Nonsense mutations in CABC1/ADCK3 cause progressive cerebellar ataxia and atrophy

Gerards, Mike; Bosch, Bianca van den; Calis, Chantal; Schoonderwoerd, Kees; Engelen, Klaartje van; Tijssen, Marina A. J.; Coo, I.F.M. de; Kooi, Anneke J. van der; Smeets, Hubert J.M.

doi:10.1016/j.mito.2010.05.008

Cited by 68 publications

(72 citation statements)

References 27 publications

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“…The Th584del has been previously described in patients with cerebellar ataxia (LagierTourenne and Tazir 2008), but the P602R mutation is novel (Lagier-Tourenne and Tazir 2008; Mollet et al 2008;Gerards et al 2010;Horvath et al 2012). The pathogenicity of the P602R is supported by a substitution of a neutral amino acid by a basic one, conservation of Proline602 among species and prediction as disease causing by three softwares.…”

Section: Discussionmentioning

confidence: 94%

“…Only 22 patients with ADCK3-associated cerebellar ataxia have been reported since the first publications in 2008 (Lagier-Tourenne and Tazir 2008; Mollet et al 2008;Gerards et al 2010;Horvath et al 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Other findings include stroke-like lesions (Mollet et al 2008), pontine atrophy (Gerards et al 2010), thin corpus callosum, and ventricular enlargement (Horvath et al 2012).…”

Section: Discussionmentioning

confidence: 99%

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Heterozygous Mutations in the ADCK3 Gene in Siblings with Cerebellar Atrophy and Extreme Phenotypic Variability

et al. 2013

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We describe a highly variable clinical presentation of cerebellar ataxia in two sisters. The younger sister demonstrates early onset rapidly progressive cerebellar ataxia accompanied by motor and nonmotor cerebellar features, as well as cognitive decline and psychiatric problems. Mitochondrial respiratory chain enzyme analysis in muscle showed a decrease in complex I + III. Progressive cerebellar atrophy was demonstrated on serial brain MR imaging. Coenzyme Q10 (CoQ10) supplementation, started at the age of 5 years, led to a significant improvement in motor and cognitive abilities with partial amelioration of the cerebellar signs. Discontinuation of this treatment resulted in worsening of the ataxia, cognitive decline, and severe depression.The older sister, who is 32 years old, has nonprogressive dysarthria and clumsiness from the age of 10 years and MRI reveals cerebellar atrophy.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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Heterozygous Mutations in the ADCK3 Gene in Siblings with Cerebellar Atrophy and Extreme Phenotypic Variability

et al. 2013

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“…Nuclear mutations affecting proteins involved in mtDNA replication-the mtDNA polymerase c (POLG) and the helicase Twinkle (c10orf2)-cause progressive myoclonic epilepsy (61) and rare forms of ataxia (62). Among rare ataxias, two further disorders have been associated directly with oxidative phosphorylation: Friedreich's ataxia, caused by mutations of frataxin involved in the synthesis of iron-sulfur proteins (63) and SCAR9, caused by mutations in ADCK3, a regulatory protein involved in the synthesis pathway of coenzyme Q (64). All other neurodegenerative diseases show only indirect links to OxPhos, because they affect mitochondrial dynamics (CMT2A, OPA1, and OPA3) or quality control (SCA28, SPG7, PARK2, PARK6, and PARK7) or related pathways.…”

Section: Neurodegenerative Diseases With Evidence For Direct Mitochonmentioning

confidence: 99%

Mitochondrial involvement in neurodegenerative diseases

Kunz

2013

IUBMB Life

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The classical bioenergetical view of the involvement of mitochondria in neurogeneration is based on the fact that mitochondria are the central players of ATP synthesis in neurons and their failure leads to neuronal dysfunction and eventually to cell death. Mutations in at least 39 genes in inherited neurodegenerative disorders seem to alter directly or indirectly mitochondrial function. Most of these mutations do not directly affect oxidative phosphorylation, but act through disturbed mitochondrial dynamics and quality control. This, however, does not invalidate the bioenergetic hypothesis.Neurodegeneration is not necessarily associated with a gross failure of ATP production, but might rather be a consequence of local insufficiencies of ATP supply in critical compartments of neurons, like the presynaptic terminal. We hypothesize that slow disease progression, at least in a subgroup of neurodegenerative diseases, can be explained by the parallel action of subcellular ATP insufficiency and clonal expansion of somatic mitochondrial DNA mutations, and particularly deletions. V C 2013 IUBMB Life, 65(3): [263][264][265][266][267][268][269][270][271][272] 2013

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“…Mutations in ADCK3 have been found in additional patients with cerebellar ataxia, cerebellar atrophy, exercise intolerance, dystonia, and mild cognitive impairment. However, the level of CoQ 10 in muscle and fibroblasts in these patients was not mentioned [Gerards et al, 2010]. Disease progression is typically slow.…”

Section: Cerebellar Ataxiamentioning

confidence: 91%

Clinical Presentations of Coenzyme Q10 Deficiency Syndrome

Quinzii

Emmanuele

Hirano³

2014

Mol Syndromol

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Coenzyme Q₁₀ (CoQ₁₀) deficiency is a clinically and genetically heterogeneous syndrome which has been associated with 5 major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) nephropathy, (4) cerebellar ataxia, and (5) isolated myopathy. Of these phenotypes, cerebellar ataxia and syndromic or isolated nephrotic syndrome are the most common. CoQ₁₀ deficiency predominantly presents in childhood. To date, causative mutations have been identified in a small proportion of patients, making it difficult to identify a phenotype-genotype correlation. Identification of CoQ₁₀ deficiency is important because the disease, in particular muscle symptoms and nephropathy, frequently responds to CoQ₁₀ supplementation.

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Nonsense mutations in CABC1/ADCK3 cause progressive cerebellar ataxia and atrophy

Cited by 68 publications

References 27 publications

Heterozygous Mutations in the ADCK3 Gene in Siblings with Cerebellar Atrophy and Extreme Phenotypic Variability

Heterozygous Mutations in the ADCK3 Gene in Siblings with Cerebellar Atrophy and Extreme Phenotypic Variability

Mitochondrial involvement in neurodegenerative diseases

Clinical Presentations of Coenzyme Q10 Deficiency Syndrome

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