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Methylmalonic acidemia: A megamitochondrial disorder affecting the kidney

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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.

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Acknowledgments

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.

Author information

Authors and Affiliations

  1. Molecular Medicine, Beth Israel Deaconess Medical Center–Harvard Medical School, Boston, MA, USA

    Zsuzsanna K. Zsengellér

  2. Pathology Department, Beth Israel Deaconess Medical Center–Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA

    Zsuzsanna K. Zsengellér, Nika Aljinovic & Seymour Rosen

  3. Pathology Department, Boston Children’s Hospital–Harvard Medical School,, Boston, MA, USA

    Lisa A. Teot & Seymour Rosen

  4. Tufts University School of Medicine, Boston, MA, USA

    Mark Korson

  5. Division of Nephrology, Boston Children’s Hospital–Harvard Medical School, Boston, MA, 02115, USA

    Nancy Rodig

  6. Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Jennifer L. Sloan & Charles P. Venditti

  7. Manton Center for Orphan Disease Research, Boston Children’s Hospital–Harvard Medical School, Boston, USA

    Gerard T. Berry

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  1. Zsuzsanna K. Zsengellér
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  2. Nika Aljinovic
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Correspondence to Zsuzsanna K. Zsengellér.

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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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Zsengellér, Z.K., Aljinovic, N., Teot, L.A. et al. Methylmalonic acidemia: A megamitochondrial disorder affecting the kidney. Pediatr Nephrol 29, 2139–2146 (2014). https://doi.org/10.1007/s00467-014-2847-y

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  • DOI: https://doi.org/10.1007/s00467-014-2847-y

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