Mitochondrial pyruvate carrier deficiency is an autosomal recessive metabolic disorder characterized by delayed psychomotor development and lactic acidosis with ...
Mitochondrial pyruvate carrier deficiency is an autosomal recessive metabolic disorder characterized by delayed psychomotor development and lactic acidosis with a normal lactate/pyruvate ratio resulting from impaired mitochondrial pyruvate oxidation (summary by Bricker et al., 2012).
▼ Clinical Features
Brivet et al. (2003) reported a girl, born of related Algerian parents, with a severe metabolic disorder resulting in death at age 19 months. At birth, she had respiratory distress, hepatomegaly, lactic acidosis, and transient hypoglycemia. Laboratory studies showed increased serum pyruvate and lactate, a normal lactate/pyruvate ratio, mildly increased ketone bodies, and excretion of organic acids. Although pyruvate dehydrogenase deficiency (see, e.g., 312170) was suspected, treatment for that disorder did not result in clinical improvement and patient fibroblasts showed normal pyruvate dehydrogenase activity. The child had an encephalopathy, with severely delayed psychomotor development, rotary nystagmus, hypotonia, extensor plantar responses, and poor visual contact. She also had dysmorphic features, including progressive microcephaly, epicanthus, long philtrum, thin upper lip, and small inverted and widely spaced nipples. Studies of patient fibroblasts showed impaired production of citric acid cycle intermediates and impaired release of CO2 from pyruvate, whereas pyruvate showed normal oxidation in cells with a disrupted mitochondrial membrane or with increasing concentrations of pyruvate. The findings were consistent with a defect in pyruvate transport across the mitochondrial membrane. In a subsequent pregnancy, an affected fetus was recognized using an assay measuring pyruvate oxidation in trophoblasts.
Bricker et al. (2012) reported 3 patients from 2 additional consanguineous families with a similar, but less severe, disorder. Affected children had psychomotor retardation, with epilepsy in 1 family and peripheral neuropathy in the other. The patients were alive at 5 to 14 years of age.
▼ Molecular Genetics
In 4 patients from 3 unrelated consanguineous families with mitochondrial pyruvate carrier deficiency, Bricker et al. (2012) identified 2 different homozygous mutations in the MPC1 gene (614738.0001 and 614738.0002). The mutations were identified by homozygosity mapping followed by candidate gene sequencing.