PDHX – Pyruvate dehydrogenase E3-binding protein deficiency

PDHX encodes the E3-binding protein (E3BP) subunit of the pyruvate dehydrogenase complex. Pathogenic biallelic PDHX variants cause autosomal recessive pyruvate dehydrogenase E3-binding protein deficiency (PDHX; pyruvate dehydrogenase E3-binding protein deficiency). E3BP is essential for assembly of the PDH complex and mitochondrial oxidative decarboxylation of pyruvate. Loss of E3BP leads to accumulation of pyruvate and lactic acidosis with early-onset encephalopathy.

A single neonatal case presented with profound congenital lactic acidosis, severe encephalopathy and large subependymal cysts on brain MRI; the patient died at 35 days of age. Molecular analysis revealed a novel homozygous deletion, c.620del (p.Pro207LeufsTer?), confirming E3BP deficiency ([PMID:12557299]).

In a cohort of 82 PDHc-deficient patients, 9 unrelated probands harbored biallelic PDHX mutations, including frameshift (c.250del), nonsense (c.850C>T [p.Arg284Ter]) and splice-site (c.161-2A>G, c.816+1G>A) variants, expanding the variant spectrum to at least seven loss-of-function alleles ([PMID:21914562]). All affected individuals exhibited neonatal lactic acidosis and developmental arrest consistent with severe PDHc impairment.

Fibroblast studies from patients with PDHX defects demonstrated markedly reduced PDHc enzymatic activity at baseline. Treatment with phenylbutyrate increased the proportion of unphosphorylated E1 subunits and partially restored complex activity in PDHX-mutant cells, supporting loss-of-function as the mechanism and suggesting a potential therapeutic approach ([PMID:25356417]).

Integration of genetic and functional data yields a Strong gene-disease association: ten probands with recessive PDHX variants, concordant biochemical deficiency and rescue of enzyme activity by phenylbutyrate. Genetic evidence is Strong (biallelic truncating and splice variants in 10 probands across multiple families). Functional evidence is Moderate (patient cell assays and drug rescue studies).

These findings support clinical genetic testing of PDHX in neonates with unexplained lactic acidosis and encephalopathy. Early diagnosis enables metabolic management and informs potential treatment with phenylbutyrate. Key Take-home: Biallelic PDHX loss-of-function causes a definitive neonatal E3BP deficiency; functional assays guide diagnosis and may predict response to phenylbutyrate.

References

• Annals of Neurology • 2003 • A new case of pyruvate dehydrogenase deficiency due to a novel mutation in the PDX1 gene. PMID:12557299
• Molecular Genetics and Metabolism • 2011 • Molecular characterization of 82 patients with pyruvate dehydrogenase complex deficiency. Structural implications of novel amino acid substitutions in E1 protein. PMID:21914562
• Annals of Clinical and Translational Neurology • 2014 • Phenylbutyrate increases pyruvate dehydrogenase complex activity in cells harboring a variety of defects. PMID:25356417

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