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The estimated European prevalence of dopa-responsive dystonia (DRD) ranges from 1/1,000,000-1/200,000. DYT5a occurs more frequently than autosomal recessive DRD (DYT5b).

Onset usually occurs in childhood (average age 6 years), and females are 2-4 times more likely to suffer from this disease than males. At onset, DYT5a is typically characterized by lower limb dystonia, most commonly with flexion-inversion of the foot (equinovarus posture) resulting in gait disturbances (that can result in stumbling and falling) with diurnal fluctuations, with symptoms worsening in the evening and improving after sleep. Physical exercise may also aggravate the symptoms. Rarely, arm dystonia, postural tremor of the hands, slowness of movements (bradykinesia) or cervical dystonia are presenting symptoms. In many patients, brisk deep-tendon reflexes and/or dystonic extension of the big toe (striatal toe) are obvious at examination. The disease usually progresses to generalized dystonia, and some patients, especially those with onset in adolescence or adulthood, also develop parkinsonism (manifesting with bradykinesia, rigidity and mainly postural tremor). There is no effect on cognitive or intellectual functioning. Patients with a later disease onset have a milder phenotype. In rare cases depression, anxiety, sleep disturbances and obsessive-compulsive disorder have been reported. Without treatment, adults may suffer from limb contractures.

DYT5a is caused by mutations in the GCH1 gene (14q22.1-q22.2), encoding the enzyme GTP cyclohydrolase 1 (GTPCH1). This enzyme is essential in the biosyntheisis of tetrahydrobiopterin (the essential co-factor for tyrosine hydroxylase), which is the rate-limiting enzyme in the biosynthesis of dopamine.

Diagnosis is based on the presence of characteristic clinical symptoms and the dramatic and sustained improvement of symptoms with the administration of low doses of oral L-dopa. Reduced levels of both total biopterin and neopterin in cerebrospinal fluid (CSF) are typically found in DYT5a patients. Reduced GTPCH1 activity in blood cells is also noted. Molecular genetic testing can identify a mutation in the GCH1 gene.

Differential diagnoses include other forms of DRD (e.g. autosomal recessive DRD), early onset torsion dystonia, myoclonic dystonia, hyperphenylalaninemia, hereditary spastic paraplegia, young adult-onset parkinsonism or cerebral palsy.

Prenatal diagnosis is possible in families with a known GCH1 mutation.

DYT5a is inherited in an autosomal dominant manner, but due to gender-based incomplete penetrance, not everyone with a mutation will display the disease phenotype. Approximately 30-50% of patients with DRD do not report a family history of dystonia. De novo mutations are also possible.

This form of dystonia shows a dramatic and sustained response to L-dopa therapy. The current suggested initial dosage of L-dopa/decarboxylase inhibitor for children is 25 mg or less, once a day, and in adults 50 mg once or twice a day. These dosages can be increased in small increments if needed, with typical optimal or maximum doses of approximately 10-20 mg/kg/day. If dyskinesia appears after administration of L-dopa, dosage should be decreased. Treatment is life-long, and alleviation of symptoms can usually be noted after a few weeks to a few months.

There is no decrease in life expectancy, and typically there is a complete or almost complete resolution of symptoms with the administration of L-dopa.