Adult onset dystonia, chorea or related movement disorder

Gene: ARX

I don't know

A review by Eldar Dedic (Independent Clinical Genetics Consultant):
Kwong, et al. (2019, PMID: 31324350) presented a Chinese family with infantile epileptic dyskinetic encephalopathy. The whole-exome-sequencing revealed ARX c.989G>A (p.Arg330His) in 13 years of age affected proband (who also suffered from dystonia), as well as in his unaffected mother and sister. Proband also had a healthy older brother who did not carry the variant. The proband’s muscle whole mitochondrial DNA analysis did not show the presence of a pathogenic variant. - Please note that ARX c.989G>A (p.Arg330His) was absent from gnomAD v2.1.1 as of December 2021 Gorman, et al. (2018, PMID: 29778428) presented 2 years of age Ohtahara syndrome male case of Romanian origin. Whole-exome-sequencing revealed ARX c.1600G>C (p.Ala534Pro) variant in a patient (who also had dystonia) and in his healthy mother (who was a low-level mosaic). The proband was negative for chromosomal array testing and had a normal brain MRI. - Please note that ARX c.1600G>C (p.Ala534Pro) was absent from gnomAD v2.1.1 as of December 2021 Charzewska, et al. (2013, PMID: 23657928) presented a family with intellectual disability and dystonia. Sequencing of ARX revealed the presence of c.4A>T (p.Ser2Cys) variant in 4 affected males (including 2 who had onset of dystonia at 2nd day of life and 12 years of age, respectively) and in 5 female carriers. - Please note that ARX c.4A>T (p.Ser2Cys) was absent from gnomAD v2.1.1 as of December 2021 Breen, et al. (2018, PMID: 29343471) presented 12 years of age male case with intellectual disability and hand dystonia. The ARX c.426_458dup (p.Gly143_Ala153dup) variant has been reported in the proband, his cousin and maternal uncle from Pakistan, both of which had hand dystonia, as well as in his unaffected mother. The patient had whole-exome-sequencing as one of the previous tests carried out. - Please note that ARX c.426_458dup (p.Gly143_Ala153dup) was absent from gnomAD v2.1.1 as of December 2021

Created: 24 Oct 2023, 10:37 a.m. | Last Modified: 24 Oct 2023, 10:37 a.m.

Panel Version: 3.16

PMID: 31324350; 29778428; 23657928; 29343471 report four ARX variants in four unrelated families, where childhood onset dystonia is apparent, together with other phenotypic features.

Created: 24 Oct 2023, 10:35 a.m. | Last Modified: 24 Oct 2023, 10:35 a.m.

Panel Version: 3.16

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Publications

• 31324350
• 29778428
• 23657928
• 29343471

I don't know

Review and rating from Emily Jones (North Bristol NHS Trust) on behalf of South West GLH for GMS Neurology specialist test group.

Created: 23 Apr 2019, 12:18 p.m.

I don't know

Gene is associated with wide spectrum of disease. Partington syndrome has characteristic hand dystonia, but dystonia can be a feature across the ARX spectrum. More likely to present in childhood. Appears appropriate for panel but clinical input may be helpful before upgrading. A recurrent variant c.441_464dup may not be detected by clinical exome due to polyalanine tract in exon 2

Created: 23 Apr 2019, 12:14 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Partington Syndrome, 300382

Publications

• 29343471
• 17664398
• 26029707

Mode of pathogenicity
Other - please provide details in the comments