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

Coenzyme Q10; Mitochondria; Steroid-resistant nephrotic syndromeCoenzima Q10; Mitocondrias; Síndrome nefrótico resistente a los esteroidesCoenzim Q10; Mitocondris; Síndrome nefròtic resistent als esteroidesPrimary 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.In addition, this project has been supported by the European Reference Network for Rare Kidney Diseases (ERKNet), the PodoNet Network for Podocyte Disorders, and the German (mitoNET) and European Networks for Mitochondrial Disorders (GENOMIT). ERKNet is co-funded by the European Union within the framework of the Third Health Programme “ERN-2016 - Framework Partnership Agreement 2017-2021.” PodoNet and mitoNET/GENOMIT have received funding from the German Ministry of Education and Research, and PodoNet from the EU 7th Framework Programme (EURenOmics; grant 2012-305608) and the German Research Foundation (Scha 477/11-1). Founder effect analyses were supported by the Polish Ministry of Science and Education (2017/25/B/NZ2/00519). We would also like to thank Drs. Kei Murayama and Masaru Shimura from Chiba Children’s Hospital, Chiba, Japan, for their contribution to the clinical assessment and follow-up of 2 families. Last but not least, we gratefully acknowledge the help of Elena Levtchenko in rolling out the survey

Multicentric Carpotarsal Osteolysis Syndrome Associated Nephropathy: Novel Variants of <i>MAFB</i> Gene and Literature Review

Multicentric carpo-tarsal osteolysis (MCTO) is a rare osteolysis syndrome mainly involving carpal and tarsal bones usually presenting in early childhood. MCTO has autosomal dominant inheritance with heterozygous mutation in the MAFB gene. The skeletal disorder is often associated with chronic kidney disease. Data on clinical characterization and best treatment option of MCTO-associated nephropathy are scarce and mostly limited to case reports. With the aim to better define the phenotype and long-term outcomes of MCTO-associated nephropathy, we launched an online survey through the Workgroup for hereditary glomerulopathies of the European Rare Kidney Disease Network (ERKNet). Overall, we collected clinical and genetic data of 54 MCTO patients, of which 42 previously described and 12 new patients. We observed a high rate of kidney involvement (70%), early age of kidney disease onset, nephrotic-range proteinuria, and a kidney survival around of 40% at long-term follow-up. Our finding confirmed the heterogeneity of clinical manifestations and widen the spectrum of phenotypes resulting from MCTO-associated nephropathy. Furthermore, we report the first case of complete remission after treatment with cyclosporine A. We demonstrated that multidisciplinary care is essential for MCTO patients and early referral to nephrologists is therefore warranted to facilitate prompt treatment