Coenzyme Q deficiency and cerebellar ataxia associated with an aprataxin mutation. Neurology

Department of Neurology, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA
Neurology (Impact Factor: 8.29). 03/2005; 64(3):539-41. DOI: 10.1212/01.WNL.0000150588.75281.58
Source: PubMed

ABSTRACT Primary muscle coenzyme Q10 (CoQ10) deficiency is an apparently autosomal recessive condition with heterogeneous clinical presentations. Patients with these disorders improve with CoQ10 supplementation. In a family with ataxia and CoQ10 deficiency, analysis of genome-wide microsatellite markers suggested linkage of the disease to chromosome 9p13 and led to identification of an aprataxin gene (APTX) mutation that causes ataxia oculomotor apraxia (AOA1 [MIM606350]). The authors' observations indicate that CoQ10 deficiency may contribute to the pathogenesis of AOA1.

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    • "Disease progression is typically slow. Supplementation with CoQ 10 has been associated with increased strength and energy level and disappearance of seizures in the affected individuals with aprataxin mutations we described [Musumeci et al., 2001; Quinzii et al., 2005], and with mild clinical improvement in patients with cerebellar ataxia associated with mutations in ADCK3 / CABC1 [Lagier-Tourenne et al., 2008; Mollet et al., 2008; Liu et al., 2013; Mignot et al., 2013]. More recently , Pineda et al. [2010] assessed the clinical outcome in 14 patients with cerebellar ataxia with and without documented CoQ 10 deficiency in muscle and/or fibroblasts and unknown molecular defect and observed that all patients with CoQ 10 deficiency responded to therapy. "
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    ABSTRACT: 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.
    Molecular syndromology 07/2014; 5(3-4):141-6. DOI:10.1159/000360490
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    • "The lack of clinical improvement may have been due to low dosage, poor penetration of CoQ 10 formulation , the severity of brain damage prior to oral supplementation , or a combination of these factors. Patients with secondary deficiency in CoQ 10 and cerebellar ataxias also improved with CoQ 10 supplementation [Quinzii et al., 2005; Gempel et al., 2007] or even resulted in full recovery [Gempel et al., 2007]. Furthermore , myopathic CoQ 10 deficiency also responded dramatically to CoQ 10 supplementation, and after 8 months of treatment, excessive lipid storage resolved, CoQ 10 level normalized, mitochondrial enzymes increased, and the proportion of apoptotic fibers decreased from 30 to 10% in 2 brothers with myopathic CoQ 10 deficiency [Di Giovanni et al., 2001]. "
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    ABSTRACT: For a number of years, coenzyme Q10 (CoQ10) was known for its key role in mitochondrial bioenergetics; later studies demonstrated its presence in other subcellular fractions and in blood plasma, and extensively investigated its antioxidant role. These two functions constitute the basis for supporting the clinical use of CoQ10. Also at the inner mitochondrial membrane level, CoQ10 is recognized as an obligatory co-factor for the function of uncoupling proteins and a modulator of the mitochondrial transition pore. Furthermore, recent data indicate that CoQ10 affects expression of genes involved in human cell signalling, metabolism, and transport and some of the effects of CoQ10 supplementation may be due to this property. CoQ10 deficiencies are due to autosomal recessive mutations, mitochondrial diseases, ageing-related oxidative stress and carcinogenesis processes, and also statin treatment. Many neurodegenerative disorders, diabetes, cancer and muscular and cardiovascular diseases have been associated with low CoQ10 levels, as well as different ataxias and encephalomyopathies. CoQ10 treatment does not cause serious adverse effects in humans and new formulations have been developed that increase CoQ10 absorption and tissue distribution. Oral CoQ10 is a frequent antioxidant strategy in many diseases that may provide a significant symptomatic benefit.
    Molecular syndromology 07/2014; DOI:10.1159/000360101
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    • "Oral supplementation is so far the best approach to increase CoQ 10 levels in patients [Ogasahara et al., 1989; Rotig et al., 2000; Salviati et al., 2005]. However, several studies have reported that the improvement obtained by oral supplementation does not generally apply to all cases and depends on the symptoms detected in patients and the genetic origin of the deficiency [Musumeci et al., 2001; Lamperti et al., 2003; Aure et al., 2004; Quinzii et al., 2005; Artuch et al., 2006; Mollet et al., 2008; Lagier- Tourenne and Tazir, 2008]. The treatment of patients has been afforded by the use of CoQ 10 analogs such as MitoQ [Tauskela, 2007] or idebenone [Meier and Buyse, 2009]. "
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    ABSTRACT: Coenzyme Q (CoQ) is a mitochondrial lipid, which functions mainly as an electron carrier from complex I or II to complex III at the mitochondrial inner membrane, and also as antioxidant in cell membranes. CoQ is needed as electron acceptor in β-oxidation of fatty acids and pyridine nucleotide biosynthesis, and it is responsible for opening the mitochondrial permeability transition pore. The yeast model has been very useful to analyze the synthesis of CoQ, and therefore, most of the knowledge about its regulation was obtained from the Saccharomyces cerevisiae model. CoQ biosynthesis is regulated to support 2 processes: the bioenergetic metabolism and the antioxidant defense. Alterations of the carbon source in yeast, or in nutrient availability in yeasts or mammalian cells, upregulate genes encoding proteins involved in CoQ synthesis. Oxidative stress, generated by chemical or physical agents or by serum deprivation, modifies specifically the expression of some COQ genes by means of stress transcription factors such as Msn2/4p, Yap1p or Hsf1p. In general, the induction of COQ gene expression produced by metabolic changes or stress is modulated downstream by other regulatory mechanisms such as the protein import to mitochondria, the assembly of a multi-enzymatic complex composed by Coq proteins and also the existence of a phosphorylation cycle that regulates the last steps of CoQ biosynthesis. The CoQ biosynthetic complex assembly starts with the production of a nucleating lipid such as HHB by the action of the Coq2 protein. Then, the Coq4 protein recognizes the precursor HHB acting as the nucleus of the complex. The activity of Coq8p, probably as kinase, allows the formation of an initial pre-complex containing all Coq proteins with the exception of Coq7p. This pre-complex leads to the synthesis of 5-demethoxy-Q6 (DMQ6), the Coq7p substrate. When de novo CoQ biosynthesis is required, Coq7p becomes dephosphorylated by the action of Ptc7p increasing the synthesis rate of CoQ6. This critical model is needed for a better understanding of CoQ biosynthesis. Taking into account that patients with CoQ10 deficiency maintain to some extent the machinery to synthesize CoQ, new promising strategies for the treatment of CoQ10 deficiency will require a better understanding of the regulation of CoQ biosynthesis in the future.
    Molecular syndromology 07/2014; 5(3-4):107-18. DOI:10.1159/000362897
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