PDHA1 – Pyruvate Dehydrogenase Deficiency

Pyruvate dehydrogenase E1 alpha subunit (PDHA1) is encoded by HGNC:8806 and is the most common genetic cause of pyruvate dehydrogenase complex deficiency (MONDO:0019169). Loss-of-function variants in PDHA1 disrupt the oxidative decarboxylation of pyruvate to acetyl-CoA, leading to primary lactic acidosis and a spectrum of neurological impairments.

Genetic evidence has established a robust X-linked association. Pathogenic variants include frameshifts such as c.1142_1145dup (p.Trp383Ter) and missense changes like c.379C>T (p.Arg127Trp) identified in unrelated individuals ([PMID:1338114]; [PMID:8024267]; [PMID:8771169]). Skewed X-chromosome inactivation in heterozygous females unmasks the hemizygous phenotype, as shown by maternal transmission and variable expressivity ([PMID:8024267]).

Inheritance is X-linked; affected males typically exhibit early-onset lactic acidosis and severe encephalopathy, while heterozygous females present with variable neurological signs depending on X-inactivation patterns. Segregation analysis across two families demonstrated co-segregation of PDHA1 variants with disease in 2 affected relatives.

Functional assays confirm pathogenicity: in vitro expression of R302C/H alleles abolishes PDH enzymatic activity, demonstrating loss of function ([PMID:9671272]). Immunoblotting in patient fibroblasts reveals rapid proteasomal degradation of mutant E1α subunits, underscoring haploinsufficiency as the disease mechanism.

The variant spectrum in PDHA1 spans truncating, missense, splice-site, and deep intronic changes, often clustering in exons encoding the active site or subunit interfaces. Phenotypic presentations range from fatal neonatal Leigh-like syndrome to milder chronic ataxia or isolated neuropathy, with lactic acidosis (HP:0003128) and seizures (HP:0001250) common features.

Collectively, genetic and experimental data support a Strong clinical validity for the PDHA1–pyruvate dehydrogenase deficiency association (7 probands; multi-family segregation; concordant functional assays). Genetic testing for PDHA1 should be prioritized in males and symptomatic females with unexplained lactic acidosis. Functional studies further aid in classifying variants of uncertain significance.

Key Take-home: Hemizygous or heterozygous PDHA1 loss-of-function variants cause X-linked pyruvate dehydrogenase deficiency, and early molecular diagnosis enables tailored metabolic management.

References

• Journal of inherited metabolic disease • 1992 • Mutation of E1 alpha gene in a female patient with pyruvate dehydrogenase deficiency due to rapid degradation of E1 protein PMID:1338114
• Annals of neurology • 1994 • Pyruvate dehydrogenase deficiency: molecular basis for intrafamilial heterogeneity PMID:8024267
• Pediatric neurology • 1995 • Association of cerebral dysgenesis and lactic acidemia with X-linked PDH E1 alpha subunit mutations in females PMID:8771169
• Human mutation • 1998 • Arginine 302 mutations in the pyruvate dehydrogenase E1alpha subunit gene: identification of further patients and in vitro demonstration of pathogenicity PMID:9671272

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