CHAPTER 37
Disorder: Pyruvate
dehydrogenase deficiency
1 Synonyms
PDH deficiency, pyruvate dehydrogenase complex deficiency.
2 Brief Synopsis
2.1 Incidence
Unknown, rare.
2.2 Etiology
Pyruvate dehydrogenase deficiency (PDH deficiency, OMIM # 312170,
614111, 245348, 245349) is a disorder of pyruvate metabolism caused by
multiple defects in the pyruvate dehydrogenase multienzyme complex. Py-
ruvate sits at a highly regulated crossroads of metabolism and can be further
metabolized in any of four directions, depending on the metabolic needs
of the body. Pyruvate can be converted to lactate by lactate dehydrogenase,
to alanine by alanine transaminase, to oxaloacetate by pyruvate carboxylase,
or to acetyl CoA by the pyruvate dehydrogenase complex. Deficiency in
PDH results in a massive back-up to lactate (Fig. 37.1) and a deficiency in
cellular energy production, which cause life-threatening sequelae. Pyru-
vate dehydrogenase (EC1.2.4.1) is an enzyme in the pyruvate dehydroge-
nase multienzyme complex, which has subunits in common with both the
2-ketoglutarate dehydrogenase and the branch chain α-ketoacid dehy-
drogenase multienzyme complexes. Like these two other complexes PDH
multienzyme complex is comprised of three catalytic enzymes and two
regulatory enzymes that control the complex activities. Defects in this com-
plex enzyme system lead to PDH deficiency.
The most common cause of PDH deficiency are mutations in the
PDHA1 gene which accounts for 60%–80% of cases. This gene codes for
the E1 alpha subunit of pyruvate dehydrogenase. Its chromosomal location
is Xp22.12 and it is inherited in an X-linked fashion. Mutations in PDHB
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188 A Quick Guide to Metabolic Disease Testing Interpretation
Figure 37.1 Pathway showing the enzyme defect in PDH deficiency.
(coding for E1 beta subunit), DLAT (coding for E2 enzyme), PDHX
(coding for E3 protein) and PDP1 (coding for the pyruvate dehydroge-
nase phosphatase regulatory enzyme) have all been seen in individuals with
PDH deficiency. PDH deficiency caused by these other mutations is inher-
ited in an autosomal recessive manner.
3 Clinical presentation
Pyruvate dehydrogenase deficiency demonstrates a wide range of presenta-
tions from fatal congenital lactic acidosis with brain malformations to a later
age presentation of mild ataxia and some neuropathy with normal cognitive
function. Most cases of PDH deficiency present like other mitochondrial
disorders with severe lactic acidosis, brain abnormalities, hypotonia, feeding
difficulties, seizures and Leigh's syndrome of rapidly progressive encepha-
lopathy with some constellation of symptoms including optic atrophy, op-
thalmoplegia, psychomotor regression, dystonia, ataxia, and central respira-
tory difficulties.
There is no proven treatment for PDH deficiency, however, empiri-
cally it makes sense that replacing carbohydrate with a ketogenic diet
should bypass the metabolic block. Avoiding carbohydrates and supple-
menting ketones is the usual treatment, although those individuals with
severe neurological impairment do not appear to benefit. Outcomes of
Disorder: Pyruvate dehydrogenase deficiency 189
PDH deficiency range from early death to survival with varying amounts
of cognitive defects.
4 Diagnostic compounds
4.1 Urine organic acid profile
Urine organic acid analysis shows a pattern of lactic acid excretion.
4.2 Acylcarnitine profile
Non-diagnostic for PDH.
4.3 Amino acids
Alanine is frequently elevated, especially during times of high lactic acidosis.
4.4 Other important diagnostic/monitoring compounds
CSF lactate and pyruvate measurement can be useful if the blood lactate is
normal.
5 Newborn screening
PDH is not included as a core condition on the RUSP, nor as a secondary
condition for newborn screening, and is not screened for.
6 Follow-up/confirmatory testing
Elevated plasma concentrations of both lactate and pyruvate with a normal
lactate to pyruvate (L:P) ratio is suggestive of this disorder along with an
elevated alanine, however biochemical markers are not diagnostic. Con-
firmatory tests rely on proven pathogenic mutations upon genetic testing.
Because mutations in PDHA are X-linked and lyonization occurs, females
may or may not show reduced enzyme activity, and have more variability in
symptoms than males.
7 Interferences and assay or interpretation quirks
None applicable.
190 A Quick Guide to Metabolic Disease Testing Interpretation
Further reading
[1] NIH Genetic and Rare Diseases Information Center. Pyruvate Dehydrogenase Defi-
ciency. https://rarediseases.info.nih.gov/diseases/7513/pyruvate-dehydrogenase-defi-
ciency accessed 12/13/2019.
[2] Genetics Home Reference, NIH US National Library of Medicine. https://ghr.nlm.nih.
gov/condition/pyruvate-dehydrogenase-deficiency# accessed 12/13/2019.
[3] Kerr DS, Bedoyan JK. Disorders of pyruvate metabolism and the tricarboxylic acid cycle.
In: Sarafoglou K, Hoffman GF, Roth KS, editors. Pediatric endocrinology and inborn
errors of metabolism. 2nd ed. New York: McGraw-Hill Co; 2017. p. 105–24.
