Autosomal Dominant DOPA-Responsive Dystonia via the GCH1 Gene

Autosomal Dominant DOPA-Responsive Dystonia (AD-DRD) is characterized by a childhood-onset dystonia that responds well to low doses of oral levodopa. It is a heterogeneous disorder in respect to age of onset, clinical features, and disease progression. Average age of onset is about 6 years. Dystonia of the foot is usually the presenting feature and results in gait disturbance. Patients occasionally present with arm dystonia, hand tremor, or slowness of movements. Additional features include brisk deep-tendon reflexes in the leg, ankle or big toe and spasticity. Symptoms can increase in severity later in the day and/or following physical exertion. They are lessened after a night's sleep (Ichinose et al. 1994; Grimes et al. 2002; Klein et al. 2002). Psychiatric manifestations in the form of depression, anxiety, obsessive compulsive behavior, eating disorders, sleep disorders have been reported in rare cases (Hahn et al. 2001; Van Hove et al. 2006). Localized symptoms often progress gradually to a more generalized dystonia, although dystonic movements are prevalent in the legs during the entire course of the disease. Parkinson-like symptoms in the form of postural tremor, bradykinesia and rigidity may develop at later ages. AD-DRD does not affect life expectancy (Furukawa 2015).

DRD is estimated to affect about 0.5 in 1,000,000 individuals worldwide (Nygaard et al. 1993).

Autosomal dominant DRD is inherited with gender-related incomplete penetrance. The disease is 3-4 times more prevalent in female patients than in males, with no clear evidence for genetic imprinting (Furukawa et al. 1998). An apparently negative family history is reported in a significant number of affected individuals (Cai et al. 2013). It is unclear how many of the apparently sporadic cases are inherited with low penetrance.

Pathogenic variants in the GCH1 gene are the major genetic cause of AD-DRD. About 200 causative variants have been reported to date. All types of variants have been reported. About half of these are missense. The other half is made mostly of truncating variants, including large deletions (Ichinose et al. 1994; Hagenah et al. 2005; Furukawa et al. 2000; Klein et al. 2002; Steinberger et al. 2007). De novo GCH1 pathogenic variants have been reported in patients with AD-DRD, and a relatively high spontaneous mutation rate in the gene has been speculated (Furukawa et al. 1998). Pathogenic variants in GCH1 have been reported in patients with AD-DRD from various geographic and ethnic origins (Bandmann et al. 1996; Steinberger et al. 2000; Ohta et al. 2006; Scola et al. 2007; Camargos et al. 2008).

GCH1 encodes the GTP cyclohydrolase 1 enzyme, which catalyzes the first step of tetrahydrobiopterin synthesis. Tetrahydrobiopterin is a co-factor for the rate-limiting enzyme tyrosine hydroxylase that is involved in the biosynthesis of catecholamines, including dopamine.

This test will detect pathogenic variants in the GCH1 gene in up to 87% of patients with a clinical diagnosis of dystonia and marked and sustained response to levodopa treatment (Hagenah et al. 2005: Clot et al. 2009).

This test will detect large pathogenic deletions involving the GCH1 gene in up to 11% of patients with a clinical diagnosis of dystonia and marked and sustained response to levodopa treatment (Steinberger et al. 2007; Clot et al. 2009).

This test provides full coverage of all coding exons of the GCH1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.