Phenotype of five patients with dopa-responsive dystonia and mutations in GCH1

Abstract

Autosomal dominant dystonia with diurnal variation, also known as DOPA-responsive dystonia (DRD, Segawa syndrome; MIM#128230), can be caused by mutations in the GTP cyclohydrolase I gene GCHI on chromosome 14q22.1-q22.2. Reports on patients with thoroughly characterized DRD phenotypes and GCHI mutations have disclosed marked phenotypic variability. Here, we report on five patients of two unrelated families with DRD and heterozygous nonsense (c.181G > T) or heterozygous splice site mutations (WS5 + 3insT) of GCHI. Symptoms reported by these patients include gait abnormality, foot deformity, torticollis, muscle weakness, muscle cramps, myalgia, tremor, depression, and attention deficit. The severity of symptoms varied from mild involvement with good response to levodopa to severe dystonia with marked gait disturbances and only incomplete amelioration of symptoms upon levodopa treatment. The affected parent of each index patient had been misdiagnosed with a psychiatric andlor neurological disorder; the correct diagnosis was assigned only after the diagnosis of DRD had been established in their children. Our report adds further features to the phenotype of DRD caused by GCHl gene mutations.