[Pyruvate dehydrogenase deficiency and cerebral malformations]

Area of Science:

• Biochemistry
• Genetics
• Neurology

Background:

• Pyruvate dehydrogenase (PDH) deficiency is a significant genetic cause of primary lactic acidosis and severe global developmental delay.
• Deficiency in the PDH E1 alpha subunit is a primary driver of congenital lactic acidosis, with its gene located on the X-chromosome.
• A specific presentation involves isolated 'cerebral' lactic acidosis coupled with cerebral dysgenesis.

Observation:

• This study details two female patients (6 months and 26 months) presenting with severe developmental delay, microcephaly, and dysmorphic features.
• Neuroimaging revealed severe corpus callosum hypoplasia, cerebral atrophy, and ventricular dilatation.
• Both patients exhibited elevated serum lactate levels without systemic acidosis, alongside characteristic urinary organic acid profiles.

Findings:

• Biochemical analyses in case 1 showed increased CSF lactate and pyruvate, with reduced PDH and PDH E1 activities in muscle and fibroblasts.
• Case 2 demonstrated decreased total PDH activity in muscle but not fibroblasts.
• Genetic sequencing in case 1 identified a deletion in exon 7 of the PDH E1á gene.

Implications:

• Dysmorphic features and severe cerebral malformations in females warrant metabolic investigation for PDH deficiency.
• Measuring lactate and pyruvate levels in cerebrospinal fluid (CSF) is a key diagnostic step.
• Understanding the genetic basis and clinical spectrum of PDH deficiency aids in early diagnosis and management.