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Congenital lactic acidaemia in children is often caused by pyruvate dehydrogenase complex deficiency. Researchers identified specific defects, including E1 decarboxylase deficiency, and associated clinical features like facial dysmorphism.
Area of Science:
- Biochemistry
- Genetics
- Pediatric Medicine
Background:
- Congenital lactic acidaemia is a group of poorly understood genetic disorders.
- Pyruvate dehydrogenase complex deficiency is the most common cause.
- This study investigates the genetic and clinical spectrum of these deficiencies.
Purpose of the Study:
- To characterize the genetic defects in childhood lactic acidaemia.
- To correlate specific enzyme deficiencies with clinical presentations and dysmorphic features.
- To investigate the molecular basis of pyruvate carboxylase deficiency.
Main Methods:
- Diagnosis of 23 cases of congenital lactic acidaemia.
- Enzyme assays to identify pyruvate dehydrogenase complex and lipoamide dehydrogenase defects.
- Clinical evaluation for facial dysmorphism, microcephaly, and agenesis of the corpus callosum.
- Biochemical analysis of pyruvate carboxylase protein status (CRM +ve/-ve).
Main Results:
- 18 of 23 cases had pyruvate decarboxylase (E1) deficiency; 5 had lipoamide dehydrogenase deficiency.
- Ten cases with E1 deficiency showed facial dysmorphism or microcephaly; two had agenesis of the corpus callosum.
- Two forms of isolated pyruvate carboxylase deficiency were identified: one with non-catalytic protein (CRM +ve) and another with absent protein (CRM -ve).
Conclusions:
- Pyruvate dehydrogenase complex deficiency, particularly E1 component, is a major cause of congenital lactic acidaemia.
- Specific enzyme defects correlate with distinct clinical phenotypes, including neurological and dysmorphic features.
- Molecular heterogeneity exists in pyruvate carboxylase deficiency, impacting protein expression and catalytic activity.
Abstract:
Congenital childhood lactic acidaemia is a poorly understood group of genetic diseases. The most common underlying inherited defect encountered in this group is deficiency of the pyruvate dehydrogenase complex. Of 23 cases we have diagnosed, 18 have a deficiency in the first component of the complex, the E1 decarboxylase, while the other five have multiple alpha-keto acid dehydrogenase deficiency due to a defect in lipoamide dehydrogenase. In addition to the lactic acidosis associated with pyruvate decarboxylase deficiency, ten of the cases showed evidence of facial dysmorphism consisting of a narrow head, wide nasal bridge and flared nostrils or gross microcephaly. Two further patients had agenesis of the corpus callosum. Isolated pyruvate carboxylase deficiency was found to present in two different forms, one with lactic acidaemia and mental retardation, the other with lactic acidaemia, hyperammonaemia citrullinaemia and hyperlysinaemia. The former presentation we have shown to be associated with the presence of a biotinylated pyruvate carboxylase protein of the correct subunit molecular weight (125 kd) which has no catalytic activity (CRM + ve). The latter we have shown to be associated with the absence of any recognizable pyruvate carboxylase protein (CRM - ve).