Environmental modifiers of DYT1 dystonia - A case control study

Objective: To assess, in a case-control design, whether any environmental factors are significantly associated with clinical manifestation of dystonia in patients carrying the DYT1 mutation. Background: DYT1 dystonia is an autosomal dominant disorder caused by a GAG deletion in the DYT1/TOR1A gene on chromosome 9q34. Clinical penetrance is only 30%. Although a genetic modifier of DYT1 mutation penetrance, (the D216H polymorphism) has been identified, it explains only a small proportion of reduced penetrance. Here we studied whether any environmental factors might influence penetrance. Methods: A questionnaire detailing a number of potential environmental factors was completed by 39 manifesting DYT1 carriers, (23 females, mean age 37.5; range 9-74), 23 non-manifesting DYT1 carriers, (17 females; mean age 53.7; range 21-86) and 48 DYT1 negative family members, (28 females; mean age 54.8; range 28-86) belonging to 22 families from the UK, Poland, France and Italy who were recruited between 2000 and 2010. The case-control questionnaire recorded items including pregnancy and birth history, development, past medical history, injuries, vaccination, medications and drugs. The cut off for consideration of environmental factors was taken as the age at onset of dystonia in the manifesting DYT1 group. Results: Frequency of abnormal delivery, (p= 0,026), wisdom, (p= 0,006) and other teeth, (p= 0,007) removal and early smoking, (p=0,031) were significantly higher in DYT1 manifesting carriersthan in two control groups. There were no significant differences for other environmental factors including infections or peripheral trauma. Conclusions: Abnormal delivery appears to be a risk factor for the appearance of dystonic symptoms in DYT1 mutation carriers. It is not known if brain injury during delivery might trigger the later development of dystonia, or if sub-clinical dystonic symptoms contribute to difficult delivery in patients who will later manifest with dystonia.