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Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate
W Lissens1, L De Meirleir, S Seneca
1Center for Medical Genetics, University Hospital, Vrije Universiteit Brussel, Brussels, Belgium. lgenlsw@az.vub.ac.be
Insights
Pyruvate dehydrogenase (PDH) complex defects cause lactic acidosis. Mutations in the PDHA1 gene, primarily X-linked, explain varied symptoms and near-equal male/female incidence due to X-inactivation and lethality.
Area of Science:
- Biochemistry
- Genetics
- Pediatric Metabolism
Background:
- Pyruvate dehydrogenase (PDH) complex deficiencies are a leading cause of primary lactic acidosis in children.
- These deficiencies present with diverse clinical symptoms, and a near-equal sex distribution suggests autosomal recessive inheritance.
- However, mutations in the X-linked PDHA1 gene are the primary cause, with X-inactivation and male lethality influencing presentation.
Purpose of the Study:
- To analyze the spectrum of mutations in the PDHA1 gene.
- To investigate the correlation between genotype and clinical presentation in PDH deficiency.
- To understand the inheritance patterns and origins of PDHA1 mutations.
Main Methods:
- Mutation analysis of the PDHA1 gene in 130 patients from 123 families.
- Categorization of mutations into missense/nonsense and insertion/deletion types.
- Segregation analysis in parental DNA to determine mutation origin.
Main Results:
- 37 missense/nonsense and 39 insertion/deletion mutations were identified in 130 patients (61 females, 69 males).
- Insertion/deletion mutations predominantly affect exons 10 and 11; missense/nonsense mutations occur across all exons.
- Males show a higher prevalence of missense/nonsense mutations in specific exons, with three recurrent mutations accounting for half.
- Females have fewer missense/nonsense mutations but a higher proportion of insertion/deletion mutations.
- Parental studies revealed 16% of mothers as carriers, with new mutations arising from both paternal and maternal origins.
Conclusions:
- PDHA1 mutations are the main cause of PDH deficiency and lactic acidosis.
- The X-linked inheritance, coupled with X-inactivation and developmental lethality in males, explains the varied clinical spectrum and apparent recessive inheritance.
- Distinct mutation patterns exist between sexes, highlighting the complexity of PDHA1-related metabolic disorders.
Abstract:
Defects in the pyruvate dehydrogenase (PDH) complex are an important cause of primary lactic acidosis, a frequent manifestation of metabolic disease in children. Clinical symptoms can vary considerably in patients with PDH complex deficiencies, and almost equal numbers of affected males and females have been identified, suggesting an autosomal recessive mode of inheritance of the disease. However, the great majority of PDH complex deficiencies result from mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1). The major factors that contribute to the clinical variation in E1alpha deficiency and its resemblance to a recessive disease are developmental lethality in some males with severe mutations and the pattern of X-inactivation in females. To date, 37 different missense/nonsense and 39 different insertion/deletion mutations have been identified in the E1alpha subunit gene of 130 patients (61 females and 69 males) from 123 unrelated families. Insertion/deletion mutations occur preferentially in exons 10 and 11, while missense/nonsense mutations are found in all exons. In males, the majority of missense/nonsense mutations are found in exons 3, 7, 8 and 11, and three recurrent mutations at codons R72, R263 and R378 account for half of these patients with missense/nonsense mutations (25 of 50). A significantly lower number of females is found with missense/nonsense mutations (25). However, 36 females out of 55 affected patients have insertion/deletion mutations. The total number of female and male patients is thus almost the same, although a difference in the distribution of the type of mutations is evident between both sexes. In many families, the parents of the affected patients were studied for the presence of the PDHA1 mutation. The mutation was never present in the somatic cells of the father; in 63 mothers studied, 16 were carriers (25%). In four families, the origin of the new mutation was determined to be twice paternal and twice maternal.