Dopamine-Responsive Dystonia 

Updated: Mar 25, 2019
Author: Nirjal K Nikhar, MD, FRCP; Chief Editor: Amy Kao, MD 

Overview

Background

Dopamine-responsive dystonia (DRD), also known as dopa-responsive dystonia or as hereditary progressive dystonia with diurnal variation (HPD), is an inherited dystonia typically presenting in the first decade of life (although it may present in the second to early third decades, or even later). It is characterized by diurnal fluctuations, exquisite responsiveness to levodopa, and mild parkinsonian features, as well as by striatal dopamine deficiency with preservation of the striatonigral terminals. Segawa provided an early and detailed description (1976). (See Etiology, Treatment, and Medication.)[1, 2]

In healthy individuals, enzyme activity in the striatonigral dopaminergic neurons shows variation with circadian rhythm and age. Dopamine production increases through the night with each cycle of rapid eye movement (REM) sleep. The activity at the striatonigral terminals is therefore maximal in the early morning; nocturnal variation is more marked in young children and decreases with age.

In DRD, these physiologic variations are preserved. Therefore, dopamine activity in striatonigral terminals, which already is reduced in patients with DRD, declines further during the course of the day (as well as with increasing age), exacerbating symptoms toward evening and with increasing age.

Late onset

Although, as stated above, the onset of DRD is typically in the first decade of life,[3, 4] late-onset DRD was reported in a 67-year-old woman who presented with neck and trunk dystonia with diurnal fluctuations and no parkinsonian features. (See Epidemiology.)[5]

Numerous cases of patients with late-onset parkinsonian features who responded to very low doses of levodopa have been reported. Cases of adult-onset focal dystonias have also been shown to be responsive to levodopa. (See Treatment and Medication.)

Likewise, family members of patients with DRD who have a parkinsonian syndrome in late life (like patients with DRD) have increased sensitivity to low doses of levodopa. (The late-onset condition is considered a forme fruste of DRD.)

Etiology

Patients with DRD have selective striatonigral dopamine deficiency without neuronal loss, caused by genetic defects in dopamine synthesis.

Dopamine is produced from tyrosine by the action of tyrosine hydroxylase (TH) , which uses tetrahydrobiopterin (BH4) as a cofactor. BH4 is also a cofactor for tryptophan and serotonin synthesis, as well as for the enzyme nitrous oxide synthetase. TH activity and, therefore, BH4 production are high in the postnatal period and remain high until the end of the first decade of life. The activity peaks during the first decade and progressively declines with age. The rate of decline in TH activity is marked initially and then progresses until it reaches a plateau in the third decade.[6]

A point mutation in the gene for TH has been shown to result in autosomal-recessive DRD. This mutation, at the Gln 381 Lys locus in the tyrosine gene, results in TH activity that is only 15% of normal,[7] with a resultant decrease in dopamine production.

With regard to BH4 deficiencies, more than 190 different mutant alleles or molecular lesions have been identified, including in the genes for guanosine triphosphate cyclohydrolase (GCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), sepiapterin reductase (SR), carbinolamine-4a-dehydratase (PCD), and dihydropteridine reductase (DHPR).

The first rate-limiting step for BH4 synthesis is GCH. The gene for GCH has been cloned to 14q 22.1-22.2 and is the gene responsible for autosomal-dominant DRD/HPD. This gene in humans contains 6 exons, and various mutations (missense, frameshift, base insertions, base deletions) have been described. These mutations result in markedly reduced GCH values (2-20%), with a resultant decrease in dopamine content. Many cases of GCH1 gene mutation negative have been discovered to harbor exon deletions in the GCH gene.[8, 9]

Mutations in the GCH1 gene are found across the entire gene; 99 of the 104 mutant alleles are present in a heterozygous state and cause DRD in a dominant fashion with reduced penetrance.[10] More than 50% of patients with autosomal-dominant inherited DRD have mutations in the GCH1 gene.[11, 12, 13, 14]

Point mutation in the gene for SR has been detected in patients who have autosomal-recessive DRD. SR-related DRD has been shown to be similar to, yet somewhat more severe than, TH-deficient DRD.[15, 16]

Despite advances in the understanding of DRD, genetic testing is not definitive. Thirty percent to 40% of patients with DRD do not show the common mutations. Some of these coding region mutation-negative cases may represent autosomal-recessive, TH-deficient DRD, while others are apparently sporadic. These sporadic cases may be explained by either incomplete penetrance/expression of GCH1 gene mutations or by de novo mutations or deletions in the gene.[17] Asymptomatic carriers of mutated genes also have been described, suggesting that neurologic function may be normal even when dopamine metabolism is altered.[18, 19]

Based on a mathematical model, it has been hypothesized that the diurnal fluctuations in motor function may be explained by presynaptic mechanisms.[20]

Epidemiology

Epidemiologic studies on DRD are not available, but most cases of DRD have been reported from Japan and Southeast Asia. With increasing awareness of this condition, more cases are being reported from other parts of the world as well.

Sex-related demographics

Females are involved more frequently than males, with a ratio varying from 2:1 to 4.3:1. The penetrance of GCH gene mutations is reportedly 2.3 times higher in females than in males.[21]

Age-related demographics

As previously stated, the onset of DRD typically occurs in the first decade of life,[3, 4] although it may present in the second to early third decades. Late-onset DRD was reported in a 67-year-old woman who presented with neck and trunk dystonia with diurnal fluctuations and no parkinsonian features.[5] Numerous cases of patients with late-onset parkinsonian features who responded to very low doses of levodopa have been reported.

Prognosis

The prognosis for patients with dopamine-responsive dystonia is good with adequate and early treatment. Limb contractures and growth retardation can occur in untreated patients.

Marked gait difficulty (not uncommonly misdiagnosed as spastic diplegia or cerebral palsy) requiring wheelchair ambulation has been reported. No data are available on mortality associated with DRD, but patients surviving beyond the fifth decade with treatment have been reported. Patients with autosomal recessive forms of DRD from TH or sepiapterin reductase deficiency show considerable motor and mental developmental delay, with early mortality.

 

Presentation

History

The most common presenting symptom of dopamine-responsive dystonia (DRD) is a gait disturbance. These patients may be misdiagnosed as having cerebral palsy.

Typically, the dystonia starts in 1 lower limb (with evening exacerbation), resulting in a tiptoe (equinus) walking pattern. Early in the disease course, patients are symptom free in the morning. Diurnal aggravation of symptoms depends more on the number of waking hours than on physical activity.

The disease progresses markedly in the first 15 years, with postural dystonia progressing to all 4 limbs (even in the morning) by the end of the second decade. Progression slows in the third decade and plateaus thereafter.[22]

Variations in DRD clinical presentation have been described. These include trunk and focal dystonias, such as spasmodic torticollis, oromandibular dystonia, and writer's cramp.[5, 23, 24]

Clinical features described here are those characterized for dominant DRD with GCH1 gene mutations. Some of the TH-deficient patients have predominant parkinsonism features without diurnal fluctuations.[17, 25, 26]

The onset and clinical severity of disease are variable, sometimes even within a single family, due to putative gender effects on allele penetrance.[27]

Physical Examination

The patient may have stunted growth with short stature if the disease was not treated in childhood. This improves if treatment is started early in the disease course. The dystonia is variable in severity, depending on the duration of disease prior to treatment.

Gait disturbance is characterized by leg stiffness and a tendency to walk in an equinus posture. The great toe is dorsiflexed. Gait tends to worsen later in the day. With increasing age and without treatment, dystonia spreads to involve the trunk and all 4 extremities.

Postural tremor, which is not observed in childhood, appears after the third decade. Resting tremor and rigidity are absent, and interlimb coordination is preserved (even in advanced cases).

Bradykinesia may develop. This is not due to failure of initiation and poverty of movement as in parkinsonism; rather, it is due to failure of reciprocal innervation resulting from the dystonia.[28]

Muscle tone is increased and deep tendon reflexes are exaggerated (with ankle clonus). The plantar reflex is flexor, although striatal toe is common.[22]

Clinical manifestations have significant heterogeneity, with intrafamilial variation in clinical phenotype, including the degree of levodopa responsiveness.[29]

 

DDx

Diagnostic Considerations

Primarily dystonic juvenile parkinsonism and AREPDF

Dystonia predominates in dystonic juvenile parkinsonism (DJP) and autosomal-recessive early onset parkinsonism with diurnal fluctuation (AREPDF). Parkinsonism (in addition to dystonia) is apparent in dopamine-responsive dystonia (DRD).[30]

DJP presents in the first half of the second decade[31] with stumbling, pes equinovarus, and upper limb involvement that is typically asymmetrical. Forward bending of the head and trunk appear later. Symptoms vary diurnally, with aggravation during activity and improvement with sleep. The long-term levodopa benefit is limited.[32]

Sustained response to levodopa without adverse effects of long-term treatment distinguishes DRD from early onset parkinsonism with dystonia.

Early onset idiopathic parkinsonism

This presents in the fourth decade, whereas DRD presents in childhood. Positron emission tomography (PET) scan studies show normal striatal fluorodopa uptake in DRD, whereas patients with Parkinson disease have reduced uptake. Patients with DRD presenting in infancy or early childhood may be misdiagnosed with cerebral palsy or spastic diplegia. Extrapyramidal signs may occur later; disappearance of spasticity and extrapyramidal signs following levodopa therapy confirms the diagnosis of DRD.[33]

A case report of spinocerebellar ataxia type 3 and adult-onset spastic paraplegia have been shown to clinically present as DRD.

In early onset dystonia, Wilson disease, Hallervorden-Spatz disease, and neuroacanthocytosis should be considered.

The variations in presentation of DRD (eg, spasmodic torticollis, oromandibular dystonia, writer's cramp) should be differentiated from idiopathic (ie, dopamine-nonresponsive) focal dystonias. A therapeutic trial with levodopa is the definitive way to establish the diagnosis.

Additional considerations

Conditions to consider in the differential diagnosis of DRD also include the following:

  • Oromandibular dystonia

  • Focal dystonia

  • Cerebral palsy

  • Dystonia musculorum deformans

  • Dyspeptic dystonia with hiatal hernia (Sandifer syndrome)

  • Medication reactions - Eg, phenothiazines, butyrophenones

  • Metabolic diseases - Eg, GM2 gangliosidosis, phenylketonuria, hypothyroidism, Leigh disease

Differential Diagnoses

 

Workup

Approach Considerations

Lab studies used in the diagnosis and evaluation of dopamine-responsive dystonia (DRD) include the following:

  • Complete blood count (CBC) with peripheral smear examination - To rule out acanthocytosis

  • Serum studies for blood urea nitrogen (BUN), creatinine, liver function, copper, and ceruloplasmin

  • Cerebrospinal fluid (CSF) studies

  • Ceruloplasm

CSF examination is not performed routinely, but some subjects may show significant reductions in CSF levels of neopterin and biopterin.[34]

Measuring CSF pterins[17] may be useful in distinguishing the 3 disorders that are responsive to levodopa: GTPCH-deficient DRD (decreased biopterin and neopterin), TH-deficient DRD (normal biopterin and neopterin), and early-onset parkinsonism (reduced biopterin and normal neopterin).

Polysomnography

Polysomnography in DRD shows a decreased number of twitch movements during REM sleep (approximately 20% of normal). The ratio does not decrease with age, and it does not follow the decremental age variation and incremental nocturnal variation of healthy subjects.[35]

Phenylalanine loading test

Abnormality in phenylalanine metabolism has been useful in diagnosing DRD for most (50% of patients), but not all, patients.[36, 37, 38] The basis for this test is that BH4 is required as a cofactor in the breakdown of phenylalanine to tyrosine. In DRD, BH4 deficiency results in accumulation of phenylalanine.

Molecular biology

This can confirm the diagnosis in some cases.[39]

Histology

In one autopsy case, the only neuropathologic finding was a decrease in melanin-pigmented neurons in the pars compacta of the substantia nigra. TH immunoreactivity in the substantia nigra was normal, no inclusion bodies or gliosis was noted, and no evidence of a degenerative process in the striatum was observed.[40]

Imaging Studies

MRI

Brain magnetic resonance imaging (MRI) may show abnormalities in the basal ganglia, suggesting Wilson disease or Hallervorden-Spatz disease.

PET scanning

PET scan uptake of [18 F]dopamine may be reduced in early onset Parkinson disease, but it is normal in DRD.[41, 42, 43]

A multitracer PET study has shown that the availability of the striatal dopamine D2 receptors is increased in DRD, whereas dopamine D1 receptors and dopamine transporter ligand binding are unchanged. The pattern of changes in the striatal dopaminergic system in DRD is different from that reported in juvenile Parkinson disease. The increased D2 receptor availability may be due to reduced competition by endogenous dopamine and/or compensatory response to dopamine deficiency.[44]

SPECT scanning

Single-photon emission computed tomography (SPECT) scanning with iodine-123 (123 I) 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane (b-CIT) can differentiate DRD (normal) from early onset Parkinson disease (reduced).[45]

 

Treatment

Approach Considerations

All patients with dopamine-responsive dystonia (DRD) should be treated with the levodopa/carbidopa combination. Early treatment can prevent morbidity and contracture formation. In patients with autosomal recessive TH or SR deficiency, early treatment with levodopa may also reduce the motor and intellectual developmental delay.

Surgical care

A fixed equinovarus foot deformity has been corrected surgically after treating the dystonia with levodopa.[46]

Consultations

Physical therapy is particularly important if the patient has a contracture or chronic gait disturbance.

Diet

An in vitro study suggested that oral BH4 supplementation could have a potential benefit in disorders associated with TH misfolding, such as DRD[47] ; however, this awaits further confirmation.

Follow-up

Regular outpatient follow-up is required for patients with DRD to assess the efficacy of treatment and to adjust the dopamine dose accordingly. Although uncommon, dyskinesias and chorea may develop in treated patients. Monitor patients carefully for these conditions.

 

Medication

Medication Summary

Patients with dopamine-responsive dystonia (DRD) typically experience marked, long-term benefit with low-dose levodopa. The optimal dose differs among patients; while some respond magnificently to small doses, others require higher doses. De la Fuente-Fernández et al reported achieving adequate control with a mean daily dose of 250 mg of levodopa (range, 25-500 mg).[48] Others have reported benefit with 20 mg/kg,[49] 100 mg/d,[50] or 750 mg/d.[40] Wang et al suggested an optimal dose of 10 mg/kg.[51]

Other effective medications include the anticholinergic agents, such as trihexyphenidyl, carbamazepine, BH4, and 5-hydroxytryptophan. The use of botulinum toxin (BOTOX) injection for focal dystonia should be considered in resistant cases as it would be for any cause of focal dystonia; this recourse rarely is needed in true DRD.

Motor fluctuations (as may happen in Parkinson disease treated with levodopa) do not occur in patients with DRD.[52] Choreic dyskinesias have been reported that disappeared on reduction of the levodopa dose.[48]

Decarboxylase Inhibitors

Class Summary

In order for a dopamine agonist to offer clinical benefit, it must stimulate D2 receptors. The role of other dopamine-receptor subtypes is currently unclear.

Levodopa/Carbidopa (Sinemet, Parcopa)

The active component is an L-isomer of dopamine (ie, L-dopa). Carbidopa is a peripheral DOPA hydroxylase inhibitor; by preventing peripheral metabolism, it increases the concentration of dopamine in the central nervous system (CNS). The total L-dopa dose required varies from person to person.

Anticholinergic Agents

Class Summary

These agents are thought to work centrally by suppressing conduction in the vestibular cerebellar pathways. They may have an inhibitory effect on the parasympathetic nervous system.

Trihexyphenidyl

Trihexyphenidyl is a synthetic anticholinergic noted to have a marked benefit in muscle spasm conditions, such as dystonia.

Benztropine (Cogentin)

By blocking striatal cholinergic receptors, benztropine may help balance cholinergic and dopaminergic activity in striatum. This agent can be used as an alternative to trihexyphenidyl.

Anticonvulsants

Class Summary

These agents are used to treat severe muscle spasms.

Carbamazepine (Tegretol, Equetro, Carbatrol)

Carbamazepine may reduce polysynaptic responses and block posttetanic potentiation.

Neuromuscular Blockers, Botulinum Toxins

Class Summary

Botulinum toxin causes presynaptic paralysis of the myoneural junction and reduces abnormal contractions. Its therapeutic effects may last 3-6 months.

OnabotulinumtoxinA (BOTOX)

Botulinum toxin type A (BTA) is useful in reducing excessive, abnormal contractions associated with DRD. It binds to receptor sites on motor nerve terminals, and after uptake it inhibits the release of acetylcholine, blocking transmission of impulses in neuromuscular tissue. Reexamine patients 7-14 days after administering the initial dose to assess for satisfactory response. Double the previously administered dose for patients who experience incomplete paralysis of the target muscle. Do not exceed 50U when giving BTA as a single injection, or 400U as a cumulative dose in 30-day period.

IncobotulinumtoxinA (Xeomin)

IncobotulinumtoxinA is botulinum toxin type A that is free of complexing proteins found in the natural toxin from Clostridium botulinum. This drug is an acetylcholine release inhibitor and neuromuscular blocking agent. IncobotulinumtoxinA is indicated in adults for cervical dystonia in botulinum toxin–naive patients, and it is also indicated for blepharospasm in adults previously treated with onabotulinumtoxinA (BOTOX).