Pyruvate Dehydrogenase Deficiency
Pathogenesis (Mitochondrial Disorder)
- Lactic acid build-up (lactic acidosis), which first manifests shortly after birth. In addition to lactic acidosis, there is failure of energy production, thus large energy requiring organ systems, such as the brain are profoundly affected.
Clinical
- Systemic manifestations: Nausea/Vomiting, Cardiopulmonary abnormalities.
- Neurological manifestations: Cognitive delay, Seizures, and Motor abnormalities (hypotonia, incoordination, and poor gait).
- Neurologic findings: Callosal hypoplasia, Cortical atrophy, Multifocal lesions.
- Prognosis: Unlikely to survive into adolescence or adulthood.
Genetics
- The pyruvate dehydrogenase complex comprises multiple copies of several enzymes referred to as E1, E2, and E3, all of which are involved in the conversion of pyruvate to acetyl-CoA.
- X-linked gene mutation of the PDHA1 gene in the production of E1 is the most common cause; this mutation leads to reduced activity of pyruvate dehydrogenase complex.
- The E3 binding protein (protein X) attaches E3 to the complex and provides the correct structure for the pyruvate dehydrogenase complex complex to convert pyruvate to acetyl-CoA. Mutations in the production of E3 also occur.
- Note that: Pyruvate dehydrogenase phosphatase activates the pyruvate dehydrogenase complex.
- Note that: Pyruvate dehydrogenase kinase inhibits the pyruvate dehydrogenase complex.
References
- Calvo, Sherri; Collins, Heather; Greenberg, Kathleen, et. al at US National Library of Medicine, Genetics Home Reference. https://ghr.nlm.nih.gov