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

Wang, Na; Zheng, Yun; Zhang, Lingzi; Tian, Xiong; Fang, Yicheng; Qi, Ming; Du, Juping; Chen, Shuaishuai; Chen, Shiyong; Li, Jun; Shen, Bo; Wang, Lizhen

doi:10.3389/fgene.2021.811833

Cited by 9 publications

(4 citation statements)

References 29 publications

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“…The brother of this patient, also suffering COQ6 deficiency, received a computed tomography (CT) of the brain at the age of 5 months, which showed a similar pathology with signs of frontotemporal brain atrophy [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders

et al. 2023

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Coenzyme Q10 (CoQ10) is an endogenously synthesized lipid molecule. It is best known for its role as a cofactor within the mitochondrial respiratory chain where it functions in electron transfer and ATP synthesis. However, there are many other cellular pathways that also depend on the CoQ10 supply (redox homeostasis, ferroptosis and sulfide oxidation). The CoQ10 biosynthesis pathway consists of several enzymes, which are encoded by the nuclear DNA. The majority of these enzymes are responsible for modifications of the CoQ-head group (benzoquinone ring). Only three enzymes (PDSS1, PDSS2 and COQ2) are required for assembly and attachment of the polyisoprenoid side chain. The head-modifying enzymes may assemble into resolvable domains, representing COQ complexes. During the last two decades, numerous inborn errors in CoQ10 biosynthesis enzymes have been identified. Thus far, 11 disease genes are known (PDSS1, PDSS2, COQ2, COQ4, COQ5, COQ6, COQ7, COQ8A, COQ8B, COQ9 and HPDL). Disease onset is highly variable and ranges from the neonatal period to late adulthood. CoQ10 deficiency exerts detrimental effects on the nervous system. Potential consequences are neuronal death, neuroinflammation and cerebral gliosis. Clinical features include encephalopathy, regression, movement disorders, epilepsy and intellectual disability. Brain magnetic resonance imaging (MRI) is the most important tool for diagnostic evaluation of neurological damage in individuals with CoQ10 deficiency. However, due to the rarity of the different gene defects, information on disease manifestations within the central nervous system is scarce. This review aims to provide an overview of brain MRI patterns observed in primary CoQ10 biosynthesis disorders and to highlight disease-specific findings.

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Section: Resultsmentioning

confidence: 99%

Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders

et al. 2023

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“…Using ES in NPHS2 negative cases, we identified multiple biallelic disease-causing NPHS1 variants, two heterozygous disease-causing WT1 variants as well as biallelic disease-causing variants in COQ6, ARHGDIA, NUP205 , and SGPL . Disease-causing variants in COQ6 represent a very rare cause of SRNS with until completion of this study less than 20 disease-causing alleles reported to date in the literature ( 30 , 31 ) ( Figure 2 ). Very recently, Drovandi et al reported additional COQ6 cases as part of a large cohort of 116 individuals with primary coenzyme Q10 deficiency in which CoQ10 replacement had beneficial effects regarding disease progression ( 32 , 33 ).…”

Section: Discussionmentioning

confidence: 97%

High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases

Najafi

Riedhammer²,

Rad³

et al. 2022

Front. Pediatr.

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BackgroundSteroid resistant nephrotic syndrome (SRNS) represents a significant renal disease burden in childhood and adolescence. In contrast to steroid sensitive nephrotic syndrome (SSNS), renal outcomes are significantly poorer in SRNS. Over the past decade, extensive genetic heterogeneity has become evident while disease-causing variants are still only identified in 30% of cases in previously reported studies with proportion and type of variants identified differing depending on the age of onset and ethnical background of probands. A genetic diagnosis however can have implications regarding clinical management, including kidney transplantation, extrarenal disease manifestations, and, in some cases, even causal therapy. Genetic diagnostics therefore play an important role for the clinical care of SRNS affected individuals.Methodology and resultsHere, we performed NPHS2 Sanger sequencing and subsequent exome sequencing in 30 consanguineous Iranian families with a child affected by SRNS with a mean age of onset of 16 months. We identified disease-causing variants and one variant of uncertain significance in 22 families (73%), including variants in NPHS1 (30%), followed by NPHS2 (20%), WT1 (7%) as well as in NUP205, COQ6, ARHGDIA, SGPL1, and NPHP1 in single cases. Eight of these variants have not previously been reported as disease-causing, including four NPHS1 variants and one variant in NPHS2, ARHGDIA, SGPL1, and NPHP1 each.ConclusionIn line with previous studies in non-Iranian subjects, we most frequently identified disease-causing variants in NPHS1 and NPHS2. While Sanger sequencing of NPHS2 can be considered as first diagnostic step in non-congenital cases, the genetic heterogeneity underlying SRNS renders next-generation sequencing based diagnostics as the most efficient genetic screening method. In accordance with the mainly autosomal recessive inheritance pattern, diagnostic yield can be significantly higher in consanguineous than in outbred populations.

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“…In this case, supplementation with the CoQ10 analogue idebenone, which has been used for the treatment of other types of optic neuropathy, improved visual impairment without affecting deafness. Wang et al [ 69 ] identified two Chinese siblings with COQ10D6 who presented with severe metabolic acidosis, proteinuria, hypoalbuminemia, growth retardation, and muscle hypotonia and died in early infancy (mutations: [c.249C>G] [p.Tyr83Ter] in Exon 2 and [c.1381C>T] [p.Gln461Ter] in Exon 12 of COQ6 ). A 19-month-old patient with cardiomyopathy was found to have the COQ6 variant [c763G>A] [p.Gly255Arg]; the patient died from cardiorespiratory failure before CoQ10 supplementation could be started [ 70 ].…”

Section: Clinical Studies Relating To Coq Gene Mutationsmentioning

confidence: 99%

“…In this case, supplementation with the CoQ10 analogue idebenone, which has been used for the treatment of other types of optic neuropathy, improved visual impairment without affecting deafness. Wang et al [69] identified two Chinese siblings with COQ10D6 who presented with severe metabolic acidosis, proteinuria, hypoalbuminemia, growth retardation, and muscle hypotonia and died in early infancy (mutations: The total number of patients identified with a COQ6-related primary CoQ10 deficiency is currently 45, with 14 of these responding to CoQ10 supplementation (where attempted).…”

Section: Coq6mentioning

confidence: 99%

Primary Coenzyme Q10 Deficiency: An Update

Mantle,

Millichap,

Castro-Marrero

et al. 2023

Antioxidants

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Coenzyme Q10 (CoQ10) has a number of vital functions in all cells, both mitochondrial and extra-mitochondrial. In addition to its key role in mitochondrial oxidative phosphorylation, CoQ10 serves as a lipid soluble antioxidant and plays an important role in fatty acid beta-oxidation and pyrimidine and lysosomal metabolism, as well as directly mediating the expression of a number of genes, including those involved in inflammation. Due to the multiplicity of roles in cell function, it is not surprising that a deficiency in CoQ10 has been implicated in the pathogenesis of a wide range of disorders. CoQ10 deficiency is broadly divided into primary and secondary types. Primary CoQ10 deficiency results from mutations in genes involved in the CoQ10 biosynthetic pathway. In man, at least 10 genes are required for the biosynthesis of functional CoQ10, a mutation in any one of which can result in a deficit in CoQ10 status. Patients may respond well to oral CoQ10 supplementation, although the condition must be recognised sufficiently early, before irreversible tissue damage has occurred. In this article, we have reviewed clinical studies (up to March 2023) relating to the identification of these deficiencies, and the therapeutic outcomes of CoQ10 supplementation; we have attempted to resolve the disparities between previous review articles regarding the usefulness or otherwise of CoQ10 supplementation in these disorders. In addition, we have highlighted several of the potential problems relating to CoQ10 supplementation in primary CoQ10 deficiency, as well as identifying unresolved issues relating to these disorders that require further research.

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

Cited by 9 publications

References 29 publications

Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders

Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders

High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases

Primary Coenzyme Q10 Deficiency: An Update

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