Alternative titles; symbols
SNOMEDCT: 702423009; ORPHA: 3213, 52368; DO: 0050757;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq22.1 | Mohr-Tranebjaerg syndrome | 304700 | X-linked recessive | 3 | TIMM8A | 300356 |
A number sign (#) is used with this entry because Mohr-Tranebjaerg syndrome (MTS) is caused by mutation in the DDP gene (TIMM8A; 300356) on chromosome Xq22.
Mohr-Tranebjaerg syndrome (MTS) is characterized by early childhood onset of postlingual progressive sensorineural deafness followed by progressive dystonia, mental deterioration, cortical blindness, spasticity, and psychiatric manifestations (summary by Ujike et al., 2001).
Mohr and Mageroy (1960) described a Norwegian family in which males in 4 generations were affected with a progressive form of deafness. Sufficient hearing was present at first such that speech developed normally, then deteriorated. Impaired hearing first became evident at age 3 to 5 years. The first individual deduced to be a heterozygous carrier lived in Nordvik, a small fishing village on an island in north Norway, about midway between Narvik and Trondheim.
Although originally reported as nonsyndromic X-linked recessive deafness, Tranebjaerg et al. (1992) and Tranebjaerg et al. (1995) found on reinvestigation several ocular features in the family of Mohr and Mageroy (1960), including myopia, decreased visual acuity, constricted visual fields, and abnormal electroretinogram. The deafness was shown to be part of a progressive syndrome that included visual disability leading to cortical blindness, dystonia, fractures, and mental deficiency.
In 2 and perhaps 3 males in 3 successive generations, connected through possible carrier females, Scribanu and Kennedy (1976) observed dystonia and deafness. Deafness, first recognized at age 2 years in the affected member most fully studied, was progressive. Severe dysarthria, striking deterioration of handwriting, occasional bizarre posturing of head and neck, and hyperactivity were evident by age 8, and he died at age 11. The proband's maternal uncle had onset of deafness at age 6 years, followed by progressive dystonia such that after age 18 years he was unable to walk or talk. He died at age 20. A nephew of the proband, at age 6, has sensorineural deafness but no clear evidence of motor disorder. Pathologic changes were mainly neuronal loss and gliosis in the basal ganglia.
Pelletier and Tanguay (1975) described a family in which 8 males in 4 generations became deaf in adolescence.
Jensen (1981) described a 3-year-old boy and his 2 maternal uncles, aged 33 and 41 years, with a seemingly 'new' syndrome characterized by profound sensorineural hearing loss with onset in infancy, followed in adolescence by progressive optic nerve atrophy with loss of vision and in adulthood by progressive dementia. Jensen et al. (1987, 1989) gave follow-up on this Danish family. The new data indicated that the syndrome is a generalized degenerative disease of the central nervous system and strengthened the original proposal that the syndrome is genetic with X-linked recessive inheritance. Both of the uncles died at the age of about 40 years in a state of general deterioration. In one of them the most striking finding at autopsy was the presence of extensive calcification located in all parts of the central nervous system and affecting all structures, including meninges, vessels, and neurons. Calcification was thought to be secondary to the degenerative changes. Moderate diffuse wasting of skeletal muscles was found. Tranebjaerg et al. (2001) studied the affected nephew in this family, who was then 21 years old. He had a cerebral scan at age 9, which showed moderate cortical atrophy. At age 19, he had dysphagia and moderate ataxic gait. There was no dystonia. He was mildly 'demented.' Positron emission tomography scan showed abnormally low uptake by the parietal and temporal lobes, and especially low uptake by the medial and frontal areas of the temporal lobes, similar to the abnormal pattern seen in Alzheimer dementia. Unlike his maternal uncles, he had ophthalmologically normal optic discs and no subjective visual complaints despite progressive visual evoked potential abnormalities. Tranebjaerg et al. (2001) thought that the optic nerve atrophy in the uncles was probably an end-stage expression of a widespread diffuse neuropathy supported by the neuropathologic findings in the family. Based on a comparison of the features in the Danish family, originally thought to have a distinct syndrome called Jensen syndrome, and the features in the original Norwegian family that led to the description of the Mohr-Tranebjaerg syndrome, Tranebjaerg et al. (2001) concluded that the disorders should 'be lumped into one deafness-dystonia-optic neuropathy syndrome.'
Hayes et al. (1998) used the designation X-linked dystonia-deafness syndrome for the disorder in an Australian family of Anglo-Saxon extraction. The kindred contained 2 pairs of half brothers, each with the same mother.
Ujike et al. (2001) reported the first non-white family with the disorder, affecting 5 males in 4 generations of a Japanese family. Deafness presented at an early age, followed by varying degrees of dystonia presenting at ages 15 to 30 years. Two individuals had mild mental deterioration, and visual disability was absent in all.
Clinical Variability
The 3 families in which Jin et al. (1996) demonstrated mutations in the DDP gene (see MOLECULAR GENETICS) displayed overlapping but not identical deafness phenotypes. The disease was most severe in the original Norwegian family, in which mental deterioration and blindness were evident in virtually every affected individual, and least severe in another patient with a large deletion (300356.0006) and his affected relatives who suffered from only deafness and dystonia. However, the mental deterioration and blindness associated with MTS typically occur later in life, and no affected male in the large deletion family had survived beyond the age of 9 years due to the higher morbidity associated with having X-linked agammaglobulinemia.
Full studies of the original Norwegian family by Tranebjaerg et al. (1995) indicated that in the 16 affected males in 5 generations, X-linked recessive inheritance and postlingual progressive sensorineural deafness were quite certain. Some obligate carrier females showed signs of minor neuropathy and mild hearing impairment.
Linkage analysis performed by Tranebjaerg et al. (1992) yielded a maximum lod score of 3.96 with DXS17, which is localized to Xq22 and is closely linked to the COL4A5 gene (303630), the site of the mutation in X-linked Alport syndrome (301050). However, there was no family history of renal disease, and in the linkage studies, 1 recombinant with COL4A5 was observed. Linkage analysis by Tranebjaerg et al. (1995) indicated that the locus was linked to DXS101 in Xq22 with a lod score of 5.37 (zero recombination).
Koehler et al. (1999) determined the function of the DDP gene and concluded that the Mohr-Tranebjaerg syndrome is a novel type of mitochondrial disease that is most likely caused by a defective mitochondrial protein-import system.
Wallace and Murdock (1999) commented that the demonstrated involvement of DDP in the import of mitochondrial proteins implies that the underlying defect of the Mohr-Tranebjaerg syndrome is a defect in mitochondrial oxidative phosphorylation (OXPHOS), specifically due to deficiencies in carrier proteins. They found this conclusion particularly satisfying, since the phenotypes associated with the systemic OXPHOS defects resulting from mutations in mitochondrial DNA give an array of clinical symptoms that overlap with those of the Mohr-Tranebjaerg syndrome. Hence, deafness and dystonia associated with basal ganglia degeneration can now be linked to mitochondrial defects resulting from nuclear DNA as well as mitochondrial DNA mutations.
The biogenesis of the mitochondrial inner membrane is dependent on 2 distinct 70-kD protein complexes, one of which is formed by TIMM8A and TIMM13 (607383) in the mitochondrial intermembrane space. The TIMM8A/TIMM13 complex facilitates the import of the inner membrane substrate TIMM23 (605034). Roesch et al. (2004) determined that citrin (SLC25A13; 603859) and aralar (SLC25A12; 603667), which are Ca(2+)-binding aspartate/glutamate carriers (AGC) of the mitochondrial inner membrane, are substrates for the TIMM8A/TIMM13 complex. The AGCs function in the aspartate-malate NADH shuttle that moves reducing equivalents from the cytosol to the mitochondrial matrix. A lymphoblast cell line derived from an MTS patient had decreased NADH levels and defects in mitochondrial protein import. Protein expression studies indicated that DDP1 and TIMM13 showed nonuniform expression in mammals, and expression was prominent in the large neurons in the brain, which is in agreement with the expression pattern of SLC25A12. Roesch et al. (2004) hypothesized that insufficient NADH shuttling, linked with changes in Ca(2+) concentration, in sensitive cells of the CNS might contribute to the pathologic process associated with MTS.
Using positional information from a patient with sensorineural deafness and dystonia and a 21-kb deletion in Xq22, Jin et al. (1996) characterized a novel transcript lying within the deletion as a candidate for the complex syndrome of Mohr and Tranebjaerg. Jin et al. (1996) suggested that this gene, which they termed DDP (300356), was necessary for normal human neurologic development.
Jin et al. (1996) determined that the large 21-kb deletion resulted in deletion of the entire DDP gene (300356.0006), as well as disruption of the BTK gene, which is involved in the immunodeficiency X-linked agammaglobulinemia (300755). In 2 additional families, Jin et al. (1996) discovered 2 small deletions in DPP: a 1-bp deletion (300356.0001) in the original Norwegian family and a 10-bp deletion (300356.0002) in a third family with deafness, dystonia, and mental deficiency, but not blindness.
In a male patient from the Dutch family thought to have a distinct disorder called Jensen syndrome, Tranebjaerg et al. (1997) identified a nonsense mutation in the TIMM8A gene (E24X; 300356.0003). Tranebjaerg et al. (2001) identified the same mutation in the patient's 21-year-old nephew and considered Jensen syndrome to be the same as Mohr-Tranebjaerg syndrome.
Tranebjaerg et al. (2000) reported the first de novo mutation in the DDP gene in an 11-year-old Dutch boy with deafness and dystonia. Previously reported mutations had all been frameshifts/nonsense mutations or deletion of the entire gene. In this case a missense mutation (C66W; 300356.0004) caused an equally severe clinical picture.
Ujike et al. (2001) identified a novel mutation (300356.0007) in the DDP gene in 3 individuals in a Japanese family with dystonia-deafness syndrome.
Hayes, M. W., Ouvrier, R. A., Evans, W., Somerville, E., Morris, J. G. L. X-linked dystonia-deafness syndrome. Mov. Disord. 13: 303-308, 1998. [PubMed: 9539345] [Full Text: https://doi.org/10.1002/mds.870130217]
Jensen, P. K. A., Reske-Nielsen, E., Hein-Sorensen, O., Warburg, M. The syndrome of opticoacoustic nerve atrophy with dementia. Am. J. Med. Genet. 28: 517-518, 1987. [PubMed: 3425626] [Full Text: https://doi.org/10.1002/ajmg.1320280234]
Jensen, P. K. A., Reske-Nielsen, E., Hein-Sorensen, O. The syndrome of opticoacoustic nerve atrophy with dementia: a new X-linked recessive syndrome with extensive calcifications of the central nervous system. (Abstract) Clin. Genet. 35: 222-223, 1989.
Jensen, P. K. A. Nerve deafness, optic nerve atrophy, and dementia: a new X-linked recessive syndrome? Am. J. Med. Genet. 9: 55-60, 1981. [PubMed: 7195649] [Full Text: https://doi.org/10.1002/ajmg.1320090110]
Jin, H., May, M., Tranebjaerg, L., Kendall, E., Fontan, G., Jackson, J., Subramony, S. H., Arena, F., Lubs, H., Smith, S., Stevenson, R., Schwartz, C., Vetrie, D. A novel X-linked gene, DDP, shows mutations in families with deafness (DFN-1), dystonia, mental deficiency and blindness. Nature Genet. 14: 177-180, 1996. [PubMed: 8841189] [Full Text: https://doi.org/10.1038/ng1096-177]
Koehler, C. M., Leuenberger, D., Merchant, S., Renold, A., Junne, T., Schatz, G. Human deafness dystonia syndrome is a mitochondrial disease. Proc. Nat. Acad. Sci. 96: 2141-2146, 1999. [PubMed: 10051608] [Full Text: https://doi.org/10.1073/pnas.96.5.2141]
Mohr, J., Mageroy, K. Sex-linked deafness of a possibly new type. Acta Genet. Statist. Med. 10: 54-62, 1960. [PubMed: 13771732] [Full Text: https://doi.org/10.1159/000151118]
Pelletier, L., Tanguay, R. B. X-linked recessive inheritance of sensorineural hearing loss expressed during adolescence. Am. J. Hum. Genet. 27: 609-613, 1975. [PubMed: 1163535]
Roesch, K., Hynds, P. J., Varga, R., Tranebjaerg, L., Koehler, C. M. The calcium-binding aspartate/glutamate carriers, citrin and aralar1, are new substrates for the DDP1/TIMM8a-TIMM13 complex. Hum. Molec. Genet. 13: 2101-2111, 2004. [PubMed: 15254020] [Full Text: https://doi.org/10.1093/hmg/ddh217]
Scribanu, N., Kennedy, C. Familial syndrome with dystonia, neural deafness, and possible intellectual impairment: clinical course and pathological findings. Adv. Neurol. 14: 235-243, 1976. [PubMed: 181965]
Tranebjaerg, L., Hamel, B. C. J., Gabreels, F. J. M., Renier, W. O., Van Ghelue, M. A de novo missense mutation in a critical domain of the X-linked DDP gene causes the typical deafness-dystonia-optic atrophy syndrome. Europ. J. Hum. Genet. 8: 464-467, 2000. [PubMed: 10878669] [Full Text: https://doi.org/10.1038/sj.ejhg.5200483]
Tranebjaerg, L., Jensen, P. K. A., Van Ghelue, M., Vnencak-Jones, C. L., Sund, S., Elgjo, K., Jakobsen, J., Lindal, S., Warburg, M., Fuglsang-Frederiksen, A., Skullerud, K. Neuronal cell death in the visual cortex is a prominent feature of the X-linked recessive mitochondrial deafness-dystonia syndrome caused by mutations in the TIMM8a gene. Ophthalmic Genet. 22: 207-223, 2001. [PubMed: 11803487] [Full Text: https://doi.org/10.1076/opge.22.4.207.2220]
Tranebjaerg, L., Schwartz, C., Eriksen, H., Andreasson, S., Ponjavic, V., Dahl, A., Stevenson, R. E., May, M., Arena, F., Barker, D., Elverland, H. H., Lubs, H. A new X linked recessive deafness syndrome with blindness, dystonia, fractures, and mental deficiency is linked to Xq22. J. Med. Genet. 32: 257-263, 1995. [PubMed: 7643352] [Full Text: https://doi.org/10.1136/jmg.32.4.257]
Tranebjaerg, L., Schwartz, C., Huggins, K., Barker, D., Stevenson, R., Arena, J. F., Gedde-Dahl, T., Mikkelsen, M., Mellgren, S., Andersen, K., Hansen, E., Dahl, A., Eriksen, H., Lubs, H. X-linked recessive mental retardation with progressive sensorineural deafness, blindness, spastic paraplegia and dystonia. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A47 only, 1992.
Tranebjaerg, L., van Ghelue, M., Nilssen, O., Hodes, M. E., Dlouhy, S. R., Farlow, M. R., Hamel, B., Arts, W. F. M., Jankovic, J., Beach, J., Jensen, P. K. A. Jensen syndrome is allelic to Mohr-Tranebjaerg syndrome and both are caused by stop mutations in the DDP gene. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A349 only, 1997.
Ujike, H., Tanabe, Y., Takehisa, Y., Hayabara, T., Kuroda, S. A family with X-linked dystonia-deafness syndrome with a novel mutation of the DDP gene. Arch. Neurol. 58: 1004-1007, 2001. [PubMed: 11405816] [Full Text: https://doi.org/10.1001/archneur.58.6.1004]
Wallace, D. C., Murdock, D. G. Mitochondria and dystonia: the movement disorder connection? Proc. Nat. Acad. Sci. 96: 1817-1819, 1999. [PubMed: 10051550] [Full Text: https://doi.org/10.1073/pnas.96.5.1817]