Pyruvate dehydrogenase deficiency. Clinical presentation and molecular genetic characterization of five new patients

Matthews, Paul M.; Brown, Ruth; Otero, Lucy J.; Marchington, David R.; LeGris, M.; Howes, Rosalind E.; Meadows, Laurence S.; Shevell, Michael; Scriver, Charles R.; Brown, G. K.

doi:10.1093/brain/117.3.435

Cited by 36 publications

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“…This transition was reported as a pathogenic missense mutation in one female patient with convincing clinical presentation with family history of congenital lactic acidaemia, normal enzyme activity in cultured fibroblasts, and the skewed X-inactivation pattern (Matthews et al 1994). However, case 1 was homozygous for this transition and had normal PDH complex activity in cultured skin fibroblasts.…”

Section: Resultsmentioning

confidence: 94%

DNA diagnosis of pyruvate dehydrogenase deficiency in female patients with congenital lactic acidaemia

Matsuda

Naito

et al. 1995

J of Inher Metab Disea

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The diagnosis of pyruvate dehydrogenase (PDH) E1 alpha deficiency, which is an X-linked inborn error of metabolism, is usually established by the measurement of PDH complex activity in cultured cells. However, heterozygous female patients with PDH E1 alpha deficiency may be misdiagnosed when the normal X chromosome is predominantly expressed in the cultured cells. Therefore, in female patients with convincing clinical presentations of PDH E1 alpha deficiency and the normal enzyme activity, the X-inactivation pattern should be analysed and the PDH E1 alpha gene screened for mutations. For this screening, we applied the method of single-strand conformational polymorphism (SSCP) and DNA sequencing and examined 11 female patients with congenital lactic acidaemia whose PDH complex activity was normal in cultured cells. In 2 of the 11 female patients, we found distinct pathogenic missense mutations in the PDH E1 alpha gene (G89S and G291R). Both affected patients showed a similar clinical presentation and had been diagnosed as West syndrome. In 3 of the 11 patients, we found a polymorphic base-pair substitution in exon 9 of the PDH E1 alpha gene which resulted in a changed amino acid residue (M282L). We conclude that PCR-SSCP analysis of the PDH E1 alpha gene, followed by DNA sequencing, is a useful method to screen for mutations of the PDH E1 alpha gene in female patients with congenital lactic acidaemia who have normal enzyme activities in available samples, normal ratio of lactate to pyruvate, and predominantly raised lactate concentration in cerebrospinal fluid.

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Section: Resultsmentioning

confidence: 94%

DNA diagnosis of pyruvate dehydrogenase deficiency in female patients with congenital lactic acidaemia

Matsuda

Naito

et al. 1995

J of Inher Metab Disea

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“…A silent mutation introduced in the same position reduces the homology score to an even greater extent and resulted in a similar abnormal splicing pattern to that observed in the patient. Several other mutations involving the codon for tyrosine 243 in the PDHA1 gene have been described Matthews, et al, 1994), although these have not been reported to result in mis-splicing. These mutations do reduce the homology score of the putative SRp40 binding site at position c.727-732, but, unlike the nonsense and silent mutations studied here, they strengthen, rather than weaken the score of an overlapping 5' SRp40 site.…”

Section: Discussionmentioning

confidence: 99%

A putative exonic splicing enhancer in exon 7 of thePDHA1 gene affects splicing of adjacent exons

Ridout¹,

Keighley²,

Krywawych³

et al. 2008

Hum. Mutat.

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A nonsense mutation (c.729C>A, Y243X) in exon 7 of the PDHA1 gene in a patient with pyruvate dehydrogenase deficiency results in aberrant splicing of the primary transcript with production of stable mRNAs which lack either both exons 6 and 7 or exon 7 alone. Transfection and expression of genomic constructs covering exons 5 to 8 of the mutant PDHA1 gene reproduced this aberrant splicing in vitro. The same pattern of abnormal splicing was found when a silent mutation was introduced at the same position. Both the nonsense and silent mutations alter a strong consensus site for the binding of SRp40, suggesting that they may interfere with an exonic splicing enhancer in exon 7 of the gene. However, this appears to affect splicing of not only exon 7, but also the adjacent upstream exon. The splice acceptor site of intron 5 has weak homology to the consensus sequence and this may contribute to the combined splicing defect.

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“…Of these, 42 mutations have only been found once,whereas 6 (R72C, R263G, R302C, S312fs, Q382fs, S388fs) have been observed more than twice. Interestingly, the latter are specific for one sex, except for one mutation (R378H), which has been found in both sexes (5 males and 1 female; the children died between ages 4-41 months; Hansen et al 1991;Matthews et al 1994;Chun et al 1995;.…”

Section: Discussionmentioning

confidence: 99%

Biochemical and genetic studies of four patients with pyruvate dehydrogenase E1α deficiency

et al. 1997

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We report studies of four patients with pyruvate dehydrogenase complex (PDH) deficiency caused by mutations in the E1 alpha subunit. Two unrelated male patients presented with Leigh syndrome and a R263G missense mutation in exon 8. This mutation has previously been described in males with the same phenotype. The two other patients had different novel mutations: (1) an 8-bp deletion at the C-terminus (exon 11) was found in one allele of a young girl suffering from microcephaly and (2) a C88S missense mutation (exon 3) in a boy who only presented with motor neuropathy. These mutations were not found in the mothers of any of the four cases. Immunoblot analysis revealed decreased immunoreactivity for the E1 alpha and E1 beta subunits in three out of the four patients. These findings confirm that: (1) PDH deficiencies are genetically heterogeneous, (2) the R263G mutation is more frequent in male cases than are other mutations and this amino acid is a hot spot for gene mutations, (3) the last eight amino acids may be important for the conformation of the tetrameric E1-PDH enzyme, and (4) the amino acids at positions 88, 263 and 382-387 are essential for the linking of the alpha subunit with the beta subunit and for the activity of the holoenzyme.

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Pyruvate dehydrogenase deficiency. Clinical presentation and molecular genetic characterization of five new patients

Cited by 36 publications

References 0 publications

DNA diagnosis of pyruvate dehydrogenase deficiency in female patients with congenital lactic acidaemia

DNA diagnosis of pyruvate dehydrogenase deficiency in female patients with congenital lactic acidaemia

A putative exonic splicing enhancer in exon 7 of thePDHA1 gene affects splicing of adjacent exons

Biochemical and genetic studies of four patients with pyruvate dehydrogenase E1α deficiency

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