Glomerular basement membrane ultrastructural changes in a patient with COQ2 glomerulopathy: A case report.

Primary coenzyme Q10 deficiency-1, caused by COQ2 disease-causing variants, is an autosomal recessive disorder, and genetic testing is the gold standard for diagnosing this condition. A Chinese boy with steroid-resistant nephrotic syndrome, focal segmental glomerulosclerosis, and progressive kidney insufficiency was included in the study. Electron microscopy revealed the glomerular basement membrane with irregular thickness and lamellation with diffuse effacement of foot processes in the podocytes, and swollen mitochondria with abnormal cristae in the podocytes. Coenzyme Q10 supplementation started about 3 weeks after the onset of mild kidney dysfunction did not improve the proband's kidney outcome. Proband-only whole-exome sequencing and Sanger sequencing revealed two heteroallelic COQ2 variants: a maternally inherited novel variant c.1013G > A[p.(Gly338Glu)] in exon 6 and a variant of unknown origin c.1159C > T[p.(Arg387*)] in exon 7. Subsequent long-read sequencing demonstrated these two variants were located on different alleles. Our report extends the phenotypic and genotypic spectrum of COQ2 glomerulopathy.

Epilepsy and Coenzyme Q10 deficiency with COQ4 variants.

Coenzyme Q10 (CoQ10) is one of the essential substances for mitochondrial energy synthesis and extra-mitochondrial vital function. Primary CoQ10 deficiency is a rare disease resulting from interruption of CoQ10 biosynthetic pathway and biallelic COQ4 variants are one of the genetic etiologies recognized in this hereditary disorder. The clinical heterogenicity is broad with wide onset age from prenatal period to adulthood. The typical manifestations include early pharmacoresistant seizure, severe cognition and/or developmental delay, dystonia, ataxia, and spasticity. Patients may also have multisystemic involvements such as cardiomyopathy, lactic acidosis or gastro-esophageal regurgitation disease. Oral CoQ10 supplement is the major therapeutic medication currently. Among those patients, c.370G > A variant is the most common pathogenic variant detected, especially in Asian population. This phenomenon also suggests that this specific allele may be the founder variants in Asia. In this article, we report two siblings with infantile onset seizures, developmental delay, cardiomyopathy, and diffuse brain atrophy. Genetic analysis of both two cases revealed homozygous COQ4 c.370G > A (p.Gly124Ser) variants. We also review the clinical manifestations of primary CoQ10 deficiency patients and possible treatment categories, which are still under survey. As oral CoQ10 supplement may improve or stabilize disease severity, early precise diagnosis of primary CoQ10 deficiency and early treatment are the most important issues. This review article helps to further understand clinical spectrum and treatment categories of primary CoQ10 deficiency with COQ4 variant.

Oral Coenzyme Q10 supplementation leads to better preservation of kidney function in steroid-resistant nephrotic syndrome due to primary Coenzyme Q10 deficiency.

Primary Coenzyme Q10 (CoQ10) deficiency is an ultra-rare disorder caused by defects in genes involved in CoQ10 biosynthesis leading to multidrug-resistant nephrotic syndrome as the hallmark kidney manifestation. Promising early results have been reported anecdotally with oral CoQ10 supplementation. However, the long-term efficacy and optimal prescription remain to be established. In a global effort, we collected and analyzed information from 116 patients who received CoQ10 supplements for primary CoQ10 deficiency due to biallelic pathogenic variants in either the COQ2, COQ6 or COQ8B genes. Median duration of follow up on treatment was two years. The effect of treatment on proteinuria was assessed, and kidney survival was analyzed in 41 patients younger than 18 years with chronic kidney disease stage 1-4 at the start of treatment compared with that of an untreated cohort matched by genotype, age, kidney function, and proteinuria. CoQ10 supplementation was associated with a substantial and significant sustained reduction of proteinuria by 88% at 12 months. Complete remission of proteinuria was more frequently observed in COQ6 disease. CoQ10 supplementation led to significantly better preservation of kidney function (5-year kidney failure-free survival 62% vs. 19%) with an improvement in general condition and neurological manifestations. Side effects of treatment were uncommon and mild. Thus, our findings indicate that all patients diagnosed with primary CoQ10 deficiency should receive early and life-long CoQ10 supplementation to decelerate the progression of kidney disease and prevent further damage to other organs.

Bi-Allelic COQ4 Variants Cause Adult-Onset Ataxia-Spasticity Spectrum Disease.

BACKGROUND: COQ4 codes for a mitochondrial protein required for coenzyme Q10 (CoQ10 ) biosynthesis. Autosomal recessive COQ4-associated CoQ10 deficiency leads to an early-onset mitochondrial multi-organ disorder. METHODS: In-house exome and genome datasets (n = 14,303) were screened for patients with bi-allelic variants in COQ4. Work-up included clinical characterization and functional studies in patient-derived cell lines. RESULTS: Six different COQ4 variants, three of them novel, were identified in six adult patients from four different families. Three patients had a phenotype of hereditary spastic paraparesis, two sisters showed a predominant cerebellar ataxia, and one patient had mild signs of both. Studies in patient-derived fibroblast lines revealed significantly reduced amounts of COQ4 protein, decreased CoQ10 concentrations, and elevated levels of the metabolic intermediate 6-demethoxyubiquinone. CONCLUSION: We report bi-allelic variants in COQ4 causing an adult-onset ataxia-spasticity spectrum phenotype and a disease course much milder than previously reported. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The dilemma of diagnosing coenzyme Q10 deficiency in muscle.

BACKGROUND: Coenzyme Q10 (CoQ10) is an important component of the mitochondrial respiratory chain (RC) and is critical for energy production. Although the prevalence of CoQ10 deficiency is still unknown, the general consensus is that the condition is under-diagnosed. The aim of this study was to retrospectively investigate CoQ10 deficiency in frozen muscle specimens in a cohort of ethnically diverse patients who received muscle biopsies for the investigation of a possible RC deficiency (RCD). METHODS: Muscle samples were homogenized whereby 600 ×g supernatants were used to analyze RC enzyme activities, followed by quantification of CoQ10 by stable isotope dilution liquid chromatography tandem mass spectrometry. The experimental group consisted of 156 patients of which 76 had enzymatically confirmed RCDs. To further assist in the diagnosis of CoQ10 deficiency in this cohort, we included sequencing of 18 selected nuclear genes involved with CoQ10 biogenesis in 26 patients with low CoQ10 concentration in muscle samples. RESULTS: Central 95% reference intervals (RI) were established for CoQ10 normalized to citrate synthase (CS) or protein. Nine patients were considered CoQ10 deficient when expressed against CS, while 12 were considered deficient when expressed against protein. In two of these patients the molecular genetic cause could be confirmed, of which one would not have been identified as CoQ10 deficient if expressed only against protein content. CONCLUSION: In this retrospective study, we report a central 95% reference interval for 600 ×g muscle supernatants prepared from frozen samples. The study reiterates the importance of including CoQ10 quantification as part of a diagnostic approach to study mitochondrial disease as it may complement respiratory chain enzyme assays with the possible identification of patients that may benefit from CoQ10 supplementation. However, the anomaly that only a few patients were identified as CoQ10 deficient against both markers (CS and protein), while the majority of patients where only CoQ10 deficient against one of the markers (and not the other), remains problematic. We therefore conclude from our data that, to prevent possibly not diagnosing a potential CoQ10 deficiency, the expression of CoQ10 levels in muscle on both CS as well as protein content should be considered.

CoQ10-related sustained remission of proteinuria in a child with COQ6 glomerulopathy-a case report.

BACKGROUND: Treatment of steroid resistant nephrotic syndrome is still a challenge for physicians. There are a growing number of studies exploring genetic background of steroid-resistant glomerulopathies. CASE DIAGNOSIS/TREATMENT: We present the case of a 4-year-old girl with steroid-resistant glomerulopathy due to a COQ6 defect with no additional systemic symptoms. The disease did not respond for second-line therapy with calcineurin inhibitor, but it remitted completely after oral treatment with 30 mg/kg/d of coenzyme Q10 (CoQ10). The patient was identified to be a compound heterozygote for two pathogenic variants in COQ6 gene: a known missense substitution c.1078C > T (p.R360W) and a novel frameshift c.804delC mutation. After 12 months of CoQ10 therapy, the child remains in full remission, her physical development accelerated, frequent respiratory airways diseases subsided. CONCLUSIONS: Genetic assessment of children with steroid-resistant nephrotic proteinuria enables therapy optimization. Proteinuria caused by a COQ6 gene defect can be successfully treated with CoQ10.

COQ2 nephropathy: a treatable cause of nephrotic syndrome in children.

BACKGROUND: Nephrotic syndrome can be caused by a subgroup of mitochondrial diseases classified as primary coenzyme Q10 (CoQ10) deficiency. Pathogenic COQ2 variants are a cause of primary CoQ10 deficiency and present with phenotypes ranging from isolated nephrotic syndrome to fatal multisystem disease. CASE-DIAGNOSIS/TREATMENT: We report three pediatric patients with COQ2 variants presenting with nephrotic syndrome. Two of these patients had normal leukocyte CoQ10 levels prior to treatment. Pathologic findings varied from mesangial sclerosis to focal segmental glomerulosclerosis, with all patients having abnormal appearing mitochondria on kidney biopsy. In two of the three patients treated with CoQ10 supplementation, the nephrotic syndrome resolved; and at follow-up, both have normal renal function and stable proteinuria. CONCLUSIONS: COQ2 nephropathy should be suspected in patients presenting with nephrotic syndrome, although less common than disease due to mutations in NPHS1, NPHS2, and WT1. The index of suspicion should remain high, and we suggest that providers consider genetic evaluation even in patients with normal leukocyte CoQ10 levels, as levels may be within normal range even with significant clinical disease. Early molecular diagnosis and specific treatment are essential in the management of this severe yet treatable condition.

Coenzyme Q biosynthesis in health and disease.

Coenzyme Q (CoQ, or ubiquinone) is a remarkable lipid that plays an essential role in mitochondria as an electron shuttle between complexes I and II of the respiratory chain, and complex III. It is also a cofactor of other dehydrogenases, a modulator of the permeability transition pore and an essential antioxidant. CoQ is synthesized in mitochondria by a set of at least 12 proteins that form a multiprotein complex. The exact composition of this complex is still unclear. Most of the genes involved in CoQ biosynthesis (COQ genes) have been studied in yeast and have mammalian orthologues. Some of them encode enzymes involved in the modification of the quinone ring of CoQ, but for others the precise function is unknown. Two genes appear to have a regulatory role: COQ8 (and its human counterparts ADCK3 and ADCK4) encodes a putative kinase, while PTC7 encodes a phosphatase required for the activation of Coq7. Mutations in human COQ genes cause primary CoQ(10) deficiency, a clinically heterogeneous mitochondrial disorder with onset from birth to the seventh decade, and with clinical manifestation ranging from fatal multisystem disorders, to isolated encephalopathy or nephropathy. The pathogenesis of CoQ(10) deficiency involves deficient ATP production and excessive ROS formation, but possibly other aspects of CoQ(10) function are implicated. CoQ(10) deficiency is unique among mitochondrial disorders since an effective treatment is available. Many patients respond to oral CoQ(10) supplementation. Nevertheless, treatment is still problematic because of the low bioavailability of the compound, and novel pharmacological approaches are currently being investigated. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.

Disruption of the human COQ5-containing protein complex is associated with diminished coenzyme Q10 levels under two different conditions of mitochondrial energy deficiency.

BACKGROUND: The Coq protein complex assembled from several Coq proteins is critical for coenzyme Q6 (CoQ6) biosynthesis in yeast. Secondary CoQ10 deficiency is associated with mitochondrial DNA (mtDNA) mutations in patients. We previously demonstrated that carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) suppressed CoQ10 levels and COQ5 protein maturation in human 143B cells. METHODS: This study explored the putative COQ protein complex in human cells through two-dimensional blue native-polyacrylamide gel electrophoresis and Western blotting to investigate its status in 143B cells after FCCP treatment and in cybrids harboring the mtDNA mutation that caused myoclonic epilepsy with ragged-red fibers (MERRF) syndrome. Ubiquinol-10 and ubiquinone-10 levels were detected by high-performance liquid chromatography. Mitochondrial energy status, mRNA levels of various PDSS and COQ genes, and protein levels of COQ5 and COQ9 in cybrids were examined. RESULTS: A high-molecular-weight protein complex containing COQ5, but not COQ9, in the mitochondria was identified and its level was suppressed by FCCP and in cybrids with MERRF mutation. That was associated with decreased mitochondrial membrane potential and mitochondrial ATP production. Total CoQ10 levels were decreased under both conditions, but the ubiquinol-10:ubiquinone-10 ratio was increased in mutant cybrids. The expression of COQ5 was increased but COQ5 protein maturation was suppressed in the mutant cybrids. CONCLUSIONS: A novel COQ5-containing protein complex was discovered in human cells. Its destabilization was associated with reduced CoQ10 levels and mitochondrial energy deficiency in human cells treated with FCCP or exhibiting MERRF mutation. GENERAL SIGNIFICANCE: The findings elucidate a possible mechanism for mitochondrial dysfunction-induced CoQ10 deficiency in human cells.

COQ6 Mutations in Children With Steroid-Resistant Focal Segmental Glomerulosclerosis and Sensorineural Hearing Loss.

The phenotypic combination of steroid-resistant focal segmental glomerulosclerosis (SR-FSGS) and sensorineural hearing loss has been mainly reported in patients with mitochondrial cytopathies, including primary coenzyme Q10 (CoQ10) deficiency. In this report of 10 children with SR-FSGS and sensorineural hearing loss, we found 6 patients with biallelic COQ6 mutations. Median age at the onset of nephrotic syndrome was 29 (range, 15-47) months. All patients progressed to end-stage renal disease within a median of 13 (range, 1-27) months after the onset. Kidney biopsy revealed abnormal mitochondrial proliferation in podocytes in all 6 patients. None of the 5 patients who underwent kidney transplantation developed recurrence of FSGS. Primary CoQ10 deficiency due to COQ6 mutations should be considered in children presenting with both SR-FSGS and sensorineural hearing loss. An early diagnosis of COQ6 mutations is essential because the condition is treatable when CoQ10 supplementation is started at the early stage. We recommend early kidney biopsy because detection of abnormal mitochondrial proliferation in podocytes might provide an earlier diagnostic clue.

Focal segmental glomerulosclerosis and medullary nephrocalcinosis in children with ADCK4 mutations.

BACKGROUND: Mutations in the AarF domain containing kinase 4 gene (ADCK4), one of the novel genes causing steroid-resistant nephrotic syndrome (SRNS), usually manifest as isolated adolescent-onset focal segmental glomerulosclerosis (FSGS). ADCK4 interacts with components of the coenzyme Q10 (CoQ10) biosynthesis pathway. METHODS: The incidence and phenotypes of patients with ADCK4 mutations were investigated in a cohort of Korean pediatric patients with SRNS. RESULTS: Among the 53 patients enrolled in the study the incidence of ADCK4-associated FSGS was 7.5% (n = 4) in children aged 5 years and older with multidrug-resistant FSGS. Two additional patients were included for phenotype analyses, one detected by family screening and the other with cyclosporine-responsive FSGS. These six patients presented proteinuria without overt nephrotic syndrome at a median age of 110 (range 60-153) months, of whom five progressed to end-stage renal disease within a median period of 46 (range 36-79) months after onset. Renal biopsies revealed mitochondrial abnormalities in podocytes and tubular cells of all patients. Notably, all patients showed accompanying medullary nephrocalcinosis. None of the patients showed other extrarenal manifestations. CONCLUSIONS: ADCK4 mutations should be considered in older children presenting with steroid resistant FSGS. An early diagnosis of ADCK4 mutations is essential because the condition is treatable with CoQ10 supplementation at an early stage. The association with medullary nephrocalcinosis may be an additional diagnostic indicator.

Preparation and characterization of human ADCK3, a putative atypical kinase.

AarF domain containing kinase 3 (ADCK3) is a mitochondrial protein known to have a role in the electron transport chain. Despite being required for the biosynthesis of coenzyme Q10, a lipid-soluble electron transporter found to be essential for aerobic cellular respiration, the precise biological function of ADCK3 remains unknown. Patients with mutations in ADCK3 experience an onset of neurological disorders from childhood, including cerebellar ataxia and exercise intolerance. After extensive screening for soluble recombinant protein expression, an N-terminal fusion of maltose-binding protein was found to facilitate the overexpression of the human ADCK3 kinase domain in Escherichia coli as a soluble and biologically active entity. For the first time our work reveals Mg(2+)-dependent ATPase activity of ADCK3, providing strong support for the theoretical prediction of this protein being a functional atypical kinase.

Two Turkish patients with Primary Coenzyme Q10 Deficiency-7: case report and literature review.

OBJECTIVES: Primary Coenzyme Q10 Deficiency-7 (OMIM 616276) results from bi-allelic pathogenic variants in the COQ4 gene. Common clinical findings include hypotonia, seizures, respiratory distress, and cardiomyopathy. In this report, we present two patients diagnosed with Primary Coenzyme Q10 Deficiency-7 along with a review of previously published cases, with the aim being to provide a better understanding of the clinical and laboratory manifestations of the disease. CASE PRESENTATION: A 3-month-and-22-day-old male was admitted to our outpatient clinic due to poor feeding and restlessness. He was born following an uneventful pregnancy to a nonconsanguineous marriage. A physical examination revealed hypotonia, a dolichocephaly, periorbital edema, and long eyelashes. Blood tests revealed metabolic acidosis and elevated serum lactate levels, while the genetic analysis revealed a variant previously reported as pathogenic, c.437T>G (p.Phe146Cys), in the COQ4 gene. Genetic tests were also conducted on both mother and father, and it revealed heterozygous variant, 0.437T>G (p.Phe146Cys), in the COQ4 gene. As a result of these findings, the patient was diagnosed with neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome (Primary Coenzyme Q10 Deficiency-7). A 1-year-old male was admitted to our clinic with complaints of hypotonia, seizures, and feeding difficulties. He was born following an uneventful pregnancy to a nonconsanguineous marriage. On his first day of life, he was admitted to the neonatal intensive care unit due to poor feeding and hypotonia. A physical examination revealed microcephaly, a high palate, poor feeding, weak crying, hypotonia, bilateral horizontal nystagmus, and inability to maintain eye contact. Laboratory findings were within normal limits, while a whole exome sequencing analysis revealed a homozygous variant previously reported as pathogenic, c.458C>T (p.A153V), in the COQ4 gene. The patient was diagnosed with Primary Coenzyme Q10 Deficiency-7. CONCLUSIONS: Primary Coenzyme Q10 Deficiency-7 should be considered in the differential diagnosis of infants presenting with neurological and dysmorphic manifestations.

Coenzyme Q10 deficiency in children: frequent type 2C muscle fibers with normal morphology.

INTRODUCTION: Neurological disorders with low tissue coenzyme Q10 (CoQ10) levels are important to identify, as they may be treatable. METHODS: We evaluated retrospectively clinical, laboratory, and muscle histochemistry and oxidative enzyme characteristics in 49 children with suspected mitochondrial disorders. We compared 18 with CoQ10 deficiency in muscle to 31 with normal CoQ10 values. RESULTS: Muscle from CoQ10-deficient patients averaged 5.5-fold more frequent type 2C muscle fibers than controls (P < 0.0001). A type 2C fiber frequency of ≥ 5% had 89% sensitivity and 84% specificity for CoQ10 deficiency in this cohort. No biopsy showed active myopathy. There were no differences between groups in frequencies of mitochondrial myopathologic, clinical, or laboratory features. Multiple abnormalities in muscle oxidative enzyme activities were more frequent in CoQ10-deficient patients than in controls. CONCLUSIONS: When a childhood mitochondrial disorder is suspected, an increased frequency of type 2C fibers in morphologically normal muscle suggests CoQ10 deficiency.

Retinopathy and optic atrophy in a case of COQ2-related primary coenzyme Q10 deficiency.

PURPOSE: To describe a case of primary coenzyme Q10 deficiency in a child manifesting as early-onset renal failure, retinal dystrophy, and optic atrophy leading to progressive vision loss. METHODS: Clinical presentation and workup including visual fields, electroretinogram, and optical coherence tomography are presented. Genetic testing was performed. RESULTS: An eight-year-old female with nephropathy requiring renal transplantation subsequently developed progressive cone-rod dystrophy and optic atrophy. The patient had negative results on a targeted next-generation sequencing retinal dystrophy panel but whole-exome sequencing revealed two variants in COQ2 (likely biallelic), consistent with a diagnosis of primary coenzyme Q10 deficiency. CONCLUSIONS: Primary coenzyme Q10 deficiency is a rare disorder with variable systemic and ocular findings; there is also genetic heterogeneity. Genetic testing aids in the diagnosis of this condition, and variants in the COQ2 and PDSS1 genes appear to have the strongest association with ocular manifestations. Oral supplementation of coenzyme Q10 may slow progression of disease. This case highlights the utility of whole-exome sequencing in the diagnosis of a rare syndromic form of ocular disease and reports a novel phenotypic association for this condition.

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.

Total and reduced/oxidized forms of coenzyme Q10 in fibroblasts of patients with mitochondrial disease.

Coenzyme Q10 (CoQ10) is involved in ATP production through electron transfer in the mitochondrial respiratory chain complex. CoQ10 receives electrons from respiratory chain complex I and II to become the reduced form, and then transfers electrons at complex III to become the oxidized form. The redox state of CoQ10 has been reported to be a marker of the mitochondrial metabolic state, but to our knowledge, no reports have focused on the individual quantification of reduced and oxidized CoQ10 or the ratio of reduced to total CoQ10 (reduced/total CoQ10) in patients with mitochondrial diseases. We measured reduced and oxidized CoQ10 in skin fibroblasts from 24 mitochondrial disease patients, including 5 primary CoQ10 deficiency patients and 10 respiratory chain complex deficiency patients, and determined the reduced/total CoQ10 ratio. In primary CoQ10 deficiency patients, total CoQ10 levels were significantly decreased, however, the reduced/total CoQ10 ratio was not changed. On the other hand, in mitochondrial disease patients other than primary CoQ10 deficiency patients, total CoQ10 levels did not decrease. However, the reduced/total CoQ10 ratio in patients with respiratory chain complex IV and V deficiency was higher in comparison to those with respiratory chain complex I deficiency. Measurement of CoQ10 in fibroblasts proved useful for the diagnosis of primary CoQ10 deficiency. In addition, the reduced/total CoQ10 ratio may reflect the metabolic status of mitochondrial disease.

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.

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.

A Family Segregating Lethal Primary Coenzyme Q10 Deficiency Due to Two Novel COQ6 Variants.

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.