The Spectrum of clinical manifestations in newborns with the COQ4 mutation: case series and literature review.

Background: Coenzyme Q10 (CoQ10) plays an important role in the electron transport chain within the human mitochondrial respiratory chain. The manifestations of this deficiency exhibit a diverse range. This study investigates the clinical manifestations of primary coenzyme Q10 deficiency in neonates with the COQ4 mutation to improve the diagnosis of the disease and the prognosis through targeted treatment. Methods: We report 4 patients with primary coenzyme Q10 deficiency by COQ4 variants in neonates. A comprehensive literature search and review for original articles and case reports with COQ4 mutation published from January 1989 to November 2023 was performed through Pubmed. We review clinical manifestations, diagnostic approaches, and treatment monitoring in these and 20 previously reported patients. Results: Within the cohort of four cases examined, three females and one male were identified from two distinct families. Specifically, case 1 and 2 consisted of monoamniotic twins. Cases 3 and 4 were siblings. A comprehensive review of 20 cases involving neonatal-onset COQ4 mutation was conducted. Half of the cases are Chinese. There was no statistically significant difference in the mortality between Chinese (9/12, 75%) and other regions (11/12, 91.7%) (P = 0.27). The survival time for the 24 cases was 60.0 ± 98.0 days (95% confidence interval CI: 0-252.0 days). The incidence of prenatal abnormalities in preterm infants was significantly higher than that in full-term infants (66.7% vs. 16.7%, P = 0.02). Hyperlactatemia was one of the most common manifestations, accounting for 75% of cases (18/24). Twenty of the 24 cases were diagnosed by whole exome sequencing. Only 9 patients received exogenous coenzyme Q10 treatment, and all the 4 surviving patients received coenzyme Q10 supplementation. Conclusion: The prognosis of COQ4 mutation in the neonatal period indicates a low survival rate and an poor prognosis. This may be due to the incomplete understanding of the mechanism of how COQ4 gene defects lead to coenzyme Q10 deficiency and why CoQ10 supplementation does not respond well to treatment. To improve the diagnostic rate, in addition to genetic testing, mitochondrial functional verification should be prioritized in southern China, where the incidence is relatively high. It will facilitate more in-depth mechanistic studies.

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.

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.

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.

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.

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.

Primary Coenzyme Q10 Deficiency-7 and Pathogenic COQ4 Variants: Clinical Presentation, Biochemical Analyses, and Treatment.

Primary Coenzyme Q10 Deficiency-7 (COQ10D7) is a rare mitochondrial disorder caused by pathogenic COQ4 variants. In this review, we discuss the correlation of COQ4 genotypes, particularly the East Asian-specific c.370G > A variant, with the clinical presentations and therapeutic effectiveness of coenzyme Q10 supplementation from an exon-dependent perspective. Pathogenic COQ4 variants in exons 1-4 are associated with less life-threating presentations, late onset, responsiveness to CoQ10 therapy, and a relatively long lifespan. In contrast, pathogenic COQ4 variants in exons 5-7 are associated with early onset, unresponsiveness to CoQ10 therapy, and early death and are more fatal. Patients with the East Asian-specific c.370G > A variant displays intermediate disease severity with multi-systemic dysfunction, which is between that of the patients with variants in exons 1-4 and 5-7. The mechanism underlying this exon-dependent genotype-phenotype correlation may be associated with the structure and function of COQ4. Sex is shown unlikely to be associated with disease severity. While point-of-care high-throughput sequencing would be useful for the rapid diagnosis of pathogenic COQ4 variants, whereas biochemical analyses of the characteristic impairments in CoQ10 biosynthesis and mitochondrial respiratory chain activity, as well as the phenotypic rescue of the CoQ10 treatment, are necessary to confirm the pathogenicity of suspicious variants. In addition to CoQ10 derivatives, targeted drugs and gene therapy could be useful treatments for COQ10D7 depending on the in-depth functional investigations and the development of gene editing technologies. This review provides a fundamental reference for the sub-classification of COQ10D7 and aim to advance our knowledge of the pathogenesis, clinical diagnosis, and prognosis of this disease and possible interventions.

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.

A rare case of primary coenzyme Q10 deficiency due to COQ9 mutation.

Background Coenzyme Q10 (CoQ10) serves as a shuttle for electrons from complexes I and II to complex III in the respiratory chain, and has important functions within the mitochondria. Primary CoQ10 deficiency is a mitochondrial disorder which has devastating effects, and which may be partially treated with exogenous CoQ10 supplementation. Case presentation A 9-month-old girl patient was referred to our clinic due to growth retardation, microcephaly and seizures. She was the third child of consanguineous parents (first-degree cousins) of Pakistani origin, born at 38 weeks gestation, weighing 2000 g after an uncomplicated pregnancy, and was hospitalized for 3 days due to respiratory distress. She had sustained clonic seizures when she was 4 months old. Physical examination showed microcephaly, truncal hypotonia and dysmorphic features. Metabolic tests were inconclusive. Abdominal ultrasonography revealed cystic appearance of the kidneys. Non-compaction of the left ventricle was detected in echocardiography. Cranial magnetic resonance imaging (MRI) showed hypoplasia of the cerebellar vermis and brain stem, corpus callosum agenesis, and cortical atrophy. A panel testing of 450 genes involved in inborn errors of metabolism (IEM) was performed that showed a novel frameshift c.384delG (Gly129Valfs*17) homozygous mutation in COQ9. A treatment of 5 mg/kg/day exogenous CoQ10 was started when she was 10 months old, and the dosage was increased to 50 mg/kg/day after the exact diagnosis. No objective neurological improvement could be observed after the adjustment of the drug dosage. Conclusions We report a case of CoQ10 deficiency due to a novel COQ9 gene mutation that adds clinical data from a newly diagnosed patient. Our case also outlines the importance of genetic panels used for specific diseases including IEM.

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.