diagnosis of DMD is based on clinical features, markedly

and counseling elevated plasma creatine kinase (CK) levels, muscle biopsy (with
immunohistochemistry using monoclonal antibodies to dystrophin),
and mutation testing. Routine genetic testing can only detect intragenic
deletions and duplications. Testing for point mutations in DMD is only
undertaken in a few specialized research laboratories and is best
performed on dystrophin mRNA extracted from a fresh or frozen
muscle biopsy.
Genetic counseling is on an X-linked recessive basis. Female relatives
of affected males who have an intragenic deletion or duplication can be
offered carrier testing. Carrier females have a 50% chance of having an
affected son, and can be offered a reliable genetic prenatal test for this
condition by chorionic villus sampling.
There is a two-thirds chance that the mother of a sporadic case
(single affected male with no family history) is a carrier. The mother
of a sporadic case can also have somatic or gonadal mosaicism for the
DMD mutation. Therefore, there is a 10%–15% recurrence risk of DMD
in a subsequent pregnancy for the mother of a sporadic case. In DMD
families in which the DMD mutation cannot be identified, carrier testing
involves linkage analysis and serial plasma CK assays. Linkage analysis
using intragenic and flanking markers can also be used for prenatal
diagnosis in these families.

6 Duchenne Muscular Dystrophy

P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 7

Facioscapulohumeral Muscular Dystrophy

(also known as: FSHMD)

MIM 158900 (type 1A)

158901 (type 1B)

Clinical features This is a slowly progressive muscular dystrophy. The affected patient
usually presents with facial weakness, shoulder-girdle weakness and
wasting, and scapular winging. Later, there is involvement of feet
and hip-girdle dorsiflexors. There is often striking wasting of the neck
muscles and the muscles of the upper arm. Retinal vasculopathy and
high-frequency sensorineural hearing loss are also recognized features.

Age of onset Late childhood or adolescence.

Epidemiology The incidence of FSHMD is approximately 1 in 20,000.

Inheritance Autosomal dominant

Chromosomal Type 1A: 4q35

location Type 1B: unknown

Gene Unknown (both types)

Mutational Most cases of FSHMD are type 1A. Although the gene for this
spectrum condition has not yet been identified, almost all patients have a
chromosomal rearrangement in the subtelomeric region of the long
arm of chromosome 4 (4q35). This region contains a polymorphic
3.3-kb repeat element termed D4Z4. In the general population, the
number of D4Z4 repeats varies from 10 to more than 100. Affected
individuals have a deletion in this region that reduces the number
of D4Z4 repeats to less than 10. This reduction is the basis of
a diagnostic molecular genetic test for FSHMD type 1A.

Molecular Unknown. It has been suggested that deletion of the D4Z4 repeat
pathogenesis sequences could interfere with the expression of a gene located some
distance away on the long arm of chromosome 4 by a “position effect”.
Recent work suggests that an element within the D4Z4 repeat sequence
specifically binds a multiprotein complex that mediates transcriptional
repression of genes at 4q35. Deletion of D4Z4 sequences below a certain
number could result in a reduction in the number of repressor complexes.

Progressive Ataxias and Neurologic Disorders 7

P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 8

This could decrease or abolish the transcriptional repression of 4q35

genes, with overexpression of one or more of these genes resulting
in the FSHMD phenotype.

Genetic diagnosis Genetic testing is routinely available and enables a diagnosis to

and counseling be made in most cases. Counseling is on the basis of autosomal
dominant inheritance. About 30% of patients represent new mutations.
The condition demonstrates 95% penetrance by the age of 20 years,
although penetrance is lower in females. Anticipation has been
described in some families. Prenatal testing can be done by
genetic testing or, in suitable families, by linkage analysis.

Friedreich Ataxia
MIM 229300 (Friedreich ataxia 1)
601992 (Friedreich ataxia 2)

Clinical features This is the most common cause of cerebellar ataxia in childhood.
Affected children present with dysarthria and progressive ataxia of
their gait. Neurologic examination demonstrates weakness of the
lower limbs, absent knee and ankle jerks, extensor plantar reflexes,
decreased position and vibration sense in legs, positive Romberg
sign, and pes cavus. Other features include scoliosis, diabetes
mellitus, optic atrophy, and deafness. Nerve conduction studies
show reduced or absent sensory action potentials, but normal
motor-nerve conduction velocities. Echocardiograms show
features of hypertrophic cardiomyopathy in 70% of patients.

Age of onset Usually between 5 and 15 years of age. Almost all cases present
before the age of 25 years, although onset after this age has also
been described (late-onset form).

Epidemiology The estimated population prevalence is 1–2 per 50,000. The carrier
(heterozygote) frequency is between 1 in 60 and 1 in 110.

Inheritance Autosomal recessive

Chromosomal Friedreich ataxia 1: 9q13

location Friedreich ataxia 2: 9p11–p23

8 Friedreich Ataxia
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 9

Gene Friedreich ataxia 1: FRDA (frataxin)

Friedreich ataxia 2: unknown

Mutational FRDA has seven exons that are subject to alternative splicing. The major
spectrum protein product of this gene is the 210-amino-acid protein frataxin.
This is encoded by exons 1–4 spliced to exon 5A. The majority of
patients (~96%) are homozygous for an expansion of a GAA triplet
repeat motif in the first intron of the gene. The normal number of
GAA triplet repeats is 9–22. In affected individuals the size range is
66–1,700 repeats, with most patients having 600–1,200 repeats.
The remaining patients are compound heterozygotes for a pathogenic
GAA repeat expansion in one FRDA allele and an inactivating mutation
(nonsense or frame-shift) in the other allele.

Molecular Frataxin is located in the inner mitochondrial membrane, where it plays

pathogenesis an important role in oxidative phosphorylation and iron homeostasis.
The GAA repeat expansion interferes with the transcription of FRDA,
resulting in frataxin deficiency. This is associated with a defect of
mitochondrial oxidative phosphorylation and accumulation of iron
within the mitochondria. Thus, Friedreich ataxia is essentially a
mitochondrial disorder and this is reflected in its clinical features.

Genetic diagnosis Genetic testing is available from diagnostic laboratories. However,

and counseling it is limited to testing for the pathogenic GAA repeat expansion.
Counseling is on the basis of autosomal recessive inheritance.
The sibling recurrence risk is 25%, but there can be marked
variability in the expression of the condition in members of the
same family. This can manifest as a different age of onset and/or
a difference in the rate of progression.
Carrier testing and prenatal diagnosis are available in families where
molecular genetic analysis has confirmed that the affected individual
is homozygous for a GAA repeat expansion.

Progressive Ataxias and Neurologic Disorders 9

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Hereditary Motor and Sensory Neuropathy

(also known as: HMSN; Charcot–Marie–Tooth disease; peroneal muscular atrophy)

The hereditary motor and sensory neuropathies are a clinically and genetically heterogeneous
group of disorders. Four main clinical phenotypes can be recognized: classical HMSN,
Dejerine–Sottas syndrome, congenital hypomyelinating neuropathy (CHN), and hereditary
neuropathy with liability to pressure palsies (HNPP). Each of these phenotypes is discussed
in turn. Table 1 summarizes the classification, distinguishing clinical features, inheritance
patterns, and molecular genetics of the various forms of HMSN.

MIM See Table 1.

Clinical Features Classical HMSN/HMSN I & II

Patients with classical HMSN present with distal weakness and wasting of
the legs, often associated with pes cavus and loss of ankle jerks. Sensory
symptoms are usually mild and include paresthesia of the hands and feet.
The condition progresses at a variable rate to involve the small muscles of
the hands and proximal parts of the lower limbs. Classical HMSN patients
can be divided into two groups based on their nerve conduction velocities
(NCVs). Patients with HMSN I have a demyelinating neuropathy with
reduced NCVs (patients over the age of 2 years have a motor NCV of
<38 m/s in the median nerve). Patients with HMSN II have an axonal form
of neuropathy, with normal or only slightly reduced NCVs (patients over
the age of 2 years have a motor NCV of >38 m/s in the median nerve).
Dejerine–Sottas syndrome/HMSN III
The Dejerine–Sottas syndrome phenotype is more severe than that of
classical HMSN, and patients with this condition present with hypotonia,
generalized muscle weakness, motor developmental delay, ataxia, and
areflexia. They often have palpable peripheral nerves. Muscle weakness
tends to progress more rapidly than in classical HMSN, and patients are
often nonambulatory by adolescence. However, the condition is quite
variable in its severity and progression. Nerve conduction studies show
very low NCVs (often <10 m/s), in association with demyelination
with onion-bulb formation or hypomyelination on sural nerve biopsy.
HMSN IV
Autosomal recessive forms of HMSN I are designated HMSN IV.
The phenotype is similar to that of HMSN I, but HMSN IV tends to
present earlier and progress more rapidly. NCVs are usually <20 m/s.

10 Hereditary Motor and Sensory Neuropathy

P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 11

Congenital hypomyelinating neuropathy

This is the most severe form of HMSN. Affected children present in
infancy with severe hypotonia, generalized weakness, and areflexia.
The condition can mimic spinal muscular atrophy, though nerve
conduction studies show very slow or unrecordable NCVs and sural
nerve biopsy shows amyelination or hypomyelination of nerve fibers.
Affected children can have respiratory and swallowing difficulties,
and an arthrogryposis-like presentation has also been described.
CHN can take a lethal course, causing early death, though
improvement has been described in some children.
Hereditary neuropathy with liability to pressure palsies
This is the mildest form of HMSN. Affected individuals present with
recurrent peroneal- and ulnar-nerve pressure palsies, from which they
often make a complete recovery. Nerve conduction studies show slightly
reduced NCVs, with prolonged distal motor latencies of median and
peroneal nerves. Sural nerve biopsy shows sausage-shaped swellings of
the myelin sheath of nerve fibers. These swellings are called tomaculae.

Age of onset HMSN I and II usually present in the first decade of life, but onset can
also occur in adult life.
HMSN III usually presents in the first 2 years of life.
HMSN IV usually presents in the first decade of life.
CHN usually presents at birth or during early infancy.
HNPP usually presents in adult life.

Epidemiology The population prevalence of all forms of HMSN is about 1 in 2,500.

Inheritance, See Table 1.

chromosomal
location, gene, and
mutational spectrum

Molecular PMP22 is composed of four exons. It is expressed in Schwann cells

pathogenesis and encodes a 160-amino-acid integral membrane protein called
peripheral myelin protein 22. This protein is involved in the formation
and compaction of myelin in peripheral nerves. Mutations in PMP22
cause HMSN I, HMSN III, and HNPP. Duplication of PMP22 is believed
to cause HMSN IA by a dosage effect. It has been suggested that
overexpression of PMP22 could cause the protein to accumulate

Progressive Ataxias and Neurologic Disorders 11

P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 12

in the late Golgi-cell membrane compartment of Schwann cells, which

could interfere with normal myelin assembly. Deletions of PMP22 cause
HNPP as a result of haploinsufficiency. Point mutations in PMP22
are associated with a more severe phenotype than duplications of this
gene, and are believed to cause HMSN by a dominant-negative effect
(ie, the mutant protein interferes with the function of the normal
protein produced by the normal allele of this gene).
MPZ has seven exons and encodes a 248-amino-acid integral
membrane protein called myelin protein zero. This protein has
a large extracellular domain containing an immunoglobulin V-type
fold, a single transmembrane segment, and a short cytoplasmic
C-terminal end. Myelin protein zero is a major structural component
of the myelin of peripheral nerves and is involved in the formation
and compaction of myelin. Mutations in this gene can cause HMSN I,
II, III, and CHN by interfering with the function of the protein in the
myelin sheath of peripheral nerves.
LITAF is a widely expressed gene with four exons that encodes a
161-amino-acid protein called lipopolysaccharide-induced tumor
necrosis factor-α factor. This protein plays an important role in the
regulation of tumor necrosis factor-α and could play a role in protein
degradation pathways. Missense mutations in this gene cause
HMSN IC, but the precise molecular mechanism is unknown.
EGR2 has two exons and encodes a transcription factor protein (early
growth response 2) with 476 amino acids. This protein is involved
in the differentiation and maintenance of Schwann cells by regulating
transcription of MPZ and PRX. Mutations in EGR2 can cause HMSN I,
HMSN III, and CHN.
NEFL contains four exons. It encodes the neurofilament protein
(light polypeptide) that has 543 amino acids. This protein is one of
three components of neurofilaments. Neurofilaments are cytoplasmic
intermediate filaments of neurons. They are believed to play a role
in the maturation of regenerating myelinated nerve fibers, and mutations
in NEFL could lead to HMSN IF and IIE by interfering with this function.
CX32 (or GJB1) is a small gene with only two exons. It is expressed in
myelinated peripheral nerves and codes for connexin 32, a gap-junction
protein with 283 amino acids. Gap junctions are involved in cell–cell
communication. Mutations in CX32 result in an X-linked dominant form

12 Hereditary Motor and Sensory Neuropathy

 Classification MIM Distinguishing Inheritance Chromosomal Gene Product Mutational spectrum
clinical features location

HMSN IA 118220 Slow NCVs Autosomal 17p11.2 PMP22 Peripheral myelin A 1.5-Mb duplication of
dominant protein 22 17p11.2 including PMP22
is the most common
cause of HMSN IA. Point
mutations in this gene
have also been identified,
including missense and
frame-shift mutations
P481_GenForPed_Complete.qxd

HMSN IB 118200 Slow NCVs Autosomal 1q22 MPZ Myelin protein zero Missense mutations
dominant
HMSN IC 601098 Slow NCVs Autosomal 16p12–p13.3 LITAF Lipopolysaccharide- Missense mutations
dominant induced tumor
necrosis factor-α factor
7/9/04

HMSN ID 607678 Very slow NCVs Autosomal 10q21.1–q22.1 EGR2 Early growth Missense mutation

Progressive Ataxias and Neurologic Disorders

dominant response 2 (Arg409Trp)
HMSN IF 607734 Slow NCVs, onset Autosomal 8p21 NEFL Neurofilament In-frame deletion or
16:04

in infancy or early dominant protein, light missense mutation

childhood polypeptide (Pro8Arg)
HMSN X 302800 Males are more X-linked Xq13.1 CX32 Connexin 32 Missense mutations
severely affected dominant account for ~75% of all
than females. Males: mutations. Nonsense and
slow NCVs. Females: frame-shift mutations, as
Page 13

normal or slow NCVs well as in-frame deletions

and insertions have also
been identified
HMSN IIA 118210 Normal or slightly Autosomal 1p36.2 KIF1B Kinesin family Missense mutations
reduced NCVs dominant member 1B
HMSN IIB 600882 Ulcero-mutilating Autosomal 3q21 RAB7 RAS-related GTP- Missense mutations
features, normal or dominant binding protein 7
slightly reduced NCVs
HMSN IIB1 605588 Slow NCVs Autosomal 1q21.2 LMNA Lamin A/C Missense mutation
recessive (Arg298Cys)
HMSN IIC 606071 Weakness of vocal cord Autosomal Unknown Unknown Unknown Unknown
and intercostal muscles, dominant
normal NCVs
HMSN IID 601472 Weakness and wasting Autosomal 7p15 GARS Glycyl-tRNA Missense mutations
of hand at onset, dominant synthetase

13
normal NCVs
 Classification MIM Distinguishing Inheritance Chromosomal Gene Product Mutational spectrum

14
clinical features location

HMSN IIE 607684 Normal or slightly Autosomal 8p21 NEFL Neurofilament protein, Missense mutations
reduced NCVs dominant light polypeptide
MSN IIF 606595 Normal NCVs Autosomal 7q11–q21 Unknown Unknown Unknown
dominant
HMSN IIG 607706 Normal or slightly Autosomal 8q13–q21.1 GDAP1 Ganglioside-induced Nonsense mutations
reduced NCVs with recessive differentiation-
vocal cord paresis associated protein 1
HMSN IIH 607731 – Autosomal 8q21.3 Unknown Unknown Unknown
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recessive
HMSN II I 607677 Normal or slightly Autosomal 1q22 MPZ Myelin protein zero Missense mutations (two
reduced NCVs dominant patients had three different
missense mutations in
7/9/04

the same allele)

HMSN IIJ 607736 Normal or slightly Autosomal 1q22 MPZ Myelin protein zero Missense mutations
reduced NCVs with dominant (Thr124Met or Asp75Val)
papillary abnormalities
16:04

and deafness
HMSN IIK 607831 Slightly reduced NCVs Autosomal 8q13–q21.1 GDAP1 Ganglioside-induced Homozygosity for
with onset in early recessive differentiation- Ser194Stop
childhood associated protein 1 mutation
HMSN III/ 145900 See text Autosomal 17p11.2 PMP22 Peripheral myelin Missense and
Page 14

Dejerine–Sottas dominant protein 22 frame-shift mutation

syndrome
Autosomal 1q22 MPZ Myelin protein zero Missense mutations
dominant
Autosomal 10q21.1–q22.1 EGR2 Early growth Missense mutation
dominant response 2 (Arg359Trp)
Autosomal 17p11.2 PMP22 Peripheral myelin 1.5-Mb duplication of
recessive protein 22 17p11.2, including
PMP22 in both alleles or
duplication of one allele
and a point mutation
(usually a missense
mutation) in the other allele
Autosomal 19q13.1–q13.2 PRX Periaxin Nonsense and
recessive frame-shift mutations

Hereditary Motor and Sensory Neuropathy

 Classification MIM Distinguishing Inheritance Chromosomal Gene Product Mutational spectrum
clinical features location

HMSN IVA 214400 Both a demyelinating Autosomal 8q13–q21.1 GDAP1 Ganglioside-induced Demyelinating type:
and an axonal form recessive differentiation- nonsense and
are recognized. associated missense mutations
Axonal type: protein 1 Axonal type:
patients can have nonsense, missense, and
vocal cord paresis frame-shift mutations
HMSN IVB1 601382 Slow NCVs Autosomal 11q22 MTMR2 Myotubularin-related Nonsense, frame-shift,
recessive protein 2 and splice-site mutations
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HMSN IVB2 604563 Slow NCVs Autosomal 11p15 SBF2 SET-binding factor 2 Nonsense mutations
recessive and in-frame deletion

HMSN IVC 601596 Slow NCVs Autosomal 5q32 Unknown Unknown Unknown
7/9/04

recessive

Progressive Ataxias and Neurologic Disorders

HMSN IVD/ 601455 Onset in first decade, Autosomal 8q24.3 NDRG1 N-myc downstream- Nonsense mutation
HMSN L early-onset deafness, recessive regulated gene 1 (Arg148Stop)
(see text) slow NCVs protein
16:04

HNPP 162500 See text Autosomal 17p11.2 PMP22 Peripheral myelin Over 85% of patients
dominant protein 22 have a 1.5-Mb deletion
of 17p11.2, including
PMP22. The remainder
Page 15

have frame-shift or splice-

site mutations that result in
loss of function of the gene
CHN 605253 See text Autosomal 1q22 MPZ Myelin protein zero Nonsense mutation
dominant
Autosomal 10q21.1–q22.1 EGR2 Early growth Double missense mutation
dominant response 2 (on same allele)
Autosomal 10q21.1–q22.1 EGR2 Early growth Missense mutation
recessive response 2

Table 1. Hereditary motor and sensory neuropathies (HMSNs): classifications, inheritance patterns, and molecular genetics. CHN: congenital hypomyelinating
neuropathy; HNPP: hereditary neuropathy with liability to pressure palsies; NCV: nerve conduction velocity.

15
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 16

of HMSN. Mutant protein may have an increased tendency to form

conducting hemichannels compared with normal protein. This could
prevent the normal functioning of Schwann cells and neurons by
increasing their membrane permeability.
KIF1B has 47 exons and encodes an N-terminal-type motor protein
with 1,816 amino acids. It acts as a motor for the anterograde transport
of mitochondria. A mutation in this gene could result in the production
of a mutant protein without any motor activity. The precise mechanism
by which a mutation in this gene causes HMSN IIA is unknown.
RAB7 has six exons and encodes a ubiquitously expressed protein
with 207 amino acids called RAS-associated protein 7. This is a small
GTPase, which is a member of the RAS-related GTP-binding protein
family. It is believed to be involved in vesicular transport of proteins.
It is not understood how mutations in this gene result in HMSN IIB.
LMNA has 10 exons and codes for two proteins by alternative splicing
of its exons. The gene products include lamin A and lamin C. Both
proteins are components of the nuclear lamina. The mechanisms by
which mutations in this gene cause HMSN IIB1 are not understood.
Mutations in LMNA can cause several other conditions (see LGMD
entry, p.18).
GARS has 17 exons and encodes glycyl-tRNA synthetase. This is
an enzyme with 685 amino acids that catalyses the esterification
of glycine to its cognate tRNA during protein synthesis. Missense
mutations in GARS cause HMSN IID and an autosomal dominant
form of distal spinal muscular atrophy (type V, MIM 600794) by
an unknown mechanism.
GDAP1 has six exons and codes for ganglioside-induced differentiation-
associated protein. This has 358 amino acids and may be involved in
the signal transduction pathway in neuronal development. The precise
mechanism by which mutations in GDAP1 cause HMSN IIG, IIK, and
IVA is not understood.
PRX contains six exons and produces two mRNA transcripts. One
transcript produces L-periaxin and the other S-periaxin. Both proteins
are expressed in Schwann cells and interact with the C-termini of
plasma membrane proteins and with cytoskeletal proteins, and are
required for the maintenance of peripheral nerve myelin. Mutations
in this gene cause a form of HMSN III.

16 Hereditary Motor and Sensory Neuropathy

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MTMR2 is composed of 15 exons. Its protein product, myotubularin-

related protein 2, has 643 amino acids and is ubiquitously expressed.
It is a dual-specificity phosphatase with homology to myotubularin.
It is not understood how mutations in this gene cause HMSN IVB1.
SBF2 is a large gene with 43 exons. Its protein product, SET-binding
factor 2, has 1,849 amino acids and is a member of the pseudophosphatase
branch of myotubularin-related proteins. It is expressed in fetal brain,
spinal cord, and peripheral nerves and is involved in the differentiation
of Schwann cells during myelination. Mutations in SBF2 cause HMSN IVB2.
NDRG1 has 16 exons. Its protein product has 394 amino acids and
is ubiquitously expressed. It appears to be expressed at particularly
high levels in Schwann cells. NDRG1 protein is involved in growth
arrest and cell differentiation, and it appears to have a role in Schwann
cell signaling that is necessary for axonal survival. Mutations in NDRG1
cause HMSN IVD (this condition is also called HMSN, Lom type, or
HMSN L because it only affects members of the Gypsy community
of Lom in Bulgaria).

Genetic diagnosis PMP22, MPZ, and CX32 mutation analysis is available from several
and counseling diagnostic laboratories. However, testing for mutations in the other
genes is not routinely available at this time. All autosomal dominant
and sporadic cases of HMSN I should be tested for mutations in
PMP22 and MPZ. Patients from X-linked dominant HMSN families,
sporadic male cases with HMSN I, and sporadic female cases with
HMSN II should also be tested for mutations in CX32.

Detailed pedigree analysis can often establish the mode of inheritance

of HMSN in a family and allow accurate genetic advice to be given to
other family members. HMSN I can show remarkable interfamilial and
intrafamilial variability of expression. Therefore, parents of an apparently
sporadic case should be carefully examined and offered nerve conduction
studies to determine whether one parent is mildly affected. Predictive
testing can be offered to at-risk members of families in which a mutation
has been identified.

Counseling in HNPP families is carried out on an autosomal-

dominant basis.

Progressive Ataxias and Neurologic Disorders 17

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Limb-girdle Muscular Dystrophy

(also known as: LGMD)

The LGMDs are a group of hereditary muscle disorders that predominantly affect the shoulder
and pelvic girdles. There are several autosomal dominant (LGMD1) and autosomal recessive
(LGMD2) forms with remarkable locus heterogeneity. Table 2 summarizes the classification,
distinguishing clinical features, inheritance pattern, and molecular genetics of the various
forms of LGMD.

MIM See Table 2.

Clinical features The LGMDs are a clinically and genetically heterogeneous group
of disorders. Affected individuals present with proximal weakness
of the upper and lower limbs.

Age of onset See Table 2.

Epidemiology LGMDs affect all populations, but their incidence varies in different
populations. Autosomal dominant forms only account for about 10% of
cases. Mutations in one of the sarcoglycan genes (sarcoglycanopathies)
can be seen in 8%–25% of patients with LGMD. In most populations
the most frequently seen form of LGMD is LGMD2A, which accounts
for 40%–45% of cases. However, LGMD2I is probably the most
common form of LGMD in the UK.

Inheritance, See Table 2.

chromosomal
location,
and gene

Molecular TTID is composed of 10 exons and codes for a structural muscle protein
pathogenesis with 498 amino acids called titin immunoglobulin domain protein or
myotilin. This is a thin, filament-associated, Z-disc protein that binds to
α-actinin, F-actin, and filamin c. It cross-links actin filaments and controls
sarcomere assembly, and is believed to play an important role in the
stabilization and anchorage of thin filaments. Mutations in TTID probably
cause LGMD by interfering with the proper organization of Z-discs.
LMNA contains 10 exons and encodes two proteins as a result of
alternative splicing of its exons. These proteins include lamin A
(664 amino acids) and lamin C (572 amino acids). Both lamins

18 Limb-girdle Muscular Dystrophy

P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 19

are nuclear envelope proteins. How mutations in LMNA cause LGMD

is not known. Mutations in LMNA have also been described in several
other conditions, including an autosomal dominant form of dilated
cardiomyopathy (type 1A, MIM 115200), an autosomal dominant form
of Emery–Dreifuss muscular dystrophy (MIM 181350), Dunnigan type
partial lipodystrophy (MIM 151660), an autosomal recessive form of
HMSN (HMSN IIB1, MIM 605588 – see p.13), and two dysmorphic
syndromes associated with premature ageing: Hutchinson-Gilford
syndrome or progeria (MIM 176670) and mandibuloacral dysplasia
(MIM 248370).
CAV3 contains three exons and encodes caveolin 3, which has
131 amino acids. Caveolin 3 is the muscle-specific form of the caveolin
protein family. Caveolins are the main protein components of caveolae
(50–100 nm invaginations of plasma membranes). Mutations in CAV3
act in a dominant-negative manner by interfering with oligomerization
of caveolin 3. This disrupts caveolae formation in the sarcolemmal
membrane. Caveolin 3 interacts with dysferlin at the surface of the
sarcolemmal membrane, and is also involved in normal expression
of α-dystroglycan at the sarcolemmal surface. Caveolin 3 deficiency
could therefore result in muscular dystrophy by interfering with the
normal expression of dysferlin and α-dystroglycan.
CAPN3 has 24 exons and encodes an 821-amino-acid protein called
calpain 3. This is a muscle-specific, calcium-dependent protease.
It appears to have a role in controlling the levels of muscle-specific
transcription factors, though the precise role of calpain 3 in muscle
and the mechanism by which a deficiency of this protein causes
muscular dystrophy are unknown.
DYSF is a large gene with 55 exons. It encodes dysferlin, a 2,080
amino-acid protein that localizes to the sarcolemmal membrane and
co-immunoprecipitates with caveolin 3 in skeletal muscle. It is expressed
very early in human development. Studies in mice have shown that
dysferlin has an essential role in the resealing of the sarcolemma in
response to injury. Therefore, mutations in DYSF probably cause
muscular degeneration by disrupting the muscle membrane repair
machinery. Mutations in DYSF have also been identified in Miyoshi
myopathy, an autosomal recessive distal myopathy (MIM 254130).
SGCA has eight exons and encodes α-sarcoglycan (also called 50-kDa
dystrophin-associated glycoprotein [DAG]), which has 387 amino acids.

Progressive Ataxias and Neurologic Disorders 19

 Classification MIM Distinctive Age of Inheritance Chromosomal Gene Protein product Mutational spectrum

20
clinical onset location
features

LGMD1A 159000 Dysarthria 18–35 years Autosomal 5q31 TTID Titin immunoglobulin- Missense mutations
dominant domain protein or
myotilin
LGMD1B 159001 Cardiac involvement, 4–38 years Autosomal 1q21.2 LMNA Lamin A/C Missense and splice-site
particularly cardiac dominant mutations, 3-bp deletion
conduction defects
LGMD1C 601253 Muscle cramps, ~5 years Autosomal 3p25 CAV3 Caveolin 3 Missense mutations
P481_GenForPed_Complete.qxd

calf hypertrophy, dominant and 9-bp deletion

moderately elevated
CK levels
LGMD1D 603511 None Adulthood Autosomal 7q Unknown Unknown Unknown
7/9/04

dominant
LGMD with 602067 Dilated 15–20 years Autosomal 6q23 Unknown Unknown Unknown
dilated cardiomyopathy dominant
cardiomyopathy with cardiac
16:04

conduction
defects
LGMD2A 253600 Contractures of 8–15 years Autosomal 15q15.1–q21.1 CAPN3 Calpain 3 Missense and splice-site
tendo-Achilles and recessive mutations, small deletions
Page 20

other sites, scapular and insertions

winging, hip
abductors spared
LGMD2B 603009 Inability to walk on Late teens Autosomal 2p13.1–p13.3 DYSF Dysferlin Missense, frame-shift,
tiptoe, calf atrophy, recessive and splice-site mutations
markedly elevated
CK levels
LGMD2C 253700 Calf hypertrophy Childhood Autosomal 13q12 SGCG γ-Sarcoglycan Small deletions
recessive
LGMD2D 600119 Toe-walking, muscle 3–15 years Autosomal 17q12–q21.33 SGCA α-Sarcoglycan Nonsense, missense,
cramps, scapular recessive and splice-site mutations,
winging, calf duplications. Exon 3
hypertrophy mutational hotspot.
Arg77Cys mutation accounts
for ~40% of all mutations

Limb-girdle Muscular Dystrophy

 Classification MIM Distinctive Age of Inheritance Chromosomal Gene Protein product Mutational spectrum
clinical onset location
features

LGMD2E 604286 None Childhood Autosomal 4q12 SGCB β-Sarcoglycan Missense and protein-
recessive truncating mutations
LGMD2F 601287 Cardiomyopathy, 4–10 years Autosomal 5q33 SGCD δ-Sarcoglycan Frame-shift, missense,
very severe clinical recessive and nonsense mutations,
course with loss of 3-bp deletion
ambulation between
9–16 years and
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death between
9–19 years
LGMD2G 601954 Foot drop, proximal 9–15 years Autosomal 17q12 TCAP Telethonin Nonsense and
and distal lower recessive frame-shift mutations
7/9/04

limb weakness

Progressive Ataxias and Neurologic Disorders

present at onset,
mild to moderate
elevation of CK
16:04

levels, rimmed
vacuoles on
muscle biopsy
LGMD2H 254110 Weakness of facial, 8–27 years Autosomal 9q31–q34.1 TRIM32 Tripartite motif- All patients are
Page 21

trapezius and recessive containing homozygous for the

deltoid muscles late protein 32 missense mutation
in disease course, Asp487Asn
mild to moderate
elevation of CK levels
LGMD2I 607155 None 6 months to Autosomal 19q13.3 FKRP Fukutin-related Most affected individuals
40 years recessive protein are homozygous for the
missense mutation
Leu276Ile. The remainder
are compound heterozygotes
for this mutation and a
4-bp deletion that results
in premature protein
truncation

Table 2. Limb-girdle muscular dystrophies (LGMDs): classification, clinical features, and molecular genetics. CK: creatine kinase.

21
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SGCB has only six exons and encodes a protein with 318 amino acids,
which is called β-sarcoglycan (43-kDa DAG). SGCD has nine exons
and encodes δ-sarcoglycan (35-kDa DAG), which has 290 amino acids.
SGCG is composed of eight exons and codes for γ-sarcoglycan (35-kDa
DAG). This protein also has 290 amino acids. The sarcoglycans are
transmembrane proteins that are an important component of the
dystrophin–glycoprotein complex at the sarcolemmal membrane.
The components of this complex link dystrophin inside the sarcolemma
to the laminin α2 chain of merosin and other proteins in the extracellular
matrix. The dystrophin–glycoprotein complex is believed to play a
critical role in maintaining the integrity of the sarcolemmal membrane,
particularly during muscle contraction. Therefore, absence or deficiency
of the critical components of this complex can result in the phenotype
of muscular dystrophy. Heterozygous mutations in SGCD can also
cause one form of dilated cardiomyopathy type 1L (MIM 606685).
TCAP is a small gene with only two exons. It encodes a structural
sarcomeric protein called titin cap or telethonin. This protein has
167 amino acids and localizes to the Z-disc of adult skeletal muscle.
TRIM32 has two exons and encodes a protein with 653 amino acids.
Its protein product, TRIM 32 protein, is thought to be an E3 ubiquitin
ligase. The mechanism by which mutations in this gene result in the
LGMD phenotype is unknown.
FKRP is composed of four exons and encodes fukutin-related protein,
which has 495 amino acids. Fukutin-related protein is probably a
Golgi-resident glycosyltransferase that is involved in the glycosylation
of α-dystroglycan. This protein links the dystrophin–glycoprotein
complex to various extracellular proteins, including the laminin α2
chain of merosin, neurexin, and agrin. Deficiency of fukutin-related
protein probably results in muscular dystrophy due to aberrant
glycosylation of α-dystroglycan.

Genetic diagnosis The diagnosis of LGMD is made by the combination of clinical features,
and counseling immunohistochemistry on a muscle biopsy sample, and molecular genetic
analysis. Immunohistochemistry and genetic testing are only available
from a few specialized laboratories. Interpretation of the results of muscle
immunohistochemistry is difficult and should only be carried out by
laboratories experienced in the use of this technique. It is important to
rule out facioscapulohumeral muscular dystropy and Emery–Dreifuss

22 Limb-girdle Muscular Dystrophy

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muscular dystrophy in families that appear to have an autosomal

dominant form of LGMD. In large families with an autosomal recessive
form of LGMD, linkage analysis might allow the precise form of LGMD
to be identified. However, this should always be confirmed by muscle
immunohistochemistry or mutation analysis of the relevant gene.
Because of the genetic heterogeneity of LGMD, genetic counseling is
difficult. Accurate genetic counseling and prenatal diagnosis are only
possible in families where a definitive diagnosis can be made by muscle
immunohistochemistry and genetic testing. Accurate counseling is
also possible in large families with several affected members, where
it is possible to determine the precise mode of inheritance (autosomal
recessive or dominant). Isolated cases of LGMD could represent an
autosomal recessive form of LGMD or a new autosomal dominant mutation.

Myotonic Dystrophy
(also known as: MD; dystrophia myotonica; Steinert disease.
Includes proximal myotonic myopathy [PROMM])

MIM 160900 (MD1)

602668 (MD2)
600109 (PROMM)

Clinical features Four forms of MD1 can be recognized based on age of onset and clinical
features. These include a mild form, an adult or classical form, a congenital
form, and a childhood or juvenile form. Patients with mild MD usually
present with presenile cataracts. The classical form of MD is a multisystem
disorder. Symptoms include: muscle weakness and wasting, grip and
percussion myotonia, cardiac arrhythmias that can present as syncope
or sudden death, gastrointestinal problems, cataracts, an increased
incidence of diabetes mellitus, and testicular atrophy in males.
The distribution of muscle weakness and wasting is characteristic and
is responsible for the well-recognized facial features of this condition.
These include frontal balding, ptosis, facial weakness, bitemporal
narrowing (due to wasting of the temporalis muscles), wasting of the jaw
muscles, and a slender neck due to wasting of the sternomastoids. Early
appearance and progression of male pattern baldness is also a feature.
Distal limb muscles tend to be affected earlier than proximal muscles.

Progressive Ataxias and Neurologic Disorders 23

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Congenital MD is the most severe form of this disease and is the result
of anticipation. It can present antenatally as reduced fetal movements
and polyhydramnios, or in the neonatal period as severe hypotonia,
respiratory distress (often requiring ventilation), feeding difficulties,
facial weakness, cardiac problems (cardiomyopathy or arrhythmias),
and talipes or arthrogryposis. A chest X-ray will often show thin ribs.
Many patients with congenital MD die in childhood. Survivors show
delayed development and have learning difficulties and characteristic
facies (facial diplegia, an open-mouthed appearance with a tented
upper lip, and a prominent, everted lower lip).
A childhood or juvenile form of this condition has also been described.
These patients usually present between 1 and 10 years of age with
speech and language delay and learning difficulties, although some
patients present with muscle weakness and myotonia at school age.
MD2 and PROMM are probably a single entity as they have similar
clinical features and are allelic or have very closely linked genes.
Patients with these conditions present with slowly progressive proximal
muscle weakness, mild myotonia, cardiac arrhythmias, and late-onset
cataracts. White matter changes have been described in some families.
Features that help to distinguish these conditions from the classical form
of MD1 include the absence of facial weakness and the characteristic
facial features that are seen in patients with classical MD, absent
or minimal distal limb weakness, and the presence of myalgia.

Age of onset The mild form of MD1 presents in late adult life, the classical form
presents in late adolescence or early adult life, the congenital form
presents antenatally or in the neonatal period, and the childhood
or juvenile form presents in early childhood.
MD2 and PROMM present in adulthood.

Epidemiology MD1 has an estimated incidence of 1 in 8,000. It appears to be

particularly prevalent in the Saguenay-Lac-St-Jean region of Canada,
where its prevalence is 1 in 475.
MD2 and PROMM are rare disorders. Their population incidence
and prevalence are unknown.

Inheritance MD1: autosomal dominant

MD2/PROMM: autosomal dominant

24 Myotonic Dystrophy
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Chromosome MD1: 19q13.3

location MD2/PROMM: 3q13.3–q24

Genes MD1: DMPK (dystrophia myotonica protein kinase)

MD2/PROMM: ZNF9 (zinc finger protein 9)

Mutational MD1 is caused by the expansion of a CTG triplet repeat motif in

spectrum the 3´-untranslated region of the last exon of DMPK. In the general
population, the number of CTG repeats varies from 5 to 37. Affected
individuals have more than 50 repeats and there appears to be a
correlation between the number of repeats and the severity of the
phenotype. Repeat sizes of 50–100 are associated with the mild form
of MD, whereas repeat sizes of between 500 and 1,500 result in the
congenital MD phenotype. Expansions of between 100 and 500 are
usually associated with classical MD, but it is not possible to predict
the age of onset or the severity of disease in this group of patients.
The CTG repeat shows meiotic instability and its size tends to increase
in successive generations. This is responsible for the phenomenon of
anticipation, in which the phenotype of a disease increases in severity
in successive generations. Maternal transmission can be associated
with a large expansion in the CTG repeat number, whereas paternal
transmission is usually associated with a modest expansion of the
repeat or, in some cases, a decrease in the number of repeats. Thus,
congenital MD, which is caused by very large CTG repeat expansions,
is almost always maternally transmitted. In contrast, the childhood
or juvenile form of MD is more frequently paternally transmitted.
Patients with MD2/PROMM have an expansion of a CCTG repeat
motif in the first intron of ZNF9. Affected individuals have between
75 and 11,000 repeats, with an average of 5,000.

Molecular DMPK has 15 exons and produces two main protein isoforms of 71 kDa
pathogenesis and 80 kDa as a result of alternative splicing. Both of these isoforms are
predominantly expressed in skeletal and cardiac muscle. The precise
mechanism by which the CTG repeat expansion causes MD1 is unknown.
Interest has focused on the possibility that the allele with the CTG repeat
expansion produces mRNA that inappropriately binds to proteins via
CUG repeats (thymidine is replaced by uridine in RNA). One particular
protein (CUG-binding protein) is involved in processing mRNA from

Progressive Ataxias and Neurologic Disorders 25

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several other genes, including cardiac troponin T. Binding of CUG-binding

protein to the mRNA product of the DMPK allele with the CTG repeat
expansion could interfere with its ability to process the mRNAs of
several other genes, and altered expression of these genes could
result in the MD1 phenotype. Thus, the CTG repeat expansion
in DMPK would appear to be a gain-of-function mutation.
ZNF9 has five exons and encodes a protein with 177 amino acids.
This protein has seven zinc-finger domains and is believed to be an
RNA-binding protein. Mutant ZNF9 mRNA accumulates in the nucleus
and probably results in the MD2/PROMM phenotype in a manner
analogous to the expansions in the DMPK gene that cause MD1.

Genetic diagnosis Genetic testing for MD1 is widely available, so all patients with MD
and counseling should have genetic testing to confirm the diagnosis. Patients whose
clinical features are suggestive of MD but who test negative for the
CTG repeat expansion in DMPK are likely to have MD2/PROMM or an
alternative myotonic disorder. Counseling is on the basis of autosomal
dominant inheritance. Women with MD1 should be told that their
children could be affected with congenital MD as a result of anticipation.
Women who have neuromuscular disease or who have previously had
an affected child with congenital MD are particularly at risk of having
a baby with congenital MD. Patients with MD should be told that they
are at risk of developing cardiac arrhythmias, cataracts, and diabetes
mellitus, and they should be under the care of a physician. They should
also be told about the complications of general anesthesia, including
malignant hyperthermia and postanesthetic apnea. Patients should
be asked to carry an alert card or bracelet. Presymptomatic/predictive
genetic testing can be offered to those from families where a CTG repeat
expansion has been previously documented in an affected individual
(and who therefore have a 50% risk of being affected). Prenatal diagnosis
is also available by testing DNA extracted from either a chorionic villus
sample or cultured amniocytes for the CTG repeat expansion.
Genetic testing for MD2/PROMM is only available on a research basis.
Counseling is as for autosomal dominant inheritance. Anticipation
does occur, but is milder than that seen in MD1.

26 Myotonic Dystrophy
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Spinal Muscular Atrophy

(also known as: SMA)

MIM 253300 (SMA type I/Werdnig–Hoffmann disease)

253550 (SMA type II)
253400 (SMA type III/Kugelberg–Welander syndrome)

Clinical features Children with SMA present with generalized muscle weakness and wasting,
hypotonia, and areflexia. The muscle weakness begins proximally,
and characteristically involves the intercostal muscles and later the
diaphragm, but spares the extraocular muscles and facial muscles.
Fasciculation of the tongue and other muscles is a helpful diagnostic
clue. Childhood SMA is classified into three types based on age of onset,
extent of motor development, and prognosis. The most severe form is
SMA type I. Children with this condition never learn to sit and usually
die by the age of 2 years. Patients with SMA type II learn to sit without
support, but never learn to walk unaided. The prognosis is variable, with
some patients dying in childhood and others surviving to adulthood.
Patients with SMA type III are able to walk independently. They have
slowly progressive muscle weakness, and survive into adulthood.
Diagnosis can be confirmed by electromyography (which shows a
neurogenic pattern) and by muscle biopsy (which shows grouped
atrophy of both type I and II fibers, with hypertrophy of type I fibers).

Age of onset SMA type I: before 3 months

SMA type II: 3–18 months
SMA type III: after 18 months

Epidemiology The incidence of all forms of SMA is about 1 in 10,000 live births.
SMA has been described in all ethnic groups. The heterozygote (carrier)
frequency is about 1 in 50.

Inheritance All forms of childhood SMA are inherited in an autosomal recessive

manner. However, a small proportion (~2%) of those with type II or III
may have a form inherited in an autosomal dominant manner.

Chromosomal 5q12.2–q13.3
location

Gene SMN1 (survival of motor neuron 1)

Progressive Ataxias and Neurologic Disorders 27

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Mutational There are two copies of the SMN gene: a telomeric copy (SMN1)
spectrum and a centromeric copy (SMN2). There are only minor differences in
the coding sequence of these two genes. Both genes are expressed,
but SMN1 produces much higher levels of the functional full-length
transcript than SMN2. Because of the homology between these two
genes, gene conversion events are frequent, resulting in the conversion
of SMN1 to SMN2.
The vast majority of patients with SMA (~96%) are homozygous for a
deletion or gene conversion of SMN1. A small number of patients (~4%)
are compound heterozygotes with a deletion or gene conversion affecting
one SMN1 allele and a different mutation in the other allele. Other
mutations in SMN1 are rare, but can include point mutations (mostly
missense mutations and splice-site mutations) and frame-shift mutations.
The presence of multiple copies of SMN2 in patients homozygous for
a deletion or gene conversion of SMN1 can modify the phenotype and
lead to less severe disease (SMA types II or III). Other genetic modifiers
of the phenotype have also been described (eg, splicing mechanisms
of the SMN2 gene and deletion of the H4F5 gene that lies upstream
of SMN1).

Molecular The protein product of the SMN1 and SMN2 genes is expressed in
pathogenesis several areas, including the central nervous system, skeletal muscle,
heart, liver, kidneys, lungs, thymus, and pancreas. Within the central
nervous system it is expressed in the anterior horn cells of the spinal
cord. The SMN protein is localized to the cytoplasm and nucleus.
In the nucleus it is localized in small, discrete, dot-like structures called
“gems”. It interacts with several small nuclear ribonucleoproteins and
appears to have an important role in the generation of the pre-mRNA
splicing machinery, and, therefore, in mRNA processing in the cell.
Although SMN1 is ubiquitously expressed, loss of function of this
gene only results in degeneration of spinal motor neurons because
these cells are believed to need high levels of SMN protein to survive.

Genetic diagnosis Genetic testing for SMA is routinely available. Carrier testing for
and counseling SMA is also available from diagnostic laboratories. Counseling is
on an autosomal recessive basis. Prenatal diagnosis can be offered
to parents of children with SMA in whom the diagnosis has been
confirmed by genetic testing.

28 Spinal Muscular Atrophy

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2
2. Cerebral Malformations and Mental
Retardation Syndromes

Angelman Syndrome 30
Fragile X Syndrome 34
Holoprosencephaly 36
Hunter Syndrome 40
Huntington Disease 41
Lesch–Nyhan Syndrome 43
Lissencephaly 45
Lowe Syndrome 52
Neuronal Ceroid Lipofuscinosis 53
Pelizaeus–Merzbacher Syndrome 57
Prader–Willi Syndrome 59
Rett Syndrome 61
X-linked Adrenoleukodystrophy 62
X-linked α-Thalassemia and Mental Retardation Syndrome 64
X-linked Hydrocephalus 66
P481_GenForPed_Complete.qxd 7/9/04 16:04 Page 30

Angelman Syndrome
(also known as: AS; happy puppet syndrome)

MIM 105830

Clinical features Affected children show severe developmental delay with very limited
speech, ataxia, and easily provoked laughter; they have a happy
demeanor and excitable personality. Convulsions occur in 80%,
usually with onset in early childhood. Other common features include
microcephaly, drooling, prognathism, hypopigmentation, and a scoliosis
(this can progress and require surgical correction). Life expectancy
is relatively normal.

Age of onset The diagnosis is usually made in early childhood. With the benefit
of hindsight, it often becomes apparent that problems were first
evident in infancy.

Epidemiology The incidence is estimated to be between 1 in 10,000 and

1 in 40,000.

Inheritance The mode of inheritance is complex, as four different causes of AS

are recognized: class I (maternally derived chromosome 15q11–q13
interstitial deletion), class II (paternal uniparental disomy [UPD] for
chromosome 15), class III (imprinting defect involving the Prader–Willi
syndrome [PWS]/AS critical region), and class IV (mutation in UBE3A).

Chromosomal 15q11–q13
location

Gene UBE3A (ubiquitin protein ligase E3A)

Mutational Missense, nonsense, splice-site, and frame-shift mutations.

spectrum

Molecular AS is caused by abnormal expression of the maternally imprinted

pathogenesis UBE3A gene, which contains 16 exons and encodes a ubiquitin protein
ligase that is thought to play a role in the localization of proteins in the
brain. UBE3A is chiefly expressed in the hippocampus and cerebellum
and is expressed only from the maternal allele in brain (ie, it shows
tissue-specific imprinting).

30 Angelman Syndrome
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Class I. There is an interstitial deletion involving 15q11–q13 in the

maternally derived chromosome 15. This accounts for approximately
70% of all cases. Most such deletions occur de novo. Rarely, a more
complex chromosome rearrangement involving deletion of 15q11–q13
is identified, possibly as a de novo finding or as a result of malsegregation
of a maternally balanced rearrangement.
Class II. Paternal UPD for chromosome 15 accounts for around 2% of
all cases. In this situation, both number 15 chromosomes are of paternal
origin. This may be due to nondisjunction in paternal meiosis, resulting in
a disomic sperm. The disomic sperm may then have fertilized a monosomic
ovum, resulting in transient trisomy 15 in the zygote with subsequent loss
of the maternally derived chromosome 15 (“trisomy rescue”).
Class III. Imprinting defects account for approximately 4% of all cases.
Roughly half of these are caused by very small deletions involving the
PWS/AS imprinting box/center (see Figure 1). The cause of the remaining
50% is uncertain.

Class IV. Mutations in UBE3A are found in 5%–10% of cases. Most

of these arise de novo, but the mother is a carrier in up to 20% of cases
through either inheriting a “silent” mutation from her father or showing
germ-line mosaicism.

In around 10%–15% of cases no chromosomal or molecular abnormality

can be identified. In these situations there may be an alternative diagnosis,
such as Rett syndrome (p.61–2), or there may be a mutation in an as
yet unidentified UBE3A-related gene.

M P P P M
Centromere qter
SNRPN

UBE3A

AS PWS
antisense UBE3A

IC IC

Figure 1. Simplified diagram of the PWS/AS (Prader–Willi syndrome/Angelman syndrome) critical region
on chromosome 15. In the maternal chromosome the AS imprinting center (IC) is active and methylates
(silences) the SNRPN promoter. UBE3A is expressed. In the paternal chromosome the PWS IC activates
SNRPN and other adjacent genes, including antisense UBE3A, which silences UBE3A. M and P refer to
maternally and paternally derived patterns of expression, respectively.

Cerebral Malformations and Mental Retardation Syndromes 31

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Genotype–phenotype Children with class I microdeletions are the most severely affected,
correlation with the highest incidence of microcephaly and seizures and the
most severe learning disability, with absent speech. They alone show
hypopigmentation, almost certainly because of haploinsufficiency for
the P gene, which is located at 15q11–q13 and deficiency of which
causes type II oculocutaneous albinism (MIM 203200). The next most
severely affected children are those with class IV UBE3A mutations.
These children often have microcephaly and seizures, but demonstrate
better developmental progress than children in class I. Children with
UPD (class II) and imprinting mutations (class III) are the least severely
affected, with a low incidence of microcephaly and seizures, but they
still show severe learning disability with only very limited speech.

Genetic diagnosis Diagnosis in classes I–III can be made by methylation analysis using
and counseling a methylation-sensitive restriction enzyme and a probe from the PWS/AS
critical region (see Figure 2). This reveals the presence of only a paternal
band. Microdeletion analysis by fluorescence in situ hybridization (FISH)
identifies all class I cases (see Figure 3). If a chromosomal abnormality
is identified, parental chromosome studies should be undertaken.
Paternal UPD (class II) is identified by restriction fragment length
polymorphism or microsatellite analysis. Class IV cases (UBE3A
mutations) can only be detected by mutation analysis (usually single-
strand conformation polymorphism screening followed by direct
sequencing). Most microdeletions identified by FISH are de novo
and have a low risk of recurrence of less than 1%, which is attributable
to maternal germ-line mosaicism. The recurrence risk for paternal UPD
cases (class II) is negligible. If an imprinting center microdeletion or
UBE3A mutation is present in the affected child’s mother then the
recurrence risk is 50%; otherwise, the recurrence risk is low but
not negligible because of possible maternal germ-line mosaicism.

32 Angelman Syndrome
Another Random Scribd Document
with Unrelated Content
It may be contended, too, that while it does violence to our established
way of thinking, this mode of interpreting the facts is not without its
difficulties. Something seems to be gained by restricting the application
of the title individual, to organisms which, being in all respects fully
developed, possess the power of producing their kind after the ordinary
sexual method, and denying this title to those incomplete organisms
which have not this power. But the definition does not really establish
this distinction for us. On the one hand, we have cases in which, as in
the working bee, the whole of the germ-product is aggregated into a
single organism; and yet, though an individual according to the
definition, this organism has no power of reproducing its kind. On the
other hand, we have cases like that of the perfect Aphis, where the
organism is but an infinitesimal part of the germ product, and yet has
that completeness required for sexual reproduction. Further, it might be
urged with some show of reason, that if the conception of individuality
involves the conception of completeness, then, an organism which
possesses an independent power of reproducing itself, being more
complete than an organism in which this power is dependent on the aid
of another organism, is more individual.

§ 74. There is, indeed, as already implied, no definition of individuality

that is unobjectionable. All we can do is to make the best practicable
compromise.

As applied either to an animate or an inanimate object, the word

individual ordinarily connotes union among the parts of the object and
separateness from other objects. This fundamental element in the
conception of individuality, we cannot with propriety ignore in the
biological application of the word. That which we call an individual plant
or animal must, therefore, be some concrete whole and not a discrete
whole. If, however, we say that each concrete living whole is to be
regarded as an individual, we are still met by the question—What
constitutes a concrete living whole? A young organism arising by
internal or external gemmation from a parent organism, passes
gradually from a state in which it is an indistinguishable part of the
parent organism to a state in which it is a separate organism of like
structure with the parent. At what stage does it become an individual?
And if its individuality be conceded only when it completely separates
from the parent, must we deny individuality to all organisms thus
produced which permanently retain their connexions with their parents?
Or again, what must we say of the Hectocotylus, which is an arm of the
Cuttle-fish that undergoes a special development and then, detaching
itself, lives independently for a considerable period? And what must we
say of the larval nemertine worm the pilidium of which with its nervous
system is left to move about awhile after the developing worm has
dropped out of it?

To answer such questions we must revert to the definition of life. The

distinction between individual in its biological sense, and individual in its
more general sense, must consist in the manifestation of Life, properly
so called. Life we have seen to be, "the definite combination of
heterogeneous change, both simultaneous and successive, in
correspondence with external co-existences and sequences." Hence, a
biological individual is any concrete whole having a structure which
enables it, when placed in appropriate conditions, to continuously adjust
its internal relations to external relations, so as to maintain the
equilibrium of its functions. In pursuance of this conception, we must
consider as individuals all those wholly or partially independent
organized masses which arise by multicentral and multiaxial
development that is either continuous or discontinuous (§ 50). We must
accord the title to each separate aphis, each polype of a polypedom,
each bud or shoot of a lowering plant, whether it detaches itself as a
bulbil or remains attached as a branch.

By thus interpreting the facts we do not, indeed, avoid all anomalies.

While, among flowering plants, the power of independent growth and
development is usually possessed only by shoots or axes; yet, in some
cases, as in that of the Begonia-leaf awhile since mentioned, the
appendage of an axis, or even a small fragment of such appendage, is
capable of initiating and carrying on the functions of life; and in other
cases, as shown by M. Naudin in the Drosera intermedia, young plants
are occasionally developed from the surfaces of leaves. Nor among
forms like the compound Hydrozoa, does the definition enable us to
decide where the line is to be drawn between the individuality of the
group and the individualities of the members: merging into each other,
as these do, in different degrees. But, as before said, such difficulties
must necessarily present themselves if organic forms have arisen by
insensible gradations. We must be content with a course which commits
us to the smallest number of incongruities; and this course is, to
consider as an individual any organized mass which is capable of
independently carrying on that continuous adjustment of inner to outer
relations which constitutes Life.
 CHAPTER VIA.

CELL-LIFE AND CELL-MULTIPLICATION.

§ 74a. The progress of science is simultaneously towards simplification

and towards complication. Analysis simplifies its conceptions by
resolving phenomena into their factors, and by then showing how each
simple mode of action may be traced under multitudinous forms; while,
at the same time, synthesis shows how each factor, by cooperation with
various other factors in countless modes and degrees, produces
different results innumerable in their amounts and varieties. Of course
this truth holds alike of processes and of products. Observation and the
grouping into classes make it clear that through multitudinous things
superficially unlike there run the same cardinal traits of structure; while,
along with these major unities, examination discloses innumerable
minor diversities.

A concomitant truth, or the same truth under another aspect, is that

Nature everywhere presents us with complexities within complexities,
which go on revealing themselves as we investigate smaller and smaller
objects. In a preceding chapter (§§ 54a, 54b) it was pointed out that
each primitive organism, in common with each of the units out of which
the higher and larger organisms are built, was found a generation ago
to consist of nucleus, protoplasm, and cell-wall. This general conception
of a cell remained for a time the outcome of inquiry; but with the
advance of microscopy it became manifest that within these minute
structures processes and products of an astonishing nature are to be
seen. These we have now to contemplate.

In the passages just referred to it was said that the external layer or
cell-wall is a non-essential, inanimate part produced by the animate
contents. Itself a product of protoplasmic action, it takes no part in
protoplasmic changes, and may therefore here be ignored.
§ 74b. One of the complexities within complexities was disclosed when
it was found that the protoplasm itself has a complicated structure.
Different observers have described it as constituted by a network or
reticulum, a sponge-work, a foam-work. Of these the first may be
rejected; since it implies a structure lying in one plane. If we accept the
second we have to conceive the threads of protoplasm, corresponding
to the fibres of the sponge, as leaving interstices filled either with liquid
or solid. They cannot be filled with a continuous solid, since all motion
of the protoplasm would be negatived; and that their content is not
liquid seems shown by the fact that its parts move about under the
form of granules or microsomes. But the conception of moving granules
implies the conception of immersion in a liquid or semi-liquid substance
in which they move—not a sponge-work of threads but a foam-work,
consisting everywhere of septa interposed among the granules. This is
the hypothesis which sundry microscopists espouse, and which seems
mechanically the most feasible: the only one which consists with the
"streaming" of protoplasm. Ordinarily the name protoplasm is applied to
the aggregate mass—the semi-liquid, hyaline substance and the
granules or microsomes it contains.

What these granules or microsomes are—whether, as some have

contended, they are the essential living elements of the protoplasm, or
whether, as is otherwise held, they are nutritive particles, is at present
undecided. But the fact, alleged by sundry observers, that the
microsomes often form rows, held together by intervening substance,
seems to imply that these minute bodies are not inert. Leaving aside
unsettled questions, however, one fact of significance is manifest—an
immense multiplication of surfaces over which inter-action may take
place. Anyone who drops into dilute sulphuric acid a small nail and then
drops a pinch of iron filings, will be shown, by the rapid disappearance
of the last and the long continuance of the first, how greatly the
increasing of surfaces by multiplication of fragments facilitates change.
The effect of subdivision in producing a large area in a small space, is
shown in the lungs, where the air-cells on the sides of which the blood-
vessels ramify, are less than 1⁄100th of an inch in diameter, while they
number 700,000,000. In the composition of every tissue we see the
same principle. The living part, or protoplasm, is divided into
innumerable protoplasts, among which are distributed the materials and
agencies producing changes. And now we find this principle carried still
deeper in the structure of the protoplasm itself. Each microscopic
portion of it is minutely divided in such ways that its threads or septa
have multitudinous contacts with those included portions of matter
which take part in its activities.

Concerning the protoplasm contained in each cell, named by some

cytoplasm, it remains to say that it always includes a small body called
the centrosome, which appears to have a directive function. Usually the
centrosome lies outside the nucleus, but is alleged to be sometimes
within it. During what is called the "resting stage," or what might more
properly be called the growing stage (for clearly the occasional divisions
imply that in the intervals between them there has been increase) the
centrosome remains quiescent, save in the respect that it exercises
some coercive influence on the protoplasm around. This results in the
radially-arranged lines constituting an "aster." What is the nature of the
coercion exercised by the centrosome—a body hardly distinguishable in
size from the microsomes or granules of protoplasm around—is not
known. It can scarcely be a repelling force; since, in a substance of
liquid or semi-liquid kind, this could not produce approximately straight
lines. That it is an attractive force seems more probable; and the nature
of the attraction would be comprehensible did the centrosome augment
in bulk with rapidity. For if integration were in progress, the drawing in
of materials might well produce converging lines. But this seems
scarcely a tenable interpretation; since, during the so-called "resting
stage," this star-like structure exists—exists, that is, while no active
growth of the centrosome is going on.

Respecting this small body we have further to note that, like the cell as
a whole, it multiplies by fission, and that the bisection of it terminates
the resting or growing stage and initiates those complicated processes
by which two cells are produced out of one: the first step following the
fission being the movement of the halves, with their respective
completed asters, to the opposite sides of the nucleus.
§ 74c. With the hypothesis, now general, that the nucleus or kernel of a
cell is its essential part, there has not unnaturally grown up the dogma
that it is always present; but there is reason to think that the evidence
is somewhat strained to justify this dogma.

In the first place, beyond the cases in which the nucleus, though
ordinarily invisible, is said to have been rendered visible by a re-agent,
there are cases, as in the already-named Archerina, where no re-agent
makes one visible. In the second place, there is the admitted fact that
some nuclei are diffused; as in Trachelocerca and some other Infusoria.
In them the numerous scattered granules are supposed to constitute a
nucleus: an interpretation obviously biassed by the desire to save the
generalization. In the third place, the nucleus is frequently multiple in
cells of low types; as in some families of Algæ and predominantly
among Fungi. Once more, the so-called nucleus is occasionally a
branching structure scarcely to be called a "kernel."

The facts as thus grouped suggest that the nucleus has arisen in
conformity with the law of evolution—that the primitive protoplast,
though not homogeneous in the full sense, was homogeneous in the
sense of being a uniformly granular protoplasm; and that the
protoplasts with diffused nuclei, together with those which are multi-
nucleate, and those which have nuclei of a branching form, represent
stages in that process by which the relatively homogeneous protoplast
passed into the relatively heterogeneous one now almost universal.

Concerning the structure and composition of the developed nucleus, the

primary fact to be named is that, like the surrounding granular
cytoplasm, it is formed of two distinct elements. It has a groundwork or
matrix not differing much from that of the cytoplasm, and at some
periods continuous with it; and immersed in this it has a special matter
named chromatin, distinguished from its matrix by becoming dyed more
or less deeply when exposed to fit re-agents. During the "resting
stage," or period of growth and activity which comes between periods
of division, the chromatin is dispersed throughout the ground-
substance, either in discrete portions or in such way as to form an
irregular network or sponge-work, various in appearance. When the
time for fission is approaching this dispersed chromatin begins to gather
itself together: reaching its eventual concentration through several
stages. By its concentration are produced the chromosomes, constant in
number in each species of plant or animal. It is alleged that the
substance of the chromosomes is not continuous, but consists of
separate elements or granules, which have been named chromomeres;
and it is also alleged that, whether in the dispersed or integrated form,
each chromosome retains its individuality—that the chromomeres
composing it, now spreading out into a network and now uniting into a
worm-like body, form a group which never loses its identity. Be this as it
may, however, the essential fact is that during the growth-period the
chromatin substance is widely distributed, and concentration of it is one
of the chief steps towards a division of the nucleus and presently of the
cell.

During this process of mitosis or karyokinesis, the dispersed chromatin

having passed through the coil-stage, reaches presently the star-stage,
in which the chromosomes are arranged symmetrically about the
equatorial plane of the nucleus. Meanwhile in each of them there has
been a preparation for splitting longitudinally in such way that the
halves when separated contain (or are assumed to contain) equal
numbers of the granules or chromomeres, which some think are the
ultimate morphological units of the chromosomes. A simultaneous
change has occurred: there has been in course of formation a structure
known as the amphiaster. The two centrosomes which, as before said,
place themselves on opposite sides of the nucleus, become the terminal
poles of a spindle-shaped arrangement of fibres, arising mainly from the
groundwork of the nucleus, now continuous with the groundwork of the
cytoplasm. A conception of this structure may be formed by supposing
that the radiating fibres of the respective asters, meeting one another
and uniting in the intermediate space, thereafter exercise a tractive
force; since it is clear that, while the central fibres of the bundle will
form straight lines, the outer ones, pulling against one another not in
straight lines, will form curved lines, becoming more pronounced in
their curvatures as the distance from the axis increases. That a tractive
force is at work seems inferable from the results. For the separated
halves of the split chromosomes, which now form clusters on the two
sides of the equatorial plane, gradually part company, and are
apparently drawn as clusters towards the opposing centrosomes. As this
change progresses the original nucleus loses its individuality. The new
chromosomes, halves of the previous chromosomes, concentrate to
found two new nuclei; and, by something like a reversal of the stages
above described, the chromatin becomes dispersed throughout the
substance of each new nucleus. While this is going on the cell itself,
undergoing constriction round its equator, divides into two.

Many parts of this complex process are still imperfectly understood, and
various opinions concerning them are current. But the essential facts
are that this peculiar substance, the chromatin, at other times existing
dispersed, is, when division is approaching, gathered together and dealt
with in such manner as apparently to insure equal quantities being
bequeathed by the mother-cell to the two daughter-cells.

§ 74d. What is the physiological interpretation of these structures and

changes? What function does the nucleus discharge; and, more
especially, what is the function discharged by the chromatin? There
have been to these questions sundry speculative answers.

The theory espoused by some, that the nucleus is the regulative organ
of the cell, is met by difficulties. One of them is that, as pointed out in
the chapter on "Structure," the nucleus, though morphologically central,
is not central geometrically considered; and that its position, often near
to some parts of the periphery and remote from others, almost of itself
negatives the conclusion that its function is directive in the ordinary
sense of the word. It could not well control the cytoplasm in the same
ways in all directions and at different distances. A further difficulty is
that the cytoplasm when deprived of its nucleus can perform for some
time various of its actions, though it eventually dies without reproducing
itself.
For the hypothesis that the nucleus is a vehicle for transmitting
hereditary characters, the evidence seems strong. When it was shown
that the head of a spermatozoon is simply a detached nucleus, and that
its fusion with the nucleus of an ovum is the essential process initiating
the development of a new organism, the legitimate inference appeared
to be that these two nuclei convey respectively the paternal and
maternal traits which are mingled in the offspring. And when there
came to be discerned the karyokinesis by which the chromatin is, during
cell-fission, exactly halved between the nuclei of the daughter-cells, the
conclusion was drawn that the chromatin is more especially the agent of
inheritance. But though, taken by themselves, the phenomena of
fertilization seem to warrant this inference, the inference does not seem
congruous with the phenomena of ordinary cell-multiplication—
phenomena which have nothing to do with fertilization and the
transmission of hereditary characters. No explanation is yielded of the
fact that ordinary cell-multiplication exhibits an elaborate process for
exact halving of the chromatin. Why should this substance be so
carefully portioned out among the cells of tissues which are not even
remotely concerned with propagation of the species? If it be said that
the end achieved is the conveyance of paternal and maternal qualities
in equal degrees to every tissue; then the reply is that they do not seem
to be conveyed in equal degrees. In the offspring there is not a uniform
diffusion of the two sets of traits throughout all parts, but an irregular
mixture of traits of the one with traits of the other.

In presence of these two suggested hypotheses and these respective

difficulties, may we not suspect that the action of the chromatin is one
which in a way fulfils both functions? Let us consider what action may
do this.

§ 74e. The chemical composition of chromatin is highly complex, and its

complexity, apart from other traits, implies relative instability. This is
further implied by the special natures of its components. Various
analyses have shown that it consists of an organic acid (which has been
called nucleic acid) rich in phosphorus, combined with an albuminous
substance: probably a combination of various proteids. And the
evidence, as summarised by Wilson, seems to show that where the
proportion of phosphorized acid is high the activity of the substance is
great, as in the heads of spermatozoa; while, conversely, where the
quantity of phosphorus is relatively small, the substance approximates
in character to the cytoplasm. Now (like sulphur, present in the
albuminoid base), phosphorus is an element which, besides having
several allotropic forms, has a great affinity for oxygen; and an organic
compound into which it enters, beyond the instability otherwise caused,
has a special instability caused by its presence. The tendency to
undergo change will therefore be great when the proportion of the
phosphorized component is great. Hence the statement that "the
chemical differences between chromatin and cytoplasm, striking and
constant as they are, are differences of degree only;" and the
conclusion that the activity of the chromatin is specially associated with
the phosphorus.[26]

What, now, are the implications? Molecular agitation results from

decomposition of each phosphorized molecule: shocks are continually
propagated around. From the chromatin, units of which are thus ever
falling into stabler states, there are ever being diffused waves of
molecular motion, setting up molecular changes in the cytoplasm. The
chromatin stands towards the other contents of the cell in the same
relation that a nerve-element stands to any element of an organism
which it excites: an interpretation congruous with the fact that the
chromatin is as near to as, and indeed nearer than, a nerve-ending to
any minute structure stimulated by it.

Several confirmatory facts may be named. During the intervals between

cell-fissions, when growth and the usual cell-activities are being carried
on, the chromatin is dispersed throughout the nucleus into an irregular
network: thus greatly increasing the surface of contact between its
substance and the substances in which it is imbedded. As has been
remarked, this wide distribution furthers metabolism—a metabolism
which in this case has, as we infer, the function of generating, not
special matters but special motions. Moreover, just as the wave of
disturbance a nerve carries produces an effect which is determined, not
by anything which is peculiar in itself, but by the peculiar nature of the
organ to which it is carried—muscular, glandular or other; so here, the
waves diffused from the chromatin do not determine the kinds of
changes in the cytoplasm, but simply excite it: its particular activities,
whether of movement, absorption, or structural excretion, being
determined by its constitution. And then, further, we observe a
parallelism between the metabolic changes in the two cases; for, on the
one hand, "diminished staining capacity of the chromatin [implying a
decreased amount of phosphorus, which gives the staining capacity]
occurs during a period of intense constructive activity in the cytoplasm;"
and, on the other hand, in high organisms having nervous systems, the
intensity of nervous action is measured by the excretion of phosphates
—by the using up of the phosphorus contained in nerve-cells.

For thus interpreting the respective functions of chromatin and

cytoplasm, yet a further reason may be given. One of the earliest
general steps in the evolution of the Metazoa, is the differentiation of
parts which act from parts which make them act. The Hydrozoa show
us this. In the hydroid stage there are no specialized contractile organs:
these are but incipient: individual ectoderm cells have muscular
processes. Nor is there any "special aggregation of nerve-cells." If any
stimulating units exist they are scattered. But in the Medusa-stage
nerve-matter is collected into a ring round the edge of the umbrella.
That is to say, in the undeveloped form such motor action as occurs is
not effected by a specialized part which excites another part; but in the
developed form a differentiation of the two has taken place. All higher
types exhibit this differentiation. Be it muscle or gland or other
operating organ, the cause of its activity lies not in itself but in a
nervous agent, local or central, with which it is connected. Hence, then,
there is congruity between the above interpretation and certain general
truths displayed by animal organization at large. We may infer that in a
way parallel to that just indicated, cell-evolution was, under one of its
aspects, a change from a stage in which the exciting substance and the
substance excited were mingled with approximate uniformity, to a stage
in which the exciting substance was gathered together into the nucleus
and finally into the chromosomes: leaving behind the substance excited,
now distinguished as cytoplasm.
§ 74f. Some further general aspects of the phenomena appear to be in
harmony with this interpretation. Let us glance at them.

In Chapters III and IIIA of the First Part, reasons were given for
concluding that in the animal organism nitrogenous substances play the
part of decomposing agents to the carbo-hydrates—that the molecular
disturbance set up by the collapse of a proteid molecule destroys the
equilibrium of sundry adjacent carbo-hydrate molecules, and causes
that evolution of energy which accompanies their fall into molecules of
simpler compounds. Here, if the foregoing argument is valid, we may
conclude that this highly complex phosphorized compound which
chromatin contains, plays the same part to the adjacent nitrogenous
compounds as these play to the carbo-hydrates. If so, we see arising a
stage earlier that "general physiological method" illustrated in § 23f. It
was there pointed out that in animal organisms the various structures
are so arranged that evolution of a small amount of energy in one, sets
up evolution of a larger amount of energy in another; and often this
multiplied energy undergoes a second multiplication of like kind. If this
view is tenable, we may now suspect that this method displayed in the
structures of the Metazoa was initiated in the structures of the
Protozoa, and consequently characterizes those homologues of them
which compose the Metazoa.

When contemplated from the suggested point of view, karyokinesis

appears to be not wholly incomprehensible. For if the chromatin yields
the energy which initiates changes throughout the rest of the cell, we
may see why there eventually arises a process for exact halving of the
chromatin in a mother-cell between two daughter-cells. To make clear
the reason, let us suppose the portioning out of the chromatin leaves
one of the two with a sensibly smaller amount than the other. What
must result? Its source of activity being relatively less, its rate of growth
and its energy of action will be less. If a protozoon, the weaker progeny
arising by division of it will originate an inferior stirp, unable to compete
successfully with that arising from the sister-cell endowed with a larger
portion of chromatin. By continual elimination of the varieties which
produce unequal halving, necessarily at a disadvantage if a moiety of
their members tend continually to disappear, there will be established a
variety in which the halving is exact: the character of this variety being
such that all its members aid the permanent multiplication of the
species. If, again, the case is that of a metazoon, there will be the same
eventual result. An animal or plant in which the chromatin is unequally
divided among the cells, must have tissues of uncertain formation.
Assume that an organ has, by survival of the fittest, been adjusted in
the proportions and qualities of its parts to a given function. If the
multiplying protoplasts, instead of taking equal portions of chromatin,
have some of them smaller portions, the parts of the organ formed of
these, developing less rapidly and having inferior energies, will throw
the organ out of adjustment, and the individual will suffer in the
struggle for life. That is to say, irregular division of the chromatin will
introduce a deranging factor and natural selection will weed out
individuals in which it occurs. Of course no interpretation is thus yielded
of the special process known as karyokinesis. Probably other modes of
equal division might have arisen. Here the argument implies merely that
the tendency of evolution is to establish some mode. In verification of
the view that equal division arises from the cause named, it is pointed
out to me that amitosis, which is a negation of mitosis or karyokinesis,
occurs in transitory tissues or diseased tissues or where degeneracy is
going on.

But how does all this consist with the conclusion that the chromatin
conveys hereditary traits—that it is the vehicle in which the
constitutional structure, primarily of the species and secondarily of
recent ancestors and parents, is represented? To this question there
seems to be no definite answer. We may say only that this second
function is not necessarily in conflict with the first. While the unstable
units of chromatin, ever undergoing changes, diffuse energy around,
they may also be units which, under the conditions furnished by
fertilization, gravitate towards the organization of the species. Possibly it
may be that the complex combination of proteids, common to
chromatin and cytoplasm, is that part in which the constitutional
characters inhere; while the phosphorized component, falling from its
unstable union and decomposing, evolves the energy which, ordinarily
the cause of changes, now excites the more active changes following
fertilization. This suggestion harmonizes with the fact that the fertilizing
substance which in animals constitutes the head of the spermatozoon,
and in plants that of the spermatozoid or antherozoid, is distinguished
from the other agents concerned by having the highest proportion of
the phosphorized element; and it also harmonizes with the fact that the
extremely active changes set up by fertilization are accompanied by
decrease of this phosphorized element. Speculation aside, however, we
may say that the two functions of the chromatin do not exclude one
another, but that the general activity which originates from it may be
but a lower phase of that special activity caused by fertilization.[27]

§ 74g. Here we come unawares to the remaining topic embraced under

the title Cell-Life and Cell-Multiplication. We pass naturally from asexual
multiplication of cells to sexual multiplication—from cell-reproduction to
cell-generation. The phenomena are so numerous and so varied that a
large part of them must be passed over. Conjugation among the
Protophyta and Protozoa, beginning with cases in which there is a
mingling of the contents of two cells in no visible respect different from
one another, and developing into a great variety of processes in which
they differ, must be left aside, and attention limited to the terminal
process of fertilization as displayed in higher types of organisms.

Before fertilization there occurs in the ovum an incidental process of a

strange kind—"strange" because it is a collateral change taking no part
in subsequent changes. I refer to the production and extrusion of the
"polar bodies." It is recognized that the formation of each is analogous
to cell-formation in general; though process and product are both
dwarfed. Apart from any ascribed meaning, the fact itself is clear. There
is an abortive cell-formation. Abortiveness is seen firstly in the
diminutive size of the separated body or cell, and secondly in the
deficient number of its chromosomes: a corresponding deficiency being
displayed in the group of chromosomes remaining in the egg—
remaining, that is (on the hypothesis here to be suggested), in the
sister-cell, supposing the polar body to be an aborted cell. It is currently
assumed that the end to be achieved by thus extruding part of the
chromosomes, is to reduce the remainder to half the number
characterizing the species; so that when, to this group in the germ-cell,
the sperm-cell brings a similarly-reduced group, union of the two shall
bring the chromosomes to the normal number. I venture to suggest
another interpretation. In doing this, however, I must forestall a
conclusion contained in the next chapter; namely, the conclusion that
gamogenesis begins when agamogenesis is being arrested by
unfavourable conditions, and that the failing agamogenesis initiates the
gamogenesis. Of numerous illustrations to be presently given I will, to
make clear the conception, name only one—the formation of fructifying
organs in plants at times when, and in places where, shoots are falling
off in vigour and leaves in size. Here the successive foliar organs,
decreasingly fitted alike in quality and dimensions for carrying on their
normal lives, show us an approaching cessation of asexual
multiplication, ending in the aborted individuals we call stamens; and
the fact that sudden increase of nutrition while gamogenesis is being
thus initiated, causes resumption of agamogenesis, shows that the
gamogenesis is consequent upon the failing agamogenesis. See then
the parallel. On going back from multicellular organisms to unicellular
organisms (or those homologues of them which form the reproductive
agents in multicellular organisms), we find the same law hold. The polar
bodies are aborted cells, indicating that asexual multiplication can no
longer go on, and that the conditions leading to sexual multiplication
have arisen. If this be so, decrease in the chromatin becomes an initial
cause of the change instead of an accompanying incident; and we need
no longer assume that a quantity of precious matter is lost, not by
passive incapacity, but by active expulsion. Another anomaly
disappears. If from the germ-cell there takes place this extrusion of
superfluous chromatin, the implication would seem to be that a parallel
extrusion takes place from the sperm-cell. But this is not true. In the
sperm-cell there occurs just that failure in the production of chromatin
which, according to the hypothesis above sketched out, is to be
expected; for, in the process of cell-multiplication, the cells which
become spermatozoa are left with half the number of chromosomes
possessed by preceding cells: there is actually that impoverishment and
declining vigour here suggested as the antecedent of fertilization. It
needs only to imagine the ovum and the polar body to be alike in size,
to see the parallelism; and to see that obscuration of it arises from the
accumulation of cytoplasm in the ovum.

A test fact remains. Sometimes the first polar body extruded undergoes
fission while the second is being formed. This can have nothing to do
with reducing the number of chromosomes in the ovum.
Unquestionably, however, this change is included with the preceding
changes in one transaction, effected by one influence. If, then, it is
irrelevant to the decrease of chromosomes, so must the preceding
changes be irrelevant: the hypothesis lapses. Contrariwise this fact
supports the view suggested above. That extrusion of a polar body is a
process of cell-fission is congruous with the fact that another fission
occurs after extrusion. And that this occurs irregularly shows that the
vital activities, seen in cell-growth and cell-multiplication, now succeed
in producing further fission of the dwarfed cell and now fail: the
energies causing asexual multiplication are exhausted and there arises
the state which initiates sexual multiplication.

Maturation of the ovum having been completed, entrance of the

spermatozoon, sometimes through the limiting membrane and
sometimes through a micropyle or opening in it, takes place. This
instantly initiates a series of complicated changes: not many seconds
passing before there begins the formation of an aster around one end
of the spermatozoon-head. The growth of this aster, apparently by
linear rangings of the granules composing the reticulum of the germ-
cell, progresses rapidly; while the whole structure hence arising moves
inward. Soon there takes place the fusion of this sperm-nucleus with
the germ-nucleus to form the cleavage-nucleus, which, after a pause,
begins to divide and subdivide in the same manner as cells at large: so
presently forming a cluster of cells out of which arise the layers
originating the embyro. The details of this process do not concern us. It
suffices to indicate thus briefly its general nature.

And now ending thus the account of genesis under its histological
aspect, we pass to the account of genesis under its wider and more
significant aspects.
 CHAPTER VII.

GENESIS.

§ 75. Having, in the last chapter but one, concluded what constitutes an
individual, and having, in the last chapter, contemplated the histological
process which initiates a new individual, we are in a position to deal
with the multiplication of individuals. For this, the title Genesis is here
chosen as being the most comprehensive title—the least specialized in
its meaning. By some biologists Generation has been used to signify
one method of multiplication, and Reproduction to signify another
method; and each of these words has been thus rendered in some
degree unfit to signify multiplication in general.

Here the reader is indirectly introduced to the fact that the production
of new organisms is carried on in fundamentally unlike ways. Up to
quite recent times it was believed, even by naturalists, that all the
various processes of multiplication observable in different kinds of
organisms, have one essential character in common: it was supposed
that in every species the successive generations are alike. It has now
been proved, however, that in many plants and in numerous animals,
the successive generations are not alike; that from one generation there
proceeds another whose members differ more or less in structure from
their parents; that these produce others like themselves, or like their
parents, or like neither; but that eventually, the original form re-
appears. Instead of there being, as in the cases most familiar to us, a
constant recurrence of the same form, there is a cyclical recurrence of
the same form. These two distinct processes of multiplication, may be
aptly termed homogenesis and heterogenesis.[28] Under these heads let
us consider them.

There are two kinds of homogenesis, the simplest of them, probably

once universal but now exceptional, being that in which there is no
other form of multiplication than one resulting from perpetual
spontaneous fission. The rise of distinct sexes was doubtless a step in
evolution, and before it took place the formation of new individuals
could have arisen only by division of the old, either into two or into
many. At present this process survives, so far as appears, among
Bacteria, certain Algæ, and sundry Protozoa; though it is possible that a
rarely-occurring conjugation has in these cases not yet been observed.
It is a probable conclusion, however, that in the Bacteria at any rate,
the once universal mode of multiplication still survives as an exceptional
mode. But now passing over these cases, we have to note that the kind
of genesis (once supposed to be the sole kind), in which the successive
generations are alike, is sexual genesis, or, as it has been otherwise
called—gamogenesis. In every species which multiplies by this kind of
homogenesis, each generation consists of males and females; and from
the fertilized germs they produce the next generation of similar males
and females arises: the only needful qualification of this statement
being that in many Protophyta and Protozoa the conjugating cells or
protoplasts are not distinguishable in character. This mode of
propagation has the further trait, that each fertilized germ usually gives
rise to but one individual—the product of development is organized
round one axis and not round several axes, Homogenesis in contrast
with heterogenesis as exhibited in species which display distinct
sexuality, has also the characteristic that each new individual begins as
an egg detached from the maternal tissues, instead of being a portion
of protoplasm continuous with them, and that its development proceeds
independently. This development may be carried on either internally or
externally; whence results the division into the oviparous and the
viviparous. The oviparous kind is that in which the fertilized germ is
extruded from the parent before it has undergone any considerable
development. The viviparous kind is that in which development is
considerably advanced, or almost completed, before extrusion takes
place. This distinction is, however, not a sharply-defined one: there are
transitions between the oviparous and the viviparous processes. In ovo-
viviparous genesis there is an internal incubation; and though the young
are in this case finally extruded from the parent in the shape of eggs,
they do not leave the parent's body until after they have assumed
something like the parental form. Looking around, we find that
homogenesis is universal among the Vertebrata. Every vertebrate
animal arises from a fertilized germ, and unites into its single
individuality the whole product of this fertilized germ. In the mammals
or highest Vertebrata, this homogenesis is in every case viviparous; in
birds it is uniformly oviparous; and in reptiles and fishes it is always
essentially oviparous, though there are cases of the kind above referred
to, in which viviparity is simulated. Passing to the Invertebrata, we find
oviparous homogenesis universal among the Arachnida (except the
Scorpions, which are ovo-viviparous); universal among the higher
Crustacea, but not among the lower; extremely general, though not
universal, among Insects; and universal among the higher Mollusca
though not among the lower. Along with extreme inferiority among
animals, we find homogenesis to be the exception rather than the rule;
and in the vegetal kingdom there appear to be no cases, except among
the Algæ and a few aberrant parasites like the Rafflesiaceæ, in which
the centre or axis which arises from a fertilized germ becomes the
immediate producer of fertilized germs.

In propagation characterized by unlikeness of the successive

generations, there is asexual genesis with occasionally-recurring sexual
genesis; in other words—agamogenesis interrupted more or less
frequently by gamogenesis. If we set out with a generation of perfect
males and females, then, from their ova arise individuals which are
neither males nor females, but which produce the next generation from
buds. By this method of multiplication many individuals originate from a
single fertilized germ. The product of development is organized round
more than one centre or axis. The simplest form of heterogenesis is
that seen in most uniaxial plants. If, as we find ourselves obliged to do,
we regard each separate shoot or axis of growth as a distinct individual,
homogenesis is seen in those which have absolutely terminal flowers;
but in all other uniaxial plants, the successive individuals are not
represented by the series A, A, A, A, &c., but they are represented by
the series A, B, A, B, A, B, &c. For in the majority of plants which were
classed as uniaxial (§ 50), and which may be conveniently so
distinguished from other plants, the axis which shoots up from the
seed, and substantially constitutes the plant, does not itself flower but
gives lateral origin to flowering axes. Though in ordinary uniaxial plants
the fructifying apparatus appears to be at the end of the primary,
vertical axis; yet dissection shows that, morphologically considered,
each fructifying axis is an offspring from the primary axis. There arises
from the seed a sexless individual, from which spring by gemmation
individuals having reproductive organs; and from these there result
fertilized germs or seeds that give rise to sexless individuals. That is to
say, gamogenesis and agamogenesis alternate: the peculiarity being
that the sexual individuals arise from the sexless ones by continuous
development. The Salpæ show us an allied form of heterogenesis in the
animal kingdom. Individuals developed from fertilized ova, instead of
themselves producing fertilized ova, produce, by gemmation, strings of
individuals from which fertilized ova again originate. In multiaxial plants,
we have a succession of generations represented by the series A, B, B,
B, &c., A, B, B, B, &c. Supposing A to be a flowering axis or sexual
individual, then, from any fertilized germ it casts off, there grows up a
sexless individual, B; from this there bud-out other sexless individuals,
B, and so on for generations more or less numerous, until at length,
from some of these sexless individuals, there bud-out seed-bearing
individuals of the original form A. Branched herbs, shrubs, and trees,
exhibit this form of heterogenesis: the successive generations of sexless
individuals thus produced being, in most cases, continuously developed,
or aggregated into a compound individual, but being in some cases
discontinuously developed. Among animals a kind of heterogenesis
represented by the same succession of letters, occurs in such
compound polypes as the Sertularia, and in those of the Hydrozoa
which assume alternately the polypoid form and the form of the
Medusa. The chief differences presented by these groups arise from the
fact that the successive generations of sexless individuals produced by
budding, are in some cases continuously developed, and in others
discontinuously developed; and from the fact that, in some cases, the
sexual individuals give off their fertilized germs while still growing on
the parent-polypedom, but in other cases not until after leaving the
parent-polypedom and undergoing further development. Where, as in
all the foregoing kinds of agamogenesis, the new individuals bud out,
not from any specialized reproductive organs but from unspecialized
parts of the parent, the process has been named, by Prof. Owen,
metagenesis. In most instances the individuals thus produced grow
from the outsides of the parents—the metagenesis is external. But there
is also a kind of metagenesis which we may distinguish as internal.
Certain entozoa of the genus Distoma exhibit it. From the egg of a
Distoma there results a rudely-formed creature known as a sporocyst
and from this a redia. Gradually, as this divides and buds, the greater
part of the inner substance is transformed into young animals called
Cercariæ (which are the larvæ of Distomata); until at length it becomes
little more than a living sac full of living offspring. In the Distoma
pacifica, the brood of young animals thus arising by internal gemmation
are not Cercariæ, but are like their parent: themselves becoming the
producers of Cercariæ, after the same manner, at a subsequent period.
So that now the succession of forms is represented by the series A, B,
A, B, &c., now by the series A, B, B, A, B, B, &c., and now by A, B, B, C,
A. Both cases, however, exemplify internal metagenesis in contrast with
the several kinds of external metagenesis described above. That
agamogenesis which is carried on in a reproductive organ—either an
ovarium or the homologue of one—has been called, by Prof. Owen,
parthenogenesis. It is the process familiarly exemplified in the Aphides.
Here, from the fertilized eggs laid by perfect females there grow up
imperfect females, in the ovaria of which are developed ova that though
unfertilized, rapidly assume the organization of other imperfect females,
and are born viviparously. From this second generation of imperfect
females, there by-and-by arises, in the same manner, a third generation
of the same kind; and so on for many generations: the series being thus
symbolized by the letters A, B, B, B, B, B, &c., A. Respecting this kind of
heterogenesis it should be added that, in animals as in plants, the
number of generations of sexless individuals produced before the re-
appearance of sexual ones, is indefinite; both in the sense that in the
same species it may go on to a greater or less extent according to
circumstances, and in the sense that among the generations of
individuals proceeding from the same fertilized germ, a recurrence of
sexual individuals takes place earlier in some of the diverging lines of
multiplication than in others. In trees we see that on some branches
flower-bearing axes arise while other branches are still producing only
leaf-bearing axes; and in the successive generations of Aphides a
parallel fact has been observed. Lastly has to be set down that kind of
heterogenesis in which, along with gamogenesis, there occurs a form of
agamogenesis exactly like it, save in the absence of fecundation. This is
called true parthenogenesis—reproduction carried on by virgin mothers
which are in all respects like other mothers. Among silk-worm-moths
this parthenogenesis is exceptional rather than ordinary. Usually the
eggs of these insects are fertilized; but if they are not they are still laid,
and some of them produce larvæ. In certain Lepidoptera, however, of
the groups Psychidæ and Tineidæ, parthenogenesis appears to be a
normal process—indeed, so far as is known, the only process; for of
some species the males have never been found.

A general conception of the relations among the different modes of

Genesis, thus briefly described, will be best given by the following
tabular statement.

Oviparous
or
Ovo-
Homogenesis, which is usually
viviparous
Gamogenesis
or
Viviparous
Genesis
is or
Gamogenesis
alternating
Heterogenesis, with Parthenogenesis
which is Agamogenesis or Internal
Metagenesis or
External

This, like all other classifications of such phenomena, presents

anomalies. It may be justly objected that the processes here grouped
under the head agamogenesis, are the same as those before grouped
under the head of discontinuous development (§ 50): thus making
development and genesis partially coincident. Doubtless it seems
awkward that what are from one point of view considered as structural
changes are from another point of view considered as modes of
multiplication.[29] There is, however, nothing for us but a choice of
imperfections. We cannot by any logical dichotomies accurately express
relations which, in Nature, graduate into one another insensibly. Neither
the above, nor any other scheme, can do more than give an
approximate idea of the truth.

§ 76. Genesis under every form is a process of negative or positive

disintegration; and is thus essentially opposed to that process of
integration which is the primary process in individual evolution.
Negative disintegration occurs in those cases where, as among the
compound Hydrozoa, there is a continuous development of new
individuals by budding from the bodies of older individuals; and where
the older individuals are thus prevented from growing to a greater size,
or reaching a higher degree of integration. Positive disintegration occurs
in those forms of agamogenesis where the production of new
individuals is discontinuous, as well as in all cases of gamogenesis. The
degrees of disintegration are various. At the one extreme the parent
organism is completely broken up, or dissolved into new individuals;
and at the other extreme each new individual forms but a small
deduction from the parent organism. Protozoa and Protophyta show us
that form of disintegration called spontaneous fission: two or more
individuals being produced by the splitting-up of the original one. The
Volvox and the Hydrodictyon are plants which, having developed broods
within themselves, give them exit by bursting; and among animals the
one lately referred to which arises from the Distoma egg, entirely loses
its individuality in the individualities of the numerous Distoma-larvæ
with which it becomes filled. Speaking generally, the degree of
disintegration becomes less marked as we approach the higher organic
forms. Plants of superior types throw off from themselves, whether by
gamogenesis or agamogenesis, parts that are relatively small; and
among superior animals there is no case in which the parent
individuality is habitually lost in the production of new individuals. To
the last, however, there is of necessity a greater or less disintegration.
The seeds and pollen-grains of a flowering plant are disintegrated
portions of tissue; as are also the ova and spermatozoa of animals. And
whether the fertilized germs carry away from their parents small or
large quantities of nutriment, these quantities in all cases involve
further negative or positive disintegrations of the parents.

Except in spore-producing plants, new individuals which result from

agamogenesis usually do not separate from the parent-individuals until
they have undergone considerable development, if not complete
development. The agamogenetic offspring of those lowest organisms
which develop centrally, do not, of course, pass beyond central
structure; but the agamogenetic offspring of organisms which develop
axially, commonly assume an axial structure before they become
independent. The vegetal kingdom shows us this in the advanced
organization of detached bulbils, and of buds that root themselves
before separating. Of animals, the Hydrozoa, the Trematoda, and the
Salpæ, present us with different kinds of agamogenesis, in all of which
the new individuals are organized to a considerable extent before being
cast off. This rule is not without exceptions, however. The statoblasts of
the Plumatella (which play the part of winter eggs), developed in an
unspecialized part of the body, furnish a case of metagenesis in which
centres of development, instead of axes, are detached; and in the
above-described parthenogenesis of moths and bees, such centres are
detached from an ovarium.

When produced by gamogenesis, the new individuals become (in a

morphological sense) independent of the parents while still in the shape
of centres of development, rather than axes of development; and this
even where the reverse is apparently the case. The fertilized germs of
those inferior plants which are central, or multicentral, in their
development, are of course thrown off as centres; and the same is
usually the case even in those which are uniaxial or multiaxial. In the
higher plants, of the two elements that go to the formation of the
fertilized germ, the pollen-cell is absolutely separated from the parent-
plant under the shape of a centre, and the egg-cell, though not
absolutely separated from the parent, is still no longer subordinate to
the organizing forces of the parent. So that when, after the egg-cell has
been fertilized by matter from the pollen-tube, the development
commences, it proceeds without parental control: the new individual,
though remaining physically united with the old individual, becomes
structurally and functionally separate: the old individual doing no more
than supply materials. Throughout the animal kingdom, the new
individuals produced by gamogenesis are obviously separated in the
shape of centres of development wherever the reproduction is
oviparous: the only conspicuous variation being in the quantity of
nutritive matter bequeathed by the parent at the time of separation.
And though, where the reproduction is viviparous, the process appears
to be different, and in one sense is so, yet, intrinsically, it is the same.
For in these cases the new individual really detaches itself from the
parent while still only a centre of development; but instead of being
finally cast off in this state it is re-attached, and supplied with nutriment
until it assumes a more or less complete axial structure.

§ 77. As we have lately seen, the essential act in gamogenesis is the

union of two cell-nuclei, produced in the great majority of cases by
different parent organisms. Nearly always the containing cells, often
called gametes, are unlike: the sperm-cell being the male product, and
the germ-cell the female. But among some Protozoa and many of the
lower Algæ and Fungi, the uniting cells show no differentiation.
Sexuality is only nascent.

There are very many modes and modifications of modes in which these
cells are produced; very many modes and modifications of modes by
which they are brought into contact; and very many modes and
modifications of modes by which the resulting fertilized germs have
secured to them the fit conditions for their development. But passing
over these divergent and re-divergent kinds of sexual multiplication,
which it would take too much space here to specify, the one universal
trait is this coalescence of a detached portion of one organism with a
more or less detached portion of another.

Such simple Algæ as the Desmidieæ, which are sometimes called

unicellular plants, show us a coalescence, not of detached portions of
two organisms, but of two entire organisms: the entire contents of the
individuals uniting to form the germ-mass. Where, as among the
Confervoideæ, we have aggregated cells whose individualities are
scarcely at all subordinate to that of the aggregate, the gamogenetic
act is often effected by the union "of separate motile protoplasmic
masses produced by the division of the contents of any cell of the
aggregate. These free-swimming masses of protoplasm, which are quite
similar to (but generally smaller than) the agamogenetic 'zoospores' of
the same plants, and to the free-swimming individuals of many
Protophyta, are apparently the primitive type of gametes (conjugating
cells); but it is noteworthy that such a gamete nearly always unites with
one derived from another cell or from another individual. The same fact
holds with regard to the gametes of the Protophytes themselves, which
are formed in the same way from the single cell of the mother
individual. In the higher types of Confervoideæ, and in Vaucheria, we
find these equivalent, free-swimming, gametes replaced by sexually
differentiated sperm- and germ-cells, in some cases arising in different
organs set apart for their production, and essentially representing those
found in the higher plants. Transitional forms, intermediate between
these and the cases where equivalent gametes are formed from any cell
of the plant are also known."

Recent investigations concerning the conjugation of Protozoa have

shown that there is not, as was at one time thought, a fusion of two
individualities, but a fusion of parts of their nuclei. The macro-nucleus
having disappeared, and the micro-nucleus having broken up into
portions, each individual receives from the other one of these portions,
which becomes fused with its own nuclear matter. So that even in these
humble forms, where there is no differentiation of sexes, the union is
not between elements that have arisen in the same individual but
between those which have arisen in different individuals: the parts
being in this case alike.

The marvellous phenomena initiated by the meeting of sperm-cell and

germ-cell, or rather of their nuclei, naturally suggest the conception of
some quite special and peculiar properties possessed by these cells. It
seems obvious that this mysterious power which they display of
originating a new and complex organism, distinguishes them in the
broadest way from portions of organic substance in general.
Nevertheless, the more we study the evidence the more are we led
towards the conclusion that these cells are not fundamentally different
from other cells. The first fact which points to this conclusion is the fact
recently dwelt upon (§ 63), that in many plants and inferior animals, a
small fragment of tissue which is but little differentiated, is capable of
developing into an organism like that from which it was taken. This
implies that the component units of tissues have inherent powers of
arranging themselves into the forms of the organisms which originated
them. And if in these component units, which we distinguished as
physiological, such powers exist,—if, under fit conditions, and when not
much specialized, they manifest such powers in a way as marked as
that in which the contents of sperm-cells and germ-cells manifest them;
then, it becomes clear that the properties of sperm-cells and germ-cells
are not so peculiar as we are apt to assume. Again, the organs emitting
sperm-cells and germ-cells have none of the specialities of structure
which might be looked for, did sperm-cells and germ-cells need
endowing with properties unlike those of all other organic agents. On
the contrary, these reproductive centres proceed from tissues
characterized by their low organization. In plants, for example, it is not
appendages that have acquired considerable structure which produce
the fructifying particles: these arise at the extremities of the axes where
the degree of structure is the least. The cells out of which come the egg
and the pollen-grains, are formed from undifferentiated tissue in the
interior of the ovule and of the stamen. Among many inferior animals
devoid of special reproductive organs, such as the Hydra, the ova and
spermatozoa originate from the interstitial cells of the ectoderm, which
lie among the bases of the functional cells—have not been
differentiated for function; and in the Medusæ, according to Weismann,
they arise in the homologous layer, save where the medusoid form
remains attached, and then they arise in the endoderm and migrate to
the ectoderm: lack of specialization being in all cases implied. Then in
the higher animals these same generative agents appear to be merely
modified epithelium-cells—cells not remarkable for their complexity of
structure but rather for their simplicity. If, by way of demurrer to this
view, it be asked why other epithelium-cells do not exhibit like
properties; there are two replies. The first is that other epithelium-cells
are usually so far changed to fit them to their special functions that they
are unfitted for assuming the reproductive function. The second is that
in some cases, where they are but little specialized, they do exhibit the
like properties: not, indeed, by uniting with other cells to produce new
germs but by producing new germs without such union. I learn from Dr.
Hooker that the Begonia phyllomaniaca habitually develops young
plants from the scales of its stem and leaves—nay, that many young
plants are developed by a single scale. The epidermal cells composing
one of these scales swell, here and there, into large globular cells; form
chlorophyll in their interiors; shoot out rudimentary axes; and then, by
spontaneous constrictions, cut themselves off; drop to the ground; and
grow into Begonias. Moreover, in a succulent English plant, the Malaxis
paludosa, a like process occurs: the self-detached cells being, in this
case, produced by the surfaces of the leaves.[30] Thus, there is no
warrant for the assumption that sperm-cells and germ-cells possess
powers fundamentally unlike those of other cells. The inference to
which the facts point, is, that they differ from the rest mainly in not
having undergone functional adaptations. They are cells which have
departed but little from the original and most general type: such
specializations as some of them exhibit in the shape of locomotive
appliances, being interpretable as extrinsic modifications which have
reference to nothing beyond certain mechanical requirements. Sundry
facts tend likewise to show that there does not exist the profound
distinction we are apt to assume between the male and female
reproductive elements. In the common polype sperm-cells and germ-
cells are developed in the same layer of indifferent tissue; and in
Tethya, one of the sponges, Prof. Huxley has observed that they occur
mingled together in the general parenchyma. The pollen-grains and
embryo-cells of plants arise in adjacent parts of the meristematic tissue
of the flower-bud; and from the description of a monstrosity in the
Passion-flower, recently given by Mr. Salter to the Linnæan Society, it
appears both that ovules may, in their general structure, graduate into
anthers, and that they may produce pollen in their interiors. Moreover,
among the lower Algæ, which show the beginning of sexual
differentiation, the smaller gametes, which we must regard as incipient
sperm-cells, are sometimes able to fuse inter se, and give rise to a
zygote which will produce a new plant. All which evidence is in perfect
harmony with the foregoing conclusion; since, if sperm-cells and germ-
cells have natures not essentially unlike those of unspecialized cells in
general, their natures cannot be essentially unlike each other.

The next general fact to be noted is that these cells whose union
constitutes the essential act of gamogenesis, are cells in which the
developmental changes have come to a close—cells which are incapable
of further evolution. Though they are not, as many cells are, unfitted for
growth and metamorphosis by being highly specialized, yet they have
lost the power of growth and metamorphosis. They have severally
reached a state of equilibrium. And while the internal balance of forces
prevents a continuance of constructive changes, it is readily overthrown
by external destructive forces. For it almost uniformly happens that
sperm-cells and germ-cells which are not brought in contact disappear.
In a plant, the egg-cell, if not fertilized, is absorbed or dissipated, while
the ovule aborts; and the unimpregnated ovum eventually decomposes:
save, indeed, in those types in which parthenogenesis is a part of the
normal cycle.

Such being the characters of these cells, and such being their fates if
kept apart, we have now to observe what happens when they are
united. In plants the extremity of the elongated pollen-cell applies itself
to the surface of the embryo-sac, and one of its nuclei having, with
some protoplasm, passed into the egg-cell, there becomes fused with
the nucleus of the egg-cell. Similarly in animals, the spermatozoon
passes through the limiting membrane of the ovum, and a mixture
takes place between the substance of its nucleus and the substance of
the nucleus of the ovum. But the important fact which it chiefly
concerns us to notice, is that on the union of these reproductive
elements there begins, either at once or on the return of favourable
conditions, a new series of developmental changes. The state of
equilibrium at which each had arrived is destroyed by their mutual
influence, and the constructive changes, which had come to a close,
recommence. A process of cell-multiplication is set up; and the resulting
cells presently begin to aggregate into the rudiment of a new organism.
Thus, passing over the variable concomitants of gamogenesis, and
confining our attention to what is constant in it, we see:—that there is
habitually, if not universally, a fusion of two portions of organic
substance which are either themselves distinct individuals, or are
thrown off by distinct individuals; that these portions of organic
substance, which are severally distinguished by their low degree of
specialization, have arrived at states of structural quiescence or
equilibrium; that if they are not united this equilibrium ends in
dissolution; but that by the mixture of them this equilibrium is
destroyed and a new evolution initiated.

§ 78. What are the conditions under which Genesis takes place? How
does it happen that some organisms multiply by homogenesis and
others by heterogenesis? Why is it that where agamogenesis prevails it
is usually from time to time interrupted by gamogenesis? A survey of
the facts discloses certain correlations which, if not universal, are too
general to be without significance.

Where multiplication is carried on by heterogenesis we find, in

numerous cases, that agamogenesis continues as long as the forces
which result in growth are greatly in excess of the antagonist forces.
Conversely, we find that the recurrence of gamogenesis takes place
when the conditions are no longer so favourable to growth. In like
manner where there is homogenetic multiplication, new individuals are
usually not formed while the preceding individuals are still rapidly
growing—that is, while the forces producing growth exceed the
opposing forces to a great extent; but the formation of new individuals
begins when nutrition is nearly equalled by expenditure. A few out of
the many facts which seem to warrant these inductions must suffice.

The relation in plants between fructification and innutrition (or rather,

between fructification and such diminished nutrition as makes growth
relatively slow) was long ago asserted by a German biologist—Wolff, I
am told. Since meeting with this assertion I have examined into the
facts for myself. The result has been a conviction, strengthened by
every inquiry, that some such relation exists. Uniaxial plants begin to
produce their lateral, flowering axes, only after the main axis has
developed the great mass of its leaves, and is showing its diminished
nutrition by smaller leaves, or shorter internodes, or both. In multiaxial
plants two, three, or more generations of leaf-bearing axes, or sexless
individuals, are produced before any seed-bearing individuals show
themselves. When, after this first stage of rapid growth and
agamogenetic multiplication, some gamogenetic individuals arise, they
do so where the nutrition is least;—not on the main axis, or on
secondary axes, or even on tertiary axes, but on axes that are the most
removed from the channels which supply nutriment. Again, a flowering
axis is commonly less bulky than the others: either much shorter or, if
long, much thinner. And further, it is an axis of which the terminal
internodes are undeveloped: the foliar organs, which instead of
becoming leaves become sepals, and petals, and stamens, follow each
other in close succession, instead of being separated by portions of the
still-growing axis. Another group of evidences meets us when we
observe the variations of fruit-bearing which accompany variations of
nutrition in the plant regarded as a whole. Besides finding, as above,
that gamogenesis commences only when growth has been checked by
extension of the remoter parts to some distance from the roots, we find
that gamogenesis is induced at an earlier stage than usual by checking
the nutrition. Trees are made to fruit while still quite small by cutting
their roots or putting them into pots; and luxuriant branches which have
had the flow of sap into them diminished, by what gardeners call
"ringing," begin to produce flower-shoots instead of leaf-shoots.
Moreover, it is to be remarked that trees which, by flowering early in the
year, seem to show a direct relation between gamogenesis and
increasing nutrition, really do the reverse; for in such trees the flower-
buds are formed in the autumn. That structure which determines these
buds into sexual individuals is given when the nutrition is declining.
Conversely, very high nutrition in plants prevents, or arrests,
gamogenesis. It is notorious that unusual richness of soil, or too large a
quantity of manure, results in a continuous production of leaf-bearing or
sexless shoots; and a like result happens when the cutting down of a
tree, or of a large part of it, is followed by the sending out of new
shoots: these, supplied with excess of sap, are luxuriant and sexless.
Besides being prevented from producing sexual individuals by excessive
nutrition, plants are, by excessive nutrition, made to change the sexual
individuals they were about to produce, into sexless ones. This arrest of
gamogenesis may be seen in various stages. The familiar instance of
flowers made barren by the transformation of their stamens into petals,
shows us the lowest degree of this reversed metamorphosis. Where the
petals and stamens are partially changed into green leaves, the return
towards the agamogenetic structure is more marked; and it is still more
marked when, as occasionally happens in luxuriantly-growing plants,
new flowering axes, and even leaf-bearing axes, grow out of the centres
of flowers.[31] The anatomical structure of the sexual axis affords
corroborative evidence: giving the impression, as it does, of an aborted
sexless axis. Besides lacking those internodes which the leaf-bearing
axis commonly possesses, the flowering axis differs by the absence of
rudimentary lateral axes. In a leaf-bearing shoot the axil of every leaf
usually contains a small bud, which may or may not develop into a
lateral shoot; but though the petals of a flower are homologous with
leaves, they do not bear homologous buds at their bases. Ordinarily,
too, the foliar appendages of sexual axes are much smaller than those
of sexless ones—the stamens and pistils especially, which are the last
formed, being extremely dwarfed; and it may be that the absence of
chlorophyll from the parts of fructification is a fact of like meaning.
Moreover, the formation of the seed-vessel appears to be a direct
consequence of arrested nutrition. If a gloved-finger be taken to
represent a growing shoot, (the finger standing for the pith of the shoot
and the glove for the peripheral layers of meristem and young tissue, in
which the process of growth takes place); and if it be supposed that
there is a diminished supply of material for growth; then, it seems a fair
inference that growth will first cease at the apex of the axis,
represented by the end of the glove-finger; and supposing growth to
continue in those parts of the peripheral layers of young tissue that are
nearer to the supply of nutriment, their further longitudinal extension
will lead to the formation of a cavity at the extremity of the shoot, like
that which results in a glove-finger when the finger is partially
withdrawn and the glove sticks to its end. Whence it seems, both that
this introversion of the apical meristem may be considered as due to
failing nutrition, and that the ovules growing from its introverted surface
(which would have been its outer surface but for the defective nutrition)
are extremely aborted homologues of external appendages: both they
and the pollen-grains being either morphologically or literally quite
terminal, and the last showing by their dehiscence the exhaustion of the
organizing power.[32]

Those kinds of animals which multiply by heterogenesis, present us with

a parallel relation between the recurrence of gamogenesis and the
recurrence of conditions checking rapid growth: at least, this is shown
where experiments have thrown light on the connexion of cause and
effect; namely, among the Aphides. These creatures, hatched from eggs
in the spring, multiply by agamogenesis, which in this case is
parthenogenesis, throughout the summer. When the weather becomes
cold and plants no longer afford abundant sap, perfect males and
females are produced; and from gamogenesis result fertilized ova. But
beyond this evidence we have much more conclusive evidence. For it
has been shown, both that the rapidity of the agamogenesis is
proportionate to the warmth and nutrition, and that if the temperature
and supply of food be artificially maintained, the agamogenesis
continues through the winter. Nay more—it not only, under these
conditions, continues through one winter, but it has been known to
continue for four successive years: some forty or fifty sexless
generations being thus produced. And those who have investigated the
matter see no reason to doubt the indefinite continuance of this
agamogenetic multiplication, so long as the external requirements are
duly met. Evidence of another kind, complicated by special influences, is
furnished by the heterogenesis of the Daphnia—a small crustacean
commonly known as the Water-flea, which inhabits ponds and ditches.
From the nature of its habitat this little creature is exposed to very
variable conditions. Besides being frozen in winter, the small bodies of
water in which it lives are often unduly heated by the summer Sun, or
dried up by continued drought. The circumstances favourable to the
Daphnia's life and growth, being thus liable to interruptions which, in
our climate, have a regular irregularity of recurrence; we may, in
conformity with the hypothesis, expect to find both that the
gamogenesis recurs along with declining physical prosperity and that its
recurrence is very variable. I use the expression "declining physical
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