Heteroplasmic pathogenic m.12315G>A variant in MT-TL2 presenting with MELAS syndrome and depletion of nitric oxide donors.
MELAS
MT-TL2
arginine
citrulline
nitric oxide
stroke-like episodes
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
12 Nov 2023
12 Nov 2023
Historique:
revised:
14
09
2023
received:
20
06
2023
accepted:
19
10
2023
medline:
13
11
2023
pubmed:
13
11
2023
entrez:
12
11
2023
Statut:
aheadofprint
Résumé
The MT-TL2 m.12315G>A pathogenic variant has previously been reported in five individuals with mild clinical phenotypes. Herein we report the case of a 5-year-old child with heteroplasmy for this variant who developed neurological regression and stroke-like episodes similar to those observed in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Biochemical evaluation revealed depletion of arginine on plasma amino acid analysis and low z-scores for citrulline on untargeted plasma metabolomics analysis. These findings suggested that decreased availability of nitric oxide may have contributed to the stroke-like episodes. The use of intravenous arginine during stroke-like episodes and daily enteral L-citrulline supplementation normalized her biochemical values of arginine and citrulline. Untargeted plasma metabolomics showed the absence of nicotinamide and 1-methylnicotinamide, and plasma total glutathione levels were low; thus, nicotinamide riboside and N-acetylcysteine therapies were initiated. This report expands the phenotype associated with the rare mitochondrial variant MT-TL2 m.12315G>A to include neurological regression and a MELAS-like phenotype. Individuals with this variant should undergo in-depth biochemical analysis to include untargeted plasma metabolomics, plasma amino acids, and glutathione levels to help guide a targeted approach to treatment.
Identifiants
pubmed: 37953071
doi: 10.1002/ajmg.a.63461
doi:
Types de publication
Case Reports
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023 Wiley Periodicals LLC.
Références
Aldosary, M., Baselm, S., Abdulrahim, M., Almass, R., Alsagob, M., AlMasseri, Z., Huma, R., AlQuait, L., Al-Shidi, T., Al-Obeid, E., AlBakheet, A., Alahideb, B., Alahaidib, L., Qari, A., Taylor, R. W., Colak, D., AlSayed, M. D., & Kaya, N. (2021). SLC25A42-associated mitochondrial encephalomyopathy: Report of additional founder cases and functional characterization of a novel deletion. Journal of Inherited Metabolic Disease Reports, 60(1), 75-87. https://doi.org/10.1002/jmd2.12218
Balasubramaniam, S., Lewis, B., Mock, D. M., Said, H. M., Tarailo-Graovac, M., Mattman, A., & Christodoulou, J. (2017). Leigh-like syndrome due to homoplasmic m.8993T>G variant with hypocitrullinemia and unusual biochemical features suggestive of multiple carboxylase deficiency (MCD). Journal of Inherited Metabolic Disease Reports, 33, 99-107. https://doi.org/10.1007/8904_2016_559
Chen, H., Hu, Q., Raza, H. K., Chansysouphanthong, T., Singh, S., Rai, P., Cui, G., Zhang, Z., Ye, X., Xu, C., Liu, Y., & Jiang, H. (2020). An analysis of the clinical and imaging features of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Somatosensory & Motor Research, 37(1), 45-49. https://doi.org/10.1080/08990220.2020.1720636
Debray, F. G., Lambert, M., Allard, P., & Mitchell, G. A. (2010). Low citrulline in Leigh disease: Still a biomarker of maternally inherited Leigh syndrome. Journal of Child Neurology, 25(8), 1000-1002. https://doi.org/10.1177/0883073809351983
El-Hattab, A. W., Adesina, A. M., Jones, J., & Scaglia, F. (2015). MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options. Molecular Genetics and Metabolism, 116(1-2), 4-12. https://doi.org/10.1016/j.ymgme.2015.06.004
El-Hattab, A. W., Hsu, J. W., Emrick, L. T., Wong, L. J., Craigen, W. J., Jahoor, F., & Scaglia, F. (2012). Restoration of impaired nitric oxide production in MELAS syndrome with citrulline and arginine supplementation. Molecular Genetics and Metabolism, 105(4), 607-614. https://doi.org/10.1016/j.ymgme.2012.01.016
Elson, J. L., Swalwell, H., Blakely, E. L., McFarland, R., Taylor, R. W., & Turnbull, D. M. (2009). Pathogenic mitochondrial tRNA mutations-Which mutations are inherited and why? Human Mutation, 30(11), E984-E992. https://doi.org/10.1002/humu.21113
Enns, G. M., & Cowan, T. M. (2017). Glutathione as a redox biomarker in mitochondrial disease-implications for therapy. Journal of Clinical Medicine, 6(5), 50. https://doi.org/10.3390/jcm6050050
Fryer, R. H., Bain, J., & De Vivo, D. (2016). Mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes: A case report and critical reappraisal of treatment options. Pediatric Neurology, 56, 59-61. https://doi.org/10.1016/j.pediatrneurol.2015.12.010
Fu, K., Hartlen, R., Johns, T., Genge, A., Karpati, G., & Shoubridge, E. A. (1996). A novel heteroplasmic tRNAleu(CUN) mtDNA point mutation in a sporadic patient with mitochondrial encephalomyopathy segregates rapidly in skeletal muscle and suggests an approach to therapy. Human Molecular Genetics, 5(11), 1835-1840. https://doi.org/10.1093/hmg/5.11.1835
Ganetzky, R. D., & Falk, M. J. (2018). 8-year retrospective analysis of intravenous arginine therapy for acute metabolic strokes in pediatric mitochondrial disease. Molecular Genetics and Metabolism, 123(3), 301-308. https://doi.org/10.1016/j.ymgme.2018.01.010
Karadimas, C. L., Salviati, L., Sacconi, S., Chronopoulou, P., Shanske, S., Bonilla, E., De Vivo, D. C., & DiMauro, S. (2002). Mitochondrial myopathy and ophthalmoplegia in a sporadic patient with the G12315A mutation in mitochondrial DNA. Neuromuscular Disorders, 12(9), 865-868. https://doi.org/10.1016/s0960-8966(02)00072-x
Koenig, M. K., Emrick, L., Karaa, A., Korson, M., Scaglia, F., Parikh, S., & Goldstein, A. (2016). Recommendations for the management of strokelike episodes in patients with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes. Journal of the American Medical Association Neurology, 73(5), 591-594. https://doi.org/10.1001/jamaneurol.2015.5072
Koga, Y., Akita, Y., Junko, N., Yatsuga, S., Povalko, N., Fukiyama, R., Ishii, M., & Matsuishi, T. (2006). Endothelial dysfunction in MELAS improved by l-arginine supplementation. Neurology, 66(11), 1766-1769. https://doi.org/10.1212/01.wnl.0000220197.36849.1e
Nagamani, S. C., Erez, A., Bader, P., Lalani, S. R., Scott, D. A., Scaglia, F., Plon, S. E., Tsai, C. H., Reimschisel, T., Roeder, E., Malphrus, A. D., Eng, P. A., Hixson, P. M., Kang, S. H., Stankiewicz, P., Patel, A., & Cheung, S. W. (2011). Phenotypic manifestations of copy number variation in chromosome 16p13.11. European Journal of Human Genetics, 19(3), 280-286. https://doi.org/10.1038/ejhg.2010.184
Parfait, B., de Lonlay, P., von Kleist-Retzow, J. C., Cormier-Daire, V., Chrétien, D., Rötig, A., Rabier, D., Saudubray, J. M., Rustin, P., & Munnich, A. (1999). The neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome mtDNA mutation (T8993G) triggers muscle ATPase deficiency and hypocitrullinaemia. European Journal of Pediatrics, 158(1), 55-58. https://doi.org/10.1007/s004310051009
Parikh, S., Goldstein, A., Koenig, M. K., Scaglia, F., Enns, G. M., Saneto, R., Anselm, I., Cohen, B. H., Falk, M. J., Greene, C., Gropman, A. L., Haas, R., Hirano, M., Morgan, P., Sims, K., Tarnopolsky, M., Van Hove, J. L., Wolfe, L., & DiMauro, S. (2015). Diagnosis and management of mitochondrial disease: A consensus statement from the Mitochondrial Medicine Society. Genetics in Medicine, 17(9), 689-701. https://doi.org/10.1038/gim.2014.177
Pirinen, E., Auranen, M., Khan, N. A., Brilhante, V., Urho, N., Pessia, A., Hakkarainen, A., Kuula, J., Heinonen, U., Schmidt, M. S., Haimilahti, K., Piirilä, P., Lundbom, N., Taskinen, M. R., Brenner, C., Velagapudi, V., Pietiläinen, K. H., & Suomalainen, A. (2020). Niacin cures systemic NAD+ deficiency and improves muscle performance in adult-onset mitochondrial myopathy. Cell Metabolism, 31(6), 1078-1090.e5. https://doi.org/10.1016/j.cmet.2020.04.008
Smits, B. W., Westeneng, H. J., van Hal, M. A., van Engelen, B. G., & Overeem, S. (2012). Sleep disturbances in chronic progressive external ophthalmoplegia. European Journal of Neurology, 19(1), 176-178. https://doi.org/10.1111/j.1468-1331.2011.03496.x
Valente, L., Piga, D., Lamantea, E., Carrara, F., Uziel, G., Cudia, P., Zani, A., Farina, L., Morandi, L., Mora, M., Spinazzola, A., Zeviani, M., & Tiranti, V. (2009). Identification of novel mutations in five patients with mitocondrial encephalomyopathy. Biochimica et Biophysica Acta, 1787(5), 491-501. https://doi.org/10.1016/j.bbabio.2008.10.001
Vallance, P., & Chan, N. (2001). Endothelial function and nitric oxide: Clinical relevance. Heart, 85(3), 342-350. https://doi.org/10.1136/heart.85.3.342