Focal segmental glomerulosclerosis (FSGS) is caused by various etiologies, with mitochondrial dysfunction being one of the causes. FSGS is known to be associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which is a subclass of mitochondrial disease. However, it has rarely been reported in other mitochondrial disease subclasses. Here, we reported a 20-year-old man diagnosed with FSGS associated with chronic progressive external ophthalmoplegia (CPEO) due to mitochondrial DNA (mtDNA) 3243A>G mutation. He presented with left ptosis, short stature, mild sensorineural deafness, and cardiac conduction block. A renal biopsy sample showed segmental sclerosis and adhesions between capillaries and Bowman’s capsule, indicating FSGS. Electron microscopy demonstrated abnormal aggregated mitochondria in podocytes, and the basement membrane and epithelial cells of Bowman’s capsule. Skeletal muscle biopsy also showed accumulation of abnormal mitochondria. mtDNA analysis identified heteroplasmic mtDNA 3243A>G mutation with no large-scale deletions. From these findings, we diagnosed the case as CPEO with multi-organ involvement including FSGS. Our report demonstrates that CPEO, as well as MELAS, can be associated with FSGS. Because mitochondrial disease presents with a variety of clinical symptoms, atypical cases with non-classical manifestations are observed. Thus, mitochondrial disease should be considered as an underlying cause of FSGS with systemic manifestations even with atypical phenotypes.

1.
Doleris LM, Hill GS, Chedin P, Nochy D, Bellanne-Chantelot C, Hanslik T, Bedrossian J, Caillat-Zucman S, Cahen-Varsaux J, Bariety J: Focal segmental glomerulosclerosis associated with mitochondrial cytopathy. Kidney Int 2000; 58: 1851–1858.
2.
Mihai CM, Catrinoiu D, Toringhibel M, Stoicescu RM, Hancu A: De Toni-Debre-Fanconi syndrome in a patient with Kearns-Sayre syndrome: a case report. J Med Case Rep 2009; 3: 101.
3.
Lopez-Gallardo E, Lopez-Perez MJ, Montoya J, Ruiz-Pesini E: CPEO and KSS differ in the percentage and location of the mtDNA deletion. Mitochondrion 2009; 9: 314–317.
4.
Binder V, Steenpass L, Laws HJ, Ruebo J, Borkhardt A: A novel mtDNA large-scale mutation clinically exclusively presenting with refractory anemia: is there a chance to predict disease progression? J Pediatr Hematol Oncol 2012; 34: 283–292.
5.
Ban S, Mori N, Saito K, Mizukami K, Suzuki T, Shiraishi H: An autopsy case of mitochondrial encephalomyopathy (MELAS) with special reference to extra-neuromuscular abnormalities. Acta Pathol Jpn 1992; 42: 818–825.
6.
Luft R, Ikkos D, Palmieri G, Ernster L, Afzelius B: A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: a correlated clinical, biochemical, and morphological study. J Clin Invest 1962; 41: 1776–1804.
7.
Nishigaki Y, Ueno H, Coku J, Koga Y, Fujii T, Sahashi K, Nakano K, Yoneda M, Nonaka M, Tang L, Liou CW, Paquis-Flucklinger V, Harigaya Y, Ibi T, Goto Y, Hosoya H, DiMauro S, Hirano M, Tanaka M: Extensive screening system using suspension array technology to detect mitochondrial DNA point mutations. Mitochondrion 2010; 10: 300–308.
8.
Hotta O, Inoue CN, Miyabayashi S, Furuta T, Takeuchi A, Taguma Y: Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation. Kidney Int 2001; 59: 1236–1243.
9.
Gucer S, Talim B, Asan E, Korkusuz P, Ozen S, Unal S, Kalkanoglu SH, Kale G, Caglar M: Focal segmental glomerulosclerosis associated with mitochondrial cytopathy: report of two cases with special emphasis on podocytes. Pediatr Dev Pathol 2005; 8: 710–717.
10.
Mehrazin M, Shanske S, Kaufmann P, Wei Y, Coku J, Engelstad K, Naini A, De Vivo DC, DiMauro S: Longitudinal changes of mtDNA A3243G mutation load and level of functioning in MELAS. Am J Med Genet A 2009; 149A:584–587.
11.
Bosbach S, Kornblum C, Schroder R, Wagner M: Executive and visuospatial deficits in patients with chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome. Brain 2003; 126: 1231–1240.
12.
Caballero PE, Candela MS, Alvarez CI, Tejerina AA: Chronic progressive external ophthalmoplegia: a report of 6 cases and a review of the literature. Neurologist 2007; 13: 33–36.
13.
Nesbitt V, Pitceathly RD, Turnbull DM, Taylor RW, Sweeney MG, Mudanohwo EE, Rahman S, Hanna MG, McFarland R: The UK MRC mitochondrial disease patient cohort study: clinical phenotypes associated with the m.3243A>G mutation – implications for diagnosis and management. J Neurol Neurosurg Psychiatry 2013; 84: 936–938.
14.
Dvorakova V, Kolarova H, Magner M, Tesarova M, Hansikova H, Zeman J, Honzik T: The phenotypic spectrum of fifty Czech m.3243A>G carriers. Mol Genet Metab 2016; 118: 288–295.
15.
Johns DR: Seminars in medicine of the Beth Israel Hospital, Boston. Mitochondrial DNA and disease. N Engl J Med 1995; 333: 638–644.
16.
Grunfeld JP, Niaudet P, Rotig A: Renal involvement in mitochondrial cytopathies. Nephrol Dial Transplant 1996; 11: 760–761.
17.
Motoda A, Kurashige T, Sugiura T, Nakamura T, Yamawaki T, Arihiro K, Matsumoto M: [A case of MELAS with G13513A mutation presenting with chronic kidney disease long before stroke-like episodes]. Rinsho Shinkeigaku 2013; 53: 446–451.
18.
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, Hildebrandt F: A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J Am Soc Nephrol 2015; 26: 1279–1289.
19.
Harita Y: Application of next-generation sequencing technology to diagnosis and treatment of focal segmental glomerulosclerosis. Clin Exp Nephrol 2017, Epub ahead of print.
20.
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, Rotig A, Nurnberg G, Becker C, Wang S, Ozaltin F, Topaloglu R, Bakkaloglu A, Bakkaloglu SA, Muller D, Beissert A, Mir S, Berdeli A, Varpizen S, Zenker M, Matejas V, Santos-Ocana C, Navas P, Kusakabe T, Kispert A, Akman S, Soliman NA, Krick S, Mundel P, Reiser J, Nurnberg P, Clarke CF, Wiggins RC, Faul C, Hildebrandt F: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest 2011; 121: 2013–2024.
21.
Ashraf S, Gee HY, Woerner S, Xie LX, Vega-Warner V, Lovric S, Fang H, Song X, Cattran DC, Avila-Casado C, Paterson AD, Nitschke 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, Bockenhauer 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: ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest 2013; 123: 5179–5189.
22.
Mkaouar-Rebai E, Chamkha I, Kammoun T, Chabchoub I, Aloulou H, Fendri N, Hachicha M, Fakhfakh F: A case of Kearns-Sayre syndrome with two novel deletions (9.768 and 7.253 kb) of the mtDNA associated with the common deletion in blood leukocytes, buccal mucosa and hair follicles. Mitochondrion 2010; 10: 449–455.
23.
Matsuhashi T, Sato T, Kanno SI, Suzuki T, Matsuo A, Oba Y, Kikusato M, Ogasawara E, Kudo T, Suzuki K, Ohara O, Shimbo H, Nanto F, Yamaguchi H, Saigusa D, Mukaiyama Y, Watabe A, Kikuchi K, Shima H, Mishima E, Akiyama Y, Oikawa Y, Hsin-Jung HO, Akiyama Y, Suzuki C, Uematsu M, Ogata M, Kumagai N, Toyomizu M, Hozawa A, Mano N, Owada Y, Aiba S, Yanagisawa T, Tomioka Y, Kure S, Ito S, Nakada K, Hayashi KI, Osaka H, Abe T: Mitochonic acid 5 (MA-5) facilitates ATP synthase oligomerization and cell survival in various mitochondrial diseases. EBioMedicine 2017; 20: 27–38.
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