Narrowing the DYT6 dystonia region and evidence for locus heterogeneity in the Amish–Mennonites

Abstract

The DYT6 gene for primary torsion dystonia (PTD) was mapped to chromosome 8p21-q22 in two Amish-Mennonite families who shared a haplotype of marker alleles across a 40 cM linked region. The objective of this study was to narrow the DYT6 region, clinically characterize DYT6 dystonia in a larger cohort, and to determine whether DYT6 is associated with dystonia in newly ascertained multiplex families. We systematically examined familial Amish-Mennonite dystonia cases, identifying five additional members from the original families, as well as three other multiplex Amish-Mennonite families, and evaluated the known DYT6 haplotype and recombination events. One of the three new families carried the shared haplotype, whereas the region was excluded in the two other families, suggesting genetic heterogeneity for PTD in the Amish-Mennonites. Clinical features in the five newly identified DYT6 carriers were similar to those initially described. In contrast, affected individuals from the excluded families had a later age of onset (46.9 years vs. 16.1 years in the DYT6), and the dystonia was both more likely to be of focal distribution and begin in the cervical muscles. Typing of additional markers in the DYT6-linked families revealed recombinations that now place the gene in a 23 cM region surrounding the centromere. In summary, the DYT6 gene is in a 23 cM region on chromosome 8q21-22 and does not account for all familial PTD in Amish-Mennonites.

The genetics of the dystonias – a review based on the new classification of the dystonias

“…Lifetime penetrance of this disorder is estimated to be approximately 60% with no sex differences identified 9 . The DYT6 gene (THAP1) consists of three exons and codes for the THAP1 protein 10,11 .…”

Inherited Isolated Dystonia: Clinical Genetics and Gene Function

“…This form of dystonia was characterized and mapped initially in the Amish-Mennonite population [30,31]. Similar to DYT1 dystonia, the disease in this population typically begins in childhood, with a mean age at onset of~16 years.…”

“…Similar to DYT1 dystonia, the disease in this population typically begins in childhood, with a mean age at onset of~16 years. In contrast to DYT1 dystonia, however, roughly 50% of DYT6 subjects initially develop dystonia of cranial muscles (larynx, tongue, face) or the neck, with only~5% initially manifesting in the leg (a common site of onset in DYT1 dystonia) [31]. While symptoms commonly spread and ultimately involve the leg(s) in many patients, leg involvement is typically mild, and disability in DYT6 dytstonia arises most commonly from craniocervical involvement.…”

New algorithm for the diagnosis of hereditary dystonia

“…Although DYT6 is phenotypically similar to DYT1, a great proportion of DYT6 cases have their onset in cranial or cervical muscles, and those who present limb symptoms, later they may develop cranial or cervical dystonia. Most of patients have involvement of the laryngeal muscles 4 . Genetic testing is available for both conditions.…”

“…Unfortunately, genes have not been yet identified for those conditions. Although only DYT2 and 17 have an autosomal recessive mode of transmission, DYT1 and DYT6 have an incomplete penetrance (30 and 60%, respectively), which can be easily confounded and misinterpreted as sporadic, or be due to an autosomal recessive inheritance 4,7 .…”