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Disorders of pyruvate carboxylase and the pyruvate dehydrogenase complex
B H Robinson1, N MacKay, K Chun
1Department of Biochemistry, University of Toronto, Ontario, Canada.
Insights
Pyruvate dehydrogenase (PDH) deficiency, often due to E1 alpha gene mutations, causes varied symptoms in males and females. Pyruvate carboxylase deficiency, an autosomal recessive disease, presents differently based on ethnic groups and enzyme cross-reactivity.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Pyruvate dehydrogenase (PDH) complex deficiency is a common metabolic disorder.
- Mutations in the X-linked E1 alpha gene are the most frequent cause of PDH deficiency.
- Clinical presentations vary significantly between males and females due to X-inactivation patterns.
Purpose of the Study:
- To review the genetic basis and clinical manifestations of PDH E1 alpha gene mutations.
- To differentiate PDH deficiency from pyruvate carboxylase deficiency.
- To highlight ethnic predispositions and clinical outcomes in pyruvate carboxylase deficiency.
Main Methods:
- Review of genetic mutations in PDH E1 alpha gene.
- Analysis of clinical data from affected males and females.
- Comparison of PDH deficiency with pyruvate carboxylase deficiency phenotypes.
Main Results:
- Males with PDH deficiency often have missense mutations, while females are more prone to DNA rearrangements.
- A specific missense mutation confers thiamin responsiveness in PDH deficiency.
- Pyruvate carboxylase deficiency shows ethnic clustering, with CRM+ve and CRM-ve subtypes impacting survival.
Conclusions:
- X-linked E1 alpha gene mutations lead to diverse PDH deficiency phenotypes.
- Pyruvate carboxylase deficiency has distinct genetic and clinical profiles in different ethnic populations.
- Understanding these enzyme deficiencies is crucial for diagnosis and management.
Abstract:
The most common defect associated with deficiency of the pyruvate dehydrogenase (PDH) complex occurs in the E1 component, specifically due to mutations in the X-linked E1 alpha gene. Clinical sequelae of these mutations, which range from severe neonatal lactic acidosis to carbohydrate-sensitive ataxia, can be different in males and females depending on the nature of the mutation and, in the case of females, on the X-inactivation pattern in different tissues. Males have a high representation of missense mutations among the patient cohort, while females are much more likely to have DNA rearrangements, particularly toward the 3' end of the coding sequence of the gene. Missplicing mutations involving exon 6 deletion have been reported, as has a missense mutation conferring true thiamin-responsiveness of the enzyme and the patient's clinical symptoms. Pyruvate carboxylase deficiency, on the other hand, is a true autosomal recessive disease, though it has high occurrences in particular ethnic groups, especially in Algonkian-speaking Amerindians and in Arabs. In the former group the defect is a simple type in which material cross-reactive to pyruvate carboxylase antibody is present in cultured cells (CRM+ve). In the latter group, cross-reacting material is rarely present (CRM-ve). The CRM+ve patients can survive into teenage years with careful supervision, while the CRM-ve patients have complications due to hyperammonaemia and dysfunction of the urea cycle and rarely survive beyond 3 months of life.