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Central Nervous System Imaging in Mitochondrial Disorders

Published online by Cambridge University Press:  02 December 2014

Josef Finsterer
Josef Finsterer*
Affiliation:
Krankenanstalt Rudolfstiftung, Vienna, Austria, Europe
*
Postfach 20, 1180 Vienna, Austria, Europe
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Abstract

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Imaging of central-nervous-system (CNS) abnormalities is important in patients with mitochondrial disorders (MCDs) since the CNS is the organ second most frequently affected in MCDs and some of them are potentially treatable. Clinically relevant imaging techniques for visualization of CNS abnormalities in MCDs are computed tomography, magnetic resonance imaging, and MR-spectroscopy. The CNS abnormalities in MCDs visualized by imaging techniques include stroke-like lesions with cytotoxic or vasogenic edema, laminar cortical necrosis, basal ganglia necrosis, focal or diffuse white matter lesions, focal or diffuse atrophy, intra-cerebral calcifications, cysts, lacunas, hypometabolisation, lactacidosis, hemorrhages, cerebral hypo- or hyperperfusion, intra-cerebral artery stenoses, or moyamoya syndrome. The CNS lesions may proceed with or without clinical manifestations, why neuroimaging should be routinely carried out in all MCDs to assess the degree of CNS involvement. Some of these lesions may remain unchanged for years, some may show contiguous spread and progression, but some may even disappear, spontaneously or in response to medication. Dynamics of Stroke-like lesions may be positively influenced by L-arginine, dichloracetate, steroids, edavarone, or antiepileptics. Symptomatic treatment of CNS abnormalities in MCD patients may positively influence their outcome.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 36 , Issue 2 , March 2009 , pp. 143 - 153
Copyright
Copyright © The Canadian Journal of Neurological 2009

References

1.Zeviani, M, Carelli, V.Mitochondrial disorders. Curr Opin Neurol. 2007;20:564–71.CrossRefGoogle ScholarPubMed
2.Finsterer, J.Mitochondriopathies. Eur J Neurol. 2004;11:163–86.CrossRefGoogle ScholarPubMed
3.Finsterer, J, Jarius, C, Eichberger, H.Phenotype variability in 130 adult patients with respiratory chain disorder. J Inher Metab Dis. 2001;24:560–76.Google Scholar
4.Leonard, JV, Schapira, AHV.Mitochondrial respiratory chain disorders I: mitochondrial DNA defects. Lancet. 2000;355:299–304.Google Scholar
5.Berio, A, Piazzi, A.A case of Kearns-Sayre syndrome with autoimmune thyroiditis and possible Hashimoto encephalopathy. Panminerva Med. 2002;44:265–9.Google Scholar
6.Kaufmann, P, Shungu, DC, Sano, MC, Jhung, S, Engelstad, K, Mitsis, E., et al.Cerebral lactic acidosis correlates with neurological impairment in MELAS. Neurology. 2004;62:1297–302.Google Scholar
7.Ahn, MS, Sims, KB, Frazier, JA.Risperidone-induced psychosis and depression in a child with a mitochondrial disorder. J Child Adolesc Psychopharmacol. 2005;15:520–5.CrossRefGoogle Scholar
8.Gire, C, Girard, N, Nicaise, C, Einaudi, MA, Montfort, MF, Dejode, JM.Clinical features and neuroradiological findings of mitochondrial pathology in six neonates. Childs Nerv Syst. 2002;18:621–8.Google Scholar
9.Haas, R, Dietrich, R.Neuroimaging of mitochondrial disorders. Mitochondrion. 2004;4:471–90.CrossRefGoogle ScholarPubMed
10.Van Goethem, G, Luoma, P, Rantamaki, M, Al Memar, A, Kaakkola, S, Hackman, P., et al.POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement. Neurology. 2004;63:1251–7.Google Scholar
11.Millar, WS, Lignelli, A, Hirano, M.MRI of five patients with mitochondrial neurogastrointestinal encephalomyopathy. Am J Roentgenol. 2004;182:1537–41.CrossRefGoogle ScholarPubMed
12.Apostolova, LG, White, M, Moore, SA, Davis, PH.Deep white matter pathologic features in watershed regions: a novel pattern of central nervous system involvement in MELAS. Arch Neurol. 2005;62:1154–6.CrossRefGoogle ScholarPubMed
13.Dinopoulos, A, Cecil, KM, Schapiro, MB, Papadimitriou, A, Hadjigeorgiou, GM, Wong, B., et al.Brain MRI and proton MRS findings in infants and children with respiratory chain defects. Neuropediatrics. 2005;36:290–301.CrossRefGoogle ScholarPubMed
14.Lerman-Sagie, T, Leshinsky-Silver, E, Watemberg, N, Luckman, Y, Lev, D.White matter involvement in mitochondrial diseases. Mol Genet Metab. 2005;84:127–36.Google Scholar
15.Abe, K.Cerebral lactic acidosis correlates with neurological impairment in MELAS. Neurology. 2004;63:2458.Google Scholar
16.Desguerre, I, Pinton, F, Nabbout, R, Moutard, ML, N’Guyen, S, Marsac, C., et al.Infantile spasms with basal ganglia MRI hypersignal may reveal mitochondrial disorder due to T8993G mtDNA mutation. Neuropediatrics. 2003;34:265–9.Google Scholar
17.Farina, L, Chiapparini, L, Uziel, G, Bugiani, M, Zeviani, M, Savoiardo, M.MR findings in Leigh syndrome with COX deficiency and SURF-1 mutations. Am J Neuroradiol. 2002;23:1095–100.Google Scholar
18.Rossi, A, Biancheri, R, Bruno, C, Di Rocco, M, Calvi, A, Pessagno, A., et al.Leigh Syndrome with COX deficiency and SURF1 gene mutations: MR imaging findings. Am J Neuroradiol. 2003;24:1188–91.Google Scholar
19.Topcu, M, Saatci, I, Apak, RA, Soylemezoglu, F, Akcoren, Z.Leigh syndrome in a 3-year-old boy with unusual brain MR imaging and pathologic findings. Am J Neuroradiol. 2000;21:224–7.Google Scholar
20.Lev, D, Yanoov-Sharav, M, Watemberg, N, Leshinsky-Silver, E, Lerman-Sagie, T.White matter abnormalities in Leber’s hereditary optic neuropathy due to the 3460 mitochondrial DNA mutation. Eur J Paediatr Neurol. 2002;6:121–3.Google Scholar
21.Vinkler, C, Lev, D, Kalish, H, Watemberg, N, Yanoov-Sharav, M, Leshinsky-Silver, E., et al.Familial optic atrophy with white matter changes. Am J Med Genet A. 2003 1;121:263–5.Google Scholar
22.Moroni, I, Bugiani, M, Bizzi, A, Castelli, G, Lamantea, E, Uziel, G.Cerebral white matter involvement in children with mitochondrial encephalopathies. Neuropediatrics. 2002;33: 79–85.Google Scholar
23.Weinstock, A, Giglio, P, Cohen, ME, Bakshi, R, Januario, J, Balos, L.Diffuse magnetic resonance imaging white-matter changes in a 15-year-old boy with mitochondrial encephalomyopathy. J Child Neurol. 2002;17:47–9.CrossRefGoogle Scholar
24.Iizuka, T, Sakai, F, Ide, T, Miyakawa, S, Sato, M, Yoshii, S.Regional cerebral blood flow and cerebrovascular reactivity during chronic stage of stroke-like episodes in MELAS - implication of neurovascular cellular mechanism. J Neurol Sci. 2007;257: 126–38.Google Scholar
25.Feng, F, You, H, Gao, J, Li, XZ, Meng, CL, Sun, HY., et al.Evaluation of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes with magnetic resonance imaging and proton magnetic resonance spectroscopy. Chin Med Sci J. 2006; 21:234–8.Google Scholar
26.Jian-Ren, L.Precipitation of stroke-like event by chickenpox in a child with MELAS syndrome. Neurol India. 2005;53:323–5.Google Scholar
27.Kolb, SJ, Costello, F, Lee, AG, White, M, Wong, S, Schwartz, ED., et al.Distinguishing ischemic stroke from the stroke-like lesions of MELAS using apparent diffusion coefficient mapping. J Neurol Sci. 2003;216:11–5.Google Scholar
28.Ohshita, T, Oka, M, Imon, Y, Watanabe, C, Katayama, S, Yamaguchi, S., et al.Serial diffusion-weighted imaging in MELAS. Neuroradiology. 2000;42:651–6.Google Scholar
29.Oppenheim, C, Galanaud, D, Samson, Y, Sahel, M, Dormont, D, Wechsler, B., et al.Can diffusion weighted magnetic resonance imaging help differentiate stroke from stroke-like events in MELAS? J Neurol Neurosurg Psychiatry. 2000;69:248–50.Google Scholar
30.Iizuka, T, Sakai, F, Kan, S, Suzuki, N.Slowly progressive spread of the stroke-like lesions in MELAS. Neurology. 2003;61:1238–44.Google Scholar
31.Kim, HS, Kim, DI, Lee, BI, Jeong, EK, Choi, C, Lee, JD., et al.Diffusion-weighted image and MR spectroscopic analysis of a case of MELAS with repeated attacks. Yonsei Med J. 2001;42:128–33.Google Scholar
32.Mizrachi, IB, Gomez-Hassan, D, Blaivas, M, Trobe, JD.Pitfalls in the diagnosis of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes. J Neuroophthalmol. 2006;26:38–43.Google Scholar
33.Wang, XY, Noguchi, K, Takashima, S, Hayashi, N, Ogawa, S, Seto, H.Serial diffusion-weighted imaging in a patient with MELAS and presumed cytotoxic oedema. Neuroradiology. 2003;45:640–3.Google Scholar
34.Longo, N, Schrijver, I, Vogel, H, Pique, LM, Cowan, TM, Pasquali, M., et al.Progressive cerebral vascular degeneration with mitochondrial encephalopathy. Am J Med Genet A. 2008;146: 361–7.Google Scholar
35.Maeda, K, Tatsumi, M, Tahara, M, Murata, Y, Kawai, H, Yasuda, H.A case of stroke-like episode of MELAS of which progressive spread would be prevented by edaravone. Rinsho Shinkeigaku. 2005;45:416–21.Google Scholar
36.Bi, WL, Baehring, JM, Lesser, RL.Evolution of brain imaging abnormalities in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. J Neuroophthalmol. 2006;26: 251–6.Google Scholar
37.Corda, D, Rosati, G, Deiana, GA, Sechi, G.“Erratic” complex partial status epilepticus as a presenting feature of MELAS. Epilepsy Behav. 2006;8:655–8.Google Scholar
38.van der Knaap, MS, Smit, LS, Nauta, JJ, Lafeber, HN, Valk, J.Cortical laminar abnormalities-occurrence and clinical significance. Neuropediatrics. 1993;24:143–8.Google Scholar
39.Donaire, A, Carreno, M, Gómez, B, Fossas, P, Bargalló, N, Agudo, R., et al.Cortical laminar necrosis related to prolonged focal status epilepticus. J Neurol Neurosurg Psychiatry. 2006;77:104–6.Google Scholar
40.Arii, J, Tanabe, Y.Leigh syndrome: serial MR imaging and clinical follow-up. Am J Neuroradiol. 2000;21:1502–9.Google Scholar
41.Bénit, P, Slama, A, Cartault, F, Giurgea, I, Chretien, D, Lebon, S., et al.Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome. J Med Genet. 2004;41:14–7.Google Scholar
42.Chol, M, Lebon, S, Bénit, P, Chretien, D, de Lonlay, P, Goldenberg, A., et al.The mitochondrial DNA G13513A MELAS mutation in the NADH dehydrogenase 5 gene is a frequent cause of Leigh-like syndrome with isolated complex I deficiency. J Med Genet. 2003;40:188–91.CrossRefGoogle ScholarPubMed
43.Horváth, R, Abicht, A, Holinski-Feder, E, Laner, A, Gempel, K, Prokisch, H., et al.Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA). J Neurol Neurosurg Psychiatry. 2006;77:74–6.Google Scholar
44.Martin, MA, Blazquez, A, Gutierrez-Solana, LG, Fernández-Moreira, D, Briones, P, Andreu, AL., et al.Leigh syndrome associated with mitochondrial complex I deficiency due to a novel mutation in the NDUFS1 gene. Arch Neurol. 2005;62:659–61.CrossRefGoogle ScholarPubMed
45.McFarland, R, Taylor, RW, Turnbull, DM.The neurology of mitochondrial DNA disease. Lancet Neurol. 2002;1:343–51.Google Scholar
46.Bargalló, N, Burrel, M, Berenguer, J, Cofan, F, Buñesch, L, Mercader, JM.Cortical laminar necrosis caused by immunosuppressive therapy and chemotherapy. Am J Neuroradiol. 2000;21:479–84.Google Scholar
47.Barragan-Campos, HM, Vallee, JN, Lo, D, Barrera-Ramírez, CF, Argote-Greene, M, Sánchez-Guerrero, J., et al.Brain magnetic resonance imaging findings in patients with mitochondrial cytopathies. Arch Neurol. 2005;62:737–42.Google Scholar
48.Geldof, K, Ramboer, K, Goethals, JM, Verhaeghe, L.CT and MRI appearance of mitochondrial encephalopathy. JBR-BTR. 2007; 90:288–9.Google Scholar
49.Scaglia, F, Wong, LJ, Vladutiu, GD, Hunter, JV.Predominant cerebellar volume loss as a neuroradiologic feature of pediatric respiratory chain defects. Am J Neuroradiol. 2005;26:1675–80.Google Scholar
50.Kim, J, Lee, SK, Kim, EY, Kim, DI, Lee, YM, Lee, JS., et al.Neuroradiologic findings in children with mitochondrial disorder: correlation with mitochondrial respiratory chain defects. Eur Radiol. 2008;18:1741–8.Google Scholar
51.van Straaten, HL, van Tintelen, JP, Trijbels, JM, van den Heuvel, LP, Troost, D, Rozemuller, JM., et al.Neonatal lactic acidosis, complex I/IV deficiency, and fetal cerebral disruption. Neuropediatrics. 2005;36:193–9.Google Scholar
52.Keng, WT, Pilz, DT, Minns, B, FitzPatrick, DR.A3243G mitochondrial mutation associated with polymicrogyria. Dev Med Child Neurol. 2003;45:704–8.Google Scholar
53.Walker, M, Samii, A, Bird, T.Coexistence of tuberous sclerosis and Friedreich ataxia. J Neurol Sci. 2004;221:91–3.Google Scholar
54.Finsterer, J.Central nervous system manifestations of mitochondrial disorders. Acta Neurol Scand. 2006;114:217–38.Google Scholar
55.Riggs, JE, Schochet, SS Jr, Fakadej, AV, Riggs, JE, Schochet, SS Jr, Fakadej, AV., et al.Mitochondrial encephalomyopathy with decreased succinate-cytochrome c reductase activity. Neurology. 1984;34:48–53.Google Scholar
56.Kotagal, S, Peterson, PL, Martens, ME, Lee, CP, Nigro, M, Archer, CR.Impaired NADH-CoQ reductase activity in a child with moyamoya syndrome. Pediatr Neurol. 1988;4:241–4.Google Scholar
57.Iizuka, T, Sakai, F, Suzuki, N, Hata, T, Tsukahara, S, Fukuda, M, et al.Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome. Neurology. 2002;59:816–24.CrossRefGoogle ScholarPubMed
58.Petruzzella, V, Zoccolella, S, Amati, A, Torraco, A, Lamberti, P, Carnicella, F, et al.Cerebellar ataxia as atypical manifestation of the 3243A>G MELAS mutation. Clin Genet. 2004;65:64–5.Google Scholar
59.Younes-Mhenni, S, Thobois, S, Streichenberger, N, Giraud, P, Mousson-de-Camaret, B, Montelescaut, ME, et al.Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) associated with a Fahr disease and cerebellar calcifications. Rev Med Interne. 2002;23:1027–9.CrossRefGoogle ScholarPubMed
60.Breningstall, GN, Lockman, LA.Massive focal brain swelling as a feature of MELAS. Pediatr Neurol. 1988;4:366–70.Google Scholar
61.Taylor, RW, Schaefer, AM, Barron, MJ, McFarland, R, Turnbull, DM.The diagnosis of mitochondrial muscle disease. Neuromuscul Disord. 2004;14:237–45.Google Scholar
62.Sakuta, R, Honzawa, S, Murakami, N, Goto, Y, Nagai, T.Atypical MELAS associated with mitochondrial tRNA(Lys) gene A8296G mutation. Pediatr Neurol. 2002;27:397–400.CrossRefGoogle ScholarPubMed
63.Brown, GK.Congenital brain malformations in mitochondrial disease. J Inherit Metab Dis. 2005;28:393–401.Google Scholar
64.Majoie, CB, Akkerman, EM, Blank, C, Barth, PG, Poll-The, BT, den Heeten, GJ.Mitochondrial encephalomyopathy: comparison of conventional MR imaging with diffusion-weighted and diffusion tensor imaging: case report. Am J Neuroradiol. 2002;23:813–6.Google Scholar
65.Ulmer, S, Flemming, K, Hahn, A, Stephani, U, Jansen, O.Detection of acute cytotoxic changes in progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome) using diffusion-weighted MRI and MR spectroscopy. J Comput Assist Tomogr. 2002;26:641–6.Google Scholar
66.Wolf, NI, Seitz, A, Harting, I, Smeitink, JA, Trijbels, F, van den Heuvel, LP, et al.New pattern of brain MRI lesions in isolated complex I deficiency. Neuropediatrics. 2003;34:156–9.Google Scholar
67.Argov, Z, Arnold, DL.MR spectroscopy and imaging in metabolic myopathies. Neurol Clin. 2000;18:35–52.Google Scholar
68.Bianchi, MC, Tosetti, M, Battini, R, Manca, ML, Mancuso, M, Cioni, G, et al.Proton MR spectroscopy of mitochondrial diseases: analysis of brain metabolic abnormalities and their possible diagnostic relevance. Am J Neuroradiol. 2003;24:1958–66.Google ScholarPubMed
69.Gulati, S, Shah, T, Menon, S, Jayasundar, R, Kalra, V.Magnetic resonance spectroscopy in pediatric neurology. Indian J Pediatr. 2003;70:317–25.Google Scholar
70.Jeppesen, TD, Schwartz, M, Hansen, K, Danielsen, ER, Wibrand, F, Vissing, J.Late onset of stroke-like episode associated with a 3256C->T point mutation of mitochondrial DNA. J Neurol Sci. 2003;214:17–20.Google Scholar
71.Kamada, K, Takeuchi, F, Houkin, K, Kitagawa, M, Kuriki, S, Ogata, A, et al.Reversible brain dysfunction in MELAS: MEG, and (1)H MRS analysis. J Neurol Neurosurg Psychiatry. 2001;70:675–8.Google Scholar
72.Lin, DD, Crawford, TO, Barker, PB.Proton MR spectroscopy in the diagnostic evaluation of suspected mitochondrial disease. Am J Neuroradiol. 2003;24:33–41.Google Scholar
73.Moller, HE, Kurlemann, G, Putzler, M, Wiedermann, D, Hilbich, T, Fiedler, B.Magnetic resonance spectroscopy in patients with MELAS. J Neurol Sci. 2005;229–30Google Scholar
74.Moller, HE, Wiedermann, D, Kurlemann, G, Hilbich, T, Schuierer, G.Application of NMR spectroscopy to monitoring MELAS treatment: a case report. Muscle Nerve. 2002;25:593–600.Google Scholar
75.Otsuki, T, Kanamatsu, T, Tsukada, Y, Goto, Y, Okamoto, K, Watanabe, H.Carbon 13-labeled magnetic resonance spectroscopy observation of cerebral glucose metabolism: metabolism in MELAS: case report. Arch Neurol. 2005;62:485–7.Google Scholar
76.Rango, M, Bonifati, C, Bresolin, N.Parkinson’s disease and brain mitochondrial dysfunction: a functional phosphorus magnetic resonance spectroscopy study. J Cereb Blood Flow Metab. 2006;26:283–90.Google Scholar
77.Sciacco, M, Prelle, A, D’Adda, E, Lamperti, C, Bordoni, A, Rango, M, et al.Familial mtDNA T8993C transition causing both the NARP and the MILS phenotype in the same generation. A morphological, genetic and spectroscopic study. J Neurol. 2003;250:1498–500.Google Scholar
78.Wilichowski, E, Pouwels, PJ, Frahm, J, Hanefeld, F.Quantitative proton magnetic resonance spectroscopy of cerebral metabolic disturbances in patients with MELAS. Neuropediatrics. 1999;30:256–63.Google Scholar
79.Lodi, R, Carelli, V, Cortelli, P, Iotti, S, Valentino, ML, Barboni, P, et al.Phosphorus MR spectroscopy shows a tissue specific in vivo distribution of biochemical expression of the G3460A mutation in Leber’s hereditary optic neuropathy. J Neurol Neurosurg Psychiatry. 2002;72:805–7.CrossRefGoogle Scholar
80.Valentino, ML, Barboni, P, Ghelli, A, Bucchi, L, Rengo, C, Achilli, A, et al.The ND1 gene of complex I is a mutational hot spot for Leber’s hereditary optic neuropathy. Ann Neurol. 2004;56: 631–41.Google Scholar
81.Sijens, PE, Smit, GP, Rödiger, LA, van Spronsen, FJ, Oudkerk, M, Rodenburg, RJ, et al.MR spectroscopy of the brain in Leigh syndrome. Brain Dev. In Press 2008.Google Scholar
82.José da Rocha, A, Túlio Braga, F, Carlos Martins Maia, A Jr, Jorge da Silva, C, Toyama, C, Pereira Pinto Gama, H, et al.Lactate detection by MRS in mitochondrial encephalopathy: optimization of technical parameters. J Neuroimaging. 2008;18: 1–8.Google Scholar
83.Bianchi, MC, Sgandurra, G, Tosetti, M, Battini, R, Cioni, G.Brain magnetic resonance in the diagnostic evaluation of mitochondrial encephalopathies. Biosci Rep. 2007;27:69–85.Google Scholar
84.Saneto, RP, Friedman, SD, Shaw, DW.Neuroimaging of mitochondrial disease. Mitochondrion. In Press 2008.Google Scholar
85.Dubeau, F, De Stefano, N, Zifkin, BG, Arnold, DL, Shoubridge, EA.Oxidative phosphorylation defect in the brains of carriers of the tRNAleu(UUR) A3243G mutation in a MELAS pedigree. Ann Neurol. 2000;47:179–85.Google Scholar
86.Turconi, AC, Benti, R, Castelli, E, Pochintesta, S, Felisari, G, Comi, G, et al.Focal cognitive impairment in mitochondrial encephalomyopathies: a neuropsychological and neuroimaging study. J Neurol Sci. 1999;170:57–63.Google Scholar
87.Minnerop, M, Kornblum, C, Joe, AY, Tatsch, K, Kunz, WS, Klockgether, T, et al.Dopamine transporter SPECT in patients with mitochondrial disorders. J Neurol Neurosurg Psychiatry. 2005;76:118–20.CrossRefGoogle ScholarPubMed
88.Peng, NJ, Liu, RS, Li, JY, Tsay, DG, Kong, KW, Kwok, CG, et al.Increased cerebral blood flow in MELAS shown by Tc-99m HMPAO brain SPECT. Neuroradiology. 2000;42:26–9.Google Scholar
89.Thajeb, P, Wu, MC, Shih, BF, Tzen, CY, Chiang, MF, Yuan, RY.Brain single photon emission computed tomography in patients with A3243G mutation in mitochondrial DNA tRNA. Ann N Y Acad Sci. 2005;1042:48–54.Google Scholar
90.Luoma, P, Melberg, A, Rinne, JO, Kaukonen, JA, Nupponen, NN, Chalmers, RM, et al.Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet. 2004;364:875–82.Google Scholar
91.Damian, MS, Hertel, A, Seibel, P, Reichmann, H, Bachmann, G, Schachenmayr, W, et al.Follow-up in carriers of the ‘MELAS’ mutation without strokes. Eur Neurol. 1998;39:9–15.Google Scholar