Long-term Outcome and Clinical Spectrum of 73 Pediatric Patients With Mitochondrial Diseases

Debray, François-Guillaume; Lambert, Marie; Chevalier, Isabelle; Robitaille, Yves; Decarie, Jean-Claude; Shoubridge, Eric A.; Robinson, Brian H.; Mitchell, Grant A.

doi:10.1542/peds.2006-1866

Cited by 162 publications

(141 citation statements)

References 41 publications

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“…In a recent series, 66 patients (90%) among 73 children affected by a mitochondrial disease presented clinical signs of cerebral involvement. 1 Mitochondrial disorders are also increasingly being recognized as the causes of epilepsy associated with encephalopathy. In the series of 73 children, seizures were observed in 25 patients (34%) 1 and in 61% of cases in another cohort of 38 children with mitochondrial encephalopathies.…”

Section: Introductionmentioning

confidence: 99%

“…1 Mitochondrial disorders are also increasingly being recognized as the causes of epilepsy associated with encephalopathy. In the series of 73 children, seizures were observed in 25 patients (34%) 1 and in 61% of cases in another cohort of 38 children with mitochondrial encephalopathies. 2 Focal epilepsy seems to be predominant in adults, 3 whereas pediatric series report a great predominance of generalized epilepsy syndromes.…”

Section: Introductionmentioning

confidence: 99%

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Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

et al. 2012

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We report two children, born from consanguineous parents, who presented with early-onset refractory epilepsy associated with psychomotor delay, failure to thrive, blindness and deafness. Polarographic and spectrophotometric analyses in fibroblasts and liver revealed a respiratory chain (RC) dysfunction. Surprisingly, we identified a homozygous nonsense mutation in the GM3 synthase gene by using exome sequencing. GM3 synthase catalyzes the formation of GM3 ganglioside from lactosylceramide, which is the first step in the synthesis of complex ganglioside species. Mass spectrometry analysis revealed that the complete absence of GM3 ganglioside and its biosynthetic derivatives was associated with an upregulation of the alternative globoside pathway in fibroblasts. The accumulation of Gb3 and Gb4 globosides likely has a role in RC dysfunction and in the decrease of mitochondrial membrane potential leading to apoptosis, which we observed in fibroblasts. We show for the first time that GM3 synthase deficiency, responsible for early-onset epilepsy syndrome, leads to a secondary RC dysfunction. Our study highlights the role of secondary mitochondrial disorders that can interfere with the diagnosis and the evolution of other metabolic diseases.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

et al. 2012

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“…Its clinical presentation and course are variable but most patients exhibit progressive neurological degeneration and either persistent or episodic elevation of lactate in blood, cerebrospinal fluid or both [2][3][4]. By far the majority of biochemically proven cases of PDH deficiency are due to defects in the E1α subunit.…”

Section: Introductionmentioning

confidence: 99%

A combined therapeutic approach for pyruvate dehydrogenase deficiency using self-complementary adeno-associated virus serotype-specific vectors and dichloroacetate

Han

Berendzen

Zhong

et al. 2008

Molecular Genetics and Metabolism

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We determined the ability of self-complementary adeno-associated virus (scAAV) vectors to deliver and express the pyruvate dehy-drogenase E1α subunit gene (PDHA1) in primary cultures of skin fibroblasts from 3 patients with defined mutations in PHDA1 and 3 healthy subjects. Cells were transduced with scAAV vectors containing the cytomegalovirus promoter-driven enhanced green fluorescent protein (EGFP) reporter gene at a vector:cell ratio of 200. Transgene expression was measured 72 h later. The transduction efficiency of scAAV2 and scAAV6 vectors was 3-to 5-fold higher than that of the other serotypes, which were subsequently used to transduce fibroblasts with wild-type PDHA1 cDNA under the control of the chicken beta-action (CBA) promoter at a vector:cell ratio of 1000. Total PDH-specific activity and E1α protein expression were determined 10 days posttransduction. Both vectors increased E1α expression 40-60% in both control and patient cells, and increased PDH activity in two patient cell lines. We also used dichloroacetate (DCA) to maximally activate PDH through dephosphorylation of E1α. Exposure for 24 h to 5 mM DCA increased PDH activity in non-transduced control (mean 37% increase) and PDH deficient (mean 44% increase) cells. Exposure of transduced patient fibroblasts to DCA increased PDH activity up to 90% of the We have proposed that the PDH complex, specifically the E1α subunit, should be considered an important target for gene therapy of mitochondrial energy failure [10]. As proof of concept, we demonstrated that recombinant adeno-associated virus (AAV) could be used to package gene targeting vectors as single-strand molecules carrying the wild-type PDHA1 cDNA, deliver the vector to cultured mammalian cells [11] and partially restore PDH activity in a primary culture of skin fibroblasts from a patient with E1α deficiency [12]. However the efficiency of transgene expression was low (~25% of cells) due to the single-stranded nature of the recombinant vector genome. Moreover, only one AAV serotype was evaluated (AAV2) and the findings were limited to cells from a single patient.Therefore, to optimize the delivery and expression of PDHA1, we employed here doublestranded DNA-containing self-complementary AAV (scAAV) vectors that by-pass the requirement of viral second-strand DNA synthesis. We then investigated the relative transduction efficiency of several scAAV-enhanced green fluorescent protein (EGFP) serotype vectors in both normal and E1α-deficient cultured fibroblasts. Finally, we determined the effectiveness of scAAV-mediated gene transfer alone and combined with DCA to restore PDH activity in defective cells. Materials and methods Cell culture, treatment and plasmidsPrimary cultures of fibroblasts were established from skin biopsies of three healthy subjects and three patients (one male and two females) with PDH E1α deficiency. The patients had the following mutations in the PDHA1 gene: patient 1, c.1163_1166dupAAGT in exon 11; patient 2, c.904C>T in exon 10; and patient 3, c.642G>T in exon...

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“…38,39 These so-called 'mitochondrial epilepsies' are clinically and genetically heterogeneous diseases; disease-causing mutations have been reported in many of the 37 mitochondrially encoded genes and at least 31 nuclear genes (reviewed in Rahman 40 ). Mutated genes encode different subunits of the respiratory chain or proteins that have a role in mitochondrial genome maintenance, translation and replication, as well as enzymes involved in the biosynthesis of coenzyme Q10 or the mitochondrial glutamate carrier SLC25A22 (reviewed in Rahman 40 ).…”

Section: Discussionmentioning

confidence: 99%

West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1

et al. 2015

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West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births. To get better insights on the genetic of this pathology, we exomesequenced the members of a consanguineous family affected with isolated WS. We identified a homozygous variant (c.1825G4T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings. GUF1 encodes a protein essential in conditions that counteract faithful protein synthesis: it is able to remobilize stuck ribosomes and transiently inhibit the elongation process to optimize protein synthesis. The variant identified in the WS family changes an alanine residue conserved in all eukaryotic organisms and positioned within the tRNA-binding moiety of this nuclear genome-encoded mitochondrial translational elongation factor. Yeast complementation assays show that the activity of GUF1 A609S is modified in suboptimal environments. We suggest a new link between improper assembly of respiratory chain complexes and WS.

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Long-term Outcome and Clinical Spectrum of 73 Pediatric Patients With Mitochondrial Diseases

Abstract: Mitochondrial diseases in children span a wide range of symptoms and severities. Age at first symptoms is the strongest predictor mortality. Despite a high mortality rate in the cohort, 62% of patients aged >5 years have only mild impairment or normal functional outcome.

Cited by 162 publications

References 41 publications

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

A combined therapeutic approach for pyruvate dehydrogenase deficiency using self-complementary adeno-associated virus serotype-specific vectors and dichloroacetate

West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1

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