PDP1 – Pyruvate dehydrogenase phosphatase deficiency

Pyruvate dehydrogenase phosphatase deficiency is an autosomal recessive metabolic disorder presenting in the neonatal period with hypotonia, lactic acidosis, and impaired pyruvate dehydrogenase complex (PDHc) activation. Biallelic pathogenic variants in PDP1, encoding the catalytic subunit of pyruvate dehydrogenase phosphatase 1, disrupt dephosphorylation of the PDHc E1α subunit, leading to reduced oxidative decarboxylation of pyruvate.

Genetic evidence arises from three affected individuals in two unrelated families. In a consanguineous kindred, two brothers homozygous for c.851_853del (p.Leu284del) exhibited <25% native PDHc activity in fibroblasts (PMID:15855260). A separate female patient harbored a homozygous nonsense variant predicted to yield p.Glu93Ter (PMID:19184109). Segregation of homozygous variants in an autosomal recessive pattern was confirmed, with one additional affected sibling beyond the index case.

Functional assays demonstrate that the p.Leu284del variant retains <5% activity of purified PDP1 and that preincubation with wild-type recombinant PDP1 or addition of dichloroacetate restores PDHc function in patient cells (PMID:15855260). The p.Glu93Ter mutation abolishes PDP1 protein detectable by immunoblot, with PDHc activity rescue upon exogenous PDP1 or PDP2 supplementation (PMID:19184109). These in vitro complementation studies confirm loss-of-function as the primary mechanism.

No conflicting reports have been documented. The total of three AR probands with homozygous loss-of-function alleles, segregation data, and concordant functional rescue assays support a Moderate clinical validity classification under ClinGen standards.

Key Take-home: PDP1 gene sequencing should be integrated into diagnostic workflows for neonatal lactic acidosis and hypotonia; functional complementation assays provide definitive confirmation of pathogenicity and may guide personalized therapeutic strategies.

References

• The Journal of clinical endocrinology and metabolism • 2005 • Pyruvate dehydrogenase phosphatase deficiency: identification of the first mutation in two brothers and restoration of activity by protein complementation. PMID:15855260
• Human genetics • 2009 • Pyruvate dehydrogenase phosphatase 1 (PDP1) null mutation produces a lethal infantile phenotype. PMID:19184109

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