Methylmalonic acidemia: A megamitochondrial disorder affecting the kidney
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Classical (or isolated) methylmalonic acidemia (MMA) is a heterogeneous inborn error of metabolism most typically caused by mutations in the vitamin B12-dependent enzyme methylmalonyl-CoA mutase (MUT). With the improved survival of individuals with MMA, chronic kidney disease has become recognized as part of the disorder. The precise description of renal pathology in MMA remains uncertain.
Light microscopy, histochemical, and ultrastructural studies were performed on the native kidney obtained from a 19-year-old patient with mut MMA who developed end stage renal disease and underwent a combined liver–kidney transplantation.
The light microscopy study of the renal parenchyma in the MMA kidney revealed extensive interstitial fibrosis, chronic inflammation, and tubular atrophy. Intact proximal tubules were distinguished by the widespread formation of large, circular, pale mitochondria with diminished cristae. Histochemical preparations showed a reduction of cytochrome c oxidase and NADH activities, and the electron microscopy analysis demonstrated loss of cytochrome c enzyme activity in these enlarged mitochondria.
Our results demonstrate that the renal pathology of MMA is characterized by megamitochondria formation in the proximal tubules in concert with electron transport chain dysfunction. Our findings suggest therapies that target mitochondrial function as a treatment for the chronic kidney disease of MMA.
KeywordsMethylmalonic acidemia Methylmalonyl-CoA mutase Megamitochondria Cytochrome c oxidase End stage renal disease Functional electron microscopy Vitamin B12
We thank Ms. Lena Ellezian for cryosectioning and electron microscopy processing at Department of Pathology at BIDMC. We also thank Ms. Andrea Calhoun at the Electron Microscopy Core Laboratory of BIDMC for her assistance with the COX–electron microscopy study.
- 1.Manoli I, Venditti CP (2005, update 2010). Methylmalonic acidemia. In: Pagon RA, Bird TD, Dolan CR et al (eds) GeneReviews™. University of Washington, Seattle. Available at: 1993 http://www.ncbi.nlm. nih.gov/books/NBK1231/
- 3.Nicolaides P, Leonard J, Surtees R (1998) Neurological outcome of methylmalonic acidaemia. Arch Dis Child 78: 1508–512Google Scholar
- 4.van der Meer SB, Poggi F, Spada M, Bonnefont JP, Ogier H, Hubert P, Depondt E, Rapoport D, Rabier D, Charpentier C, ParvyP BJ, Kamoun P, Saudubray JM (1994) Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia. J Pediatr 125(6 Pt 1):903–908PubMedCrossRefGoogle Scholar
- 9.Cosson MA, Benoist JF, Touati G, Déchaux M, Royer N, Grandin L, Jais JP, Boddaert N, Barbier V, Desguerre I, Campeau PM, Rabier D, Valayannopoulos V, Niaudet P, de Lonlay P (2009) Long-term outcome in methylmalonic aciduria: a series of 30 French patients. Mol Genet Metab 97:172–178PubMedCrossRefGoogle Scholar
- 10.Kruszka PS, Manoli I, Sloan JL, Kopp JB, Venditti CP (2013) Renal growth in isolated methylmalonic acidemia. Genet Med 15(12):990–996. doi: 10.1038/gim.2013.42
- 16.Krahenbuhl S, Chang M, Brass EP, Hoppel CL (1991) Decreased activities of ubiquinol:ferricytochrome c oxidoreductase (complex III) and ferrocytochrome c:oxygen oxidoreductase (complex IV) in liver mitochondria from rats with hydroxycobalamin [c-lactam]-induced methylmalonic aciduria. J Biol Chem 266:20998–21003PubMedGoogle Scholar
- 18.Dubowitz V (1985) Muscle biopsy: A practical approach, 2nd edn. Lavenham Press, Lavenham, SuffolkGoogle Scholar
- 23.Zsengellér ZK, Ellezian L, Brown D, Horváth B, Mukhopadhyay P, Kalyanaraman B, Parikh SM, Karumanchi SA, Stillman IE, Pacher P (2012) Cisplatin nephrotoxicity involves mitochondrial injury with impaired tubular mitochondrial enzyme activity. J Histochem Cytochem 7:521–529Google Scholar
- 26.Fuchshuber A, Mucha B, Baumgartner ER, Vollmer M, Hildebrandt F (2000) mut0 methylmalonic acidemia: eleven novel mutations of the methylmalonyl CoA mutase including a deletion-insertion mutation. Hum Mutat 2:179Google Scholar
- 27.Crane AM, Ledley FD (1994) Clustering of mutations in methylmalonyl CoA mutase associated with mut- methylmalonic acidemia. Am J Hum Genet 1:42–50Google Scholar
- 28.Manoli I, Sysola JR, Lib L, Houillier P, Garone C, Wang C, Zerfas PM, Cusmano-Ozog K, Young S, Trived Niraj S, Cheng J, Sloan J, Chandler R, Abu-Asab M, Tsokos M, Elkahloun A, Rosen S, Enns G, Berry G, Hoffmann V, DiMauro S, Schnermann J, Venditti CP (2013) Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia. Proc Natl Acad Sci USA 110:13552–13557PubMedCrossRefPubMedCentralGoogle Scholar
- 35.Hayasaka K, Metoki K, Satoh T, Narisawa K, Tada K, Kawakami T, Matsuo N, Aoki T (1982) Comparison of cytosolic and mitochondrial enzyme alterations in the livers of propionic or methylmalonic acidemia: a reduction of cytochrome oxidase activity. Tohoku J Exp Med 137:329–334PubMedCrossRefGoogle Scholar
- 36.de Keyzer Y, Valayannopoulos V, Benoist JF, Batteux F, Lacaille F, Hubert L, Chrétien D, Chadefeaux-Vekemans B, Niaudet P, Touati G, Munnich A, de Lonlay P (2009) Multiple OXPHOS deficiency in the liver, kidney, heart, and skeletal muscle of patients with methylmalonic aciduria and propionic aciduria. Pediatr Res 66:91–95PubMedCrossRefGoogle Scholar