PDHA1 – Leigh Syndrome

X-linked recessive variants in PDHA1, encoding the E1α subunit of the pyruvate dehydrogenase complex (PDHc), are established causes of Leigh syndrome (LS), a subacute necrotizing encephalopathy characterized by lactic acidosis and neurodegeneration. Patients present in infancy with hypotonia, developmental regression, seizures, and basal ganglia lesions on MRI. Early enzymatic and genetic testing facilitates prompt diagnosis and management.

Genetic Evidence

PDHA1-associated LS follows X-linked recessive inheritance, with affected hemizygous males and carrier females exhibiting variable expressivity. Segregation analysis in a family with two affected brothers carrying PDHA1 c.407C>T (p.Ala136Val) confirmed maternal transmission and cosegregation of the variant with PDHc deficiency ([PMID:15558317]). Additional sporadic cases include a neonatal LS patient with c.599A>C (p.Asn200Thr) demonstrating poor response to dichloroacetate but benefit from pyruvate therapy ([PMID:21454027]), and a thiamine-responsive infant with c.131A>G (p.His44Arg) who experienced transient clinical improvement ([PMID:29204204]). In a cohort of 67 Australian LS patients, six unrelated cases harbored PDHA1 mutations ([PMID:8602753]), and a large survey of 124 Chinese LS or LS-like patients identified one PDHA1 variant ([PMID:17323145]).

PDHA1 exhibits broad allelic heterogeneity, with over 80 unique variants reported to date. Missense substitutions predominate, notably at conserved arginine residues (Arg302, Arg88, Arg263), along with splice‐site, frameshift, and large rearrangements. Recurrent hotspots include R302 (nine families) and R88 (multiple pedigrees). Deep intronic and synonymous splicing defects also contribute to hypomorphic alleles.

Functional Evidence

Biochemical assays demonstrate markedly reduced PDHc activity in patient fibroblasts and muscle, with residual enzyme activity correlating with phenotype severity. In vitro transfection of R302C and R302H mutant cDNAs into E1α-null fibroblasts yielded catalytically inactive proteins ([PMID:9671272]). A hippocampal-specific Pdha1 knockout mouse recapitulates neurodegeneration and lactic acid accumulation, supporting a loss-of-function mechanism and implicating lactate-mediated CREB pathway inhibition in cognitive impairment ([PMID:34720870]). Phenylbutyrate and thiamine supplementation have been shown to partially restore PDHc activity in missense variant fibroblasts, highlighting potential therapeutic avenues.

Integration and Clinical Utility

The convergence of genetic segregation, biochemical assays, and animal modeling provides strong evidence for PDHA1 loss-of-function in LS. Diagnostic laboratories should include PDHA1 in mitochondrial panels for early infantile encephalopathy, and clinicians should pursue PDHc enzyme testing in unexplained lactic acidosis. Identification of specific variants guides genetic counseling, carrier testing, and consideration of cofactor supplementation (thiamine, phenylbutyrate, pyruvate) as adjunct therapies.

Key Take-home: PDHA1 pathogenic variants cause X-linked Leigh syndrome by impairing PDHc activity, warranting early enzymatic and genetic evaluation to enable targeted therapies and counseling.

References

• European journal of pediatrics • 2005 • A family with pyruvate dehydrogenase complex deficiency due to a novel C>T substitution at nucleotide position 407 in exon 4 of the X-linked Epsilon1alpha gene. [PMID:15558317]
• Brain & development • 2012 • Beneficial effect of pyruvate therapy on Leigh syndrome due to a novel mutation in PDH E1α gene [PMID:21454027]
• Journal of pediatric neurosciences • 2017 • Thiamine Responsive Pyruvate Dehydrogenase Complex Deficiency: A Potentially Treatable Cause of Leigh's Disease. [PMID:29204204]
• Annals of neurology • 1996 • Leigh syndrome: clinical features and biochemical and DNA abnormalities. [PMID:8602753]
• Journal of inherited metabolic disease • 2007 • Clinical and molecular survey in 124 Chinese patients with Leigh or Leigh-like syndrome. [PMID:17323145]
• 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]
• Frontiers in neuroscience • 2021 • Conditional Knockout of Pdha1 in Mouse Hippocampus Impairs Cognitive Function: The Possible Involvement of Lactate. [PMID:34720870]

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