Top

Published in:

01-11-2014 | Original Article

Methylmalonic acidemia: A megamitochondrial disorder affecting the kidney

Authors: Zsuzsanna K. Zsengellér, Nika Aljinovic, Lisa A. Teot, Mark Korson, Nancy Rodig, Jennifer L. Sloan, Charles P. Venditti, Gerard T. Berry, Seymour Rosen

Published in: Pediatric Nephrology | Issue 11/2014

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Available only for authorised users

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/

Matsui SM, Mahoney MJ, Rosenberg LE (1983) The natural history of the inherited methylmalonic acidemias. N Engl J Med 308:857–861PubMedCrossRef

Nicolaides P, Leonard J, Surtees R (1998) Neurological outcome of methylmalonic acidaemia. Arch Dis Child 78: 1508–512

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):903–908PubMedCrossRef

Horster F, Baumgartner MR, Viardot C, Suormala T, Burgard P, Fowler B, Hoffmann GF, Garbade SF, Kölker S, Baumgartner ER (2007) Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB). Pediatr Res 2:225–230CrossRef

Walter JH, Michalski A, Wilson WM, Leonard JV, Barratt TM, Dillon MJ (1989) Chronic renal failure in methylmalonic acidaemia. Eur J Pediatr 148:344–348PubMedCrossRef

Baumgarter ER, Viardot C (1995) Long-term follow-up of 77 patients with isolated methylmalonic acidaemia. J Inherit Metab Dis 18:138–142PubMedCrossRef

Oberholzer VG, Levin B, Burgess EA, Young WF (1967) Methylmalonic aciduria. An inborn error of metabolism leading to chronic metabolic acidosis. Arch Dis Child 42:492–504PubMedCrossRefPubMedCentral

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 97:172–178PubMedCrossRef

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

11.

Molteni KH, Oberley TD, Wolff JA, Friedman AL (1991) Progressive renal insufficiency in methylmalonic acidemia. Pediatr Nephrol 5:323–326PubMedCrossRef

12.

Rutledge SL, Geraghty M, Mroczek E, Rosenblatt D, Kohout E (1993) Tubulointerstitial nephritis in methylmalonic acidemia. Pediatr Nephrol 7:81–82PubMedCrossRef

13.

Chandler RJ, Zerfas PM, Shanske S, Sloan J, Hoffmann V, DiMauro S, Venditti CP (2009) Mitochondrial dysfunction in mut methylmalonic acidemia. FASEB J 23:1252–61PubMedCrossRefPubMedCentral

14.

Tandler B, Krahenbuhl S, Brass EP (1991) Unusual mitochondria in the hepatocytes of rats treated with a vitamin B12 analogue. Anat Rec 231:1–6PubMedCrossRef

15.

Stabler SP, Brass EP, Marcell PD, Allen RH (1991) Inhibition of cobalamin-dependent enzymes by cobalamin analogues in rats. J Clin Invest 87:1422–1430PubMedCrossRefPubMedCentral

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 266:20998–21003PubMed

17.

Hershey SJ, Simon TW, Baste C (1975) Histochemical localization of cytochrome oxidase in gastric mucosa. J Histochem Cytochem 4:271–282CrossRef

18.

Dubowitz V (1985) Muscle biopsy: A practical approach, 2nd edn. Lavenham Press, Lavenham, Suffolk

19.

Lebrecht D, Setzer B, Rohrbach R, Walker UA (2004) Mitochondrial DNA and its respiratory chain products are defective in doxorubicin nephrosis. Nephrol Dial Transplant 19:329–336PubMedCrossRef

20.

Seligman AM, Karnovsky MJ, Wasserkrug HL, Hanker JS (1968) Nondroplet ultrastructural demonstration of cytochrome oxidase activity with a polymerizing osmiophilic reagent, diaminobenzidine (DAB). J Cell Biol 1:1–14CrossRef

21.

Anderson WA, Bara G, Seligman AM (1975) The ultrastructural localization of cytochrome oxidase via cytochrome. J Histochem Cytochem 1:13–20CrossRef

22.

Bertoni-Freddari C, Fattoretti P, Casoli T, Di Stefano G, Solazzi M, Gracciotti N, Pompei P (2001) Mapping of mitochondrial metabolic competence by cytochrome oxidase and succinic dehydrogenase cytochemistry. J Histochem Cytochem 9:1191–1192CrossRef

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 7:521–529

24.

Worgan LC, Niles K, Tirone JC, Hofmann A, Verner A, Sammak A, Kucic T, Lepage P, Rosenblatt DS (2006) Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype. Hum Mutat 1:31–43CrossRef

25.

Lempp TJ, Suormala T, Siegenthaler R, Baumgartner ER, Fowler B, Steinmann B, Baumgartner MR (2007) Mutation and biochemical analysis of 19 probands with mut0 and 13 with mut- methylmalonic aciduria: identification of seven novel mutations. Mol Genet Metab 3:284–290CrossRef

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 2:179

27.

Crane AM, Ledley FD (1994) Clustering of mutations in methylmalonyl CoA mutase associated with mut- methylmalonic acidemia. Am J Hum Genet 1:42–50

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 110:13552–13557PubMedCrossRefPubMedCentral

29.

Suzuki T, Furusato M, Takasaki S, Ishikawa E (1975) Giant mitochondria in the epithelial cells of the proximal convoluted tubules of diseased human kidneys. Lab Invest 33:578–590PubMed

30.

Mihatsch MJ, Ryffel B, Hermle M, Brunner FP, Thiel G (1986) Morphology of cyclosporine nephrotoxicity in the rat. Clin Nephrol 25[Suppl 1]:S2–8PubMed

31.

Herlitz LC, Mohan S, Stokes MB, Radhakrishnan J, D'Agati VD, Markowitz GS (2010) Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities. Kidney Int 78:1171–1177PubMedCrossRef

32.

Kitano A, Nishiyama S, Miike T, Hattori S, Ohtani Y, Matsuda I (1986) Mitochondrial cytopathy with lactic acidosis, carnitine deficiency and DeToni-Fanconi-Debré syndrome. Brain Dev 8:289–295PubMedCrossRef

33.

Davis RL, Sue CM (2011) The genetics of mitochondrial disease. Semin Neurol 31:519–530PubMedCrossRef

34.

Wakabayashi T (2002) Megamitochondria formation—physiology and pathology. J Cell Mol Med 6:497–538PubMedCrossRef

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 137:329–334PubMedCrossRef

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 66:91–95PubMedCrossRef

Title: Methylmalonic acidemia: A megamitochondrial disorder affecting the kidney
Authors: Zsuzsanna K. Zsengellér
Nika Aljinovic
Lisa A. Teot
Mark Korson
Nancy Rodig
Jennifer L. Sloan
Charles P. Venditti
Gerard T. Berry
Seymour Rosen
Publication date: 01-11-2014
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 11/2014
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-014-2847-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Methylmalonic acidemia: A megamitochondrial disorder affecting the kidney

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 11/2014

The Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry: a critical appraisal

Clinico-pathological correlations of congenital and infantile nephrotic syndrome over twenty years

Normal values for urine renalase excretion in children

Increased risk of idiopathic nephrotic syndrome in children with atopic dermatitis

Muscle involvement in Dent disease 2

Near-infrared spectroscopy for monitoring renal transplant perfusion