OVERVIEW: What every practitioner needs to know

Are you sure your patient has DOPA-responsive dystonia? What are the typical findings for this disease?

Dystonia is the simultaneous sustained contraction of agonist and antagonist muscles. Affected limbs can take distorted or painful postures. A balanced contracture produces a fixed posture, whereas one that is unbalanced causes a slow, twisting movement of a body part that often results in a fixed extreme posture.

DOPA-responsive dystonia (DRD; also known as hereditary progressive dystonia with marked diurnal fluctuation or autosomal dominant guanosine triphosphate (GTP) cyclohydrolase 1 deficiency or Segawa disease) is one of the primary dystonias, in that dystonia is the predominant feature.

The most common presenting symptoms follow:

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Dystonia of leg or foot (can be unilateral)

Diurnal fluctuation; symptoms are worse in the evening and markedly improved in the morning

Exquisite responsiveness to low-dose levodopa

Additional presenting symptoms


Focal dystonias of the arm or hand

Cervical dystonia (torticollis or retrocollis)

Poor coordination, delayed and awkward gait

Features of parkinsonism

Neuropsychiatric symptoms, including depression and mood swings

What other disease/condition shares some of these symptoms?

Patients with DRD are often misdiagnosed with cerebral palsy because of the presence of brisk lower limb reflexes and clonus, although plantar responses are usually normal in DRD. A dystonic dorsal extension of the big toes (striatal toe sign) has been confused as an extension plantar response.

The differential diagnosis of dystonia is broad. Dystonia is classically separated into primary and secondary causes.

Primary dystonias

DOPA-responsive dystonia

Idiopathic torsion dystonia (associated with
DYT1 mutation)

Secondary dystonias


Periventricular leukomalacia




Tyrosine hydroxylase deficiency

Seriapterin reductase deficiency

Lesch-Nyhan syndrome

Methylmalonic acidemia

Mitochondrial encephalopathy

Wilson diseasee

Metachromatic leukodystrophy

Glutaric aciduria



Juvenile parkinsonism

Juvenile Huntington disease

Spinocerebellar atrophy

Dentatorubral pallidoluysian atrophy


Dopamine receptor antagonists


What caused this disease to develop at this time?

DRD typically presents in first decade of life.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

To distinguish DRD from other metabolic disorders, several diagnostic tests are helpful.

Gene analysis for the mutation of the GTPCH1 gene is the most definitive test; heterozygous mutations spans a 30-kb region with six exons. If genetic analyses do not demonstrate mutations, it is important to ascertain whether analysis has included sequencing of the entire gene.

Cerebrospinal fluid (CSF) analysis shows a markedly decreased level of homovanillic acid (HVA), normal or low 5-hydroxyindoleacetic acid (5-HIAA), and reduced tetrahydrobiopterin (BH4), and neopterin.

The phenylalanine loading test has been suggested for detection of both affected and nonmanifesting GTPCH1 gene carriers. The sensitivity and specificity of this loading test, however, has been questioned.

Diminished (<30%) GTP cyclohydrolase activity is measurable in peripherial mononuclear blood cells and fibroblasts.

The diagnosis of tyrosine hydroxylase deficiency is confirmed by genetic analysis and biochemical testing showing reduced CSF levels of dopamine, norepinephrine, HVA and MHPG, with normal 5-HIAA, biopterin, and neopterin levels. The clinical presentation of patients with mutations in tyrosine hydroxylase or seriapterin reductase are usually more complex, involving psychomotor retardation, hypotonia, and oculogyric crises.

Would imaging studies be helpful? If so, which ones?

Routine imaging results are typically normal.

Neuroimaging with either fluorodopa positron emission tomography or single-photon emission computed tomography with [123I] beta CIT, is occasionally helpful to distinguish DRD from juvenile parkinsonism

Density of presynaptic terminals is normal in DRD and reduced in juvenile parkinsonism.

If you are able to confirm that the patient has DOPA-responsive dystonia, what treatment should be initiated?

Carbidopa/levodopa is the primary treatment. Carbidopa is a peripheral DOPA decarboxylase inhibitor that blocks the peripheral conversion of levodopa to dopamine. Dosage is based on the levodopa component, and the use of the 25/100 mg carbidopa/levodopa tablets is recommended.

Starting dose is 1 mg/kg/d of levodopa divided into three doses. The dose should be titrated based on efficacy or side effects. Most patients require 4-5 mg/kg/d, although some have suggested doses up to 10 mg/kg/d.

Carbidopa/levodopa should be taken at least 30 minutes before or 60 minutes after meals to avoid competition with other amino acids for gastrointestinal absorption. If side effects are disturbing, additional carbidopa can be administered 30 minutes before the levodopa. Tablets can be crushed and dissolved in orange juice or an ascorbic acid solution and used within 24 hours.

The dose of trihexyphenidyl is 0.5 mg/d in young children and 1 mg/d in older children.

In patients with homozygous or compound heterozygous GTPCH1 mutations, additional supplementation with BH4 and the precursor of serotonin (5-hydroxytryptophan) may be necessary.

Since patients with Segawa disease have a dramatic response to levodopa, all children presenting with dystonia should be given a trial with this medication.

What are the adverse effects associated with each treatment option?

Side effects of carbidopa/levodopa include somnolence, nausea/vomiting, orthostasis, dyskinesia, and hallucinations.

Side effects of trihexyphenidyl include dry mouth, nausea, constipation, drowsiness.

What are the possible outcomes of DOPA-responsive dystonia?

Patients with good responses to levodopa typically continue to have a stable course without long-term adverse effects, such as the “on-off phenomenon” seen in Parkinson disease.

Although spontaneous remissions are uncommon, after several years of treatment, a slow withdrawal has been suggested to assess the requirement for longer term therapy.

What causes this disease and how frequent is it?

Presentation is typically in the first decade of life. The condition affects females more than males (4:1 in some series). It is inherited in an autosomal dominant pattern.

The relevant mutation is in GTPCH1 gene on chromosome 14, which encodes GTP cyclohydrolase 1. New mutations are common and clinical penetrance is incomplete

Variable expressivity has occurred in families.

How do these pathogens/genes/exposures cause the disease?

GCH1 encodes GTP cyclohydrolase 1, which catalyzes tetrahydrobiopterin synthesis. Tetrahydrobiopterin is a critical cofactor for tyrosine hydrolyase, which is the rate-limiting enzyme in dopamine synthesis, and several other enzymes involved in biogenic amine synthesis.

What is the evidence?

Gordon, N. “Segawa's disease: dopa-responsive dystonia”. Int J Clin Pract. vol. 62. 2008. pp. 943-6.

Asmus, F, Gasser, T. “Dystonia-plus syndromes”. Eur J Neurol. vol. 17. 2010. pp. 37-45.

Segawa, M. “Hereditary progressive dystonia with marked diurnal fluctuation”. Brain Dev. vol. 33. 2011. pp. 195-201.

Ongoing controversies regarding etiology, diagnosis, treatment

An interesting scientific question is why dopamine deletion in Segawa disease causes dystonia, whereas in older individuals it usually results in parkinsonian symptoms. One potential explanation is a differential dopaminergic effect on striosomal and matrix components of the striatum. Further, although BH4 is also a cofactor for tryptophan hydroxylase and phenylalanine hydroxylase, its primary effect on tyrosine hydroxylase is likely due to a greater affinity for this enzyme.