A P P R OAC H T O

I N BO R N E R R O R S
O F M E TA BO L I S M
Presented by Under Guidance of -
Dr. Priyanka Sahu Dr. Nirbhay Mehta
Dr. Prachi Goyal
WHAT ARE INBORN ERRORS OF
METABOLISM ?

• Hereditary diseases that disrupt normal biochemical

processes are termed inborn errors of metabolism or
inherited metabolic diseases .
• Although IEMs are individually rare, they are collectively
common, with an overall incidence of more than 1:1,000.
• More than 500 IEMs have been recognized.
MECHANISM
• ENZYME
• RECEPTOR
• TRANSPORT VEHICLE
• MEMBRANE
DNA RNA PROTEIN COMPONENT
Gene • TRANSCRIPTIONAL
mutation Structure or amount COREGULATOR
change • STRUCTURAL ELEMENT

GARROD’S HYPOTHESIS

A
Substrate
B C
Product
(excess) (deficiency)

D
Abnormal
metabolic pathway Toxic metabolite
CLASSIFICATION

• Defects of amino acid metabolism

• Defects of Carbohydrate metabolism
• Defects of Fat metabolism
• Lysosomal enzymes defects
• Mitochondrial disorders
• Peroxisomal disorders
• Defects in purine and pyrimidine metabolism
WHEN TO SUSPECT IEM ?

• Pointers in History s/o Inborn Errors of Metabolism-

-Deterioration after a period of apparent normalcy
-Persistent feeding difficulties
-Persistent vomiting
-Recurrent seizure episodes
-Peculiar odor (urine, cerumen)
-Rapidly progressive encephalopathy and seizures of
unexplained cause
WHEN TO SUSPECT IEM ?
FAMILY HISTORY
ANTENATAL HISTORY - Parental consanguinity
MATERNAL - Family history of
-Acute fatty liver or HELLP during unexplained neonatal
pregnancy: deaths/ sudden infant
• In fetuses with long -chain - death
3 hydroxyl acyl-coenzyme - Family history
dehydrogenase deficiency X linked recessive
(LCHADD). disorders - Males
Mitochondrial disorders -
FETAL All children of affected
-Hydrops fetalis (non-immune): mother are affected
• Gaucher’s disease
• GM1 gangliosidosis “ A positive history may be
• Niemann Pick disease helpful, but a negative
• Zellweger’s disease family history doesn’t rule
out IEM. "
MODE OF INHERITANCE
• The vast majority of IEMs are inherited in an autosomal recessive manner.
• Some disorders are inherited as X linked recessive conditions –
– Fabry disease
– Hunter’s disease (MPS II)
– OTC (Ornithine TransCarbamylase) deficiency
– Pyruvate dehydrogenase complex deficiency
– Adrenoleukodystrophy
– Lesch Nyhan syndrome
– Menkes disease
• A few are inherited as Autosomal dominant trait –
– Acute Intermittent Porphyria (porphobilinogen deaminase deficiency)
– Familial Hypercholesterolemia
• Maternal Inheritance
– Mitochondrial disorders
CLINICAL PRESENTATION
• ACUTE PRESENTATION (GENERALLY PRESENT IN INFANCY)
– Poor feeding, Vomiting
– Lethargy, coma, convulsions
– Hypotonia, abnormal respiration
– Abnormal odor in urine/body
– Negative sepsis screen in a sick child

Small molecule defect disorders (defects in metabolism of water

soluble metabolites, such as glucose, ammonia, amino acids and
organic acids)
• Aminoacidopathies
• Organic acidurias
• Fatty Acid Oxidation Defects
• Mitochondrial disorders
CLINICAL PRESENTATION
• INTERMITTENT PRESENTATION (PRECIPITATED BY STRESS -
Starvation, Infection, Trauma, Surgery ; DIET)
– Repeated episodes of reduced level of consciousness
– Acidosis, or ketosis, or Hypoglycemia
– Weakness,
– Ataxia, spasticity,
– Diarrhea, vomiting

• Propionic Acidemia
• Methyl malonic aciduria
• Multiple carboxylase deficiency
• Isovaleric Acidemia
• Urea Cycle defects
CLINICAL PRESENTATION
• CHRONIC (GENERALLY PRESENT LATE IN CHILDHOOD)
– Progressive CNS degeneration
• Seizure
• Development delay
• Mental retardation
– Failure to thrive
– Hypotonia, Spasticity, Muscular weakness
– Associated organomegaly
– Dysmorphic facies
– Fundus abnormalities
Large molecule defects
• Storage disorders
• Grey/white matter disorders
ASSOCIATED WITH DYSMORPHIC
FEATURES

Zellweger’s syndrome Pyruvate Hurler’s Syndrome

dehydrogenase
deficiency
Coarse facial
appearance,
Large fontanelle, Epicanthal folds, flat
prominent glabella,
prominent forehead, nasal bridge, small
depressed nasal
flat nasal bridge, nose with anteverted
bridge, enlarged
epicanthal folds, flared alae nasi, long
tongue and lips,
hypoplastic philtrum
gingival hypertrophy,
DERMATOLOGICA
L SIGNS Alopecia/Eczema- Biotinidase deficiency
Multiple carboxylase deficiency

Jaundice – Disorders of bile acid synthesis, Galactosemia,

Zellweger’s syndrome

Abnormal kinky hair – Menke disease, Arginosuccinic

aciduria

Perioral eruptions - Multiple carboxylase deficiency

Decreased pigmentation – Phenylketonuria

Angiokeratomas – Fabry’s disease

OPHTHALMOLOGICAL SIGNS
Cataract – Galactosemia , Zellweger syndrome

Ectopia Lentis – Homocystinuria (Infero-nasal

dislocation)

Retinitis Pigmentosa – Mitochondrial Disorders,

Refsum’s Disease

Cherry Red Spots – Tay Sach’s Disease, Neimann

Pick’s Disease

Corneal Opacities – Fabry’s Disease

Corneal Clouding – Hurler Syndrome
ASSOCIATED WITH
PECULIAR ODOUR
IEM Odor
Glutaric acidemia type II Sweaty feat
Isovaleric acidemia Sweaty feat
Maple syrup urine disease Maple syrup
Cystinuria Sulfur
Tyrosinemia type I Sulfur
Hypermethioninemia Boiled Cabbage
Multiple carboxylase deficiency Tom cat urine
Phenylketonuria Mousy/Musty
NEUROLOGICAL MANIFESTATIONS
Acute Encephalopathy
Newborn period – Presents with feeding problems, lethargy, irritability, and vomiting.
Decreased level of consciousness and seizures.

Older Patients – Ataxia, disorientation, or frank psychosis, as well as loss of

consciousness
(Precipitated by catabolic stress)

• Small molecule disorders

• Urea cycle defects
• Organic acid disorders
• Maple syrup urine disease
• Glycine encephalopathy (Non Ketotic Hyperglycinemia)

• Mitochondrial electron chain disorders - elevated plasma lactate levels

 Abnormal Muscle tone

Hypotonia Hypertonia

• Mitochondrial disorders • Glutaric Aciduria type 1

• Zellweger’s syndrome • Lesch Nyhan disease
• Glycine encephalopathy (non • Arginase deficiency
ketotic hyperglycinemia) • Phenyl Ketonuria

Acute Hemiplegia (Metabolic

Stroke)

• Mitochondrial disorders
- MELAS
- Leigh’s disease
• Homocystinuria
• Organic Acidemias – MMA, PA
• OTC deficiency
HEPATIC MANIFESTATIONS
Presenting complaints – Abdomen distension, Yellowish discoloration
of skin
HEPATOMEGALY

With Jaundice (as a primary

With liver failure
feature)
Cholestatic Jaundice
• Zellweger’s syndrome
• Galactosemia
• Niemann Pick disease type
• Tyrosinemia type 1
C
• Hereditary fructose
• Gaucher’s disease
intolerance
• Alpha 1 – Antitrypsin
• Mitochondrial diseases
deficiency
• Fatty acid oxidation defects
• Inborn errors of bile acid
metabolism
Glycogen storage disorders – Presents with hepatomegaly, hypoglycemia
(Type 1 and type III) - Liver function tests are usually normal or only
slightly elevated.
Cloherty and Stark’s Manual of Neonatal Care - South Asian Edition
CARDIAC MANIFESTATIONS
Presenting complaints – Feeding difficulties, tachypnea, failure to gain weight

CARDIOMYOPATHY
Glycogen storage disease type 1I (Pompe’s disease)
Mitochondrial disorders
• Leigh syndrome
• MELAS (Metabolic encephalopathy, lactic acidosis and stroke like episodes)
• MERRF (Myoclonic epilepsy with ragged red fibres)
Disorders of fatty acid oxidation
• Very long chain acyl coenzyme A dehydrogenase (VLCAD) deficiency
• Long chain hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency
• Trifunctional protein deficiency
• Carnitine transport defect
• Carnitine acylcarnitine translocase (CAT) deficiency
• Carnitine palmitoyltransferase II (CPT II) deficiency

Cloherty and Stark’s Manual of Neonatal Care - South Asian Edition

INVESTIGATIONS
TO RULE OUT ALTERNATE ETIOLOGIES
• Complete blood count with sepsis screen (neutropenia and thrombocytopenia seen
in propionic and methylmalonic acidemia) (Panctyopenia seen in Gaucher’s
disease)
• Chest X Ray
• Echocardiography (ECHO)
• ECG
FIRST LINE INVESTIGATIONS IN SUSPECTED INBORN ERRORS OF METABOLISM
• Arterial blood gases and electrolytes
• Blood glucose
• Plasma ammonia (Normal values in newborn: 90-150 µg/dl or 64-107 µmol/L)
• Arterial blood lactate (Normal values: 0.5-1.6 mmol/L)
ANCILLARY TESTS
• Liver function tests
• Urine ketones
• Urine reducing substances.
• Serum uric acid (low in molybdenum cofactor deficiency)
CONFIRMATORY TESTS
 PATIENT WITH SUSPECTED METABOLIC DISORDER SEPSIS
Plasma
Ammonia
High
Normal

Blood pH and Blood pH and

anion gap anion gap
High anion gap
Respiratory metabolic Normal
Alkalosis Acidosis
• Aminoacidopat
No Ketosis ± lactic hies
No Ketosis • Galactosemia
Ketosis acidosis

Urea cycle Fatty acid • Organic Acidemia

defects oxidation • Mitochondrial disorders
defects • Pyruvate carboxylase
deficiency
• MSUD
 PATIENT WITH SUSPECTED METABOLIC
SEPSIS
DISORDER
Plasma
Ammonia
Normal
GALACTOSEMIA
-GALT gene – G-1-PUT deficiency
-Toxic metabolite – Galactose-1- Blood pH and
Phospate anion gap
-Jaundice
-Hepatomegaly Normal
-Hypoglycemia
-Feeding difficulties, diarrhoea
-Nuclear cataracts – Oil drop cataract
-Increased risk of E.coli sepsis
-Intellectual disability • Aminoacidopat
-Pseudotumor cerebri hies
-Diagnosis • Galactosemia
• Plasma – Galactose
• RBCs – Galactose 1 phosphate
• Urine - Galactitol
-Cause of death – liver failure; renal
failure; Sepsis
 PATIENT WITH SUSPECTED METABOLIC
SEPSIS
DISORDER
Plasma
Ammonia
High

Blood pH and UREA CYCLE DISORDERS

anion gap

Normal or, S. Ammonia

Respiratory - High -
Respiratory
Alkalosis 300µmol/L No
alkalosis (2°
(often metabolic
to
between acidosis
No Ketosis hyperventilat
500- No Ketosis
ion)
1500µmol/L
)
Urea cycle
defects
 PATIENT WITH SUSPECTED METABOLIC
SEPSIS
DISORDER
Plasma
Ammonia
High
Normal

Blood pH and Blood pH and

anion gap anion gap
High anion gap
metabolic
Acidosis

No Ketosis ± lactic Pure lactic

Ketosis acidosis Acidosis

• Mitochondrial
Fatty acid • Organic Acidemia disorders
oxidation • Maple Syrup Urine • Pyruvate
defects disorders dehydrogenase
deficiency
METABOLIC DISORDERS WITH
HYPOGLYCEMIA DISORDERS OF HEPATIC GLUCOSE RELEASE
Glycogen storage disorders
Hereditary fructose intolerance
Galactosemia
DISORDERS OF GLUCONEOGENESIS
Fructose 1,6 bisphosphatase deficiency
Pyruvate Carboxylase deficiency
Phosphoenolpyruvate carboxykinase deficiency
FATTY ACID OXIDATION DISORDERS
Carnitine cycle
Beta oxidation
Ketogenesis
OTHER METABOLIC DISORDERS
Organic Acidemias
Glycerol kinase deficiency
Mitochondrial respiratory chain defects
 Persistent Hypoglycemia
Urine for reducing
substances (non
glucose) Positive

Negative • Galactosemi
a
• Fructosemia
Hepatomegaly Present

Absen
Hepatocellular
t
dysfunction
Ketosis N Yes
Yes o
No GSD
• Infections
• MSUD 1
• Post hypoxic
• Hyperinsulinemic • Organic
states Acidemias
• Fatty Acid
oxidation
disorders Practical Paediatrics Neurology 2nd edition – Veena Kalra
KEY POINTS..
Investigations
Hyperammonemia Urea cycle defects
Ketosis + Hypoglycemia + Organic acidemias
Hyperammonemia
Ketosis + Hypoglycemia Maple Syrup Urine Disorder
Metabolic Acidosis + No Ketosis + Fatty Acid Oxidation Defects
Hypoglycemia (Hypoketotic
Hypoglycemia)
Metabolic Acidosis + High Lactic Acid + Disorders Of Pyruvate Metabolism
L/P < 20

Metabolic Acidosis + High Lactic Acid + Mitochondrial Respiratory Chain

L/P > 20 Disorders
SECOND LINE
INVESTIGATIONS
Tandem Mass Spectrometry

INVESTIGATIONS SAMPLE DETECTS DISORDERS

TMS (Tandem Mass Plasma Plasma amino acids • Organic
Spectrometry) (Dry blood on and acyl carnitine Acidemias
filter paper - profile • Urea cycle
taken by heel defects
prick) Used for neonatal • Aminoacidopathie
screening of Inborn s
Error of Metabolism • Fatty acid
oxidation defects
Gas Chromatography Mass Spectrometry

INVESTIGATIONS SAMPLE DETECTS DISORDERS

GC-MS (Gas Urine Organic Acids • Organic
Chromatography acidemias
Mass spectrometry) Other tissues
- Plasma
- Serum
- CSF
High Performance Liquid
Chromatography

INVESTIGATIONS SAMPLE DETECTS USE

HPLC -Blood Quantitative analysis of • Organic
(High performance -Urine amino acids Acidemias
liquid • Aminoacidopathie
chromatography) s
• Purine,
pyrimidine
• Vitamin levels
• Porphyrins
• Hemoglobinopath
SECOND LINE INVESTIGATIONS
INVESTIGATION DISORDER
S
Lactate/Pyruvate Disorders with elevated lactate (lactate/pyruvate ratio is
ratio increased in mitochondrial disorders)
Urinary Orotic Acid Disorders with hyperammonemia for classification of urea cycle
defects
Plasma Alanine Mitochondrial ETC disorders
Plasma VLCFA Peroxisomal disorders
Enzyme Assay For definitive diagnosis (e.g., biotinidase, GALT assay)
CSF aminoacid Non Ketotic Hyperglycinemia - CSF Glycine levels
analysis
CSF lactate and • Biotinidase deficiency
pyruvate • Mitochondrial disorders
Mutation Analysis When available AIIMS Protocols in Neonatology
NEUROIMAGING AND
INBORN ERRORS OF
METABOLISM
MRI
Corpus Callosum Agenesis • Menke’s Disease
• Pyruvate Decarboxylase Deficiency
• Non Ketotic Hyperglycinemia
Basal Ganglia Involvement • Leigh’s Disease
• Propionyl And Methylmalonic Aciduria
• Glutaric Aciduria Type 1

Megalencephaly Glutaric Aciduria Type 1

AIIMS Protocols in Neonatology

Practical Paediatrics Neurology 2nd edition – Veena Kalra

MRI
White matter involvement • Leukodystrophies
• Phenylketonuria
• Maple syrup urine disorder
• Glutaric aciduria type 1

Vascular insults (unilateral atrophy) – • Homocystinuria

Patchy ischemic damage • MELAS
• Leigh’s disease
• Glutaric aciduria (subdural
hematomas)
Magnetic resonance spectroscopy (MRS)

Lactate peak • Mitochondrial disorders

Leucine peak • MSUD

AIIMS Protocols in Neonatology

Practical Paediatrics Neurology 2nd edition – Veena Kalra

CASE SCENARIO 1
• A term, 3.5 kg male born to consanguineous parents, presented to us at 20
PND with complaints of decreased activity and not feeding well with fast
breathing. On examination, patient had tachypnea with no retractions. Chest
clear.
• An ABG was done, pH -7.2, pCO2 - 24, pO2 - 150, HCO3 – 12
• Chest X ray was normal
• Sepsis screen negative
• S. Sodium = 141, S. Chloride = 106
• Anion Gap = Na - (Cl+HCO3) = 141 - (106+12) = 22

• Anion gap 22 ---- High anion gap metabolic acidosis

• Lactate 2.7 ---- Not pure lactic acidosis
• Ketone bodies in urine +2
CASE SCENARIO 1
• Based on above investigations, there are 2 possibilities
– Organic Acidemias
– MSUD
• Next, we should do S. NH3 levels, S.NH3 = 550
• High Ammonia levels are seen in MMA (methylmalonic aciduria)
and PPA (propionic aciduria)
• Normal/ mildly elevated ammonia seen in MSUD (maple syrup urine
disease), IVA (isovaleric aciduria), GA (Glutaric aciduria).
CASE SCENARIO 1

So, as S.NH3 is high, among organic acidemias, it can be

MMA (methylmalonic aciduria)or
PPA (propionic aciduria)
Enzyme assay done –
- showed deficiency of Propionyl CoA Carboxylase
FINAL DIAGNOSIS
Propionic Aciduria
CASE SCENARIO 2
• 3 year male child presented to us with complaints of recurrent episodes of
vomiting, jaundice, beginning from the later part of infancy.
• On examination, patient had hepatomegaly, and had persistent
hypoglycemia.
• These hypoglycemia episodes have no association with intake of milk or
milk products. The mother also gives history that the child has an aversion
to sweet food.
• Sepsis Screen normal
• Urine for reducing substances was done – Fructose
• Diagnosis – Hereditary fructose intolerance
• Enzyme involved – Aldolase B (accumulation of fructose 1 phosphate)
CASE SCENARIO 3
• A 2.9 kg female born to consanguineous parents, presented at 4 PND with
lethargy, decreased activity and poor feeding. According to the mother, the
patient was being breastfeed supplemented with formula.
• On physical examination, patient had hypothermia, decreased activity, decreased
response to painful stimuli and poor suck. Capillary refill >2 seconds, oxygen
saturation at room temperature 100%
• Given intravenous NS bolus. Started on iv fluids.
• Sepsis screen negative
• S. electrolytes - Normal
• ABG – pH - 7.48, pCO2 - 29.6, pO2 - 46, HCO3 - 22.5
• Serum Ammonia - 914
• Lactate 1.4
• Urine Ketone negative
CASE SCENARIO 3 Urea cycle disorders
Plasma Citrulline
Norma
Low High
l
• S. Ammonia – High
• ABG – Respiratory alkalosis
• No ketosis Urine Plasma Plasma
Orotic Arginin ASA
• Diagnosis – Urea cycle defects Elevate Acid e ASL
d OTC Arginase deficienc
• Next step - deficienc y
deficiency
Normal y
CPS or ASS
Enzyme assay and/or NAGS HHH deficienc
molecular genetic deficiency syndrom y
e
testing for OTC – Ornithine Transcarbamylase
CPS – Carbamoyl Phosphate Synthetase
confirmation NAGS – N Acetyl Glutamate Synthase
HHH – Hyperornithinemia – Hyperammonemia –
Homocitrullinuria
ASS – Argininosuccinate Synthase
ASL – Argininosuccinate Lyase
REFRENCES

• Nelson textbook of Pediatrics 21st edition

• Cloherty and Stark’s Manual of Neonatal Care - South Asian Edition
• Practical Paediatrics Neurology 2nd edition – Veena Kalra
• AIIMS Protocols in Neonatology
THANK
YOU
 UREA CYCLE DISORDERS
Urea cycle disorders
Plasma Citrulline
Norma
Low High
l

Urine Plasma Plasma

Orotic Arginin ASA
Acid e ASL
Elevate
d OTC Arginase deficienc
deficiency deficienc y
Normal y
CPS or ASS
NAGS HHH deficienc
deficiency syndrom y
e
OTC – Ornithine Transcarbamylase
CPS – Carbamoyl Phosphate Synthetase
NAGS – N Acetyl Glutamate Synthase
HHH – Ornithine transporter defect HHH – Hyperornithinemia – Hyperammonemia –
Homocitrullinuria
ASS – Argininosuccinate Synthase
ASL – Argininosuccinate Lyase
ASA – Argininosuccinic Acid
WHEN TO SUSPECT IEM ?
ANTENATAL HISTORY
MATERNAL FAMILY HISTORY
-Acute fatty liver or HELLP during - Parental consanguinity
pregnancy: - Family history of
In fetuses with long -chain - 3 unexplained neonatal
hydroxyl acyl-coenzyme deaths/ sudden infant
dehydrogenase deficiency death
(LCHADD). -Maternal family history
Males – X linked disorders
FETAL All – Mitochondrial disorders
-Hydrops fetalis (non-immune):
Gaucher’s disease “ A positive history may be
Niemann Pick disease helpful, but a negative
Zellweger’s disease family history doesn’t rule
GSD type 4 out IEM. "
Neonatal hemochromatosis
NEUROLOGICAL MANIFESTATIONS
Chronic Encephalopathy

• Global Developmental Delay

• Cerebral palsy – with generalized spasticity
• Associated with severe irritability (infants), behavior problems (older children)

• Small molecule disease

• PKU
• Homocystinuria
• Arginase deficiency – Period of apparent normalcy, absence of history of
perinatal insult, and cerebral palsy becoming more severe
• Glutaric Aciduria type 1
• Lesch Nyhan disease

• Diseases of Organelles
NEUROLOGICAL MANIFESTATIONS
Chronic Encephalopathy

• Global Developmental Delay

• Cerebral palsy – with generalized spasticity
• Associated with severe irritability (infants), behavior problems (older children)

• Small molecule disease


PKU

Homocystinuria

Arginase deficiency

Glutaric Aciduria type 1

Lesch Nyhan disease

• Diseases of Organelles
• Peroxisomal Disorders