GTPCH1-deficient DRD

Alternate names

DYT-GCH1; Dopa-responsive dystonia autosomal dominant Segawa syndrome; DOPA-responsive dystonia, with or without hyperphenylalaninemia; GTP cyclohydrolase 1-deficient dopa-responsive dystonia; GTPCH1-deficient dopa-responsive dystonia; DYT/PARK-GCH1

Definition

A rare neurometabolic disorder characterized by childhood-onset dystonia that shows a dramatic and sustained response to low doses of levodopa (L-dopa) and that may be associated with parkinsonism at an older age.

Epidemiology

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).

Cause

• 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.

Inheritance

• 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.

Onset

Onset usually occurs in childhood (average age 6 years), and females are 2-4 times more likely to suffer from this disease than males.

Signs and symptoms

• 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.

Clinical description

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

30%-79% of people have these symptoms

• Abnormal substantia nigra morphology
• Anxiety(Excessive, persistent worry and fear)
• Babinski sign
• Brisk reflexes
• Decreased CSF homovanillic acid
• Depressivity(Depression)
• Fatigue(Tired)
• Gait ataxia(Inability to coordinate movements when walking)
• Hearing impairment(Deafness)
• Limb dystonia
• Lower limb hyperreflexia(Overactive lower leg reflex)
• Parkinsonism
• Pes cavus(High-arched foot)
• Postural tremor
• Rigidity(Muscle rigidity)
• Sleep disturbance(Difficulty sleeping)
• Talipes equinovarus(Club feet)
• Torticollis(Wry neck)
• Transient hyperphenylalaninemia

5%-29% of people have these symptoms

• Autosomal recessive inheritance
• Bradykinesia(Slow movements)
• Generalized dystonia
• Horizontal nystagmus
• Hypertension
• Hypothyroidism(Underactive thyroid)
• Impaired vibration sensation in the lower limbs(Decreased lower limb vibratory sense)
• Obsessive-compulsive behavior(Obsessive compulsive behavior)
• Paresis of extensor muscles of the big toe
• Progressive flexion contractures
• Rheumatoid arthritis
• Scoliosis

Diagnosis

• 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.

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

Treatment

• 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.

Prognosis

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.

NIH genetic and rare disease info

• NIH info on GTPCH1-deficient DRD

GTPCH1-deficient DRD is a rare disease.

GTPCH1-deficient DRD Resources
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