A Novel Variant of GCH1 in Dopa-Responsive Dystonia With Oculogyric Crises and Intrafamilial Phenotypic Heterogeneity.

Abstract

Dopa-responsive dystonia (DRD) is a rare, treatable disorder caused by the dysfunction of enzymes involved in the biosynthesis of dopamine, leading to dopamine deficiency. 1 The most common form of DRD, also known as Segawa disease, is an autosomal dominant heterozygous variant in the guanosine triphosphate cyclohydrolase-1 ( GCH1 ) gene, resulting in a deficiency of tetra-hydrobiopterin (BH4), an essential cofactor for tyrosine hydroxylase (TH), which catalyzes the rate-limiting step of dopamine synthesis. The typical presentation of Segawa disease is child-hood-onset lower limb dystonia and diurnal fluctuation worsening toward the evening, with an excellent response to low doses of levodopa. However, phenotypic and genetic heterogeneity and sex-specific differences in penetrance frequently lead to misdiagnosis, which delays levodopa treatment and results in permanent orthopedic deformities requiring unnecessary surgical procedures. 2 Oculogyric crises (OGCs) are rare dystonic movement disorders characterized by paroxysmal, conjugate, tonic, and typically upward deviation of the eyes, lasting minutes to hours