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MELAS: A Multigenerational Impact of the MTTL1 A3243G MELAS Mutation

Published online by Cambridge University Press:  23 September 2014

M. Prasad
1Western University and London Health Sciences Centre, London
B. Narayan
1Western University and London Health Sciences Centre, London
A.N. Prasad
Departments of Paediatrics, London
C.A. Rupar
Departments of Paediatrics, London Pathology and Laboratory Medicine, London Biochemistry, London Children's Health Research Institute, London
S. Levin
Departments of Paediatrics, London
J. Kronick
Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
D. Ramsay
Pathology and Laboratory Medicine, London
K.Y. Tay
Medical Imaging, London
C. Prasad*
Departments of Paediatrics, London Children's Health Research Institute, London
Children's Hospital, London Health Sciences Centre, 800 Commissioners Road East, London, Ontario, N6C 2V5, Canada. Email:
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the maternally inherited MTTL1 A3243G mutation in the mitochondrial genome causes MelaS (Mitochondrial encephalopathy lactic acidosis with Stroke-like episodes), a condition that is multisystemic but affects primarily the nervous system. Significant intra-familial variation in phenotype and severity of disease is well recognized.


retrospective and ongoing study of an extended family carrying the MTTL1 A3243G mutation with multiple symptomatic individuals. tissue heteroplasmy is reviewed based on the clinical presentations, imaging studies, laboratory findings in affected individuals and pathological material obtained at autopsy in two of the family members.


there were seven affected individuals out of thirteen members in this three generation family who each carried the MTTL1 A3243G mutation. the clinical presentations were varied with symptoms ranging from hearing loss, migraines, dementia, seizures, diabetes, visual manifestations, and stroke like episodes. three of the family members are deceased from MelaS or to complications related to MelaS.


the results of the clinical, pathological and radiological findings in this family provide strong support to the current concepts of maternal inheritance, tissue heteroplasmy and molecular pathogenesis in MelaS. neurologists (both adult and paediatric) are the most likely to encounter patients with MelaS in their practice. genetic counselling is complex in view of maternal inheritance and heteroplasmy. newer therapeutic options such as arginine are being used for acute and preventative management of stroke like episodes.

Original Article
Copyright © The Canadian Journal of Neurological 2014


1.Sproule, DM, Kaufmann, P.Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome. Ann N Y Acad Sci. 2008;1142:13358.CrossRefGoogle ScholarPubMed
2.Goto, Y, Nonaka, I, Horai, S.A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990;348:6513.CrossRefGoogle ScholarPubMed
3.Finsterer, J.Genetic, pathogenetic, and phenotypic implications of the mitochondrial A3243G tRNALeu(UUR) mutation. Acta Neurol Scand. 2007;116:114.CrossRefGoogle ScholarPubMed
4.Pavlakis, SG, Phillips, PC, DiMauro, S, De Vivo, DC, Rowland, LP.Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol. 1984;16:4818.CrossRefGoogle ScholarPubMed
5.Sarnat, HB, Marin-Garcia, J.Pathology of mitochondrial encephalomyopathies. Can J Neurol Sci. 2005;32:15266.CrossRefGoogle ScholarPubMed
6.Chomyn, A, Meola, G, Bresolin, N, Lai, ST, Scarlato, G, Attardi, G.In vitro genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathy-patient mitochondria. Mol Cell Biol. 1991;11:223644.CrossRefGoogle ScholarPubMed
7.Rahman, S, Poulton, J, Marchington, D, Suomalainen, A.Decrease of 3243 A–≯G mtDNA mutation from blood in MELAS syndrome: a longitudinal study. Am J Hum Genet. 2001;68:23840.CrossRefGoogle Scholar
8.Kaufmann, P, Shungu, DC, Sano, MC, et al. Cerebral lactic acidosis correlates with neurological impairment in MELAS. Neurology. 2004;62:1297302.CrossRefGoogle ScholarPubMed
9.Chinnery, PF, Howell, N, Lightowlers, RN, Turnbull, DM.Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes. Brain. 1997;120 (Pt 10): 171321.CrossRefGoogle ScholarPubMed
10.Sparaco, M, Simonati, A, Cavallaro, T, et al. MELAS: clinical phenotype and morphological brain abnormalities. Acta Neuropathol. 2003;106:20212.CrossRefGoogle ScholarPubMed
11.Betts, J, Jaros, E, Perry, RH, et al. Molecular neuropathology of MELAS: level of heteroplasmy in individual neurones and evidence of extensive vascular involvement. Neuropathol Appl Neurobiol. 2006;32:35973.CrossRefGoogle ScholarPubMed
12.Yokoyama, T, Hasegawa, K, Obama, R, Ishihara, T, Yagishita, S.MELAS with diffuse degeneration of the cerebral white matter: report of an autopsy case. Neuropathology. 2010;30:5660.CrossRefGoogle ScholarPubMed
13.Moran, M, Moreno-Lastres, D, Marin-Buera, L, Arenas, J, Martin, MA, Ugalde, C.Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration. Free Radic Biol Med. 2012;53:595609.CrossRefGoogle ScholarPubMed
14.Ohama, E, Ohara, S, Ikuta, F, Tanaka, K, Nishizawa, M, Miyatake, T.Mitochondrial angiopathy in cerebral blood vessels of mitochondrial encephalomyopathy. Acta Neuropathologica. 1987;74:22633.CrossRefGoogle ScholarPubMed
15.Mizukami, K, Sasaki, M, Suzuki, T, et al. Central nervous system changes in mitochondrial encephalomyopathy: light and electron microscopic study. Acta neuropathologica. 1992;83:44952.CrossRefGoogle ScholarPubMed
16.Sarnat, HB, Flores-Sarnat, L, Casey, R, Scott, P, Khan, A.Endothelial ultrastructural alterations of intramuscular capillaries in infantile mitochondrial cytopathies: “mitochondrial angiopathy”. Neuropathology. 2012;32:61727.CrossRefGoogle ScholarPubMed
17.Lax, NZ, Pienaar, IS, Reeve, AK, et al. Microangiopathy in the cerebellum of patients with mitochondrial DNA disease. Brain. 2012;135:173650.CrossRefGoogle ScholarPubMed
18.Janssen, AJ, Smeitink, JA, van, denHeuvel, LP.Some practical aspects of providing a diagnostic service for respiratory chain defects. Ann Clin Biochem. 2003;40:38.CrossRefGoogle ScholarPubMed
19.Finsterer, J.Mitochondrial disorders, cognitive impairment and dementia. J Neurol Sci. 2009;283:1438.CrossRefGoogle ScholarPubMed
20.Finsterer, J.Cognitive decline as a manifestation of mitochondrial disorders (mitochondrial dementia). J Neurol Sci. 2008;272:2033.CrossRefGoogle Scholar
21.Finsterer, J.Cognitive dysfunction in mitochondrial disorders. Acta Neurol Scand. 2012;126:111.CrossRefGoogle ScholarPubMed
22.Kaido, M, Fujimura, H, Soga, F, et al. Alzheimer-type pathology in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Acta Neuropathol. 1996;92:31218.CrossRefGoogle Scholar
23.Pfeffer, G, Majamaa, K, Turnbull, DM, Thorburn, D, Chinnery, PF.Treatment for mitochondrial disorders. Cochrane Database Syst Rev. 2012;4:CD004426.Google Scholar
24.Koga, Y, Povalko, N, Nishioka, J, Katayama, K, Yatsuga, S, Matsuishi, T.Molecular pathology of MELAS and L-arginine effects. Biochimica Biophys Acta. 2012;1820:60814.CrossRefGoogle ScholarPubMed
25.Koga, Y, Ishibashi, M, Ueki, I, et al. Effects of L-arginine on the acute phase of strokes in three patients with MELAS. Neurology. 2002;58:8278.CrossRefGoogle ScholarPubMed
26.Koga, Y, Akita, Y, Nishioka, J, et al. MELAS and L-arginine therapy. Mitochondrion. 2007;7:1339.CrossRefGoogle ScholarPubMed
27.Koga, Y, Akita, Y, Nishioka, J, et al. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology. 2005;64:71012.CrossRefGoogle ScholarPubMed
28.Hirata, K, Akita, Y, Povalko, N, et al. Effect of L-arginine on synaptosomal mitochondrial function. Brain Dev. 2008;30:23845.CrossRefGoogle ScholarPubMed
29.Naini, A, Kaufmann, P, Shanske, S, Engelstad, K, De Vivo, DC, Schon, EA.Hypocitrullinemia in patients with MELAS: an insight into the “MELAS paradox”. J Neurol Sci. 2005;229–230:18793.CrossRefGoogle Scholar
30.El-Hattab, AW, Emrick, LT, Craigen, WJ, Scaglia, F.Citrulline and arginine utility in treating nitric oxide deficiency in mitochondrial disorders. Mol Genet Metab. 2012;107:24752.CrossRefGoogle ScholarPubMed
31.Lekoubou, A, Kouame-Assouan, AE, Cho, TH, Luaute, J, Nighoghossian, N, Derex, L.Effect of long-term oral treatment with L-arginine and idebenone on the prevention of stroke-like episodes in an adult MELAS patient. Rev Neurol. 2011;167:8525.CrossRefGoogle Scholar
32.Poulton, J, Chiaratti, MR, Meirelles, FV, Kennedy, S, Wells, D, Holt, IJ.Transmission of mitochondrial DNA diseases and ways to prevent them. PLoS Genet. 2010;6 e1001066.CrossRefGoogle Scholar
33.Poulton, J, Kennedy, S, Oakeshott, P, Wells, D.Preventing transmission of maternally inherited mitochondrial DNA diseases. BMJ. 2009;338:b94.CrossRefGoogle ScholarPubMed
34.Tachibana, M, Amato, P, Sparman, M, et al. Towards germline gene therapy of inherited mitochondrial diseases. Nature. 2013;493:62731.CrossRefGoogle ScholarPubMed
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