Leigh's disease due to a new mutation in the <i>PDHX</i> gene

Schiff, Manuel; Miné, Manuèle; Brivet, M.; Marsac, Cécile; Elmaleh‐Bergès, Monique; Evrard, Philippe; Baulny, Hélène Ogier de

doi:10.1002/ana.20818

Cited by 34 publications

(7 citation statements)

References 25 publications

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“…The clinical features of our p.Arg446* homozygotes agree with previously published findings in patients with PDHX mutations (reviewed in [5][6][7]18]) as regards onset in the first months of life with lactic acidosis, survival beyond the 1st year and psychomotor retardation. The uniformity and characteristics of the neurological phenotype in our patients contrast with other studies.…”

Section: Discussionsupporting

confidence: 90%

“…The uniformity and characteristics of the neurological phenotype in our patients contrast with other studies. CP-like spasticity was present in 14/17 of our cases, but was relatively rare in other descriptions: 0/19 patients [6], 2/11 [18] and 4/24 [7], with the exception of [5] where 5/5 patients displayed a CP-like clinical picture with dystonia. Еpileptic seizures were also more common, occurring in 13/16 of our patients, while in only 4/19 patients [6], 2/11 [18], 2/5 [5] or 4/24 cases [7].…”

Section: Discussioncontrasting

confidence: 60%

“…16 to 20), the reason for seeking medical attention included delayed psychomotor development and/or seizures at age 3-6 months. In this group, hyperlactatemia had been diagnosed at a later age (patients 17,18,20).…”

Section: Clinical Featuresmentioning

confidence: 95%

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Founder p.Arg 446* mutation in the PDHX gene explains over half of cases with congenital lactic acidosis in Roma children

Ivanov

Azmanov

Ivanova

et al. 2014

Molecular Genetics and Metabolism

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Investigation of 31 of Roma patients with congenital lactic acidosis (CLA) from Bulgaria identified homozygosity for the R446* mutation in the PDHX gene as the most common cause of the disorder in this ethnic group. It accounted for around 60% of patients in the study and over 25% of all CLA cases referred to the National Genetic Laboratory in Bulgaria. The detection of a homozygous patient from Hungary and carriers among population controls from Romania and Slovakia suggests a wide spread of the mutation in the European Roma population. The clinical phenotype of the twenty R446* homozygotes was relatively homogeneous, with lactic acidosis crisis in the first days or months of life as the most common initial presentation (15/20 patients) and delayed psychomotor development and/or seizures in infancy as the leading manifestations in a smaller group (5/20 patients). The subsequent clinical picture was dominated by impaired physical growth and a very consistent pattern of static cerebral palsy-like encephalopathy with spasticity and severe to profound mental retardation seen in over 80% of cases. Most patients had a positive family history. We propose testing for the R446* mutation in PDHX as a rapid first screening in Roma infants with metabolic acidosis. It will facilitate and accelerate diagnosis in a large proportion of cases, allow early rehabilitation to alleviate the chronic clinical course, and prevent further affected births in high-risk families.

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Section: Discussionsupporting

confidence: 90%

Section: Discussioncontrasting

confidence: 60%

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Founder p.Arg 446* mutation in the PDHX gene explains over half of cases with congenital lactic acidosis in Roma children

Ivanov

Azmanov

Ivanova

et al. 2014

Molecular Genetics and Metabolism

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“…Males slightly outnumbered females and consanguinity accounted for about 7% of all cases. A majority of patients with a deficiency of E1β [132,151,157], E2 [136] or E3BP [12,58,78,126,128,140,143,171] 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

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204

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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 and 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.

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“…Symptoms that are commonly seen in PDHE1α deficiency include lactic acidosis (early-onset), severely delayed growth with slowly progressive neurological features of the brain stem, basal ganglia, and Leigh syndrome 34 . The most common features of E3BP deficiency (formerly protein X) are delayed psychomotor progress, hypotonia, and long-term survival 56,[65][66][67] . Neonatal lactic acidosis slowly progresses with thin corpus callosum and subependymal cysts.…”

Section: Clinical Signs Of Congenital Pdc Deficiencymentioning

confidence: 99%

Emerging regulatory roles of mitochondrial sirtuins on pyruvate dehydrogenase complex and the related metabolic diseases: Review

et al. 2020

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The pyruvate dehydrogenase complex (PDC) is a multi-enzyme complex of the mitochondria that provides a link between glycolysis and the Krebs cycle. PDC plays an essential role in producing acetyl-CoA from glucose and the regulation of fuel consumption. In general, PDC enzyme is regulated in two different ways, end-product inhibition and posttranslational modifications (more extensive phosphorylation and dephosphorylation subunit E1). Posttranslational modifications of this enzyme are regulated by various factors. Sirtuins are the class III of histone deacylatases that catalyze protein posttranslational modifications, including deacetylation, adenosine diphosphate ribosylation, and deacylation. Sirt3, Sirt4, and Sirt5 are mitochondrial sirtuins that control the posttranslational modifications of mitochondrial protein. Considering the comprehensive role of sirtuins in post-translational modifications and regulation of metabolic processes, the aim of this review is to explore the role of mitochondrial sirtuins in the regulation of the PDC. PDC deficiency is a common metabolic disorder that causes pyruvate to be converted to lactate and alanine rather than to acetyl-CoA. because this enzyme is in the gateway of complete oxidation, glucose products entering the Krebs cycle and resulting in physiological and structural changes in the organs. Metabolic blockage such as ketogenic diet broken up by b -oxidation and producing acetyl-CoA can improve the patients. Sirtuins play a role in the production of acetyl-CoA through oxidation of fatty acids and other pathways. Thus, we hypothesize that the targets and bioactive compounds targeting mitochondrial sirtuins can be involved in the treatment of PDC deficiency. In general, this review discusses the present knowledge on how mitochondrial sirtuins are involved in the regulation of PDC as well as their possible roles in the treatment of PDC deficiency.

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Leigh's disease due to a new mutation in the PDHX gene

Abstract: These data provide an additional case of E3BP deficiency with a unique and previously unreported deletion in the PDHX gene.

Cited by 34 publications

References 25 publications

Founder p.Arg 446* mutation in the PDHX gene explains over half of cases with congenital lactic acidosis in Roma children

Founder p.Arg 446* mutation in the PDHX gene explains over half of cases with congenital lactic acidosis in Roma children

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

Emerging regulatory roles of mitochondrial sirtuins on pyruvate dehydrogenase complex and the related metabolic diseases: Review

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