Abstract
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.
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Acknowledgments
The authors thank the patient for participation in the study and Angelika Zwirner for excellent technical assistance.
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Communicated by: Daniela Karall
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Synopsis
Mutations in SLC25A4, the gene encoding Adenine nucleotide translocase type 1 may be associated with increased urinary excretion of L-2-hydroxyglutaric acid and massive subsarcolemmal aggregations of mitochondria.
Compliance with Ethics Guidelines
Ethics Approval
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (IRB of the Charité, EA2/107/14) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from the patient for being included in the study.
Conflict of Interest
All authors declare that they have no conflict of interest.
Funding
The project was funded by the Deutsche Forschungsgemeinschaft (SFB 665 TP C4), and the NeuroCure Center of Excellence (Exc 257).
Authors’ Contributions
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Anja von Renesse analyzed and clinically verified the NGS data, interpreted the data, together with MS wrote the first draft of the manuscript,
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Susanne Morales-Gonzalez performed mtDNA deletion screening, isolated DNA from patients muscle and blood,
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Esther Gill performed DNA Sanger sequencing for confirmation of NGS results,
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Gajja S. Salomons did the L-2- and D-2-HG measurements in the urine and the L-2-HGDH enzyme activity measurements in the patient fibroblasts,
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Werner Stenzel performed the histological and electron microscopic analyses of the patient’s muscle,
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Markus Schuelke conception of the study, investigated the patient, performed the bioinformatic analyses, did the genetic counseling of the family, together with AvR wrote the first draft of the manuscript.
All authors read the final version of the manuscript for intellectual content and consented to its publication.
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© 2018 Society for the Study of Inborn Errors of Metabolism (SSIEM)
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von Renesse, A., Morales-Gonzalez, S., Gill, E., Salomons, G.S., Stenzel, W., Schuelke, M. (2018). Muscle Weakness, Cardiomyopathy, and L-2-Hydroxyglutaric Aciduria Associated with a Novel Recessive SLC25A4 Mutation. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 43. JIMD Reports, vol 43. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2018_93
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DOI: https://doi.org/10.1007/8904_2018_93
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