Dopamine-responsive dystonia: Clinical and therapeutic variability with identical genetic defect

Aims: The purpose of this study is to show the variable clinical symptomatology and response on dopamine in Segawa dystonia (DS) due to a. d. GTP cyclohydrolase (GCH) defect.

Methods: In 2 families with dystonic patients, 10 members (6 from family A and 4 from family B) were tested whether a defect in the GCH1 gene is detectable.

Results: A deletion of the GCH1 exons 3 to 6 was detectable in five members of family A. Clinically two children showed an increased leg tone and gait problems since the age of 2 years. The symptoms worsened toward evening and varied from day to day. Her two sisters (3 and 7 years old) were asymptomatic in spite of the identical gene defect. Their father suffered from gait problems since the age of 5 years and DS was diagnosed at the age of 34 years. The gait problems improved partially only under a therapy with Madopar. A better result was obtained with Selegiline in the most severely affected girl.

A mutation in exon 6 (heterocygote p.Lys224Arg) was detectable in three members of family B (asymptomatic mother and her two sons). The older boy suffered from a generalized muscle hypotonia during the first year of life and thereafter from dystonic movements and a tremor. At the age of 3 years, DS was diagnosed and he improved dramatically under a therapy with Madopar. His major problem is ADHS. His younger brother was treated since the age of 6 months and remained asymptomatic.

Conclusion: The clinical picture of DS is very variable in spite of identical GCH1 gene defect. In early childhood, a partial or generalized muscle hypotonia may be the first symptom followed by gait problems. In childhood, there is a daytime variability as well as variability from day to day. Under Madopar, the symptoms improve dramatically in the majority. The cause of the insufficient therapeutic response on Madopar in some members of family A is unclear.