From Severe Neonatal Encephalopathy to Slowly Neurologic Progressive Disease: Pyruvate Dehydrogenase Deficiency...

Area of Science:

• Biochemistry
• Genetics
• Neurology

Background:

• Pyruvate dehydrogenase complex (PDC) deficiency is a rare inherited metabolic disorder.
• It primarily results from pathogenic variants in the PDHA1 gene, affecting oxidative metabolism.
• Clinical manifestations vary, from severe neonatal forms to progressive childhood neurodegeneration.

Purpose of the Study:

• To characterize the clinical, biochemical, radiologic, and molecular features of pediatric patients with PDHA1-related PDC deficiency.
• To identify and analyze novel genetic variants associated with the disorder.
• To evaluate the efficacy of thiamine and ketogenic diet therapy.

Main Methods:

• Clinical assessment of four pediatric patients.
• Biochemical analysis including lactic acidosis evaluation.
• Molecular genetic testing (gene sequencing) to identify PDHA1 variants.
• In silico analysis and protein modeling for variant characterization.
• Radiologic imaging of brain abnormalities.

Main Results:

• Four patients with PDHA1-related PDC deficiency were characterized, including one with a novel missense variant (c.260T>C p.(Ile87Thr)).
• Clinical presentations included severe neonatal encephalopathy and progressive childhood neurodegeneration.
• All patients had lactic acidosis and brain abnormalities; three met criteria for Leigh syndrome.
• In silico analysis suggested the novel variant impairs thiamine pyrophosphate binding.
• Treatment with thiamine and a ketogenic diet led to positive outcomes in seizure control, neurodevelopment, and metabolic stability.

Conclusions:

• The study expands the known clinical and molecular spectrum of PDHA1-related PDC deficiency.
• Early diagnosis and targeted metabolic interventions (thiamine, ketogenic diet) are crucial for favorable patient outcomes.
• The findings highlight the importance of genetic analysis and in silico tools for understanding disease mechanisms.