Ataxia due to a COQ8A Novel Variant in Primary Coenzyme Q10 Deficiency.
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SUBMITTER: Chavira-Hernandez G
PROVIDER: S-EPMC10448619 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Ataxia due to a COQ8A Novel Variant in Primary Coenzyme Q10 Deficiency.
Chavira-Hernández Gerardo G Piña-Avilés Carlos Eduardo CE Zúñiga-Ramírez Carlos C
Movement disorders clinical practice 20230824 Suppl 3
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Project description:BackgroundPrimary deficiency of coenzyme Q10 deficiency-4 (COQ10D4) is an autosomal recessive cerebellar ataxia with mitochondrial respiratory chain disfunction. The main clinical manifestation involves early-onset exercise intolerance, progressive cerebellar ataxia, and movement disorders. COQ8A gene mutations are responsible for this disease. Here, we provide clinical, laboratory, and genetic findings of a patient with cerebellar ataxia caused by compound heterozygous mutations in COQ8A gene.MethodsA male patient from a non-consanguineous Chinese family underwent detailed physical and auxiliary examination. After exclusion of acquired causes of ataxia, Friedreich's Ataxia, and common types of spinocerebellar ataxia, the patient was subjected to whole exome sequencing (WES) followed by confirmation of sequence variants using Sanger sequencing. His asymptomatic parents, two brothers and one sister were genotyped for these variants.ResultsThis patient showed early-onset exercise intolerance and progressive cerebellar ataxia, wide-based gait and tremor, accompanied by symptoms of dysautonomia. His serum lactate level was elevated and plasma total Coenzyme Q10 (CoQ10) was decreased. Brain MRI showed cerebellar atrophy, and X-ray of the spine revealed thoraco-lumbar scoliosis. Compound heterozygous mutations in the COQ8A gene were identified through WES: c.1844_1845insG, p.Ser616Leufs*114 and c.902G>A, p.Arg301Gln. After treatment with ubidecarenone, 40 mg three times per day for 2 years, the symptoms dramatically improved.ConclusionsWe identified a patient with COQ10D4 caused by novel COQ8A mutations. Our findings widen the spectrum of COQ8A gene mutations and clinical manifestations.
| S-EPMC7549598 | biostudies-literature
Project description:Coenzyme Q10 (CoQ10) deficiency is a clinically and genetically heterogeneous subtype of mitochondrial disease. We report two girls with ataxia and mitochondrial respiratory chain deficiency who were shown to have primary CoQ10 deficiency. Muscle histochemistry displayed signs of mitochondrial dysfunction-ragged red fibers, mitochondrial paracrystalline inclusions, and lipid deposits while biochemical analyses revealed complex II+III respiratory chain deficiencies. MRI brain demonstrated cerebral and cerebellar atrophy. Targeted molecular analysis identified a homozygous c.1015G>A, p.(Ala339Thr) COQ8A variant in subject 1, while subject 2 was found to harbor a single heterozygous c.1029_1030delinsCA variant predicting a p.Gln343_Val344delinsHisMet amino acid substitution. Subsequent investigations identified a large-scale COQ8A deletion in trans to the c.1029_1030delinsCA allele. A skin biopsy facilitated cDNA studies that confirmed exon skipping in the fibroblast derived COQ8A mRNA transcript. This report expands the molecular genetic spectrum associated with COQ8A-related mitochondrial disease and highlights the importance of thorough investigation of candidate pathogenic variants to establish phase. Rapid diagnosis is of the utmost importance as patients may benefit from therapeutic CoQ10 supplementation.
| S-EPMC7358671 | biostudies-literature
Project description:BackgroundPrimary deficiency of coenzyme Q10 deficiency-4 (CoQ10D4) is a heterogeneous disorder affecting different age groups. The main clinical manifestation consists of cerebellar ataxia, exercise intolerance, and dystonia.Case reportWe provide a case of adolescence-onset ataxia, head tremor, and proximal muscle weakness accompanied by psychiatric features and abnormal serum urea (49.4 mg/dL), lactate (7.5 mmol/L), and CoQ10 level (0.4 µg/mL). Brain-MRI demonstrated cerebellar atrophy, thinning of the corpus callosum, and loss of white matter. Whole exome sequencing showed a homozygous missense mutation (c.911C>T; p.A304V) in CoQ8A gene which is a rare mutation and responsible variant of CoQ10D4. After supplementary treatment with CoQ10 50 mg/twice a day for 2 months the clinical symptoms improved.ConclusionThese observations highlight the significance of the early diagnosis of potentially treatable CoQ8A mutation as well as patient education and follow-up. Our findings widen the spectrum of CoQ8A phenotypic features so that clinicians be familiar with the disease not only in severe childhood-onset ataxia but also in adolescence with accompanying psychiatric problems.
| S-EPMC10354825 | biostudies-literature
Project description:Primary coenzyme Q10 deficiency-6 (COQ10D6), as a rare autosomal recessive disease caused by COQ6 mutations, is characterized by progressive infantile-onset nephrotic syndrome resulting in end-stage renal failure and sensorineural hearing loss. Here, we report two Chinese siblings with COQ10D6 who primarily presented with severe metabolic acidosis, proteinuria, hypoalbuminemia, growth retardation, and muscle hypotonia and died in early infancy. Using whole-exome sequencing and Sanger sequencing, we identified two rare recessive nonsense mutations in the COQ6 gene segregating with disease in affected family members: c.249C > G (p.Tyr83Ter) and c.1381C > T (p.Gln461Ter), resulting in two truncated protein products. Both mutations are located in a highly conserved area and are predicted to be pathogenic. Indeed, the death of our patients in early infancy indicates the pathogenicity of the p.Tyr83Ter and p.Gln461Ter variants and highlights the significance of the two variants for COQ6 enzyme function, which is necessary for the biosynthesis of coenzyme Q10. In conclusion, we discovered a novel compound heterozygous pathogenic variant of the COQ6 gene as a cause of severe COQ10D6 in the two siblings. Based on the clinical history and genetic characteristics of the patients, our cases expand the genotypic spectrum of COQ10D6 and highlight the heterogeneity and severity of clinical features associated with COQ6 mutations. For patients with clinical manifestations suggestive of COQ10D6, early testing for COQ6 mutations is beneficial for disease diagnosis and therapeutic interventions as well as disease prevention in future generations.
| S-EPMC8802230 | biostudies-literature
Project description:Primary coenzyme Q10 (CoQ10 ; MIM# 607426) deficiencies are an emerging group of inherited mitochondrial disorders with heterogonous clinical phenotypes. Over a dozen genes are involved in the biosynthesis of CoQ10 , and mutations in several of these are associated with human disease. However, mutations in COQ5 (MIM# 616359), catalyzing the only C-methylation in the CoQ10 synthetic pathway, have not been implicated in human disease. Here, we report three female siblings of Iraqi-Jewish descent, who had varying degrees of cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures, and cognitive disability. Whole-exome and subsequent whole-genome sequencing identified biallelic duplications in the COQ5 gene, leading to reduced levels of CoQ10 in peripheral white blood cells of all affected individuals and reduced CoQ10 levels in the only muscle tissue available from one affected proband. CoQ10 supplementation led to clinical improvement and increased the concentrations of CoQ10 in blood. This is the first report of primary CoQ10 deficiency caused by loss of function of COQ5, with delineation of the clinical, laboratory, histological, and molecular features, and insights regarding targeted treatment with CoQ10 supplementation.
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Project description:Ubiquinone (coenzyme Q(10) or CoQ(10)) is a lipid-soluble component of virtually all cell membranes and has multiple metabolic functions. Deficiency of CoQ(10) (MIM 607426) has been associated with five different clinical presentations that suggest genetic heterogeneity, which may be related to the multiple steps in CoQ(10) biosynthesis. Patients with all forms of CoQ(10) deficiency have shown clinical improvements after initiating oral CoQ(10) supplementation. Thus, early diagnosis is of critical importance in the management of these patients. This year, the first molecular defect causing the infantile form of primary human CoQ(10) deficiency has been reported. The availability of genetic testing will allow for a better understanding of the pathogenesis of this disease and early initiation of therapy (even presymptomatically in siblings of patients) in this otherwise life-threatening infantile encephalomyopathy.
| S-EPMC1832150 | biostudies-literature
Project description:Coenzyme Q10 deficiency is a clinically and genetically heterogeneous disorder, with manifestations that may range from fatal neonatal multisystem failure, to adult-onset encephalopathy. We report a patient who presented at birth with severe lactic acidosis, proteinuria, dicarboxylic aciduria, and hepatic insufficiency. She also had dilation of left ventricle on echocardiography. Her neurological condition rapidly worsened and despite aggressive care she died at 23 h of life. Muscle histology displayed lipid accumulation. Electron microscopy showed markedly swollen mitochondria with fragmented cristae. Respiratory-chain enzymatic assays showed a reduction of combined activities of complex I+III and II+III with normal activities of isolated complexes. The defect was confirmed in fibroblasts, where it could be rescued by supplementing the culture medium with 10 μM coenzyme Q10. Coenzyme Q10 levels were reduced (28% of controls) in these cells. We performed exome sequencing and focused the analysis on genes involved in coenzyme Q10 biosynthesis. The patient harbored a homozygous c.545T>G, p.(Met182Arg) alteration in COQ2, which was validated by functional complementation in yeast. In this case the biochemical and morphological features were essential to direct the genetic diagnosis. The parents had another pregnancy after the biochemical diagnosis was established, but before the identification of the genetic defect. Because of the potentially high recurrence risk, and given the importance of early CoQ10 supplementation, we decided to treat with CoQ10 the newborn child pending the results of the biochemical assays. Clinicians should consider a similar management in siblings of patients with CoQ10 deficiency without a genetic diagnosis.
| S-EPMC4430297 | biostudies-literature
Project description:The human syndrome of coenzyme Q (CoQ) deficiency is a heterogeneous mitochondrial disease characterized by a diminution of CoQ content in cells and tissues that affects all the electron transport processes CoQ is responsible for, like the electron transference in mitochondria for respiration and ATP production and the antioxidant capacity that it exerts in membranes and lipoproteins. Supplementation with external CoQ is the main attempt to address these pathologies, but quite variable results have been obtained ranging from little response to a dramatic recovery. Here, we present the importance of modeling human CoQ deficiencies in animal models to understand the genetics and the pathology of this disease, although the election of an organism is crucial and can sometimes be controversial. Bacteria and yeast harboring mutations that lead to CoQ deficiency are unable to grow if they have to respire but develop without any problems on media with fermentable carbon sources. The complete lack of CoQ in mammals causes embryonic lethality, whereas other mutations produce tissue-specific diseases as in humans. However, working with transgenic mammals is time and cost intensive, with no assurance of obtaining results. Caenorhabditis elegans and Drosophila melanogaster have been used for years as organisms to study embryonic development, biogenesis, degenerative pathologies, and aging because of the genetic facilities and the speed of working with these animal models. In this review, we summarize several attempts to model reliable human CoQ deficiencies in invertebrates, focusing on mutant phenotypes pretty similar to those observed in human patients.
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Project description: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.
| S-EPMC4112523 | biostudies-literature
Project description:Ubiquinone (coenzyme Q(10) or CoQ(10)) is a lipid-soluble component of virtually all cell membranes, where it functions as a mobile electron and proton carrier. CoQ(10) deficiency is inherited as an autosomal recessive trait and has been associated with three main clinical phenotypes: a predominantly myopathic form with central nervous system involvement, an infantile encephalomyopathy with renal dysfunction, and an ataxic form with cerebellar atrophy. In two siblings of consanguineous parents with the infantile form of CoQ(10) deficiency, we identified a homozygous missense mutation in the COQ2 gene, which encodes para-hydroxybenzoate-polyprenyl transferase. The A-->G transition at nucleotide 890 changes a highly conserved tyrosine to cysteine at amino acid 297 within a predicted transmembrane domain. Radioisotope assays confirmed a severe defect of CoQ(10) biosynthesis in the fibroblasts of one patient. This mutation in COQ2 is the first molecular cause of primary CoQ(10) deficiency.
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