Focal segmental glomerulosclerosis and medullary nephrocalcinosis in children with ADCK4 mutations
- 681 Downloads
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.
The incidence and phenotypes of patients with ADCK4 mutations were investigated in a cohort of Korean pediatric patients with SRNS.
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.
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.
KeywordsADCK4 mutation Coenzyme Q10 deficiency Focal segmental glomerulosclerosis Medullary nephrocalcinosis Steroid-resistant nephrotic syndrome
This study was supported by a grant (HI12C0014) from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea.
Compliance with ethical standards
This study was approved by the Institutional Review Board of the Seoul National University Hospital. Before the study, informed consent was obtained from all patients or their parents.
- 1.Bierzynska A, Soderquest K, Koziell A (2015) Genes and podocytes—new insights into mechanisms of podocytopathy. Front Endocrinol (Lausanne) 5:226Google Scholar
- 2.Lovric S, Fang H, Vega-Warner V, Sadowski CE, Gee HY, Halbritter J, Ashraf S, Saisawat P, Soliman NA, Kari JA, Otto EA, Hildebrandt F, Nephrotic Syndrome Study Group (2014) Rapid detection of monogenic causes of childhood-onset steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 9:1109–1116CrossRefPubMedPubMedCentralGoogle Scholar
- 3.Sadowski CE, Lovric S, Ashraf S, Pabst WL, Gee HY, Kohl S, Engelmann S, Vega-Warner V, Fang H, Halbritter J, Somers MJ, Tan W, Shril S, Fessi I, Lifton RP, Bockenhauer D, El-Desoky S, Kari JA, Zenker M, Kemper MJ, Mueller D, Fathy HM, Soliman NA, SRNS Study Group, Hildebrandt F (2015) A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J Am Soc Nephrol 26:1279–1289CrossRefPubMedGoogle Scholar
- 11.Diomedi-Camassei F, Di Giandomenico S, Santorelli FM, Caridi G, Piemonte F, Montini G, Ghiggeri GM, Murer L, Barisoni L, Pastore A, Muda AO, Valente ML, Bertini E, Emma F (2007) COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement. J Am Soc Nephrol 18:2773–2780CrossRefPubMedGoogle Scholar
- 12.Heeringa SF, Chernin G, Chaki M, Zhou W, Sloan AJ, Ji Z, Xie LX, Salviati L, Hurd TW, Vega-Warner V, Killen PD, Raphael Y, Ashraf S, Ovunc B, Schoeb DS, McLaughlin HM, Airik R, Vlangos CN, Gbadegesin R, Hinkes B, Saisawat P, Trevisson E, Doimo M, Casarin A, Pertegato V, Giorgi G, Prokisch H, Rötig A, Nürnberg G, Becker C, Wang S, Ozaltin F, Topaloglu R, Bakkaloglu A, Bakkaloglu SA, Müller D, Beissert A, Mir S, Berdeli A, Özen S, Zenker M, Matejas V, Santos-Ocaña C, Navas P, Kusakabe T, Kispert A, Akman S, Soliman NA, Krick S, Mundel P, Reiser J, Nürnberg P, Clarke CF, Wiggins RC, Faul C, Hildebrandt F (2011) COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest 121:2013–2024CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Ashraf S, Gee HY, Woerner S, Xie LX, Vega-Warner V, Lovric S, Fang H, Song X, Cattran DC, Avila-Casado C, Paterson AD, Nitschké P, Bole-Feysot C, Cochat P, Esteve-Rudd J, Haberberger B, Allen SJ, Zhou W, Airik R, Otto EA, Barua M, Al-Hamed MH, Kari JA, Evans J, Bierzynska A, Saleem MA, Böckenhauer D, Kleta R, El Desoky S, Hacihamdioglu DO, Gok F, Washburn J, Wiggins RC, Choi M, Lifton RP, Levy S, Han Z, Salviati L, Prokisch H, Williams DS, Pollak M, Clarke CF, Pei Y, Antignac C, Hildebrandt F (2013) ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest 123:5179–5189CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Korkmaz E, Lipska-Ziętkiewicz BS, Boyer O, Gribouval O, Fourrage C, Tabatabaei M, Schnaidt S, Gucer S, Kaymaz F, Arici M, Dinckan A, Mir S, Bayazit AK, Emre S, Balat A, Rees L, Shroff R, Bergmann C, Mourani C, Antignac C, Ozaltin F, Schaefer F, PodoNet Consortium (2016) ADCK4-associated glomerulopathy causes adolescence-onset FSGS. J Am Soc Nephrol 27:63–68CrossRefPubMedGoogle Scholar
- 15.Boyce AM, Shawker TH, Hill SC, Choyke PL, Hill MC, James R, Yovetich NA, Collins MT, Gafni RI (2013) Ultrasound is superior to computed tomography for assessment of medullary nephrocalcinosis in hypoparathyroidism. J Clin Endocrinol Metab 98(3):989–994Google Scholar
- 21.Ozturk H, Ozturk H, Yagmur Y, Buyukbayram H (2006) The effect of L-arginine methyl ester on indices of free radical involvement in a rat model of experimental nephrocalcinosis. Urol Res 34:305–314Google Scholar