Melas syndrome: a diagnostic and therapeutic approach - a report of two cases Hospital de San José, Bogotá DC.
Melas: aproximación diagnóstica y experiencia terapéutica reporte de dos casos. Hospital de San José, Bogotá DC.
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Patiño, M., & Palacios Sánchez, E. (2012). Melas syndrome: a diagnostic and therapeutic approach - a report of two cases Hospital de San José, Bogotá DC. Journal of Medicine and Surgery Repertoire, 21(4), 269–279. https://doi.org/10.31260/RepertMedCir.v21.n4.2012.830
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Abstract
Mitochondrial encephalomyopathy, lactic acidosis and stroke-Iike episodes (MELAS) is a rare syndrome featured by encephalopathy with seizures, lactic acidosis and stroke-Iike episodes which constitute a cause of cerebrovascular disease (CVC) in young adults. MELAS has extreme variability of clinical expressions in members of the same family. Its pathophysiology is based on cellular ATP depletion caused by impaired oxidative phosphorylation secondary to a mtDNA mutation. A mutation of nucleotide pair 3243 A>G is found in most cases. An adequate treatment protocol for MELAS has not yet been established and recommendationsare based on case reports or open randomized clinical trials. Coexisting conditions must receive adequate treatment considering that sorne medications can exacerbate the disease.
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References
1. 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;16:481-8.
2. Chinnery PF, Tumban DM. Epidemiology and treatment of mitochondrial disorders. Am J Med Genet. 2001;106:94-101.
3. Gerbitz K-D, van den Ouweland JMW, Maassen JA, Jaksch M. Mitochondrial diabetes mellitus: a review. Biochim Biophys Acta.1995;1271:253-60.
4. Uusimaa J, Moilanen JS, Vainionpaa L, et al. Prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children. Ann Neurol. 2007; 62:278-87.
5. Manwaring N, Jones MM, Wang JJ, et al. Population prevalence of the MELAS A3243G mutation. Mitochondrion. 2007;7:230-3.
6. 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;1142:133-58.
7. Schon EA. The Molecular and Genetic Basis of Neurologic and Psychi atric Disease. 3rd ed. New York: Butterworth-Heinemann Nestler; 2003.
8. Eirís Puñal J, Gómez Lado C, Blanco Barca MO, Castro-Gago M. Enfermedades mitocondriales. En: Protocolos Diagnóstico Terapeúticos de la AEP. Neurología Pediátrica. Madrid: AEPED; 2008. 105-15.
9. Horvath R, Reihnann R, Holinski-Feder E, Ringelstein EB, Klopstock T. The role of complex I genes in MELAS: a novel heteroplasmic mutation 3380G>A in ND1 of mtDNA. Neuromuscul Disord. 2008 Jul; 18(7):553-6.
10. Urata M, Wada Y, Kim SH, et al. High-sensitivity detection of the A3243G mutation of mitochondrial DNA by a combination of allele-specific PCR and peptide nucleic acid-directed PCR clamping. Clin Chem. 2004;50:2045-51.
11. Campos Y, Garcia A, del Hoyo P, et al. Two pathogenic mutations in the mitochondrial DNA tRNA Leu(UUR) gene (T3258C and A3280G) resulting in variable clinical phenotypes. Neuromuscul Disord. 2003 Jun; 13(5):416-20
12. Fabrizi GM, Cardaioli E, Grieco GS, et al. The A to G transition at nt 3243 of the mitochondrial tRNALeu(UUR) may cause an MERRF syndrome. J Neurol Neurosurg Psychiatry. 1996;61:47-51.
13. Yasukawa T, Suzuki T, Ishii N, Ueda T, Ohta S, Watanabe K. Defect in modification at the anticodon wobble nucleotide of mitochondrial tRNA(Lys) with the MERRF encephalomyopathy pathogenic mutation. FEBS lett. 2000;467:175-8.
14. Hirano M, Ricci E, Koenigsberger MR, et al. Metas: an original case and canica criteria for diagnosis. Neuromuscul Disord. 1992;2(2):125-35.
15. Thambisetty M, Newman NJ, Glass JD, Frankel MR. A practical approach the diagnosis and management of MELAS: case report and review. Neurologisi 2002 Sep;8(5):302-12.
16. Dougherty FE, Ernst SG, Aprille JR. Familia' recurrence of atypical symptoms i an extended pedigree with the syndrome of mitochondrial encephalomyopath' lactic acidosis, and stroke-like episodes (MELAS). J Pediatr. 1994 Nov;125(5 I 1):758-61.
17. Isaslaiki Y, Nakagawa M, Ohba N, et al. Retinal manifestations in mitochondri diseases associated with mitochondrial DNA mutation. Acta Ophthalmol Scan 1998 Feb;76(1):6-13
18. Salih MA, Abdel-Gader AG, Al-Jarallah AA, et al. Stroke in Saudi children. Epidemiology, clinical features and risk factors. Saudi Med J. 2006 Mar;27 Suppl l:Sl2-20.
19. Salih MA, Abdel-Gader AG, Zahraa JN, et al. Stroke due to mitochondrial disorders in Saudi children. Saudi Med J. 2006 Mar;27 Suppl l:S8 l-90.
20. Conforto AB, Yamamoto FI, Oba-Shinjo SM, et al. Screening far MELAS mutations in young patients with stroke of undetermined origin. Arq Neuropsiquiatr. 2007 Jun;65(2B):371-6.
21. Contreras N P, Eisa T MJ, Ramírez C D, Crutier R L. Pseudo-infarto cerebral como primera manifestación de un MELAS tardío. Rev. chil. neuro-psiquiatr. 2008;46(1 ): 35-42.
22. Grapen TI, Probovnik !, Tatemichi TK, Hirano M. Cerebral hyperemia in MELAS. Stroke. 1994;25:1873-6.
23. Lerman-Sagie T, Leshinsky-Silver E, Watemberg N, Luckman Y, Lev D. White matter involvement in mitochondrial diseases. Mol Gene! Metab. 2005 Feb;84(2): 127-36
24. Tzoulis C, Bindoff LA. Serial diffusion imaging in a case of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. Stroke. 2009; 40(2): el 5-7.
25. Thomas JE, Lee N, Thompson PO. Statins provoking MELAS syndrome. A case report. Eur Neurol. 2007;57(4):232-5
26. Finsterer J, Segall L. Drugs interfering witb mitochondrial disorders. Drug Chem Toxico!. 20!0 Apr;33(2):138-51
27. Lam CW, Lau CH, Williams JC, Chan YW, Wong LJ. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) triggered by valproate tberapy. Eur J Pediatr. 1997 Ju!; 156(7):562-4
28. Kartsounis LO, Troung DO, Morgan-Hugbes JA, Harding AE. Tbe neuropsychological features of mitochondrial myopathies and encephalomyopathies. Arch Neurol. 1992 Feb;49(2):158-60.
29. Hirano M, Pavlakis SG. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): curren! concepts. J Child Neurol. 1994 Jan;9(1):4- l 3.
30. Matsuzaki M, Takahashi R, Nakayama T, et al. Disruption of endothelial light junctions in a patient with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). Neuropediatrics. 2010;41:72-4.
31. Koga Y, Povalko N, Nishioka J, Katayama K, Kakimoto N, Matsuishi T. MELAS and L-arginine therapy: pathophysiology of stroke-like episodes. Ann N Y Acad Sci. 20!0 Jul;l201:104-IO
32. Maassen JA, LM TH, Van Essen E, et al. Mitochondrial diabetes: molecular mechanisms and clinical presentation. Diabetes. 2004;53 Suppl 1:S103-9.
33. Maassen JA, Janssen GM, t Hart LM. Molecular mechanisms of mitochondrial diabetes (MIDO). Ann Med. 2005;37(3):213-21
34. Maassen JA. Mitochondrial diabetes: pathophysiology, clinical presentation, and genetic analysis. Am J Med Genet. 2002 May 30;115(1):66-70.
35. Matsuzaki M, lzumi T, Ebato K, et al. [Hypothalamic GH Deficiency and gelastic seizures in a 10-year-old girl with MELAS]. No To Hattatsu. 1991 Jul;23(4):41 l -6
36. Finsterer J. Overview on visceral manifestations of mitochondrial disorders. Neth J Med. 2006 Mar;64(3):61-71.
37. Yilmaz A, Gdynia HJ, Ponfick M, et al. Cardiovascular magnetic resonance irnaging (CMR) reveals characteristic pattem of myocardial damage in patients with mitochondrial myopathy. Clin Res Cardiol. 2012 Apr;l 01(4):255-61
38. Lev D, Nissenkorn A, Lesbinsky-Silver E, et al. Clinical presentations of mitochondrial cardiomyopathies. Pediatr Cardiol. 2004 Sep-Oct;25(5):443-50
39. Shimotake T, Furukawa T, Inoue K, Iwai N, Takeuchi Y. Familia] occurrence of intestinal obstruction in children with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). J Pediatr Surg. 1998 Dec;33(12):1837-9.
40. Sproule DM, Dyme J, Coku J, et al. Pulmonary artery hypertension in a child with MELAS due to a point mutation of the mitochondrial tRNA((Leu)) gene (m.3243A > G). J Inherit Metab Dis. 2008 Jan 7
41. Shoji Y, Sato W, Hayasaka K, Takada G. Tissue distribution of mutan! mitochondrial DNA in mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). J lnherit Metab Dis. 1993;16(1):27-30.
42. Piccoli GB, Davico Bonina L, Campisi P, et al. Chronic kidney disease, severe arterial and arteriolar sclerosis and kidney neoplasia: on the spectrurn of kidney involvement in MELAS syndrome. BMC Nephrol. 2012 Feb 21;13:9.
43. Karvonen SL, Haapasaari KM, Kallioinen M, Oikarinen A, Hassinen IE, Majamaa K. Increased prevalence of vitiligo, but no evidence of premature ageing, in the skin of patients with bp 3243 mutation in mitochondrial DNA in the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). Br J Dermatol. 1999 Apr; 140(4):634-9.
44. Kubota Y, Ishii T, Sugihara H, Gato Y, Mizoguchi M. Skin manifestations of a patient with mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS syndrome ). J Am Acad Derrnatol. 1999 Sep;41 (3 Pt 1):469-73.
45. Horigucbi Y, Fujii T, Imamura S. Purpuric cutaneous manifestations in mitochondrial encephalomyopathy. J Dermatol. 1991 May;l8(5):295-301.
46. Sue CM, Quigley A, Katsahanis S, et al. Detection of MELAS A3243G point mutation in muscle, blood and hair follicles. J Neurol Sci. 1998 Nov 26;161(1):36-9.
47. Mathews PM, Andermann F, Silver K, Karpati G, Arnold DL. Proton MR spectroscopic characterization of differences in regional brain metabolic abnormalities in mitochondrial encephalomyopathies. Neurology. 1993;43:2484-90.
48. Hancock DK, Schwarz FP, Song F, Wong LJ, Levin BC. Design and use of a peptide nucleic acid far detection of the heteroplasmic low-frequency mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) mutation in human mitochondrial DNA. Clin Chem. 2002 Dec;48(12):2155-63.
49. Mende S, Royer L, Herr A, et al. Whole blood genome-wide expression profiling and network analysis suggest MELAS master regulators. Neurol Res. 2011 Jul; 33(6):638-55.
50. Scaglia F, Northrop JL. The mitochondrial myopathy encephalopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome: a review of treatrnent options. CNS drugs. 2006;20:443-64.
51. Kaufman KR, Zuber N, Rueda-Lara MA, Tobia A. MELAS with recurren! complex partial seizures, nonconvulsive status epilepticus, psychosis, and behavioral disturbances: case analysis with literature review. Epilepsy Behav. 2010 Aug;l 8(4):494-7
52. Tanaka J, Nagai T, Arai H, et al. Treatrnent of mitochondrial encephalomyopathy with a combination of cytochrome C and vitamins and B2. Brain Dev. 1997 Jun;1 9(4):262-7
53. Ferrari R, Merli E, Cicchitelli G, Mele D, Fucili A, Ceconi C. Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review. Ann N Y Acad Sci. 2004 Nov; 1033:79-91.
54. Krahenbuhl S, Brandner S, Kleinle S, Liechti S, Straumann D. Mitochondrial diseases represent a risk factor far valproate-induced fulminan! liver failure. Liver. 2000;20:346-8.
55. Finsterer J. Management of mitochondrial stroke-like-episodes. Eur J Neurol. 2009 Nov;l6(11):1178-84
2. Chinnery PF, Tumban DM. Epidemiology and treatment of mitochondrial disorders. Am J Med Genet. 2001;106:94-101.
3. Gerbitz K-D, van den Ouweland JMW, Maassen JA, Jaksch M. Mitochondrial diabetes mellitus: a review. Biochim Biophys Acta.1995;1271:253-60.
4. Uusimaa J, Moilanen JS, Vainionpaa L, et al. Prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children. Ann Neurol. 2007; 62:278-87.
5. Manwaring N, Jones MM, Wang JJ, et al. Population prevalence of the MELAS A3243G mutation. Mitochondrion. 2007;7:230-3.
6. 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;1142:133-58.
7. Schon EA. The Molecular and Genetic Basis of Neurologic and Psychi atric Disease. 3rd ed. New York: Butterworth-Heinemann Nestler; 2003.
8. Eirís Puñal J, Gómez Lado C, Blanco Barca MO, Castro-Gago M. Enfermedades mitocondriales. En: Protocolos Diagnóstico Terapeúticos de la AEP. Neurología Pediátrica. Madrid: AEPED; 2008. 105-15.
9. Horvath R, Reihnann R, Holinski-Feder E, Ringelstein EB, Klopstock T. The role of complex I genes in MELAS: a novel heteroplasmic mutation 3380G>A in ND1 of mtDNA. Neuromuscul Disord. 2008 Jul; 18(7):553-6.
10. Urata M, Wada Y, Kim SH, et al. High-sensitivity detection of the A3243G mutation of mitochondrial DNA by a combination of allele-specific PCR and peptide nucleic acid-directed PCR clamping. Clin Chem. 2004;50:2045-51.
11. Campos Y, Garcia A, del Hoyo P, et al. Two pathogenic mutations in the mitochondrial DNA tRNA Leu(UUR) gene (T3258C and A3280G) resulting in variable clinical phenotypes. Neuromuscul Disord. 2003 Jun; 13(5):416-20
12. Fabrizi GM, Cardaioli E, Grieco GS, et al. The A to G transition at nt 3243 of the mitochondrial tRNALeu(UUR) may cause an MERRF syndrome. J Neurol Neurosurg Psychiatry. 1996;61:47-51.
13. Yasukawa T, Suzuki T, Ishii N, Ueda T, Ohta S, Watanabe K. Defect in modification at the anticodon wobble nucleotide of mitochondrial tRNA(Lys) with the MERRF encephalomyopathy pathogenic mutation. FEBS lett. 2000;467:175-8.
14. Hirano M, Ricci E, Koenigsberger MR, et al. Metas: an original case and canica criteria for diagnosis. Neuromuscul Disord. 1992;2(2):125-35.
15. Thambisetty M, Newman NJ, Glass JD, Frankel MR. A practical approach the diagnosis and management of MELAS: case report and review. Neurologisi 2002 Sep;8(5):302-12.
16. Dougherty FE, Ernst SG, Aprille JR. Familia' recurrence of atypical symptoms i an extended pedigree with the syndrome of mitochondrial encephalomyopath' lactic acidosis, and stroke-like episodes (MELAS). J Pediatr. 1994 Nov;125(5 I 1):758-61.
17. Isaslaiki Y, Nakagawa M, Ohba N, et al. Retinal manifestations in mitochondri diseases associated with mitochondrial DNA mutation. Acta Ophthalmol Scan 1998 Feb;76(1):6-13
18. Salih MA, Abdel-Gader AG, Al-Jarallah AA, et al. Stroke in Saudi children. Epidemiology, clinical features and risk factors. Saudi Med J. 2006 Mar;27 Suppl l:Sl2-20.
19. Salih MA, Abdel-Gader AG, Zahraa JN, et al. Stroke due to mitochondrial disorders in Saudi children. Saudi Med J. 2006 Mar;27 Suppl l:S8 l-90.
20. Conforto AB, Yamamoto FI, Oba-Shinjo SM, et al. Screening far MELAS mutations in young patients with stroke of undetermined origin. Arq Neuropsiquiatr. 2007 Jun;65(2B):371-6.
21. Contreras N P, Eisa T MJ, Ramírez C D, Crutier R L. Pseudo-infarto cerebral como primera manifestación de un MELAS tardío. Rev. chil. neuro-psiquiatr. 2008;46(1 ): 35-42.
22. Grapen TI, Probovnik !, Tatemichi TK, Hirano M. Cerebral hyperemia in MELAS. Stroke. 1994;25:1873-6.
23. Lerman-Sagie T, Leshinsky-Silver E, Watemberg N, Luckman Y, Lev D. White matter involvement in mitochondrial diseases. Mol Gene! Metab. 2005 Feb;84(2): 127-36
24. Tzoulis C, Bindoff LA. Serial diffusion imaging in a case of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. Stroke. 2009; 40(2): el 5-7.
25. Thomas JE, Lee N, Thompson PO. Statins provoking MELAS syndrome. A case report. Eur Neurol. 2007;57(4):232-5
26. Finsterer J, Segall L. Drugs interfering witb mitochondrial disorders. Drug Chem Toxico!. 20!0 Apr;33(2):138-51
27. Lam CW, Lau CH, Williams JC, Chan YW, Wong LJ. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) triggered by valproate tberapy. Eur J Pediatr. 1997 Ju!; 156(7):562-4
28. Kartsounis LO, Troung DO, Morgan-Hugbes JA, Harding AE. Tbe neuropsychological features of mitochondrial myopathies and encephalomyopathies. Arch Neurol. 1992 Feb;49(2):158-60.
29. Hirano M, Pavlakis SG. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): curren! concepts. J Child Neurol. 1994 Jan;9(1):4- l 3.
30. Matsuzaki M, Takahashi R, Nakayama T, et al. Disruption of endothelial light junctions in a patient with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). Neuropediatrics. 2010;41:72-4.
31. Koga Y, Povalko N, Nishioka J, Katayama K, Kakimoto N, Matsuishi T. MELAS and L-arginine therapy: pathophysiology of stroke-like episodes. Ann N Y Acad Sci. 20!0 Jul;l201:104-IO
32. Maassen JA, LM TH, Van Essen E, et al. Mitochondrial diabetes: molecular mechanisms and clinical presentation. Diabetes. 2004;53 Suppl 1:S103-9.
33. Maassen JA, Janssen GM, t Hart LM. Molecular mechanisms of mitochondrial diabetes (MIDO). Ann Med. 2005;37(3):213-21
34. Maassen JA. Mitochondrial diabetes: pathophysiology, clinical presentation, and genetic analysis. Am J Med Genet. 2002 May 30;115(1):66-70.
35. Matsuzaki M, lzumi T, Ebato K, et al. [Hypothalamic GH Deficiency and gelastic seizures in a 10-year-old girl with MELAS]. No To Hattatsu. 1991 Jul;23(4):41 l -6
36. Finsterer J. Overview on visceral manifestations of mitochondrial disorders. Neth J Med. 2006 Mar;64(3):61-71.
37. Yilmaz A, Gdynia HJ, Ponfick M, et al. Cardiovascular magnetic resonance irnaging (CMR) reveals characteristic pattem of myocardial damage in patients with mitochondrial myopathy. Clin Res Cardiol. 2012 Apr;l 01(4):255-61
38. Lev D, Nissenkorn A, Lesbinsky-Silver E, et al. Clinical presentations of mitochondrial cardiomyopathies. Pediatr Cardiol. 2004 Sep-Oct;25(5):443-50
39. Shimotake T, Furukawa T, Inoue K, Iwai N, Takeuchi Y. Familia] occurrence of intestinal obstruction in children with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). J Pediatr Surg. 1998 Dec;33(12):1837-9.
40. Sproule DM, Dyme J, Coku J, et al. Pulmonary artery hypertension in a child with MELAS due to a point mutation of the mitochondrial tRNA((Leu)) gene (m.3243A > G). J Inherit Metab Dis. 2008 Jan 7
41. Shoji Y, Sato W, Hayasaka K, Takada G. Tissue distribution of mutan! mitochondrial DNA in mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). J lnherit Metab Dis. 1993;16(1):27-30.
42. Piccoli GB, Davico Bonina L, Campisi P, et al. Chronic kidney disease, severe arterial and arteriolar sclerosis and kidney neoplasia: on the spectrurn of kidney involvement in MELAS syndrome. BMC Nephrol. 2012 Feb 21;13:9.
43. Karvonen SL, Haapasaari KM, Kallioinen M, Oikarinen A, Hassinen IE, Majamaa K. Increased prevalence of vitiligo, but no evidence of premature ageing, in the skin of patients with bp 3243 mutation in mitochondrial DNA in the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). Br J Dermatol. 1999 Apr; 140(4):634-9.
44. Kubota Y, Ishii T, Sugihara H, Gato Y, Mizoguchi M. Skin manifestations of a patient with mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS syndrome ). J Am Acad Derrnatol. 1999 Sep;41 (3 Pt 1):469-73.
45. Horigucbi Y, Fujii T, Imamura S. Purpuric cutaneous manifestations in mitochondrial encephalomyopathy. J Dermatol. 1991 May;l8(5):295-301.
46. Sue CM, Quigley A, Katsahanis S, et al. Detection of MELAS A3243G point mutation in muscle, blood and hair follicles. J Neurol Sci. 1998 Nov 26;161(1):36-9.
47. Mathews PM, Andermann F, Silver K, Karpati G, Arnold DL. Proton MR spectroscopic characterization of differences in regional brain metabolic abnormalities in mitochondrial encephalomyopathies. Neurology. 1993;43:2484-90.
48. Hancock DK, Schwarz FP, Song F, Wong LJ, Levin BC. Design and use of a peptide nucleic acid far detection of the heteroplasmic low-frequency mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) mutation in human mitochondrial DNA. Clin Chem. 2002 Dec;48(12):2155-63.
49. Mende S, Royer L, Herr A, et al. Whole blood genome-wide expression profiling and network analysis suggest MELAS master regulators. Neurol Res. 2011 Jul; 33(6):638-55.
50. Scaglia F, Northrop JL. The mitochondrial myopathy encephalopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome: a review of treatrnent options. CNS drugs. 2006;20:443-64.
51. Kaufman KR, Zuber N, Rueda-Lara MA, Tobia A. MELAS with recurren! complex partial seizures, nonconvulsive status epilepticus, psychosis, and behavioral disturbances: case analysis with literature review. Epilepsy Behav. 2010 Aug;l 8(4):494-7
52. Tanaka J, Nagai T, Arai H, et al. Treatrnent of mitochondrial encephalomyopathy with a combination of cytochrome C and vitamins and B2. Brain Dev. 1997 Jun;1 9(4):262-7
53. Ferrari R, Merli E, Cicchitelli G, Mele D, Fucili A, Ceconi C. Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review. Ann N Y Acad Sci. 2004 Nov; 1033:79-91.
54. Krahenbuhl S, Brandner S, Kleinle S, Liechti S, Straumann D. Mitochondrial diseases represent a risk factor far valproate-induced fulminan! liver failure. Liver. 2000;20:346-8.
55. Finsterer J. Management of mitochondrial stroke-like-episodes. Eur J Neurol. 2009 Nov;l6(11):1178-84