Variation of the clinical spectrum and genotype-phenotype associations in Coenzyme Q10 deficiency associated glomerulopathy

Abstract

Primary Coenzyme Q10 deficiency is a rare mitochondriopathy with a wide spectrum of organ involvement, including steroid-resistant nephrotic syndrome mainly associated with disease-causing variants in the genes COQ2, COQ6 or COQ8B. We performed a systematic literature review, PodoNet, mitoNET, and CCGKDD registries queries and an online survey, collecting comprehensive clinical and genetic data of 251 patients spanning 173 published (47 updated) and 78 new cases. Kidney disease was first diagnosed at median age 1.0, 1.2 and 9.8 years in individuals with disease-causing variants in COQ2, COQ6 and COQ8B, respectively. Isolated kidney involvement at diagnosis occurred in 34% of COQ2, 10.8% of COQ6 and 70.7% of COQ8B variant individuals. Classic infantile multiorgan involvement comprised 22% of the COQ2 variant cohort while 47% of them developed neurological symptoms at median age 2.7 years. The association of steroid-resistant nephrotic syndrome and sensorineural hearing loss was confirmed as the distinctive phenotype of COQ6 variants, with hearing impairment manifesting at average age three years. None of the patients with COQ8B variants, but 50% of patients with COQ2 and COQ6 variants progressed to kidney failure by age five. At adult age, kidney survival was equally poor (20-25%) across all disorders. A number of sequence variants, including putative local founder mutations, had divergent clinical presentations, in terms of onset age, kidney and non-kidney manifestations and kidney survival. Milder kidney phenotype was present in those with biallelic truncating variants within the COQ8B variant cohort. Thus, significant intra- and inter-familial phenotype variability was observed, suggesting both genetic and non-genetic modifiers of disease severity. Primary Coenzyme Q10 deficiency is a rare mitochondriopathy with a wide spectrum of organ involvement, including steroid-resistant nephrotic syndrome mainly associated with disease-causing variants in the genes COQ2, COQ6 or COQ8B. We performed a systematic literature review, PodoNet, mitoNET, and CCGKDD registries queries and an online survey, collecting comprehensive clinical and genetic data of 251 patients spanning 173 published (47 updated) and 78 new cases. Kidney disease was first diagnosed at median age 1.0, 1.2 and 9.8 years in individuals with disease-causing variants in COQ2, COQ6 and COQ8B, respectively. Isolated kidney involvement at diagnosis occurred in 34% of COQ2, 10.8% of COQ6 and 70.7% of COQ8B variant individuals. Classic infantile multiorgan involvement comprised 22% of the COQ2 variant cohort while 47% of them developed neurological symptoms at median age 2.7 years. The association of steroid-resistant nephrotic syndrome and sensorineural hearing loss was confirmed as the distinctive phenotype of COQ6 variants, with hearing impairment manifesting at average age three years. None of the patients with COQ8B variants, but 50% of patients with COQ2 and COQ6 variants progressed to kidney failure by age five. At adult age, kidney survival was equally poor (20-25%) across all disorders. A number of sequence variants, including putative local founder mutations, had divergent clinical presentations, in terms of onset age, kidney and non-kidney manifestations and kidney survival. Milder kidney phenotype was present in those with biallelic truncating variants within the COQ8B variant cohort. Thus, significant intra- and inter-familial phenotype variability was observed, suggesting both genetic and non-genetic modifiers of disease severity. Steroid-resistant nephrotic syndrome (SRNS) is one of the main causes of kidney failure in the first 2 decades of life.1Trautmann A. Schnaidt S. Lipska-Zietkiewicz B.S. et al.Long-term outcome of steroid-resistant nephrotic syndrome in children.J Am Soc Nephrol. 2017; 28: 3055-3065Crossref PubMed Scopus (137) Google Scholar,2Johansen K.L. Chertow G.M. Foley R.N. et al.US Renal Data System 2020 annual data report: epidemiology of kidney disease in the United States.Am J Kidney Dis. 2021; 77: A7-A8Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar More than 60 causative genes, encoding podocyte-associated proteins, have been identified, explaining the disease etiology in up to 30% of pediatric SRNS cases. Primary coenzyme Q10 (CoQ10, ubiquinone) deficiency is the underlying disease cause in 1%–2.7% of SRNS cases, and in up to 10% of those in whom a genetic cause is identified.3Trautmann A. Bodria M. Ozaltin F. et al.Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort.Clin J Am Soc Nephrol. 2015; 10: 592-600Crossref PubMed Scopus (217) Google Scholar,4Sadowski C.E. Lovric S. Ashraf S. et al.A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome.J Am Soc Nephrol. 2015; 26: 1279-1289Crossref PubMed Scopus (456) Google Scholar The term primary CoQ10 deficiency defines a group of rare mitochondrial disorders caused by recessive disease-causing variants in genes encoding proteins of the CoQ10 biosynthesis pathway. CoQ10 is a lipid component of the respiratory chain. Its deficiency leads to bioenergetic defects, H2S depletion, and oxidative stress in multiple cell types with a wide and variable spectrum of organ involvement and disease severity, ranging from single-organ disease to complex syndromic phenotypes. Defects of the podocyte lead to proteinuria and progressive loss of glomerular function. Among the 10 genes encoding proteins involved in CoQ10 biosynthesis, a kidney phenotype has mainly been associated with biallelic disease-causing variants in COQ2, COQ6, and COQ8B (previously referred to as ADCK4).5Schijvens A.M. van de Kar N.C. Bootsma-Robroeks C.M. et al.Mitochondrial disease and the kidney with a special focus on CoQ10 deficiency.Kidney Int Rep. 2020; 5: 2146-2159Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 6Tan W. Airik R. Primary coenzyme Q10 nephropathy, a potentially treatable form of steroid-resistant nephrotic syndrome.Pediatr Nephrol. 2021; 36: 3515-3527Crossref PubMed Scopus (7) Google Scholar, 7Alcazar-Fabra M. Trevisson E. Brea-Calvo G. Clinical syndromes associated with coenzyme Q10 deficiency.Essays Biochem. 2018; 62: 377-398Crossref PubMed Scopus (78) Google Scholar The CoQ10 deficiency–associated glomerulopathies are of particular interest as they are potentially amenable to therapeutic intervention with oral CoQ10 supplementation, through targeting of the underlying molecular defect. Up to now, the rarity of the primary CoQ10 deficiency disorders has limited the assessment of their spectrum of clinical presentation, their genotype–phenotype correlation, and their natural history. To advance the state of knowledge, we systematically reviewed 251 (173 published and 78 previously unreported) cases of CoQ10 deficiency–associated glomerulopathy. A comprehensive search strategy was applied to compile the study cohort from different sources (for details, see Figure 1). A systematic search of the PubMed database yielded 44 published articles with 174 patients. Three patient registries were queried: the international PodoNet registry8International PodoNet registrywww.podonet.orgDate accessed: March 31, 2021Google Scholar for children with primary steroid-resistant nephrotic syndrome,3Trautmann A. Bodria M. Ozaltin F. et al.Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort.Clin J Am Soc Nephrol. 2015; 10: 592-600Crossref PubMed Scopus (217) Google Scholar the Chinese Children Genetic Kidney Disease Database9Chinese Children Genetic Kidney Disease Database.www.ccgkdd.com.cnDate accessed: March 31, 2021Google Scholar (CCGKDD); and the German Network for Mitochondrial Disorders (mitoNET10mitoNETGerman Network for Mitochondrial Disorders.www.mitonet.orgDate accessed: March 31, 2021Google Scholar).11Rao J. Liu X. Mao J. et al.Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system.Clin Genet. 2019; 96: 402-410Crossref PubMed Scopus (47) Google Scholar A total of 20, 17, and 7 new cases, respectively, were identified in these registries, and updated information was provided on 20,13, and 2 previously published cases. Finally, invitations to an online survey were sent to all members of the European Rare Kidney Disease Network (ERKNet), the PodoNet Consortium, the ESCAPE Clinical Research Network, and the European and Asian Societies for Pediatric Nephrology (ESPN and AsPN). Through this effort, 34 novel and 32 previously published patients, in 24 countries, were identified and documented. All patient-related data were collected in a completely deidentified manner. Names, initials, birth dates, and hospital-specific patient identifiers were not retrieved. Center identifiers were deleted from the database after checking for duplicate entries was completed, and only the country or residence was retained for demographic studies. Also, times and ages (e.g., age at diagnosis, time since diagnosis) were reported instead of calendar dates. As a result of these measures, all analyses were performed on completely anonymized datasets. All molecular diagnoses were re-evaluated by an expert geneticist, following the best practice recommendations of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) for the interpretation of sequence variants.12Richards S. Aziz N. Bale S. et al.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015; 17: 405-424Abstract Full Text Full Text PDF PubMed Scopus (17807) Google Scholar Variants classified as (likely) pathogenetic, per ACMG criteria, were considered causative and were included in the study. Two COQ2 variants with conflicting interpretations of pathogenicity according to the ClinVar database—namely NM_015697.8:c.288dupC [rs759310292] and c.683A>G [rs121918232]—were considered disease-causing due to their increased prevalence among affected individuals, compared to that among the general population, their presence in trans with another (likely) pathogenic variant in patients with highly specific phenotype, and the absence of homozygous cases in control databases. A previously published case with a homozygous COQ6 NM_182476.3:c.41G>A [rs17094161] variant was excluded from the analysis, as the variant was reclassified as benign because it is relatively frequent, is also in a homozygous state, in general populations, has been reported as benign in the CliniVar database, and is located upstream of the standard start codon of the canonical isoform of the gene. Descriptive data are presented as median and interquartile range. Patient and kidney survival rates were calculated using Kaplan–Meier lifetable analysis, with log–rank testing for analysis of significant differences. Fisher’s exact test was performed for genotype-based pairwise comparisons, with 2 × 2 and 2 × 3 contingency tables of dichotomized data. Intra- and interfamilial phenotype variability was assessed by the coefficient of variation (CV = SD/mean) of the age at kidney-disease onset. A value of P < 0.05 was considered statistically significant. Statistical analyses were performed using Prism, version 8, data analysis software system (GraphPad Software). Clinical data were available for 63, 48, and 140 patients with disease-causing variants in COQ2, COQ6, and COQ8B, respectively. A summary of the phenotype characteristics and clinical outcomes per genetic diagnosis is given in Table 1. Patient-level genotype and phenotype characteristics are provided in Supplementary Table S1.Table 1Patient characteristics and clinical outcomesPatient characteristicCOQ2COQ6COQ8BTotal number of patients (females)63 (30)48 (16)140 (65)First disease manifestationAge at first symptoms, yr1 (0.3–2)1.2 (0.6–3.4)9.8 disease at first kidney disease yr1 not outcome at age at at age at age 10 age at time from first to of at age of at age Kidney age at kidney kidney kidney are of affected number of or median as in a new kidney kidney are of affected number of or median as Patient survival was with COQ2 deficiency with of patients at of age, and at 10 years of survival from birth was for COQ6, and for COQ8B disease < Figure The cause of in COQ2 disease patients was involvement to multiorgan failure = or progressive = patients with COQ6 and COQ8B, disease was the cause of The age at disease onset on the 50% of the COQ2 and COQ6 cohort first symptoms of kidney disease within the first of and were at 3 and years of age, respectively, 50% of COQ8B disease patients age years A total of of all patients presented kidney disease years of The ages at kidney disease diagnosis were and years in patients with and respectively. Isolated kidney involvement at diagnosis was in 34% of the COQ2 10.8% of the COQ6 and 70.7% of the COQ8B cohort. Kidney involvement was in of of patients of children with COQ2 kidney manifestations were 3 were within the first of of with confirmed COQ6 a diagnosed by at 10 years of age, presented with hearing impairment but had renal symptoms at at age years. the term kidney disease we identified patients with a glomerular per kidney disease as by Kidney proteinuria was reported in of the COQ2 disease patients, of the COQ6 disease patients, and of the COQ8B disease patients. the COQ2 group presented with and but kidney of children with COQ6 disease presented with and up to presented with at the time of Children with COQ8B disease presented with the with one in at the time of proteinuria was present in and of children with COQ6 and COQ8B respectively, including a of cases of with COQ6 disease and of with COQ8B was reported at diagnosis in only and respectively, of COQ2 and COQ6 disease patients, but in of the COQ8B cohort. Kidney was performed in patients for of the Among those patients with in whom a specific was variant and were in of in were reported of all in 30% of the COQ2 of the COQ6 and 10% of the COQ8B cohort patients. 3 cases, mitochondrial identified by of kidney to the diagnosis of a mitochondriopathy to genetic of individuals progressed to 1). the COQ2 and COQ6 to than the COQ8B cohort in the first of COQ8B disease patients were to in the for all 3 a significant of years of patients were on at in the COQ2 in the COQ6 and in the COQ8B and had a kidney Disease in the was disease manifestations were and in the COQ2 and in COQ8B disease Figure manifestations occurred in 47% of the COQ2 cohort patients of patients with these included and of or symptoms within the first 3 years of in of patients 2 with and at and at years. a wide spectrum of including or involvement, of and of COQ2 disease cases were by infantile multiorgan of disorders to progressive clinical and at a median age of to these patients were reported as not symptoms at the time of symptoms developed in of patients with kidney in patients within 3 and in a 3 patients after up to years of The association of SRNS and sensorineural hearing loss was confirmed as the phenotype of COQ6 impairment was present in of of the COQ6 but in only one with COQ2, and in of those with COQ8B Among COQ6 disease patients, cases had congenital and sensorineural hearing with a median age at diagnosis of years Figure patients hearing loss the onset of renal a of the COQ6 cohort was reported in one symptoms occurred within the first 2 years of with COQ8B disease a the were including and A total of as different variants in COQ2, variants one the sequence in COQ6, and variants in COQ8B were identified Supplementary Table COQ2, the variants were the sequence of the gene. all COQ6 variants to 2 involved in the of and Figure COQ8B, 3 were and and Figure according to et A. et al.Mitochondrial an to coenzyme 2015; Full Text Full Text PDF PubMed Scopus Google Scholar The 2 are also in the A. et and molecular of a multicenter study of 2020; PubMed Scopus Google Scholar the variants located in the are specific for COQ8B. Supplementary and Supplementary for COQ8B The of the variants to founder in Intra- and interfamilial phenotype variability was assessed for variants identified in at 2 homozygous individuals from at 2 different was the case in 60 patients from COQ8B and COQ6 7 different A of the clinical by and is provided in Supplementary Figure at disease onset was variable among members of the causative variant and among members across a different causative variant Disease onset was variable different the variant and with different causative variants Figure genotype–phenotype were for variants reported in at homozygous individuals or in at were homozygous for the COQ2 variant c.683A>G had a of disease onset in the first 2 years of P = The homozygous variant present in was associated with a disease by of disease onset in the first of = of < symptoms, and multiorgan was in the of the COQ2 cohort < of the children genetic testing due to a phenotype of while SRNS was the in the COQ2 disease patients. The the variant in and populations, disease with a of symptoms within the first of = for present in and associated with a of involvement, and < The in the presented with phenotype, disease onset = and the age of 2 P = as as of = with the variant in a of kidney disease within the first years of P = homozygous for variant in patients of and disease onset P = and P = with of at diagnosis = The variant also in patients of associated with disease = and at a median age of years with another variant in patients of had a prevalence of symptoms P = individuals were reported with COQ2 and COQ6 disease at one for individuals with biallelic truncating variants located to that are to associated with M. et COQ2 genotype the of coenzyme Q10 Genet. PubMed Scopus Google Scholar the one (47 of of COQ8B disease patients had biallelic truncating variants Table biallelic truncating in COQ8B disease onset age 10 = P = and kidney failure age = P < at one with a disease-causing variant in the or were compared with the of the COQ8B population, patients with biallelic truncating was in of patients with a variant in the or the of as compared to in the = analysis was performed for patients a variant in the on at one with a variant at an the was not confirmed in the group of patients biallelic variants within the We present the international cohort collected of primary patients biallelic disease-causing variants in COQ2, COQ6, and COQ8B, the 3 causative genes associated with kidney involvement and the of the exact prevalence of CoQ10 is the of this published registry that these disorders for of of and up to of confirmed genetic SRNS C.E. Lovric S. Ashraf S. et al.A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome.J Am Soc Nephrol. 2015; 26: 1279-1289Crossref PubMed Scopus (456) Google A. Lipska-Zietkiewicz B.S. F. the clinical and genetic spectrum of nephrotic the PodoNet 2018; PubMed Scopus Google Scholar We significant with a of pathogenic variants in Asian that these are in registries, prevalence the multicenter Chinese study reported COQ8B as the cause of SRNS in their for of J. Liu X. Mao J. et al.Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system.Clin Genet. 2019; 96: 402-410Crossref PubMed Scopus (47) Google Scholar is in with the of founder in of the to the of and the and of causative variants in these study an variability in the spectrum and of associated with in of the 3 genetic associated with primary CoQ10 was for the COQ2 a associated with and We that than of patients with biallelic COQ2 variants disease at an age than 2 with a of patients SRNS or manifestations at the time of disease of the children in the first of from multiorgan patients after age and survival was we confirmed the disease phenotype as the clinical of patients with COQ6 the of both kidney and hearing impairment hearing loss from hearing impairment to congenital loss or the renal symptoms, of nephrotic but in one of cases were limited to in COQ6 disease patients with proteinuria and hearing suggesting that COQ6 disease present as a of Also, with to COQ8B a variability of disease onset and than in E. Lipska-Zietkiewicz B.S. et causes Am Soc Nephrol. PubMed Scopus Google M. E. et of patients with and the of CoQ10 Nephrol. 2017; PubMed Scopus Google Scholar Renal symptoms from reported age at 32 and a wide of proteinuria and glomerular with a of patients with and one with at the time of Kidney disease progressed with all 3 disorders. with their onset of renal symptoms, of the patients with COQ8B disease had progressed to by age as compared to 50% of the children with COQ2 and COQ6 at of adult age, kidney survival was equally poor with all underlying genetic disorders. in patients, was in the of The of clinical in particular oral CoQ10 supplementation, on proteinuria and kidney survival is the of this and in a S. B.S. Ozaltin F. et CoQ10 leads to of kidney in steroid-resistant nephrotic syndrome due to primary CoQ10 deficiency.Kidney Full Text Full Text PDF PubMed Scopus Google Scholar the present we on the of genetic of the variability of primary CoQ10 We identified a number of sequence variants with divergent clinical of these are founder that lead to variation of not only the but also the clinical of the we identified significant intra- and inter-familial phenotype variability among patients the underlying causative suggesting of variants on disease and analysis at the molecular yielded that a in CoQ10 biosynthesis is considered all patients to have of the M. et COQ2 genotype the of coenzyme Q10 Genet. PubMed Scopus Google Scholar case of COQ2 and COQ6, encoding of the all patients had at one one of the COQ8B patients biallelic truncating that proteins for this The of COQ8B and is the of is the for a as the 2 proteins have sequence The of is to for complex A. et al.Mitochondrial an to coenzyme 2015; Full Text Full Text PDF PubMed Scopus Google F. et and coenzyme deficiency through loss of Full Text Full Text PDF PubMed Scopus (78) Google on the to a or of the from the et lipid and of of the 2018; Full Text Full Text PDF PubMed Scopus Google Scholar the of is by of and We a kidney phenotype, with disease onset and to in patients with biallelic COQ8B in patients with due to variants, involvement also was in of compared to those with A. et and molecular of a multicenter study of 2020; PubMed Scopus Google Scholar both CoQ10 biosynthesis in with biallelic has been A. et al.Mitochondrial an to coenzyme 2015; Full Text Full Text PDF PubMed Scopus Google A. et and molecular of a multicenter study of 2020; PubMed Scopus Google Scholar that the 2 proteins in a or and proteins from a variant with the CoQ10 biosynthesis pathway. is by the in both disease-causing variants to the The of COQ8B with the previously A. et al.Mitochondrial an to coenzyme 2015; Full Text Full Text PDF PubMed Scopus Google F. et and coenzyme deficiency through loss of Full Text Full Text PDF PubMed Scopus (78) Google Scholar that both a to that of with completely the Variants located in the at the 2 the and are involved in both and We identified a to a for disease-causing variants in exact it that due it is involved in or within the CoQ10 biosynthesis The variant in this in increased for comprehensive analysis of 251 cases of primary CoQ10 deficiency caused by disease-causing variants in COQ2, COQ6, or COQ8B in age, renal and and natural of this mitochondrial The variability was in by but analysis of genetic and the clinical the disorders diagnosed or of the patients with the COQ2 disease of the of oral CoQ10 as a G. coenzyme Q10 in primary coenzyme Q10 J Med. PubMed Scopus Google Scholar, M. E. et al.Long-term of patients with have been diagnosed in the of of CoQ10 J 2019; PubMed Scopus Google Scholar, M. Lipska-Zietkiewicz M. of proteinuria in a with COQ6 case Nephrol. 2018; PubMed Scopus Google Scholar we that all patients with glomerular proteinuria and of for primary CoQ10 was by a by the Renal this has been by the European Network for Rare Kidney (ERKNet), the PodoNet Network for and the German and European for Mitochondrial Disorders is by the European within the of the PodoNet and have from the German of and and PodoNet from the and the German Research analyses were by the of and We also to and from for their to the clinical assessment and of 2 but not we the of in the S. N. of of of of of of All the with Supplementary with Supplementary A new for steroid-resistant nephrotic syndrome in with nephrotic those with steroid-resistant nephrotic syndrome (SRNS) have an clinical them at or after diagnosis potentially and those with a specific as is the case for CoQ10 cases. specific causes and that lead to SRNS lead to potentially highly PDF

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