Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites

Abstract

Objective: To compare the phenotype of primary-appearing dystonia due to variant ataxia-telangiectasia (A-T) with that of other dystonia ascertained for genetics research.

Methods: Movement disorder specialists examined 20 Canadian Mennonite adult probands with primary-appearing dystonia, as well as relatives in 4 families with parent-child transmission of dystonia. We screened for the exon 43 c.6200 C>A (p. A2067D) ATM mutation and mutations in DYT1 and DYT6. Clinical features of the individuals with dystonia who were harboring ATM mutations were compared with those of individuals without mutations.

Result: Genetic analysis revealed a homozygous founder mutation in ATM in 13 members from 3 of the families, and no one harbored DYT6 or DYT1 mutations. Dystonia in ATM families mimicked other forms of early-onset primary torsion dystonia, especially DYT6, with prominent cervical, cranial, and brachial involvement. Mean age at onset was markedly younger in the patients with variant A-T (n = 12) than in patients with other dystonia (n = 23), (12 years vs 40 years, p < 0.05). The patients with A-T were remarkable for the absence of notable cerebellar atrophy on MRI, lack of frank ataxia on examination, and absence of ocular telangiectasias at original presentation, as well as the presence of prominent myoclonus-dystonia in 2 patients. Many also developed malignancies.

Conclusion: Ataxia and telangiectasias may not be prominent features of patients with variant A-T treated for dystonia in adulthood, and variant A-T may mimic primary torsion dystonia and myoclonus-dystonia.

Figure 1. Pedigrees for multiplex families

Families A–C harbored the mutation; family D did not. + demarcates individuals examined. A shaded circle or square designates an individual with dystonia. No + indicates individuals affected by history.

Figure 2. Age at onset in individuals with variant ataxia-telangiectasia (A-T) compared with those with nonmutation primary dystonia

Figure 3. Brain MRI (A) and transcranial ultrasonography (B) images

(A) 1.5-T nonenhanced and enhanced MRI of the brain (for C:301) at age 59 revealed several small unidentified bright objects in the white matter of the cerebral hemispheres bilaterally as well as minimal dilatation of the ventricles and subarachnoid spaces consistent with aging, but was otherwise normal, without cerebellar atrophy. After the radiologist was informed of the diagnosis, possible vermian atrophy was noted on rereview. (B) Transcranial sonography of the midbrain: image results for a patient with Parkinson disease (left) and C:301 (right). Yellow encircling demarcates area of hyperechogenicity. In C:301 there was hyperechogenicity compared with laboratory controls.