Clinical characteristics: GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) is characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of oral administration of levodopa. This disorder typically presents with gait disturbance caused by foot dystonia, later development of parkinsonism, and diurnal fluctuation of symptoms (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep). Initial symptoms are often gait difficulties attributable to flexion-inversion (equinovarus posture) of the foot. Occasionally, initial symptoms are arm dystonia, postural tremor of the hand, or slowness of movements. Brisk deep-tendon reflexes in the legs, ankle clonus, and/or the striatal toe (dystonic extension of the big toe) are present in many affected individuals. In general, gradual progression to generalized dystonia is observed. Intellectual, cerebellar, sensory, and autonomic disturbances generally do not occur.

Diagnosis/testing: The diagnosis of GTPCH1-deficient DRD is established in a proband by identification of a heterozygous pathogenic variant in GCH1 by molecular genetic testing. In individuals with a suspected diagnosis of GTPCH1-deficient DRD and no identifiable GCH1 pathogenic variants, biochemical testing may be necessary.

Management: Treatment of manifestations: Initial suggested dose of levodopa/decarboxylase inhibitor (DCI):

1. Children age <6 years: 1-10 mg/kg levodopa/DCI daily, administered in multiple doses

2. Children age ≥6 years: 25-50 mg levodopa/DCI 1-3x daily

3. Adults: 50 mg levodopa/DCI 1-3x daily

For all, dose should be changed slowly and by small increments as needed. Motor benefit occurs immediately or within a few days of starting levodopa; full benefit occurs within several days to a few months. Maximum benefit (complete or near-complete responsiveness of symptoms) is generally achieved by <300-400 mg/day of levodopa/DCI. Although dyskinesias may appear at the beginning of levodopa therapy, they subside following dose reduction and do not reappear when the dose is gradually increased. Typically, adverse motor effects of chronic levodopa therapy (motor response fluctuations and dopa-induced dyskinesias) do not occur.

Prevention of secondary complications: Early diagnosis and therapy (with low doses of levodopa) may prevent transient dyskinesias at initiation of levodopa treatment.

Surveillance: Examination by a movement disorder specialist at least several times yearly is recommended.

Agents/circumstances to avoid: Discontinuation of levodopa treatment.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment. Molecular genetic testing cannot be used to predict the occurrence of symptoms, age of onset, severity and type of symptoms, or rate of disease progression in family members who are heterozygous for a GCH1 pathogenic variant.

Pregnancy management: Levodopa therapy is continued during pregnancy without adverse effect in most.

Genetic counseling: GTPCH1-deficient DRD is inherited in an autosomal dominant manner. Affected individuals often have an affected parent with typical GTPCH1-deficient DRD or adult-onset parkinsonism caused by a GCH1 pathogenic variant. A proband with GTPCH1-deficient DRD may have the disorder as the result of a de novo pathogenic variant. Every child of an individual with autosomal dominant GTPCH1-deficient DRD has a 50% chance of inheriting the pathogenic variant. However, because of sex-related incomplete penetrance (i.e., higher penetrance in women than in men), it is not possible to predict whether offspring with a GCH1 pathogenic variant will develop symptoms.