Somatic mosaicism for a novel PDHA1 mutation in a male with severe pyruvate dehydrogenase complex deficiency (original) (raw)
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Prague medical report, 2011
The most common cause of pyruvate dehydrogenase complex (PDHc) deficiency is the deficit of the E1α-subunit. The aim of this study was to describe distinct course of the disease in two boys with mutations in PDHA1 gene and illustrate the possible obstacles in measurement of PDHc activity. Clinical data and metabolic profiles were collected and evaluated. PDHc and E1α-subunit activities were measured using radiometric assay. Subunits of PDHc were detected by Western blot. PDHA1 gene was analysed by direct sequencing. In patient 1, the initial hypotonia with psychomotor retardation was observed since early infancy. The child gradually showed symptoms of spasticity and arrest of psychomotor development. In patient 2, the disease manifested by seizures and hyporeflexia in the toddler age. The diagnosis was confirmed at the age of seven years after attacks of dystonia and clinical manifestation of myopathy with normal mental development.
European Journal of Pediatrics, 1999
Pyruvate dehydrogenase (PDH) complex de®ciency, a common cause of congenital lactic acidosis, is mostly due to mutations in the X-linked gene coding for the E1a subunit of the complex. We have studied two unrelated girls presenting a static encephalopathy with spastic quadriplegia, microcephaly and seizures and in one girl, hypocalcaemia, a new ®nding in PDH complex de®ciency. PDH de®ciency was diagnosed in adolescence and both girls had low PDH complex activity in muscle but normal amounts of all subunits on Western blotting, and a normal lactate/pyruvate ratio in blood and CSF. Mutation analysis of the E1a gene at the cDNA or DNA level revealed an arginine to histidine substitution at amino acid position 288 (R288H) in the girl with hypocalcaemia and a 12 bp insertion, predicting a four amino acid duplication at the cterminal end of the protein in the second girl. They both carried a normal and a mutated E1a gene and X-inactivation studies showed skewed patterns. Conclusion Mutation identi®cation in pyruvate dehydrogenase complex de®ciency remains important especially for the determination of the recurrence risk and for reliable genetic counselling in couples with an aected child.
Eur J Pediat, 1999
Pyruvate dehydrogenase (PDH) complex de®ciency, a common cause of congenital lactic acidosis, is mostly due to mutations in the X-linked gene coding for the E1a subunit of the complex. We have studied two unrelated girls presenting a static encephalopathy with spastic quadriplegia, microcephaly and seizures and in one girl, hypocalcaemia, a new ®nding in PDH complex de®ciency. PDH de®ciency was diagnosed in adolescence and both girls had low PDH complex activity in muscle but normal amounts of all subunits on Western blotting, and a normal lactate/pyruvate ratio in blood and CSF. Mutation analysis of the E1a gene at the cDNA or DNA level revealed an arginine to histidine substitution at amino acid position 288 (R288H) in the girl with hypocalcaemia and a 12 bp insertion, predicting a four amino acid duplication at the cterminal end of the protein in the second girl. They both carried a normal and a mutated E1a gene and X-inactivation studies showed skewed patterns. Conclusion Mutation identi®cation in pyruvate dehydrogenase complex de®ciency remains important especially for the determination of the recurrence risk and for reliable genetic counselling in couples with an aected child.
Background : Pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA which ultimately generates ATP. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits, and the resulting phenotype, though very heterogeneous, mainly affects the neuro-encephalic system. The aim of this study is to describe and discuss the clinic, metabolic and genotypic profiles of thirteen PDC deficient patients, thus seeking to establish possible genotype-phenotype correlations. Results : The mutational spectrum revealed that seven patients (54 %) carry mutations in the PDHA1 gene , encoding the E1α subunit, five patients (38 %) carry mutations in the PDHX gene, encoding the E3 binding protein, and the remaining patient (8 %) harbors mutations in the DLD gene, encoding the E3 subunit. These data corroborate PDHA1 mutations as the predominant cause of PDC deficiency, though revealing a notable prevalence of PDHX mutations ...
A new case of pyruvate dehydrogenase deficiency due to a novel mutation in thepdx1 gene
Annals of Neurology, 2003
We report a case of neonatal congenital lactic acidosis associated with pyruvate dehydrogenase E3-binding protein deficiency in a newborn girl. She had a severe encephalopathy, and magnetic resonance imaging of the brain showed large subependymal cysts and no basal ganglia lesions. She died 35 days after birth. We detected a novel homozygous deletion (620delC) in the PDX1 gene, which encodes for the E3BP subunit of the pyruvate dehydrogenase complex.
Pyruvate dehydrogenase deficiency: Clinical and biochemical diagnosis
Pediatric Neurology, 1993
A female neonate with pyruvate dehydrogenase (PDH) deficiency is presented with clinical, radiologic, biochemical, neuropathoiogic, and molecular genetic data. She was dysmorphic, with a high forehead, lowset ears, thin upper lip, upturned nose, and rhizomelic limbs. Cranial MRI revealed severe cortical atrophy, ventricular dilatation, and corpus caliosum agenesis. Pyruvate and lactate levels were increased in CSF and blood. Urinary organic acid profile was compatible with PDH deficiency. PDH activity was normal in fibroblasts, lymphocytes, and muscle. The PDH El-or gene was sequenced and a single base mutation was found within the regulatory phosphorylation site in exon 10. It is postulated that this mutation causes a cerebral form of PDH deficiency. Tissue-specific expression of the disease could be explained by differential X chromosome inactivation because the PDH El-ct gene is located on this chromosome. Dysmorphism with severe cerebral malformations in female patients merits a metabolic evaluation, including determination of lactate and pyruvate levels in CSF.
Molecular Genetics and Metabolism, 2006
We report here the molecular analysis of a pyruvate dehydrogenase E3-binding protein (PDH-E3BP) deWciency in a new patient, born to Wrst cousin parents. She has initially presented with a non-progressive and unspeciWc encephalopathy, followed by an acute neurological deterioration at 14 years of age. E3BP subunit was undetectable on Western blot. The sequence of exons 1-9 and exon 11 of the PDHX gene were normal, but exon 10 was impossible to amplify with standard PCR. Long-range PCR including exons 9-11 (11.5 kb) was performed. The patient's sample displayed a unique PCR product of 7.5 kb, whereas the parents' samples displayed two bands (11.5 and 7.5 kb). The deletion breakpoints were determined by restriction analysis followed by direct sequencing. The homozygous deletion covered the end of intron 9, exon 10 and the beginning of intron 10 and was found to be 3913 bp long. The cDNA sequencing conWrmed the deletion of exon 10. The most probable mechanism for this gross deletion appears to be a slipped mispairing mediated by an exact direct repeat CCACTG. It is the Wrst time that a non-homologous recombination is reported in the PDHX gene causing pyruvate dehydrogenase complex (PDHc) deWciency.
Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis
Developmental Medicine & Child Neurology, 2009
METHOD Twenty-two participants with enzymologically and genetically confirmed PDHc deficiency were analysed for clinical and imaging features over a 15-year period. RESULTS Four groups were identified: (1) those with neonatal encephalopathy with lactic acidosis (one male, four females; diagnosis at birth); (2) those with non-progressive infantile encephalopathy (three males, three females; age at diagnosis 2-9mo); (3) those with Leigh syndrome (eight males; age at diagnosis 1-13mo); and (4) those with relapsing ataxia (three males; 18-30mo). Seventeen mutations involved PDHA1 (a hotspot was identified in exons 6, 7, and 8 in seven males with Leigh syndrome or recurrent ataxia). Mutations in the PDHX gene (five cases) were correlated with non-progressive encephalopathy and long-term survival in four cases. INTERPRETATION Two types of neurological involvement were identified. Abnormal prenatal brain development resulted in severe non-progressive encephalopathy with callosal agenesis, gyration anomalies, microcephaly with intrauterine growth retardation, or dysmorphia in both males and females (12 cases). Acute energy failure in infant life produced basal ganglia lesions with paroxysmal dystonia, neuropathic ataxia due to axonal transport dysfunction, or epilepsy only in males (11 cases). The ketogenic diet improved only paroxysmal dysfunction, providing an additional argument in favour of paroxysmal energy failure.
Molecular Genetics and Metabolism, 2006
Pyruvate dehydrogenase complex (PDC) deWciency is commonly due to mutations of PDHA1 on the X chromosome. Milder phenotypic manifestations occur in heterozygous females than in hemizygous males with the same mutation, and females are more likely to survive with severe mutations. The boy described here had hypotonia, moderate developmental delay, tremors, normal growth and brain MRI, and normal to slightly elevated lactate. PDC activity was low in skin Wbroblasts and skeletal muscle (27-37%) but normal in lymphocytes. PDHA1 cDNA from cultured Wbroblasts revealed two populations, one normal, the other lacking exon 6 (c.511-603 del). Genomic DNA from Wbroblasts contained both normal and mutant (g.592G!A) sequences within exon 6. Expression of minigene constructs containing exons 5, 6, and 7 with or without this mutation in 293T cells conWrmed that the mutation alters splicing of exon 6. The mutant to wild-type DNA ratio varied substantially across tissues. Immunoblotting of Wbroblast lysates detected only wild-type E1 protein. Immunocytochemistry of cultured skin Wbroblasts showed a mosaic pattern with 60% of cells positive for E1 and 40% negative, consistent with PDC activity and DNA analysis. Karyotyping, FISH analyses, and genotyping revealed a 46XY male without chimerism. These data indicate somatic mosaicism for a mutation within exon 6 that causes exon skipping and production of a non-functional protein. The mutated 592G residue is conserved among all eukaryotes. Substituting A for G apparently alters normal splicing by creating a SRp40 exonic splice enhancer site. The milder phenotype in this male is accounted for by the mixture of normal cells and cells lacking E1. Immunocytochemistry was a useful adjunct to molecular analysis for demonstrating mosaicism.