title: Methylmalonic acidemia: a megamitochondrial disorder affecting the kidney.
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.
authors.affiliation: Molecular Medicine, Beth Israel Deaconess Medical Center-Harvard Medical School, Boston, MA, USA, zzsengel@bidmc.harvard.edu.
authors.forename: Zsuzsanna K
authors.initials: ZK
authors.lastname: Zsengellér
authors.forename: Nika
authors.initials: N
authors.lastname: Aljinovic
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Teot
authors.forename: Mark
authors.initials: M
authors.lastname: Korson
authors.forename: Nancy
authors.initials: N
authors.lastname: Rodig
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Sloan
authors.forename: Charles P
authors.initials: CP
authors.lastname: Venditti
authors.forename: Gerard T
authors.initials: GT
authors.lastname: Berry
authors.forename: Seymour
authors.initials: S
authors.lastname: Rosen
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D001284:Atrophy; D018753:Diet, Protein-Restricted; D005260:Female; D006801:Humans; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000473:pathology; D008661:Metabolism, Inborn Errors / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D008765:Methylmalonyl-CoA Mutase / Q000235:genetics; D008928:Mitochondria / Q000473:pathology; D028361:Mitochondrial Diseases / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D009393:Nephritis / Q000473:pathology; D014805:Vitamin B 12 / Q000378:metabolism; D055815:Young Adult
chemical_list: D008765:Methylmalonyl-CoA Mutase; D014805:Vitamin B 12