Pyruvate dehydrogenase deficiency: identification of a novel mutation in the PDHA1 gene which responds to amino acid supplementation

Silva, Maria João; Pinheiro, António N.; Eusébio, Filomena; Gaspar, Ana; Almeida, Isabel Tavares de; Rivera, Isabel

doi:10.1007/s00431-008-0700-7

Cited by 18 publications

(9 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Males slightly outnumbered females and consanguinity accounted for about 7% of all cases. A majority of patients with a deficiency of E1β [137, 157, 163], E2 [142] or E3BP [62, 82, 131, 133, 140, 146, 149] were products of consanguinity, in which the disease often occurred in more than one family member.…”

Section: Resultsmentioning

confidence: 99%

The spectrum of pyruvate dehydrogenase complex deficiency: Clinical, biochemical and genetic features in 371 patients

Patel

O’Brien

Subramony

et al. 2012

Molecular Genetics and Metabolism

171

115

View full text Add to dashboard Cite

Context Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disorder commonly associated with lactic acidosis, progressive neurological and neuromuscular degeneration and, usually, death during childhood. There has been no recent comprehensive analysis of the natural history and clinical course of this disease. Objective We reviewed 371 cases of PDC deficiency, published between 1970-2010, that involved defects in subunits E1α and E1β and components E1, E2, E3 and the E3 Binding Protein of the complex. Data Sources and Extraction English language peer-reviewed publications were identified, primarily by using PubMed and Google Scholar search engines. Results Neurodevelopmental delay and hypotonia were the commonest clinical signs of PDC deficiency. Structural brain abnormalities frequently included ventriculomegaly, dysgenesis of the corpus callosum and neuroimaging findings typical of Leigh syndrome. Neither gender nor any clinical or neuroimaging feature differentiated the various biochemical etiologies of the disease. Patients who died were younger, presented clinically earlier and had higher blood lactate levels and lower residual enzyme activities than subjects who were still alive at the time of reporting. Survival bore no relationship to the underlying biochemical or genetic abnormality or to gender. Conclusions Although the clinical spectrum of PDC deficiency is broad, the dominant clinical phenotype includes presentation during the first year of life; neurological and neuromuscular degeneration; structural lesions revealed by neuroimaging; lactic acidosis and a blood lactate:pyruvate ratio ≤20.

show abstract

Section: Resultsmentioning

confidence: 99%

The spectrum of pyruvate dehydrogenase complex deficiency: Clinical, biochemical and genetic features in 371 patients

Patel

O’Brien

Subramony

et al. 2012

Molecular Genetics and Metabolism

171

115

View full text Add to dashboard Cite

show abstract

“…Arginine has been described to correct protein folding and suppress protein aggregation in vitro [12]. Furthermore, it has been shown that arginine supplementation restored PDHc function in a patient with pyruvate dehydrogenase deficiency [13]. The mechanism which underlies its chaperone function is unknown, but might involve conformational correction and prevention of nonproductive protein interactions [14].…”

Section: Introductionmentioning

confidence: 99%

Arginine improves peroxisome functioning in cells from patients with a mild peroxisome biogenesis disorder

Berendse

Ebberink

IJlst

et al. 2013

Orphanet J Rare Dis

View full text Add to dashboard Cite

BackgroundZellweger spectrum disorders (ZSDs) are multisystem genetic disorders caused by a lack of functional peroxisomes, due to mutations in one of the PEX genes, encoding proteins involved in peroxisome biogenesis. The phenotypic spectrum of ZSDs ranges from an early lethal form to much milder presentations. In cultured skin fibroblasts from mildly affected patients, peroxisome biogenesis can be partially impaired which results in a mosaic catalase immunofluorescence pattern. This peroxisomal mosaicism has been described for specific missense mutations in various PEX genes. In cell lines displaying peroxisomal mosaicism, peroxisome biogenesis can be improved when these are cultured at 30°C. This suggests that these missense mutations affect the folding and/or stability of the encoded protein. We have studied if the function of mutant PEX1, PEX6 and PEX12 can be improved by promoting protein folding using the chemical chaperone arginine.MethodsFibroblasts from three PEX1 patients, one PEX6 and one PEX12 patient were cultured in the presence of different concentrations of arginine. To determine the effect on peroxisome biogenesis we studied the following parameters: number of peroxisome-positive cells, levels of PEX1 protein and processed thiolase, and the capacity to β-oxidize very long chain fatty acids and pristanic acid.ResultsPeroxisome biogenesis and function in fibroblasts with mild missense mutations in PEX1, 6 and 12 can be improved by arginine.ConclusionArginine may be an interesting compound to promote peroxisome function in patients with a mild peroxisome biogenesis disorder.

show abstract

“…Amplification of the 11 individual exons of the PDHA1 gene and related intron–exon boundaries were amplified using primers already published [4] . PDHA1 and PDHA2 cDNAs were amplified under conditions previously described [5] and using primers listed in Table 1 , which were designed to annealing to regions displaying no homology between transcripts [6] .…”

Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

Data supporting the co-expression of PDHA1 gene and of its paralogue PDHA2 in somatic cells of a family

et al. 2016

Self Cite

View full text Add to dashboard Cite

This article presents a dataset proving the simultaneous presence of a 5′UTR-truncated PDHA1 mRNA and a full-length PDHA2 mRNA in the somatic cells of a PDC-deficient female patient and all members of her immediate family (parents and brother).We have designed a large set of primer pairs in order to perform detailed RT-PCR assays allowing the clear identification of both PDHA1 and PDHA2 mRNA species in somatic cells. In addition, two different experimental approaches were used to elucidate the copy number of PDHA1 gene in the patient and her mother.The interpretation and discussion of these data, along with further extensive experiments concerning the origin of this altered gene expression and its potential therapeutic consequences, can be found in “Complex genetic findings in a female patient with pyruvate dehydrogenase complex deficiency: null mutations in the PDHX gene associated with unusual expression of the testis-specific PDHA2 gene in her somatic cells” (A. Pinheiro, M.J. Silva, C. Florindo, et al., 2016) [1].

show abstract

Pyruvate dehydrogenase deficiency: identification of a novel mutation in the PDHA1 gene which responds to amino acid supplementation

Abstract: our results encourage the use of amino acid supplementation to overcome the metabolic/biochemical changes induced by PDHA1 gene specific mutations associated with mild PDHc phenotypes.

Cited by 18 publications

References 33 publications

The spectrum of pyruvate dehydrogenase complex deficiency: Clinical, biochemical and genetic features in 371 patients

The spectrum of pyruvate dehydrogenase complex deficiency: Clinical, biochemical and genetic features in 371 patients

Arginine improves peroxisome functioning in cells from patients with a mild peroxisome biogenesis disorder

Data supporting the co-expression of PDHA1 gene and of its paralogue PDHA2 in somatic cells of a family

Contact Info

Product

Resources

About