Pediatric Nephrology

, Volume 29, Issue 11, pp 2139–2146 | Cite as

Methylmalonic acidemia: A megamitochondrial disorder affecting the kidney

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



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.


Methylmalonic 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.

Supplementary material

467_2014_2847_MOESM1_ESM.pdf (82 kb)
Supplemental Fig 1 The chromatogram tracings depict heterozygous changes in the either exon 3 or exon 11 in the MUT gene from a control (top) compared to the patient (below). The nucleotide change and corresponding amino acid substitution are listed as well. (PDF 82 kb)


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Copyright information

© IPNA 2014

Authors and Affiliations

  • Zsuzsanna K. Zsengellér
    • 1
    • 2
  • Nika Aljinovic
    • 2
  • Lisa A. Teot
    • 3
  • Mark Korson
    • 4
  • Nancy Rodig
    • 5
  • Jennifer L. Sloan
    • 6
  • Charles P. Venditti
    • 6
  • Gerard T. Berry
    • 7
  • Seymour Rosen
    • 2
    • 3
  1. 1.Molecular MedicineBeth Israel Deaconess Medical Center–Harvard Medical SchoolBostonUSA
  2. 2.Pathology DepartmentBeth Israel Deaconess Medical Center–Harvard Medical SchoolBostonUSA
  3. 3.Pathology DepartmentBoston Children’s Hospital–Harvard Medical School,BostonUSA
  4. 4.Tufts University School of MedicineBostonUSA
  5. 5.Division of NephrologyBoston Children’s Hospital–Harvard Medical SchoolBostonUSA
  6. 6.Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research InstituteNational Institutes of HealthBethesdaUSA
  7. 7.Manton Center for Orphan Disease ResearchBoston Children’s Hospital–Harvard Medical SchoolBostonUSA

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