Muscle Weakness, Cardiomyopathy, and L-2-Hydroxyglutaric Aciduria Associated with a Novel Recessive SLC25A4 Mutation

  • Anja von Renesse
  • Susanne Morales-Gonzalez
  • Esther Gill
  • Gajja S. Salomons
  • Werner Stenzel
  • Markus SchuelkeEmail author
Research Report
Part of the JIMD Reports book series (JIMD, volume 43)


Background: Mutations in SLC25A4 (syn. ANT1, Adenine nucleotide translocase, type 1) are known to cause either autosomal dominant progressive external ophthalmoplegia (adPEO) or recessive mitochondrial myopathy, hypertrophic cardiomyopathy, and lactic acidosis.

Methods and Results: Whole exome sequencing in a young man with myopathy, subsarcolemmal mitochondrial aggregations, cardiomyopathy, lactic acidosis, and L-2-hydroxyglutaric aciduria (L-2-HGA) revealed a new homozygous mutation in SLC25A4 [c.653A>C, NM_001151], leading to the replacement of a highly conserved glutamine by proline [p.(Q218P); NP_001142] that most likely affects the folding of the ANT1 protein. No pathogenic mutation was found in L2HGDH, which is associated with “classic” L-2-HGA. Furthermore, L-2-HGDH enzymatic activity in the patient fibroblasts was normal. Long-range PCR and Southern blot confirmed absence of mtDNA-deletions in blood and muscle.

Conclusion: The disturbed ADP/ATP transport across the inner mitochondrial membrane may lead to an accumulation of different TCA-cycle intermediates such as 2-ketoglutarate (2-KG) in our patient. As L-2-HG is generated from 2-KG we hypothesize that the L-2-HG increase is a secondary effect of 2-KG accumulation. Hence, our report expands the spectrum of laboratory findings in ANT1-related diseases and hints towards a connection with organic acidurias.


Cardiomyopathy Giant mitochondria L-2-hydroxyglutaric aciduria Mitochondrial disease Myopathy Ragged-red-fibers 



The authors thank the patient for participation in the study and Angelika Zwirner for excellent technical assistance.

Supplementary material

477606_1_En_93_MOESM1_ESM.pdf (126 kb)
Supplementary Table 1 ■■■ (PDF 126 kb)
477606_1_En_93_MOESM2_ESM.pdf (60 kb)
Supplementary Table 2 ■■■ (PDF 60 kb)


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Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018

Authors and Affiliations

  • Anja von Renesse
    • 1
    • 2
  • Susanne Morales-Gonzalez
    • 1
  • Esther Gill
    • 1
  • Gajja S. Salomons
    • 3
  • Werner Stenzel
    • 4
  • Markus Schuelke
    • 1
    • 2
    Email author
  1. 1.NeuroCure Clinical Research CenterCharité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH)BerlinGermany
  2. 2.Department of NeuropediatricsCharité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH)BerlinGermany
  3. 3.Metabolic Unit, Department of Clinical Chemistry, Amsterdam NeuroscienceVU University Medical CenterAmsterdamThe Netherlands
  4. 4.Department of NeuropathologyCharité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH)BerlinGermany

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