Dopa-responsive dystonia revisited: diagnostic delay, residual signs, and nonmotor signs.

Objective: To investigate the delay in diagnosis, residual motor signs, and nonmotor signs of dopa-responsive dystonia (DRD) using literature and our own pilot data.

Design, setting, and patients: We searched the MEDLINE database for patients with clinically typical DRD and/or guanosine triphosphate cyclohydrolase I gene mutations from 1952 to 2011 and examined a pilot cohort of 23 outpatients with DRD and guanosine triphosphate cyclohydrolase I gene mutations.

Results: The literature search yielded 101 reports describing 576 cases. Excluding cases without proven guanosine triphosphate cyclohydrolase I gene mutations as well as homozygous and asymptomatic mutation carriers resulted in 352 cases. The mean (SD) ages at onset were 11.6 (13.4) years (literature) and 9.4 (7.7) years (pilot study). The average (SD) delays in diagnosis were 13.5 (13.3) years (literature) and 15.5 (16.3) years (pilot study); using all literature cases, they were 9.1 (7.5) years before and 15.2 (13.7) years after identification of the guanosine triphosphate cyclohydrolase I gene. Residual motor signs in patients receiving therapy were found in 28% (literature) and 39% (pilot study). Residual motor signs in the literature comprised dystonic (20%) and parkinsonian (11%) symptoms, as well as complications such as contractures or unnecessary surgical procedures. Information on nonmotor signs was given for 70 patients in the literature. Of these, 34% had depression, 19% anxiety, and 9% obsessive-compulsive disorder. Six of our own cases (32%) reported 1 or more nonmotor signs including depression and migraine.

Conclusions: The delay in diagnosis is long, despite the well-known etiology and availability of genetic testing and specific therapy. A sizable number of treated patients have residual motor signs, nonmotor signs, and complications resulting from the lack of timely therapy or unnecessary procedures.