Muscle Weakness, Cardiomyopathy, and L-2-Hydroxyglutaric Aciduria Associated with a Novel Recessive SLC25A4 Mutation Research Report First Online: 14 April 2018
Part of the
book series (JIMD, volume 43) 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. Keywords Cardiomyopathy Giant mitochondria L-2-hydroxyglutaric aciduria Mitochondrial disease Myopathy Ragged-red-fibers Electronic supplementary material
The online version of this article (
) contains supplementary material, which is available to authorized users. https://doi.org/10.1007/8904_2018_93
Communicated by: Daniela Karall
The authors thank the patient for participation in the study and Angelika Zwirner for excellent technical assistance.
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.
The project was funded by the Deutsche Forschungsgemeinschaft (SFB 665 TP C4), and the NeuroCure Center of Excellence (Exc 257).
Anja von Renesse analyzed and clinically verified the NGS data, interpreted the data, together with MS wrote the first draft of the manuscript,
Susanne Morales-Gonzalez performed mtDNA deletion screening, isolated DNA from patients muscle and blood,
Esther Gill performed DNA Sanger sequencing for confirmation of NGS results,
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,
Werner Stenzel performed the histological and electron microscopic analyses of the patient’s muscle,
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.
Deschauer M, Hudson G, Müller T et al (2005) A novel ANT1 gene mutation with probable germline mosaicism in autosomal dominant progressive external ophthalmoplegia. Neuromuscul Disord 15:311–315.
https://doi.org/10.1016/j.nmd.2004.12.004 CrossRef PubMed Google Scholar
Dolce V, Scarcia P, Iacopetta D, Palmieri F (2005) A fourth ADP/ATP carrier isoform in man: identification, bacterial expression, functional characterization and tissue distribution. FEBS Lett 579:633–637.
https://doi.org/10.1016/j.febslet.2004.12.034 CrossRef PubMed Google Scholar
Echaniz-Laguna A, Chassagne M, Ceresuela J et al (2012) Complete loss of expression of the ANT1 gene causing cardiomyopathy and myopathy. J Med Genet 49:146–150.
https://doi.org/10.1136/jmedgenet-2011-100504 CrossRef PubMed Google Scholar
Esposito LA, Melov S, Panov A et al (1999) Mitochondrial disease in mouse results in increased oxidative stress. Proc Natl Acad Sci U S A 96:4820–4825
CrossRef Google Scholar
Graham BH, Waymire KG, Cottrell B et al (1997) A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator. Nat Genet 16:226–234.
https://doi.org/10.1038/ng0797-226 CrossRef PubMed Google Scholar
James AW, Miranda SG, Culver K et al (2007) DOOR syndrome: clinical report, literature review and discussion of natural history. Am J Med Genet A 143A:2821–2831.
https://doi.org/10.1002/ajmg.a.32054 CrossRef PubMed Google Scholar
Kaufman EE, Nelson T, Fales HM, Levin DM (1988a) Isolation and characterization of a hydroxyacid-oxoacid transhydrogenase from rat kidney mitochondria. J Biol Chem 263:16872–16879
PubMed Google Scholar
Kaufman EE, Nelson T, Miller D, Stadlan N (1988b) Oxidation of γ-Hydroxybutyrate to succinic semialdehyde by a mitochondrial pyridine nucleotide-independent enzyme. J Neurochem 51:1079–1084.
https://doi.org/10.1111/j.1471-4159.1988.tb03071.x CrossRef PubMed Google Scholar
Kaukonen J, Juselius JK, Tiranti V et al (2000) Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science 289:782–785.
https://doi.org/10.1126/science.289.5480.782 CrossRef PubMed Google Scholar
Komaki H, Fukazawa T, Houzen H et al (2002) A novel D104G mutation in the adenine nucleotide translocator 1 gene in autosomal dominant progressive external ophthalmoplegia patients with mitochondrial DNA with multiple deletions. Ann Neurol 51:645–648.
https://doi.org/10.1002/ana.10172 CrossRef PubMed Google Scholar
Körver-Keularts IMLW, de Visser M, Bakker HD et al (2015) Two novel mutations in the SLC25A4 gene in a patient with mitochondrial myopathy. JIMD Rep 22:39–45.
https://doi.org/10.1007/8904_2015_409 CrossRef PubMed PubMedCentral Google Scholar
Kranendijk M, Salomons GS, Gibson KM et al (2009) Development and implementation of a novel assay for l-2-hydroxyglutarate dehydrogenase (l-2-HGDH) in cell lysates: l-2-HGDH deficiency in 15 patients with l-2-hydroxyglutaric aciduria. J Inherit Metab Dis 32:713.
https://doi.org/10.1007/s10545-009-1282-x CrossRef PubMed Google Scholar
Lek M, Karczewski KJ, Minikel EV et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291.
https://doi.org/10.1038/nature19057 CrossRef PubMed PubMedCentral Google Scholar
Liu Y, Wang X, Chen XJ (2015) Misfolding of mutant adenine nucleotide translocase in yeast supports a novel mechanism of Ant1-induced muscle diseases. Mol Biol Cell 26:1985–1994.
https://doi.org/10.1091/mbc.E15-01-0030 CrossRef PubMed PubMedCentral Google Scholar
Lorenz C, Lesimple P, Bukowiecki R et al (2017) Human iPSC-derived neural progenitors are an effective drug discovery model for neurological mtDNA disorders. Cell Stem Cell 20:659–674.e9.
https://doi.org/10.1016/j.stem.2016.12.013 CrossRef PubMed Google Scholar
Napoli L, Bordoni A, Zeviani M et al (2001) A novel missense adenine nucleotide translocator-1 gene mutation in a Greek adPEO family. Neurology 57:2295–2298
CrossRef Google Scholar
Palmieri L, Alberio S, Pisano I et al (2005) Complete loss-of-function of the heart/muscle-specific adenine nucleotide translocator is associated with mitochondrial myopathy and cardiomyopathy. Hum Mol Genet 14:3079–3088.
https://doi.org/10.1093/hmg/ddi341 CrossRef PubMed Google Scholar
Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–423.
https://doi.org/10.1038/gim.2015.30 CrossRef PubMed PubMedCentral Google Scholar
Rzem R, Vincent M-F, Schaftingen EV, Veiga-da-Cunha M (2007) L-2-hydroxyglutaric aciduria, a defect of metabolite repair. J Inherit Metab Dis 30:681.
https://doi.org/10.1007/s10545-007-0487-0 CrossRef PubMed Google Scholar
Seelow D, Schuelke M (2012) HomozygosityMapper2012 – bridging the gap between homozygosity mapping and deep sequencing. Nucleic Acids Res 40:W516–W520.
https://doi.org/10.1093/nar/gks487 CrossRef PubMed PubMedCentral Google Scholar
Stepien G, Torroni A, Chung AB et al (1992) Differential expression of adenine nucleotide translocator isoforms in mammalian tissues and during muscle cell differentiation. J Biol Chem 267:14592–14597
PubMed Google Scholar
Strauss KA, DuBiner L, Simon M et al (2013) Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup. Proc Natl Acad Sci 110:3453–3458.
https://doi.org/10.1073/pnas.1300690110 CrossRef PubMed Google Scholar
Struys EA, Jansen EEW, Verhoeven NM, Jakobs C (2004) Measurement of urinary D- and L-2-hydroxyglutarate enantiomers by stable-isotope-dilution liquid chromatography–tandem mass spectrometry after derivatization with diacetyl-L-tartaric anhydride. Clin Chem 50:1391–1395.
https://doi.org/10.1373/clinchem.2004.033399 CrossRef PubMed Google Scholar
Struys EA, Verhoeven NM, Brink HJT et al (2005) Kinetic characterization of human hydroxyacid–oxoacid transhydrogenase: relevance toD-2-hydroxyglutaric and γ-hydroxybutyric acidurias. J Inherit Metab Dis 28:921–930.
https://doi.org/10.1007/s10545-005-0114-x CrossRef PubMed Google Scholar
Tang Y, Schon EA, Wilichowski E et al (2000) Rearrangements of human mitochondrial DNA (mtDNA): new insights into the regulation of mtDNA copy number and gene expression. Mol Biol Cell 11:1471–1485.
https://doi.org/10.1091/mbc.11.4.1471 CrossRef PubMed PubMedCentral Google Scholar
The 1000 Genomes Project Consortium (2015) A global reference for human genetic variation. Nature 526:68–74.
https://doi.org/10.1038/nature15393 CrossRef PubMedCentral Google Scholar
Thompson K, Majd H, Dallabona C et al (2016) Recurrent de novo dominant mutations in SLC25A4 cause severe early-onset mitochondrial disease and loss of mitochondrial DNA copy number. Am J Hum Genet 99:860–876.
https://doi.org/10.1016/j.ajhg.2016.08.014 CrossRef PubMed PubMedCentral Google Scholar
von Renesse A, Petkova MV, Lützkendorf S et al (2014) POMK mutation in a family with congenital muscular dystrophy with merosin deficiency, hypomyelination, mild hearing deficit and intellectual disability. J Med Genet 51:275–282.
https://doi.org/10.1136/jmedgenet-2013-102236 CrossRef Google Scholar
Weissensteiner H, Pacher D, Kloss-Brandstätter A et al (2016) HaploGrep 2: mitochondrial haplogroup classification in the era of high-throughput sequencing. Nucleic Acids Res 44:W58–W63.
https://doi.org/10.1093/nar/gkw233 CrossRef PubMed PubMedCentral Google Scholar Copyright information
© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018