Mitochondrial Dysfunction due to Novel COQ8A Variation with Poor Response to CoQ10 Treatment: A Comprehensive Study and Review of Literatures.

COQ8A plays an important role in the biosynthesis of coenzyme Q10 (CoQ10), and variations in COQ8A gene are associated with primary CoQ10 deficiency-4 (COQ10D4), also known as COQ8A-ataxia. The current understanding of the association between the specific variant type, the severity of CoQ10 deficiency, and the degree of oxidative stress in individuals with primary CoQ10 deficiencies remains uncertain. Here we provide a comprehensive analysis of the clinical and genetic characteristics of an 18-year-old patient with COQ8A-ataxia, who exhibited novel compound heterozygous variants (c.1904_1906del and c.637C > T) in the COQ8A gene. These variants reduced the expression levels of COQ8A and mitochondrial proteins in the patient's muscle and skin fibroblast samples, contributed to mitochondrial respiration deficiency, increased ROS production and altered mitochondrial membrane potential. It is worth noting that the optimal treatment for COQ8A-ataxia remains uncertain. Presently, therapy consists of CoQ10 supplementation, however, it did not yield significant improvement in our patient's symptoms. Additionally, we reviewed the response of CoQ10 supplementation and evolution of patients in previous literatures in detail. We found that only half of patients could got notable improvement in ataxia. This research aims to expand the genotype-phenotype spectrum of COQ10D4, address discrepancies in previous reviews regarding the effectiveness of CoQ10 in these disorders, and help to establish a standardized treatment protocol for COQ8A-ataxia.

Primary CoQ10 deficiency with a severe phenotype due to the c.901 C > T (p.R301W) mutation in the COQ8A gene.

PURPOSE: A patient with primary CoQ10 deficiency associated with the c.901 C > T (p.R301W) (rs140246430) homozygous missense pathogenic variant in the COQ8A gene, who presented with recurrent status epilepticus, stroke-like lesions, and hypertrophic cardiomyopathy while being followed-up with early-onset autosomal recessive cerebellar ataxia will be reported in this article. CASE REPORT: A 16-year-old patient who was being followed up at an external center with a diagnosis of ataxia with cerebellar atrophy had been seen 3 different times within a year for status epilepticus. The cerebral MRI showed severe cerebellar atrophy, stroke like lesions, and an inverted double- lactate peak on spectroscopy. Her echocardiography revealed marked left ventricular hypertrophy. Mitochondrial cocktail therapy containing a standard dose of CoQ10 was started, considering mitochondrial disease. The patient died due to cardiomyopathy. Mitochondrial panel analysis revealed the presence of the c.901 C > T (p.R301W) homozygous missense mutation in the COQ8A gene. CONCLUSIONS: Primary Coenzyme Q10 deficiency should be considered in patients presenting with autosomal recessive stable-appearing progressive ataxia, emerging attacks of status epilepticus, stroke-like lesions on neuroimaging, and cardiomyopathy. Since there is a case with the same mutation with a similar fatal course in the literature, detection of c.901 C > T (p.R301W) mutation homozygously should be a warning for a severe prognosis and more aggressive treatment should be started without delay with a high dose of CoQ10 instead of the lower doses used in the treatment of mitochondrial disease.

Adolescence Onset Primary Coenzyme Q10 Deficiency With Rare CoQ8A Gene Mutation: A Case Report and Review of Literature.

Background: Primary 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 report: We 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. Conclusion: These 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.

COQ8A-Ataxia as a Manifestation of Primary Coenzyme Q Deficiency.

COQ8A-ataxia is a mitochondrial disease in which a defect in coenzyme Q10 synthesis leads to dysfunction of the respiratory chain. The disease is usually present as childhood-onset progressive ataxia with developmental regression and cerebellar atrophy. However, due to variable phenotype, it may be hard to distinguish from other mitochondrial diseases and a wide spectrum of childhood-onset cerebellar ataxia. COQ8A-ataxia is a potentially treatable condition with the supplementation of coenzyme Q10 as a main therapy; however, even 50% may not respond to the treatment. In this study we review the clinical manifestation and management of COQ8A-ataxia, focusing on current knowledge of coenzyme Q10 supplementation and approach to further therapies. Moreover, the case of a 22-month-old girl with cerebellar ataxia and developmental regression will be presented.

Loss of Drosophila Coq8 results in impaired survival, locomotor deficits and photoreceptor degeneration.

Coenzyme Q8A encodes the homologue of yeast coq8, an ATPase that is required for the biosynthesis of Coenzyme Q10, an essential component of the electron transport chain. Mutations in COQ8A in humans result in CoQ10 deficiency, the clinical features of which include early-onset cerebellar ataxia, seizures and intellectual disability. The rapid advancement of massively parallel sequencing has resulted in the identification of more than 40 new mutations in COQ8A and functional studies are required to confirm causality and to further research into determining the specific mechanisms through which the mutations result in loss of function. To that end, a Drosophila model of Coq8 deficiency was developed and characterized to determine its appropriateness as a model system to further explore the role of Coq8 in the brain, and for functional characterisation of Coq8 mutations. Pan-neuronal RNAi knockdown of Coq8 was largely lethal, with female escapers displaying severe locomotor deficits. Knockdown of Coq8 in the eye resulted in degeneration of photoreceptors, progressive necrosis and increased generation of reactive oxygen species. Reintroduction of wild-type Coq8 restored normal function, however expression of human wild-type COQ8A exacerbated the eye phenotype, suggesting it was acting as a dominant-negative. This model is therefore informative for investigating the function of Drosophila Coq8, however human COQ8A mutations cannot be assessed as hCOQ8A does not rescue Coq8 deficiency.

The cerebellar bioenergetic state predicts treatment response in COQ8A-related ataxia.

INTRODUCTION: Primary coenzyme Q10 (CoQ10) deficiency, a recessive disorder associated with various defects of CoQ10 biosynthesis and widely varying clinical presentation, is customarily managed by oral Q10 supplementation but the benefit is debated. METHODS: To address this question, we mapped individual responses in two patients with COQ8A-related ataxia following coenzyme Q10 supplementation using noninvasive imaging. Metabolic 31phosphorus magnetic resonance spectroscopy imaging (31P-MRSI) and volumetric cerebellar neuroimaging were performed to quantify the individual treatment response in two patients with COQ8A-related ataxia, each compared with eight age- and gender-matched healthy control subjects. RESULTS: Post-treatment change in energy metabolite levels differed in the two patients, with higher energy levels and improved dysarthria and leg coordination in one, and decreased energy levels without clinical benefit in the other. CONCLUSIONS: Our results suggest that the cerebellar bioenergetic state may predict treatment response in COQ8A-related ataxia and highlight the potential of pathophysiology-orientated neuroimaging evidence to inform treatment decisions.

Epilepsia Partialis Continua a Clinical Feature of a Missense Variant in the ADCK3 Gene and Poor Response to Therapy.

INTRODUCTION: Coenzyme Q10 deficiency can be due to mutations in Coenzyme Q10-biosynthesis genes (primary) or genes unrelated to biosynthesis (secondary). Primary Coenzyme Q10 deficiency-4 (COQ10D4), also known as autosomal recessive spinocerebellar ataxia-9 (SCAR9), is an autosomal recessive disorder caused by mutations in the ADCK3 gene. This disorder is characterized by several clinical manifestations such as severe infantile multisystemic illness, encephalomyopathy, isolated myopathy, cerebellar ataxia, or nephrotic syndrome. METHODS: In this study, whole-exome sequencing was performed in order to identify disease-causing variants in an affected girl with developmental regression and Epilepsia Partialis Continua (EPC). Next, Sanger sequencing method was used to confirm the identified variant in the patient and segregation analysis in her parents. CASE PRESENTATION: The proband is an affected 11-year-old girl with persistent seizures, EPC, and developmental regression including motor, cognition, and speech. Seizures were not controlled with various anticonvulsant drugs despite adequate dosing. Progressive cerebellar atrophy, stroke-like cortical involvement, multifocal hyperintense bright objects, and restriction in diffusion-weighted imaging (DWI) were seen in the brain magnetic resonance imaging (MRI). CONCLUSIONS: A novel homozygous missense variant [NM_020247.5: c.814G>T; (p.Gly272Cys)] was identified within the ADCK3 gene, which is the first mutation in this gene in the Iranian population. Bioinformatics analysis showed this variant is damaging. Based on our patient, clinicians should consider genetic testing earlier to instant diagnosis and satisfactory treatment based on exact etiology to prevent further neurologic sequelae.

Early-onset coenzyme Q10 deficiency associated with ataxia and respiratory chain dysfunction due to novel pathogenic COQ8A variants, including a large intragenic deletion.

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.

Primary coenzyme Q10 deficiency due to COQ8A gene mutations.

BACKGROUND: Primary 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. METHODS: A 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. RESULTS: This 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. CONCLUSIONS: We identified a patient with COQ10D4 caused by novel COQ8A mutations. Our findings widen the spectrum of COQ8A gene mutations and clinical manifestations.

A novel COQ8A missense variant associated with a mild form of primary coenzyme Q10 deficiency type 4.

BACKGROUND: Primary coenzyme Q10 deficiency refers to a group of diseases characterised by reduced levels of coenzyme Q10 in related tissues or cultured cells associated with the 9 genes involved in the biosynthesis of coenzyme Q10. A biallelic pathogenic variant of COQ8A gene causes the occurrence of the primary coenzyme Q10 deficiency type 4. The objective of this study was to investigate the genetic cause of muscle weakness in a proband who had a negative DMD gene test for Becker muscular dystrophy. METHODS: The DNA of the proband was sequenced using whole exome sequencing. With the help of the Human Phenotype Ontology (HPO), the range of related candidate pathogenic genes has been reduced to a certain extent based on "muscle weakness" (HP:0001324). In addition, family linkage analysis, phenotypic-genotype check and protein structure modeling were used to explore the genetic cause of the proband. RESULTS: The compound heterozygous variant c.836A > C (p.Gln279Pro) and c.1228C > T (p.Arg410Ter) in the COQ8A gene was identified in the proband. According to the 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines for the interpretation of sequence variants, the novel variant c.836A > C could be classified as "likely pathogenic" for the proband. CONCLUSION: The p.Gln279Pro was detected in the KxGQ motif and the QKE triplet of the COQ8A protein, whose structures were crucial for the structure and function of the COQ8A protein associated with the biosynthesis of coenzyme Q10 and the proband's clinical symptoms were relatively milder than those previously reported.

Dystonia-Ataxia with early handwriting deterioration in COQ8A mutation carriers: A case series and literature review.

Cerebellar ataxia is a hallmark of coenzyme Q10 (CoQ10) deficiency associated with COQ8A mutations. We present four patients, one with novel COQ8A pathogenic variants all with early, prominent handwriting impairment, dystonia and only mild ataxia. To better define the phenotypic spectrum and course of COQ8A disease, we review the clinical presentation and evolution in 47 reported cases. Individuals with COQ8A mutation display great clinical variability and unpredictable responses to CoQ10 supplementation. Onset is typically during infancy or childhood with ataxic features associated with developmental delay or regression. When disease onset is later in life, first symptoms can include: incoordination, epilepsy, tremor, and deterioration of writing. The natural history is characterized by a progression to a multisystem brain disease dominated by ataxia, with disease severity inversely correlated with age at onset. Six previously reported cases share with ours, a clinical phenotype characterized by slowly progressive or static writing difficulties, focal dystonia, and speech disorder, with only minimal ataxia. The combination of writing difficulty, dystonia and ataxia is a distinctive constellation that is reminiscent of a previously described clinical entity called Dystonia Ataxia Syndrome (DYTCA) and is an important clinical indicator of COQ8A mutations, even when ataxia is mild or absent.

Compound Heterozygous Inheritance of Mutations in Coenzyme Q8A Results in Autosomal Recessive Cerebellar Ataxia and Coenzyme Q10 Deficiency in a Female Sib-Pair.

Autosomal recessive ataxias are characterised by a fundamental loss in coordination of gait with associated atrophy of the cerebellum. There is significant clinical and genetic heterogeneity amongst inherited ataxias; however, an early molecular diagnosis is essential with low-risk treatments available for some of these conditions. We describe two female siblings who presented early in life with unsteady gait and cerebellar atrophy. Whole exome sequencing revealed compound heterozygous inheritance of two pathogenic mutations (p.Leu277Pro, c.1506+1G>A) in the coenzyme Q8A gene (COQ8A), a gene central to biosynthesis of coenzyme Q (CoQ). The paternally derived p.Leu277Pro mutation is predicted to disrupt a conserved motif in the substrate-binding pocket of the protein, resulting in inhibition of CoQ10 production. The maternal c.1506+1G>A mutation destroys a canonical splice donor site in exon 12 affecting transcript processing and subsequent protein translation. Mutations in this gene can result in primary coenzyme Q10 deficiency type 4, which is characterized by childhood onset of cerebellar ataxia and exercise intolerance, both of which were observed in this sib-pair. Muscle biopsies revealed unequivocally low levels of CoQ10, and the siblings were subsequently established on a therapeutic dose of CoQ10 with distinct clinical evidence of improvement after 1 year of treatment. This case emphasises the importance of an early and accurate molecular diagnosis for suspected inherited ataxias, particularly given the availability of approved treatments for some subtypes.

Conserved Lipid and Small-Molecule Modulation of COQ8 Reveals Regulation of the Ancient Kinase-like UbiB Family.

Human COQ8A (ADCK3) and Saccharomyces cerevisiae Coq8p (collectively COQ8) are UbiB family proteins essential for mitochondrial coenzyme Q (CoQ) biosynthesis. However, the biochemical activity of COQ8 and its direct role in CoQ production remain unclear, in part due to lack of known endogenous regulators of COQ8 function and of effective small molecules for probing its activity in vivo. Here, we demonstrate that COQ8 possesses evolutionarily conserved ATPase activity that is activated by binding to membranes containing cardiolipin and by phenolic compounds that resemble CoQ pathway intermediates. We further create an analog-sensitive version of Coq8p and reveal that acute chemical inhibition of its endogenous activity in yeast is sufficient to cause respiratory deficiency concomitant with CoQ depletion. Collectively, this work defines lipid and small-molecule modulators of an ancient family of atypical kinase-like proteins and establishes a chemical genetic system for further exploring the mechanistic role of COQ8 in CoQ biosynthesis.