Alternative titles; symbols
ORPHA: 99718; DO: 0111755;
A number sign (#) is used with this entry because the disorder is caused by mutation in the mitochondrial complex I, subunit ND6 gene (MTND6; 516006), the complex I, subunit ND4 gene (MTND4; 516003), the complex I, subunit ND1 gene (MTND1; 516000), and the MTND3 gene (516002).
Marsden et al. (1986) reported a unique disorder in 7 members of 2 families in whom dystonia was variably associated with subacute visual loss or asymptomatic optic atrophy, and striking bilateral symmetric lucencies, especially in the putamen, were found on computerized tomography. Marsden et al. (1986) suggested that the disorder in a family reported by Miyoshi et al. (1969) may have been the same, as well as that in the large kindred reported by Novotny et al. (1985).
Novotny et al. (1986) reported an American Hispanic family with Leber hereditary optic neuropathy (LHON; 535000) in which maternal relatives in the pedigree ranged from normal, to adult-onset optic atrophy, to pediatric dystonia associated with bilateral striatal necrosis. The later individuals experienced early-onset dementia with asymmetric dystonia, bulbar dysfunction, corticospinal tract abnormalities, and short stature. Computerized tomography and magnetic resonance imaging of the brain showed basal ganglia abnormalities, designated as 'infantile bilateral striatal necrosis,' with the onset of striatal necrosis between ages 1.5 and 9 years. One severely affected individual developed bilateral striatal necrosis, and later developed optic atrophy. Muscle biopsy of 1 severely affected individual showed excessive variation in fiber size and increased central nuclei, but no ragged-red fibers or ultrastructural abnormalities of mitochondria. One interesting feature of this pedigree is that LHON predominated in the earlier generations while dystonia predominated in the more recent generations. In generations I to III, of 22 maternal relatives, 7 (32%) had LHON while 2 (9%) had dystonia. By contrast, of the 20 maternal relatives in generation IV and V, 1 (5%) had LHON, 1 (5%) had both LHON and dystonia, and 12 (60%) had dystonia (Novotny et al., 1986; Wallace et al., 1985).
Spruijt et al. (2007) reported a 35-year-old woman with sequential left and right vision loss, optic nerve atrophy, and bilateral central scotoma consistent with LHON. Serum and CSF lactate levels were increased, and brain MRI showed a few punctate white matter abnormalities. Her 34-year-old brother had developed progressive spastic dystonia beginning at age 3 years. Since age 27, he was wheelchair-bound with mental retardation, scoliosis, dysarthria, strabismus without ophthalmoplegia, and accumulation of abnormal mitochondria on sural nerve biopsy. His brain MRI showed bilateral hyperintensities in the putamen. Muscle biopsies from the sister and brother showed 8% and 16% residual complex I activity, respectively.
Wang et al. (2009) reported a large Chinese Han family in which 6 members had Leber optic atrophy and dystonia. The proband, who was most severely affected, developed an abnormal gait at age 5 years after a bout of diarrhea. At age 14 years, he had painless and progressive visual loss, and lost ambulation due to dystonia. There was no evidence of mental or psychomotor retardation. By the third decade, he was unable to stand or speak clearly. Neurologic exam showed generalized spastic dystonia involving the limbs, trunk, neck, and face, with diffuse muscle wasting. Brain MRI showed abnormal signals in the basal ganglia. Other family members had a similar, but less severe, disease course with spastic gait, dystonia, visual loss, and basal ganglia lesions. Nine additional family members had sudden onset of painless vision loss due to optic atrophy between ages 14 and 30 years, but without other symptoms. A tenth patient had loss of vision and was found to have postural tremor, hyperreflexia, and unstable gait. The phenotype was variable within this family.
In Marsden's family 1, all 3 sibs were affected; the mother had parkinsonism. In his second family, 4 persons in 3 separate sibships were affected; 2 of the sibships were related as double first cousins and the single affected person of the third sibship was related as a second cousin to the others. Mitochondrial inheritance was discussed as a possibility; however, one of the affected was related to the others through his father.
On full presentation of the data in their family, Novotny et al. (1986) concluded that it was probably a mitochondrial disease.
The family reported by Novotny et al. (1986) was found by Jun et al. (1994) to harbor a Native American mtDNA and was heteroplasmic for a MTND6*LDYT14459A mutation (516006.0002) arising on the Native American haplogroup D mtDNA background. It was not found on any of 38 related mtDNA haplotypes nor in 310 control mtDNAs representing the major ethnic groups. The penetrance was high when the mutation approached homoplasmy, with 48% of maternal relatives manifesting pediatric dystonia, 10% LHON, and 3% LHON plus dystonia (Novotny et al., 1986: Wallace et al., 1985). Since the MTND6*LDYT14459A mutation is heteroplasmic in this family and approaches homoplasmy in the recent generations Jun et al. (1994) suggested that the increased severity correlated with the segregation of the mutant mtDNAs.
In a large Dutch kindred in which Leber optic atrophy was associated with hereditary spastic dystonia in some members whereas only 1 type of abnormality was found in others, De Vries et al. (1996) found 2 previously unreported mtDNA mutations: a heteroplasmic mutation in the MTND4 gene (11696A-G; 516003.0003) and a homoplasmic mutation in the MTND6 gene (14596T-A; 516006.0003).
Watanabe et al. (2006) identified the 14459G-A mutation in the MTND6 gene in 2 Japanese sisters with childhood-onset dystonia, mental deterioration, adult-onset LHON, and basal ganglia lesions.
In a woman with optic neuropathy and her brother with spastic dystonia, Spruijt et al. (2007) identified a heteroplasmic 3697G-A transition in the MTND1 gene (516000.0012). The mutation load was greater than 97% in muscle tissues of the woman with LHON and 88% in the blood of her brother.
In affected members of a Chinese Han family with Leber optic atrophy and dystonia, Wang et al. (2009) identified a homoplasmic 10197G-A mutation in the MTND3 gene (516002.0004). The mutation occurred on mitochondrial haplogroup D4b. The mutation was homoplasmic in all affected individuals and in 2 unaffected family members, indicating reduced penetrance.
De Vries, D. D., Went, L. N., Bruyn, G. W., Scholte, H. R., Hofstra, R. M. W., Bolhuis, P. A., van Oost, B. A. Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia. Am. J. Hum. Genet. 58: 703-711, 1996. [PubMed: 8644732]
Jun, A. S., Brown, M. D., Wallace, D. C. A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia. Proc. Nat. Acad. Sci. 91: 6206-6210, 1994. [PubMed: 8016139] [Full Text: https://doi.org/10.1073/pnas.91.13.6206]
Marsden, C. D., Lang, A. E., Quinn, N. P., McDonald, W. I., Abdallat, A., Nimri, S. Familial dystonia and visual failure with striatal CT lucencies. J. Neurol. Neurosurg. Psychiat. 49: 500-509, 1986. [PubMed: 3711913] [Full Text: https://doi.org/10.1136/jnnp.49.5.500]
Miyoshi, K., Matsuoka, T., Mizushima, S. Familial holotopistic striatal necrosis. Acta Neuropath. 13: 240-249, 1969. [PubMed: 5805975] [Full Text: https://doi.org/10.1007/BF00690644]
Novotny, E. J., Dorfman, L. J., Louis, A., Sogg, R. L., Steinman, L., Wallace, D. A neurodegenerative disorder with generalised dystonia: a new mitochondriopathy? Neurology 35 (suppl. 1): 273 only, 1985. [PubMed: 3155827] [Full Text: https://doi.org/10.1212/wnl.35.2.273]
Novotny, E. J., Jr., Singh, G., Wallace, D. C., Dorfman, L. J., Louis, A., Sogg, R. L., Steinman, L. Leber's disease and dystonia: a mitochondrial disease. Neurology 36: 1053-1060, 1986. [PubMed: 3736869] [Full Text: https://doi.org/10.1212/wnl.36.8.1053]
Spruijt, L., Smeets, H. J., Hendrickx, A., Bettink-Remeijer, M. W., Maat-Kievit, A., Schoonderwoerd, K. C., Sluiter, W., de Coo, I. F. Hintzen, R. Q.: A MELAS-associated ND1 mutation causing Leber hereditary optic neuropathy and spastic dystonia. Arch. Neurol. 64: 890-893, 2007. [PubMed: 17562939] [Full Text: https://doi.org/10.1001/archneur.64.6.890]
Wallace, D. C., Singh, G., Hopkins, L. C., Novotny, E. J. Maternally inherited diseases of man. In: Quagliariello, E.; Slater, E. C.; Palmieri, F.; Saccone, C.; Kroon, A. M. (eds.): Achievements and Perspectives of Mitochondrial Research. Vol. 2. Amsterdam: Elsevier (pub.) 1985. Pp. 427-436.
Wang, K., Takahashi, Y., Gao, Z.-L., Wang, G.-X., Chen, X.-W., Goto, J., Lou, J.-N., Tsuji, S. Mitochondrial ND3 as the novel causative gene for Leber hereditary optic neuropathy and dystonia. Neurogenetics 10: 337-345, 2009. [PubMed: 19458970] [Full Text: https://doi.org/10.1007/s10048-009-0194-0]
Watanabe, M., Mita, S., Takita, T., Goto, Y., Uchino, M., Imamura, S. Leber's hereditary optic neuropathy with dystonia in Japanese family. J. Neurol. Sci. 243: 31-34, 2006. [PubMed: 16380132] [Full Text: https://doi.org/10.1016/j.jns.2005.11.003]