Alternative titles; symbols
ORPHA: 98805; DO: 0090041;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.3 | Dystonia 4, torsion, autosomal dominant | 128101 | Autosomal dominant | 3 | TUBB4A | 602662 |
A number sign (#) is used with this entry because of evidence that autosomal dominant torsion dystonia-4 (DYT4) is caused by heterozygous mutation in the TUBB4A gene (602662) on chromosome 19p13.
Mutation in the TUBB4A gene can also cause hypomyelinating leukodystrophy-6 (HLD6; 612438), a more severe disorder.
Dystonia-4, also known as whispering dysphonia, is an autosomal dominant neurologic disorder characterized by onset in the second to third decade of progressive laryngeal dysphonia followed by the involvement of other muscles, such as the neck or limbs. Some patients develop an ataxic gait (summary by Hersheson et al., 2013).
Parker (1985) described an extensive Australian kindred in which persons through 4 generations and by implication a fifth had torsion dystonia manifested mainly by a whispering dysphonia. They were able to shout and yell when emotional, had no trouble communicating after drinking alcohol, and talked normally in their sleep, yet when they tried under most circumstances to speak their voices came out only in a faint whisper. The ailment sometimes progressed to the point that the affected persons were unable to utter a sound when trying to speak. In some persons the whispering dysphonia continued throughout life as an isolated feature but more commonly it was the initial presentation of a 'more pervasive disease with extremely varied expression.' One living affected person with involuntary movements had classical findings of idiopathic dystonia musculorum deformans. At least 3 deceased members had been diagnosed as having Huntington disease. Others had isolated dystonic features, particularly torticollis and spastic dysphonia. The kindred contained a brother and sister with Wilson disease (277900). The occurrence of Wilson disease in the same kindred may have been coincidental. Ahmad et al. (1993) provided a follow-up of the family reported by Parker (1985), which then contained affected members in 5 generations. The onset of symptoms ranged from 13 to 37 years.
Wilcox et al. (2011) provided another follow-up of the family reported by Parker (1985). Affected family members tended to have a thin face and body habitus, even before the development of any speech or swallowing problems. Soon after the onset of spasmodic dysphonia, the cheeks became hollowed, the lower face tapered to the chin, the tongue became bradykinetic and showed poor motor patterning, and the mouth was open. All patients had laryngeal adductor dysphonia, which was responsive to alcohol. Several patients developed generalized dystonia or an unusual 'hobby horse gait,' with toe walking, stiff legs, and skipping gait. Brain MRI was unremarkable.
Bally et al. (2021) reported 11 family members from 4 families with DYT4. The dystonia ranged from mild to very severe (death at age 13 years). Mean and median ages of onset were 17 and 21 years, respectively (range 2-30 years). The site of onset was most often the larynx (in 6), followed by arm (in 5) and neck (in 4). Nearly all patients (9 of 11) developed laryngeal involvement. Generalized dystonia was seen in 8 of the 11 patients. The rate of progression varied markedly among the patients.
The pedigree pattern of the Australian family with dystonia reported by Parker (1985) was consistent with autosomal dominant inheritance. Ahmad et al. (1993) noted that no male-to-male transmission had occurred in the family. Among patients' offspring over the age of 40 years, the ratio of affected to unaffected subjects was 21:31 (40.4% affected). Nine of 22 affected members were male. Only 2 of the males had children: 2 sons and 4 daughters, of whom only 1 daughter was affected.
By linkage analysis of the large family with DYT4 originally reported by Parker (1985), Hersheson et al. (2013) found linkage to chromosome 19p13.12 between rs12977803 and rs2303099 (maximum multipoint lod score of 6.33).
In members of the large multigenerational family of English and Australian origin with dystonia and Wilson disease originally reported by Parker (1985), Wilcox et al. (2011) identified mutations in the ATP7B gene (606882), thus explaining the Wilson disease phenotype in the family. The ATP7B mutations did not segregate with the dystonia phenotype, confirming 2 genetic disorders in the family.
In affected members of the family with dystonia originally reported by Parker (1985), Hersheson et al. (2013) identified a heterozygous mutation in the TUBB4A gene (R2G; 602662.0001). The mutation, which was found by linkage analysis and exome sequencing, was not found in several large control databases and segregated with dystonia in the family. Previous site-directed mutagenesis studies by Yen et al. (1988) had shown that mutations in the MREI domain of TUBB4A, including R2G, abrogate the autoregulatory capability of TUBB4A, which may affect the balance of tubulin subunits and interfere with proper assembly. The findings suggested a role for the cytoskeleton in dystonia pathogenesis.
Independently and simultaneously, Lohmann et al. (2013) identified a heterozygous R2G mutation in the TUBB4A gene in affected members of the family with DYT4 originally reported by Parker (1985). The mutation was found by genomewide linkage analysis combined with genome sequencing in 2 family members. The mutation was confirmed by Sanger sequencing, segregated with the disorder in the family, and was not present in 1,000 control chromosomes or in the Exome Variant Server database. Primary cells from 1 of the mutation carriers showed decreased levels of mutant TUBB4A mRNA compared to controls, suggesting that the pathogenesis involved reduced levels of TUBB4. Screening of the TUBB4A gene in 394 unrelated patients with dystonia revealed a different heterozygous missense variant (A271T; 602662.0003) in a woman with onset of spasmodic dysphonia at age 60 years; functional studies of this variant were not performed.
In 4 families with 11 family members with autosomal dominant dystonia, Bally et al. (2021) used next-generation sequencing with a dystonia gene panel or whole-exome sequencing to identify 4 novel heterozygous missense variants in the TUBB4A gene (602662) (D295N, R46M, Q424H, and R121W). Variants segregated with disease in 3 of the families, with evidence for incomplete penetrance in 2 of them; in the fourth family, 1 affected and 4 unaffected members carried the variant (D295N). All variants changed highly conserved amino acids. No functional studies were performed, but all variants were predicted to be deleterious by in silico analysis. All were confirmed by Sanger sequencing, and none was seen in population databases.
Ahmad et al. (1993) performed linkage studies in the large Australian pedigree originally reported by Parker (1985) and excluded location of the responsible locus (here symbolized DYT4) on 9q (see DYT1, 128100). Investigation for linkage using markers flanking the Wilson disease locus likewise yielded negative results, thus excluding the possibility that the disorder was due to an allele at the WND locus.
In the family with dystonia reported by Parker (1985), Jarman et al. (1999) excluded linkage to selected markers on chromosomes 8 and 18.
Ahmad, F., Davis, M. B., Waddy, H. M., Oley, C. A., Marsden, C. D., Harding, A. E. Evidence for locus heterogeneity in autosomal dominant torsion dystonia. Genomics 15: 9-12, 1993. [PubMed: 8432555] [Full Text: https://doi.org/10.1006/geno.1993.1003]
Bally, J. F., Camargos, S., Oliveira Dos Santos, C., Kern, D. S., Lee, T., Pereira da Silva-Junior, F., Puga, R. D., Cardoso, F., Barbosa, E. R., Yadav, R., Ozelius, L. J., de Carvalho Aguiar, P., Lang, A. E. DYT-TUBB4A (DYT4 dystonia). new clinical and genetic observations. Neurology 96: e1887-e1897, 2021. [PubMed: 32943487] [Full Text: https://doi.org/10.1212/WNL.0000000000010882]
Hersheson, J., Mencacci, N. E., Davis, M., MacDonald, N., Trabzuni, D., Ryten, M., Pittman, A., Paudel, R., Kara, E., Fawcett, K., Plagnol, V., Bhatia, K. P., Medlar, A. J., Stanescu, H. C., Hardy, J., Kleta, R., Wood, N. W., Houlden, H. Mutations in the autoregulatory domain of beta-tubulin 4a cause hereditary dystonia. Ann. Neurol. 73: 546-553, 2013. [PubMed: 23424103] [Full Text: https://doi.org/10.1002/ana.23832]
Jarman, P. R., del Grosso, N., Valente, E. M., Leube, B., Cassetta, E., Bentivoglio, A. R., Waddy, H. M., Uitti, R. J., Maraganore, D. M., Albanese, A., Frontali, M., Auburger, G., Bressman, S. B., Wood, N. W., Nygaard, T. G. Primary torsion dystonia: the search for genes is not over. J. Neurol. Neurosurg. Psychiat. 67: 395-397, 1999. [PubMed: 10449567] [Full Text: https://doi.org/10.1136/jnnp.67.3.395]
Lohmann, K., Wilcox, R. A., Winkler, S., Ramirez, A., Rakovic, A., Park, J.-S., Arns, B., Lohnau, T., Groen, J., Kasten, M., Bruggemann, N., Hagenah, J., and 17 others. Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene. Ann. Neurol. 73: 537-545, 2013. [PubMed: 23595291] [Full Text: https://doi.org/10.1002/ana.23829]
Parker, N. Hereditary whispering dysphonia. J. Neurol. Neurosurg. Psychiat. 48: 218-224, 1985. [PubMed: 3156966] [Full Text: https://doi.org/10.1136/jnnp.48.3.218]
Wilcox, R. A., Winkler, S., Lohmann, K., Klein, C. Whispering dysphonia in an Australian family (DYT4): a clinical and genetic reappraisal. Mov. Disord. 26: 2404-2408, 2011. [PubMed: 21956287] [Full Text: https://doi.org/10.1002/mds.23866]
Yen, T. J., Machlin, P. S., Cleveland, D. W. Autoregulated instability of beta-tubulin mRNAs by recognition of the nascent amino terminus of beta-tubulin. Nature 334: 580-585, 1988. [PubMed: 3405308] [Full Text: https://doi.org/10.1038/334580a0]