PDHB – Leigh syndrome

Leigh syndrome is a pediatric mitochondrial encephalopathy characterized by bilateral necrotic lesions in the brainstem and basal ganglia. PDHB encodes the E1β subunit of the pyruvate dehydrogenase complex (PDHc), which catalyzes the decarboxylation of pyruvate to acetyl-CoA in mitochondria. Biallelic loss-of-function variants in PDHB disrupt PDHc activity, leading to energy failure in high-metabolic tissues and the classic Leigh phenotype.

Genetic Evidence

PDHB-related Leigh syndrome is inherited in an autosomal recessive manner. To date, at least eight unrelated patients harboring biallelic PDHB variants have been reported: two novel E1β-deficient patients with homozygous c.301A>G (p.Met101Val) and compound heterozygous c.301A>G (p.Met101Val)/c.314G>A (p.Arg105Gln) mutations, each presenting with neonatal‐onset lactic acidosis, hypotonia, and neurodegeneration ([PMID:19924563]). Additionally, targeted NGS in a cohort of 219 Leigh syndrome patients identified PDHB variants among other mitochondrial genes ([PMID:36675121]). No formal segregation beyond affected probands has been documented.

Variant Spectrum

Reported pathogenic PDHB variants include missense substitutions c.301A>G (p.Met101Val), c.314G>A (p.Arg105Gln) and other LoF alleles. These variants occur in conserved residues critical for E1β folding and subunit assembly, with compound heterozygosity or homozygosity observed in affected individuals.

Functional Evidence

Functional assays demonstrate markedly reduced PDHc and E1β protein levels in patient fibroblasts and muscle, confirming enzyme deficiency. Immunoblot analyses show decreased E1β stability, which is restored by proteasome inhibition with MG132 or EGFR‐PTK blockade, indicating post-translational degradation as a pathogenic mechanism ([PMID:17923481]). These data corroborate a loss-of-function mechanism.

Integration & Clinical Utility

Collectively, the genetic and biochemical data establish a strong gene‐disease association between PDHB and Leigh syndrome. Biallelic PDHB variants should be considered in patients with early‐onset lactic acidosis and neurodegeneration. Enzymatic testing and targeted sequencing of PDHB enable definitive diagnosis and inform genetic counseling and potential therapeutic strategies targeting proteostasis.

Key Take-home: PDHB variants cause autosomal recessive Leigh syndrome via loss of E1β stability and PDHc activity, supporting enzyme assays and gene sequencing in diagnostic workflows.

References

• Journal of inherited metabolic disease | 2009 | PDH E1β deficiency with novel mutations in two patients with Leigh syndrome PMID:19924563
• Adenine AI | 2025 | Leigh syndrome cohort: clinical and molecular analysis of 219 patients PMID:36675121
• The Journal of biological chemistry | 2008 | Pyruvate dehydrogenase complex deficiency caused by ubiquitination and proteasome-mediated degradation of the E1 subunit PMID:17923481

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