Clinical or sub-clinical impairment of central and peripheral myelin is of ten part of the overlapping multisystem disorders associated with a variety of mitochondrial (mt)DNA abnormalities. Suboptimal energy metabolism of the oligodendrocytes and Schwann cells carrying mitochondrial defects may cause insufficient production of myelin. Further, edema, vascular and toxic factors may directly damage myelin. The recognition that certain mtDNA point mutations are associated with inflammatory demyelination of the central nervous system suggests that additional mechanisms besides degeneration need to be considered in the development of some forms of myelin damage.
1 De Vivo DC. (1993) Mitochondrial DNA defects: Clinical features. In: DiMauro S and Wallace DC. (eds.) Mitochondrial DNA in human pathology.Raven Press Ltd: New York pp 39–52.
2.
2 Anderson S et al. (1981) Sequence and organization of the human mitochondrial genome. Nature290: 457–464.
3.
3 Attardi G. (1993) The human mitochondrial genetic system. In: DiMauro S and Wallace DC. (eds.) Mitochondrial DNA in human pathology.Raven Press Ltd: New York pp 9–25.
4.
4 Brown MD, Wallace DC. (1994) Molecular basis for mitochondrial DNA diseases. J Bioenerg Biomemb26: 273–289.
5.
5 Harding AE. (1993) Spontaneous errors of mitochondrial DNA in human diseases. In: DiMauro S and Wallace DC (eds.) Mitochondrial DNA in human pathology.Raven Press Ltd., New York pp 53–62.
6.
6 Zeviani M, Tiranti V. (1993) Inherited mendelian defects. In: DiMauro S and Wallace DC. (eds) Mitochondrial DNA in human pathology.Raven Press Ltd: New York pp 85–95.
7.
7 Cortopassi G, Arnheim N. (1993) Accumulation of mitochondrial DNA mutation in normal aging brain and muscle. In: DiMauro S and Wallace DC, (eds). Mitochondrial DNA in human pathology.Raven Press Ltd: New York pp 125–136.
8.
8 Crof t PB et al. Ocular myopathy (progressive external ophthalmoplegia) with neuropathic complications.Acta Neurol Scand55: 169–197.
9.
9 Drachman DA. (1968) The neurodegenerative disorders associated with progressive external ophthalmoplegia. Arch Neurol18: 654–674.
10.
10 Gomez MR, Engel AG, Dyck PJ. (1972) Progressive ataxia, retinal degeneration, neuromyopathy, and mental subnormality in patient with true hypoparathyroidism, dwarfism, malabsorption, and cholelithiasis. Neurology (Minneap)22: 849–855.
11.
11 Peyronnard JM, Charron L, Bellavance A, Marchand L. (1980) Neuropathy and mitochondrial myopathy. Ann Neurol7: 262–268.
12.
12 Gemignani F et al. (1982) Polyneuropathy in progressive external ophthalmoplegia. Eur Neur21: 181–188.
13.
13 Mitsumoto H et al. (1983) Chronic progressive external ophthalmoplegia (CPEO): Clinical, morphologic and biochemical studies. Neurology (Cleveland)33: 452–461.
14.
14 Yiannikas C, McLeod JG, Pollard JD, Baverstock J. (1986) Peripheral neuropathy associated with mitochondrial myopathy. Ann Neurol20: 249–257.
15.
15 Mizusawa H, Ohkoshi N, Watanabe M, Kanazawa K. (1991) Peripheral neuropathy of mitochondrial myopathies. Rev Neurol147: 501–507.
16.
16 Schroder MJ. (1993) Neuropathy associated with mitochondrial disorders. Brain Pathol3: 177–190.
17.
17 Mukoyama M et al. (1986) Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes with acanthocytosis: a clinico-pathological study of a unique case. J Neurol233: 228–232.
18.
18 Ohara S et al. (1988) An autopsy case of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke like episodes). Clin Neurol (Tokyo)28: 303–310.
19.
19 Rusanen H et al. (1995) Demyelinating polyneuropathy in a patient with the tRNALeu(UUR) mutation at base pair 3243 of the mitochondrial DNA. Neurology45: 1188–1192.
20.
20 Oldfors A et al. (1990) Neuropathology in Kearns-Sayre syndrome. Acta Neuropathol80: 541–546.
21.
21 McKelvie PA, Morley JB, Byrne E, Marzuki S. (1991) Mitochondrial encephalomyopathies: a correlation between neuropathological findings and defects in mitochondrial DNA. J Neurol Sci102: 51–60.
22.
22 Bardosi A et al. (1987) Myo-, neuro, -gastrointestinal encephalopathy (MNGIE syndrome) due to partial deficiency of cytochrome-C-oxidase. A new mitochondrial multisystem disorder. Acta Neuropathol74: 248–258.
23.
23 Simon LT et al. (1990) Polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction: POLIP syndrome. Ann Neurol28: 349–360.
24.
24 Dorfman LJ et al. (1990) Polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction: a novel familial syndrome. Neurology40: 642S.
25.
25 Blake D et al. (1990) MNGIE syndrome: Report of two new patients. Neurology40: 643S.
26.
26 Threlkeld AB et al. (1992) Ophthalmic involvement in myo-neuro-gastrointestinal encephalopathy syndrome. Am J Ophthalmol114: 322–328.
27.
27 Uncini A et al. (1994) Ophthalmoplegia, demyelinating neuropathy, leukoencephalopathy, myopathy, and gastrointestinal dysfunction with multiple deletions of mitochondrial DNA: a mitochondrial multisystem disorder in search of a name. Muscle & Nerve17: 667–674.
28.
28 Hirano M et al. (1994) Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder. Neurology44: 721–727.
29.
29 Monpetit VJA et al. (1971) Subacute necrotizing encephalopathy: a review and a study of two families. Brain94: 1–30.
30.
30 Cavanagh JB, Harding BN. (1994) Pathologic factors underlying the lesions in Leigh's disease. Tissue responses to cellular energy deprivation and their clinico-pathological consequences. Brain117: 1357–1376.
31.
31 Jacobs JM et al. (1990) Peripheral neuropathy in Leigh's disease. Brain113: 447–462.
32.
32 Ferguson FR, Critchley M. (1928) Leber's optic atrophy and its relationship with the heredo-familial ataxias. J Neurol Psychopath9: 120–132.
33.
33 Lundsgaard R. (1944) Leber's disease. A genealogic, genetic and clinical study of 101 cases of retrobulbar optic neuritis in 20 Danish families. Acta Ophthalmol (Suppl.)21: 300–306.
34.
34 Bruyn GW, Went LN. (1964) A sex-linked heredo-degenerative neurological disorder, associated with Leber's optic atrophy. Part I. Clinical studies. J Neurol Sci1: 59–80.
36 Went LJ. (1972) Leber disease and variants. In: Handbook of Clinical Neurology. Vol. 13. Neuroretinal Degenerations.Vinken PJ and Bruyn GW (eds.) North-Holland Publishing Company, Amsterdam, and American Elsevier Publishing Co., Inc: New York pp 94–110.
37.
37 Mauksch H. (1925) Ein beitrag zur Kenntsnis der familiar-hereditared Sehnervenatrophie. Augenheilk55: 196–198.
38.
38 Coulonjou R, Renard G, Pouderoux J, Nicolet L. (1953) Syndrome neuro-ophthalmologique familial paraissant genetiquement conditionne et susceptible d'eclaircir le probleme des scleroses en plaques familiales. Rev Otoneuro-ophthal25: 461–468.
39.
39 De Weerdt CJ, Went LN. (1971) Neurological studies in families with Leber's optic atrophy. Acta Neurol Scand47: 541–544.
40.
40 Harding AE et al. (1992) Occurrence of multiple sclerosis-like illness in women who have a Leber's hereditary optic neuropathy mitochondrial DNA mutation. Brain115: 979–989.
41.
41 Flanigan KM, Johns DR. (1993) Association of the 11 778 mitochondrial DNA mutation and demyelinating disease. Neurology43: 2720–2722.
42.
42 Kellar-Wood H et al. (1994) Leber's hereditary optic neuropathy mitochondrial DNA mutations in multiple sclerosis. Ann Neurol36: 109–112.
43.
43 Olsen NK et al. (1995) Leber's hereditary optic neuropathy associated with a disorder indistinguishable from multiple sclerosis in a male harboring the mitochondrial DNA 11 778 mutation. Acta Neurol Scand91: 326–329.
44.
44 Riordan-Eva P et al. (1995) The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain118: 319–337.
45.
45 Pavlakis SG et al. (1984) Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke like episodes: a distinctive clinical syndrome. Ann Neurol16: 481–488.
46.
46 Goto Y, Nonaka I, Horai S. (1990) A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature348: 651–653.
47.
47 Love S, Nicoll JAR, Kinrade E. (1993) Sequencing and quantitative assessment of mutant and wild-type mitochondrial DNA in paraffin sections from cases of MELAS. J Pathol170: 9–14.
48.
48 Ciafaloni E et al. (1991) Widespread tissue distribution of a tRNALeu(UUR) mutation in the mitochondrial DNA of a patient with MELAS syndrome. Neurology41: 1663–1665.
49.
49 Penn AMW et al. (1992) MELAS syndrome with mitochondrial tRNALeu(UUR) mutation: Correlation of clinical state, nerve conduction, and muscle 31P magnetic resonance spectroscopy during treatment with nicotinamide and ribof lavin. Neurology42: 2147–2152.
50.
50 Fukuhara N, Tokiguchi S, Shirakawa K, Tsubaki T (1980) Myoclonus epilepsy associated with ragged red fibers (mitochondrial anomalities): disease entity or syndrome? Light and electronmicroscopic studies of two cases and review of literature. J Neurol Sci47: 117–133.
51.
51 Nakano T et al. (1982) An autopsy case of degenerative type myoclonus epilepsy associated with Friedreich's ataxia and mitochondrial myopathy. Brain Nerve (Tokyo)34: 321–332.
52.
52 Sasaki H et al. (1983) Myoclonus, cerebellar disorder, neuropathy, mitochondrial myopathy, and ACTH deficiency. Neurology33: 1288–1293.
53.
53 Pavlakis SG et al. (1988) Mitochondrial myopathies and encephalomyopathies. In: Plum F (ed.). Advances in contemporary neurology, FA Davis: Philadelphia pp 95–133.
54.
54 Shof fner JM et al. (1990) Myoclonic epilepsy and ragged-red fibers disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation. Cell61: 931–937.
55.
55 Silvestri G et al. (1992) A new mtDNA mutation in the tRNALys gene associated with myoclonic epilepsy and ragged-red fibers (MERRF). Am J Hum Genet51: 1213–1217.
58 Holt IJ, Harding AE, Morgan-Hughes JA. (1988) Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature331: 717–719.
59.
59 Zeviani M et al. (1988) Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology38: 1339–1346.
60.
60 Moraes CT et al. (1989) Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Eng J Med320: 1293–1299.
61.
61 Bastiaensen LAK et al. (1978) Ophthalmoplegia plus, a real nosological entity. Acta Neurol Scand58: 9–34.
62.
62 Ionasescu V et al. (1983) Inherited ophthalmoplegia with intestinal pseudo-obstruction. J Neurol Sci59: 215–228.
63.
63 Ionasescu V et al. (1984) Late-onset oculogastrointestinal muscular dystrophy. Am J Med Genet18: 781–788.
64.
64 Hirschkovitz BI, Groll A, Ceballos R. (1972) Hereditary nerve deafness in three sisters with absent gastric motility, small bowel diverticulitis and ulceration and progressive sensory neuropathy. Birth Defect8: 27–41.
65.
65 Steiner I et al. (1987) Familial progressive neuronal disease and chronic idiopathic intestinal pseudoobstruction. Neurology37: 1046–1050.
66.
66 Lauber J, Marsac C, Kadenbach B, Seibel P. (1991) Mutations in mitochondrial tRNA genes: a frequent cause of neuromuscular diseases. Nucleic Acid Res19: 1393–1397.
67.
67 Di Mauro S et al. (1987) Cytochrome c oxidase deficiency in Leigh syndrome. Ann Neurol22: 498–506.
68.
68 Chabrol B et al. (1994) Leigh syndrome: pyruvate dehydrogenase defect. A case with peripheral neuropathy. J Chil Neurol9: 52–55.
69.
69 Van Erden PMM et al. (1985) Subacute necrotizing encephalomyelopathy (Leigh syndrome) associated with disturbed oxidation of pyruvate, malate and 2-oxoglutarate in muscle and liver. Acta Neurol Scand72: 36–42.
70.
70 Morris AAM et al. (1996) Deficiency of respiratory chain complex I is a common cause of Leigh disease. Ann Neurol40: 25–30.
71.
71 Holt IJ, Harding AE, Petty RKH, Morgan-Hughes JA. (1990) A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet46: 428–433.
72.
72 Tatuch Y et al. (1992) Heteroplasmic mtDNA mutation (T->G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet50: 852–858.
73.
73 Shof fner JM et al. (1992) Subacute necrotizing encephalopathy: oxidative phosphorylation defects and the ATPase 6 point mutation. Neurology42: 2168–2174.
74.
74 Cianfaloni E et al. (1993) Maternally inherited Leigh syndrome. J Pediatr122: 419–422.
75.
75 Santorelli FM et al. (1993) The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome. Ann Neurol34: 827–834.
76.
76 De Vries DD et al. (1993) A second missense mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome. Ann Neurol34: 410–412.
77.
77 Miller NR. (1982) Walsh and Hoyt's Clinical neuro-ophthalmology.Fourth edition. Chapter 24: The hereditary optic neuropathies.Williams & Wilkins pp 311–328.
78.
78 Kermode AG et al. (1989) Magnetic resonance imaging in Leber's optic neuropathy. J Neurology Neurosurg Psychiatry52: 671–674.
79.
79 Adams H, Blackwood W, Wilson J. (1966) Further clinical and pathological observations on Leber's optic atrophy. Brain89: 15–26.
80.
80 Nikoskelainen EK et al. (1995) Lever's ‘plus’: neurological abnormalities in patients with Leber's hereditary optic neuropathy. J Neurol Neurosurg Psychiatry59: 160–164.
81.
81 Sommer C, Schroder JM. (1989) Hereditary motor and sensory neuropathy with optic atrophy. Arch Neurol46: 973–977.
83 Wallace DC et al. (1988) Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science242: 1427–1430.
84.
84 Brown MD. (1992) Leber's hereditary optic neuropathy: a model for mitochondrial neurodegenerative diseases. FASEB J6: 2791–2799.
85.
85 Brown MD et al. (1992) Mitochondrial DNA Complex I and III mutations associated with Leber's hereditary optic neuropathy. Genetics130: 163–173.
86.
86 Johns JM, Berman J. (1991) Alternative, simultaneous complex I mitochondrial DNA mutations in Leber's hereditary optic neuropathy. Biochem Biophys Res Com174: 1324–1330.
87.
87 Mackey D, Howell N. (1992) A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochoindrial genetic etiology. Am J Hum Genet51: 1218–1228.
88.
88 Johns DR, Neufeld MJ, Park RD. (1992) An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem Biophys Res Commun187: 1551–1557.
89.
89 Oostra RJ et al. (1994) Leber's hereditary optic neuropathy: no significant evidence for primary or secondary pathogenicity of the 15 257 mutation. Hum Genet94: 265–270.
91 Nishimura M et al. (1995) No association of the 11 778 mitochondrial DNA mutation and multiple sclerosis in Japan. Neurology45: 1333–1334.
92.
92 De Vries DD et al. (1996) Genetic and biochemical impairment of mitochondrial Complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia. Am J Hum Genet58: 703–711.
93.
93 Jun AS, Brown MD, Wallace DC. (1994) A mitochondrial DNA mutation at nucleotide pair 14 459 of the NADH dehydrogenase subunit 6 gene with maternally inherited Leber hereditary optic neuropathy and dystonia. Proc Natl Acad Sci91: 6206–6210.
94.
94 Shof fner JM et al. (1995) Leber's hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation. Ann Neurol38: 163–169.
95.
95 Bet L et al. (1994) Multiple sclerosis and mitochondrial myopathy: an unusual combination of diseases. J Neurol241: 511–516.
96.
96 Poser CM et al. (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol13: 227–231.
97.
97 Anderson TD et al. (1994) Mitochondrial schwannopathy and peripheral myelopathy in a rabbit model of dideoxycytidine neurotoxicity. Lab Invest70: 724–739.
98.
98 Feldman D, Anderson TD. (1994) Schwann cell mitochondrial alterations in peripheral nerves of rabbit treated with 2′, 3′-dideoxycytidine. Acta Neuropathol87: 71–80.
99.
99 Mackenzie-Graham AJ, Mitrovic B, Smoll A, Merril JE. (1994) Differential sensitivity to nitric oxide in immortalized, cloned murine oligodendrocyte cell lines. Dev Neurosci16: 162–171.
100.
100 Mitrovic B. (1994) Nitric oxide as a potential pathological mechanism in demyelination: its differential effect on primary glial cells in vitro. Neuroscience61: 575–585.
101.
101 McFarlin DE, McFarland H. (1982) Multiple sclerosis. N Engl J Med307: 1183–1188.
102.
102 Pallini R et al. (1988) Is Leber's hereditary optic atrophy (LHOA) a mitochondrial disease? Clinical, biochemical and histological study of several families (abstract). J Neurol235: S7.
103.
103 Smith PR et al. (1995) Antibodies to human optic nerve in Leber's hereditary optic neuropathy. J Neurol Sci130: 134–138.
104.
104 Schapira AHV et al. (1990) A mitochondrial encephalomyopathy with specific deficiencies of two respiratory chain polypeptides and a circulating auto-antibody to a mitochondrial matrix protein. Brain113: 419–432.
105.
105 Loveland B et al. (1990) Maternally transmitted histocompatibility antigen of mice: A hydrophobic peptide of a mitochondrially encoded protein. Cell60: 971–980.
106.
106 Chalmers RM et al. (1995) Sequence of the human homologue of a mitochondrially encoded murine transplantation antigen in patients with multiple sclerosis. J Neurol242: 332–334.
107.
107 Brenard R, Geubel AP. (1991) Antimitochondrial and antinuclear antibodies in primary biliary cirrhosis: an update in relation to their biochemical characterization and clinical significance. Review. Acta Clin Belg46: 305–312.
108.
108 Lohr H et al. (1993) Autoreactive liver infiltrating T cells in primary biliary cirrhosis recognize inner mitochondrial epitopes and the pyruvate-dehydrogenase complex. J Hepatol18: 322–327.
109.
109 Hanefeld FA, Ernst BP, Wilichowski E, Cristen H-J. (1994) Leber's hereditary optic neuropathy mitochondrial DNA mutations in childhood multiple sclerosis. Neuropediatrics25: 331.
110.
110 Kalman B, Lublin FD, Alder H. (1995) Mitochondrial DNA mutations in multiple sclerosis. Multiple Sclerosis1: 32–36.
111.
111 Kalman B, Lublin F, Alder H. (1996) Characterization of the mitochondrial DNA in multiple sclerosis. J Neurol Sci140: 75–89.
112.
112 Adams CWH. (1972) Research on Multiple Sclerosis.CC Thomas, Springfield, J11.
