Pyruvate dehydrogenase deficiency
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A newborn with lactic acidosis and hypotonia has agenesis of the corpus callosum on MRI. Lactate:pyruvate ratio is normal (distinguishing from respiratory chain defects).
- XLD: PDHA1 (E1α subunit) - most common
- AR: PDHB, DLAT, DLD, others
- Lactic acidosis (present from birth)
- Normal lactate:pyruvate ratio (unlike respiratory chain defects)
- Hypotonia, seizures
- Developmental delay/intellectual disability
- Structural brain anomalies (corpus callosum agenesis, ventriculomegaly)
- Leigh-like syndrome in some
- Wide phenotypic spectrum
- Elevated blood/CSF lactate and pyruvate with a normal lactate:pyruvate ratio (distinguishes from respiratory chain defects, which raise the ratio)
- PDH complex enzyme activity in fibroblasts/leukocytes; brain MRI for structural anomalies (corpus callosum agenesis, Leigh-like changes)
- Confirm with molecular testing (PDHA1 most common, X-linked; also PDHB, DLAT, DLD); not on newborn screening
- Ketogenic diet, thiamine (some responsive), dichloroacetate
PDH links glycolysis to the TCA cycle: pyruvate dehydrogenase converts pyruvate to acetyl-CoA, the entry point into the TCA cycle. When PDH is deficient, pyruvate accumulates and is converted to lactate (lactic acidosis).
PDHA1 is X-linked: girls can have agenesis of the corpus callosum (mosaic severity due to X-inactivation). Boys with mild mutations have ataxia, hypotonia, and developmental delay. Elevated lactate and pyruvate with normal lactate:pyruvate ratio (unlike respiratory chain defects, which have an elevated ratio).
Ketogenic diet + thiamine: ketogenic diet bypasses the PDH step by providing ketone bodies directly. Thiamine (B1) is a cofactor for PDH.