J Child Neurol. 2025 Dec 23:8830738251404115. doi: 10.1177/08830738251404115. Online ahead of print.

ABSTRACT

Pyruvate dehydrogenase complex (PDC) deficiency is a rare mitochondrial disorder characterized by impaired oxidative metabolism, predominantly due to pathogenic variants in the PDHA1 gene. We present the clinical, biochemical, radiologic, and molecular characterization of 4 Argentine pediatric patients with PDHA1-related PDC deficiency, including a novel missense variant, c.260T>C p.(Ile87Thr). Clinical presentations ranged from severe neonatal encephalopathy with central apneas to a more slowly progressive neurodegenerative course in childhood. All patients exhibited lactic acidosis and structural brain abnormalities, with 3 fulfilling criteria for Leigh syndrome. Molecular studies identified 4 missense variants located in conserved regions of the E1α subunit. In silico analysis of the novel p.(Ile87Thr) variant suggested impaired thiamine pyrophosphate binding. All patients received thiamine and a ketogenic diet, with favorable outcomes in seizure control, neurodevelopment, and metabolic stability. Our findings expand the clinical and molecular spectrum of PDHA1-related PDC deficiency and underscore the importance of early diagnosis and targeted metabolic therapy. Furthermore, we report a previously undescribed radiologic pattern in one patient and propose potential structural implications of the novel variant based on protein modeling.

PMID:41432672 | DOI:10.1177/08830738251404115

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