DO: 0060937;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20p13 | Dystonia 30 | 619291 | Autosomal dominant | 3 | VPS16 | 608550 |
A number sign (#) is used with this entry because of evidence that dystonia-30 (DYT30) is caused by heterozygous mutation in the VPS16 gene (608550) on chromosome 20p13. One family with a homozygous mutation in the VPS16 gene has been reported (Cai et al., 2016).
Dystonia-30 (DYT30) is an autosomal dominant neurologic disorder characterized by the onset of symptoms in the first decades of life. Patients present with oromandibular, cervical, bulbar, or upper limb dystonia, and usually show slow progression to generalized dystonia. Some patients may lose ambulation. A subset of patients may also have neurocognitive impairment, including mild intellectual disability or psychiatric manifestations (summary by Steel et al., 2020).
In a review of the pathogenesis of disorders with prominent dystonia, Monfrini et al. (2021) classified DYT30 as belonging to a group of neurologic disorders termed 'HOPS-associated neurologic disorders' (HOPSANDs), which are caused by mutations in genes encoding various components of the autophagic/endolysosomal system, including VPS16.
Steel et al. (2020) reported 19 patients from 14 unrelated families of European descent with DYT30. The patients were ascertained through international collaboration and the GeneMatcher program. The patients, who ranged from 17 to 69 years of age, presented with progressive early-onset dystonia at a median age of 12 years (range 3 to 50). Initial features included oromandibular, bulbar, cervical, and upper limb involvement, including speech difficulties, dysphonia, and writer's cramp. Most patients developed generalized dystonia, although only a minority (16%) lost independent ambulation. About one-third of patients had mild to moderate intellectual disability and/or psychiatric manifestations, including mood disorders, impulsivity, OCD, and PTSD. Brain imaging, performed in 4 patients, showed generalized cerebral atrophy, small caudate and putamen, and T2-weighted signal abnormalities in the basal ganglia and midbrain. There was also some evidence of iron deposition.
Pott et al. (2021) reported a 42-year-old German man with DYT30. He developed right-sided writer's cramp at age 16 years, which progressed to involve the tongue, pharynx, neck, and trunk, accompanied by myoclonic jerks. He responded well to deep brain stimulation. The legs were not affected. He had no cognitive involvement, and brain imaging was unremarkable except for mild nonspecific gliosis.
Li et al. (2021) reported a 28-year-old Chinese woman with early-onset multifocal dystonia. She developed torticollis at age 11, but had a history of leg shaking at age 8. The dystonia was progressive, and she had orofacial dyskinesia, bulbar dystonia, and leg dystonia. Dysphonia and swallowing difficulties were present. The trunk was not affected, and she did not have neuropsychiatric symptoms.
Autosomal Recessive Inheritance
Cai et al. (2016) reported a large multigenerational Chinese family in which 5 individuals had onset of torticollis between 11 and 14 years of age. The dystonia became generalized in 4 patients and remained focal in 1. The 4 patients with generalized dystonia had involvement of the oropharyngeal area, limbs, and trunk. Brain imaging of 1 patient was normal.
Steel et al. (2020) and Pott et al. (2021) reported good response to deep brain stimulation in some patients with DYT30.
The transmission pattern of DYT30 in the families reported by Steel et al. (2020) was consistent with autosomal dominant inheritance and incomplete penetrance.
In 19 patients from 14 unrelated families with DYT30, Steel et al. (2020) identified heterozygous loss-of-function mutations in the VPS16 gene (see, e.g., 608550.0001-608550.0004). The mutations, which were found by exome sequencing, were absent from the gnomAD database, except for 1 (R635X), which was found once (1 of 248,918 alleles). There were 4 frameshift, 3 nonsense, and 3 splice site mutations; 1 patient had a de novo microdeletion encompassing the VPS16 gene. Four mutations were inherited from a symptomatic parent, and 4 were inherited from an asymptomatic parent, consistent with incomplete penetrance. The inheritance pattern in the remaining patients was unknown. Functional studies of the variants were not performed, but all were predicted to result in haploinsufficiency. Electron microscopic studies of fibroblasts derived from 2 unrelated patients showed increased clusters of vacuoles, some containing particulate or laminated inclusions, suggesting lysosomal dysfunction.
In a 42-year-old German man with DYT30, Pott et al. (2021) identified a heterozygous frameshift mutation in the VPS16 gene (608550.0005). The mutation was found by direct Sanger sequencing; functional studies of the variant were not performed.
In a 28-year-old Chinese woman with DYT30, Li et al. (2021) identified a heterozygous frameshift mutation in the VPS16 gene (Arg643fsTer). The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from her unaffected father, indicating incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed.
Autosomal Recessive Dystonia 30
In 5 members of a multigenerational consanguineous Chinese family with autosomal recessive inheritance of DYT30, Cai et al. (2016) identified a homozygous missense mutation in the VPS16 gene (N52K; 608550.0006). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Studies of patient cells were not performed, but generation of mice carrying the N52K mutation using CRISPR-Cas9 technology showed that the mutation caused progressively impaired motor function compared to controls. There was also a decrease in mutant VPS16 protein levels in blood from mutant mice.
Cai, X., Chen, X., Wu, S., Liu, W., Zhang, X., Zhang, D., He, S., Wang, B., Zhang, M., Zhang, Y., Li, Z., Luo, K., Cai, Z., Li, W. Homozygous mutation of VPS16 gene is responsible for an autosomal recessive adolescent-onset primary dystonia. Sci. Rep. 6: 25834, 2016. [PubMed: 27174565] [Full Text: https://doi.org/10.1038/srep25834]
Li, L.-X., Jiang, L.-T., Liu, Y., Zhang, X.-L., Pan, Y.-G., Pan, L.-Z., Nie, Z.-Y., Wan, X.-H., Jin, L.-J. Mutation screening of VPS16 gene in patients with isolated dystonia. Parkinsonism Relat. Dis. 83: 63-65, 2021.
Monfrini, E., Zech, M., Steel, D., Kurian, M. A., Winkelmann, J., Di Fonzo, A. HOPS-associated neurological disorders (HOPSANDs): linking endolysosomal dysfunction to the pathogenesis of dystonia. Brain 144: 2610-2615, 2021. [PubMed: 33871597] [Full Text: https://doi.org/10.1093/brain/awab161]
Pott, H., Bruggemann, N., Reese, R., Zeuner, K. E., Gandor, F., Gruber, D., DysTract Study Group, Klein, C., Volkmann, J., Lohmann, K. Truncating VPS16 mutations are rare in early onset dystonia. Ann. Neurol. 89: 625-626, 2021. [PubMed: 33305852] [Full Text: https://doi.org/10.1002/ana.25990]
Steel, D., Zech, M., Zhao, C., Barwick, K. E. S., Burke, D., Demailly, D., Kumar, K. R., Zorzi, G., Nardocci, N., Kaiyrzhanov, R., Wagner, M., Iuso, A., and 41 others. Loss-of-function variants in HOPS complex genes VPS16 and VPS41 cause early onset dystonia associated with lysosomal abnormalities. Ann. Neurol. 88: 867-877, 2020. [PubMed: 32808683] [Full Text: https://doi.org/10.1002/ana.25879]