AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

Dopamine- or dopa-responsive dystonia (DRD), also known as hereditary progressive dystonia with diurnal variation (HPD), is an inherited dystonia typically presenting in the first decade of life. It is characterized by diurnal fluctuations, exquisite responsiveness to levodopa, and mild parkinsonian features. Segawa provided an early and detailed description (1976).

Nygard et al (1983) demonstrated linkage mapping of the autosomal-dominant DRD to chromosome 14q. In 1994, Ichinose et al identified the gene at the DRD locus in chromosome arm 14q to be responsible for the production of GTP cyclohydrolase I (GCH). Since the discovery of the gene mutation, many different mutations in the GCH 1 gene, TH gene (tyrosine hydroxylase), and SR (sepiapterin reductase) genes have been identified to cause levodopa responsive dystonic disorders, particularly of the autosomal recessive form of DRD.

Pathophysiology

DRD is characterized by striatal dopamine deficiency with preservation of nigrostriatal terminals. In healthy individuals, the enzyme activity in the nigrostriatal dopaminergic neurons shows variation with circadian rhythm and age. In DRD, these physiologic variations are preserved.

TH activity and therefore tetrahydrobiopterin (BH4) production is high in the postnatal period, decreasing after infancy. 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.

The activity of these dopaminergic neurons also has circadian variation. Dopamine production increases through the night with each cycle of rapid eye movement (REM) sleep. The activity at the nigrostriatal terminals is therefore maximal in the early morning; nocturnal variation is more marked in young children and decreases with age. Dopamine activity in nigrostriatal 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.

Dopamine is produced from tyrosine by the action of TH, which uses BH4 as a cofactor. BH4 is also a cofactor for tryptophan and serotonin synthesis, and also for the enzyme nitrous oxide synthetase.

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 GCH 1 mutation negative have been discovered to harbor exon deletions in the GCH gene.

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 (Lüdecke et al, 1995), with a resultant decrease in dopamine production.

Sepiapterin reductase deficiency, by point mutation, has also been shown to have a similar yet somewhat more severe picture of dopa-responsive dystonia.

Despite these advances, genetic testing is not definitive. Thirty to forty percent 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 de novo mutations or deletions in the gene (Furukawa and Kish, 1999). Asymptomatic carriers of mutated genes also have been described, suggesting that neurological function may be normal even when dopamine metabolism is altered (Takahashi et al, 1994).

Frequency

United States

Epidemiological studies are not available.

International

Epidemiological studies are not available, but most cases 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.

Mortality/Morbidity

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. Autosomal recessive forms of DRD from TH deficiency and sepiapetrin deficiency show considerable motor and mental developmental delay with early mortality.

Race

Most cases have been reported from Japan, but an increasing number of reports are coming from other parts of the world. No clear racial predilection has been noted in European studies.

Sex

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 reported to be 2.3 times higher in females than in males (Furukawa et al, 1998).

Age

Typically, the onset is in the first decade of life (Chen et al, 1996; Nygaard, 1995), although it may present in the second to early third decades. Late-onset DRD has been reported in a 67-year-old woman who presented with neck and trunk dystonia with diurnal fluctuations and no parkinsonian features (Maruta et al, 1993).

• Numerous cases of patients with late-onset parkinsonian features who responded to very low doses of levodopa have been reported. Lately, cases of adult-onset focal dystonias have also been shown to be responsive to levodopa and identified to GCH 1 deficiency.
• 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 forms are considered a forme fruste of DRD.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

The most common presenting symptom is a gait disturbance. These patients may be misdiagnosed as having cerebral palsy.

• Typically, the dystonia starts in one lower limb (with evening exacerbation) which results in a tiptoe walking pattern (equinus). 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 (Segawa et al, 1986).
• Recently, variations in DRD clinical presentation have been described. These include trunk and focal dystonia such as spasmodic torticollis, oromandibular dystonia, and writer's cramp (Deona et al, 1997, Steinberger et al, 1999, Maruta et al, 1993).
• 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 (Brautigam et al, 1998, Lüdecke et al, 1996, Furukawa and Kish, 1999).

Physical

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.
• Muscle tone is increased and deep tendon reflexes are exaggerated (with ankle clonus). Plantar reflex is flexor, although striatal toe is common (Segawa et al, 1986).
• Clinical manifestations have significant heterogeneity, with intrafamilial variation in clinical phenotype, including the degree of levodopa responsiveness (Robinson et al, 1999).

Causes

Patients with DRD have selective nigrostriatal dopamine deficiency without neuronal loss caused by genetic defects in dopamine synthesis. Over 50% of patients with autosomal-dominant inherited DRD have mutations in the GTPCH (GCH1) gene. Mutations in the TH and sepiapterin reductase deficiency gene have been detected in patients with autosomal-recessive DRD (Gasser, 1999; Bartholome and Lüdecke, 1998).

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

Primarily dystonic juvenile parkinsonism (DJP) and autosomal-recessive early onset parkinsonism with diurnal fluctuation (AREPDF)

• Dystonia predominates in DJP and AREPDF. Parkinsonism (in addition to dystonia) is apparent in DRD (Segawa et al, 1999). DJP presents in the first half of the second decade (Yokochi, 1979) 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. Long-term levodopa benefit is limited (Jeon, 1998).
• 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) studies show normal striatal fluorodopa uptake in DRD, while 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 (Nygaard et al, 1994).
• 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 (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.

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• CBC with peripheral smear examination - To rule out acanthocytosis
• Serum for BUN, creatinine, liver function tests, copper, and ceruloplasmin
• Cerebrospinal fluid
• • Cerebrospinal fluid (CSF) examination is not performed routinely, but some subjects may show significant reductions in CSF levels of neopterin and biopterin (Fujita and Shintaku, 1990).
  • Measuring CSF pterins (Furukawa and Kish, 1999) 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).

Imaging Studies

• Brain MRI may show abnormalities in the basal ganglia, suggesting Wilson or Hallervorden-Spatz disease. No specific abnormalities are seen in DRD.
• PET scan uptake of [¹⁸F]dopamine may be reduced in early onset Parkinson disease, but is normal in DRD (Snow et al, 1993; Sawle et al, 1991).
• Single-photon emission computed tomography (SPECT) with iodine I 123 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane (b-CIT) can differentiate DRD (normal) from early onset Parkinson disease (reduced).

Other Tests

• Polysomnography in DRD shows a decreased number of twitch movements during REM sleep (~20% of normal). The ratio does not decrease with age, nor does it follow the decremental age variation and incremental nocturnal variation of healthy subjects (Segawa and Nomura, 1993).
• Phenylalanine loading test: Abnormality in phenylalanine metabolism has been useful in diagnosing DRD for most (50% of patients) but not all patients (Hyland et al, 1997; Saunders-Pullman et al, 1998).
• • 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 (Furukawa et al, 1996).

Histologic Findings

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 (Rajput et al, 1994).

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Medical Care

All patients with DRD should be treated with the levodopa/carbidopa combination. Early treatment can prevent morbidity and contracture formation. In patients with autosomal recessive TH and 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 (Hsu et al, 1995).

Consultations

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

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Patients with 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 (1999) reported achieving adequate control with a mean daily dose of 250 mg of levodopa (range 25-500 mg). Others have reported benefit with 20 mg/kg (Hwu et al, 1989), 100 mg/d (Gherpelli et al, 1995), or 750 mg/d (Rajput et al, 1994). Wang (1994) suggested an optimal dose of 10 mg/kg.

Other effective medications include the anticholinergic agents, such as trihexyphenidyl, carbamazepine, tetrahydrobiopterin, and 5-hydroxytryptophan (Ishida et al, 1988). The use of botulinum toxin injection for focal dystonia should be considered in resistant cases as it would be for all causes 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 (Dewey et al, 1998). Choreic dyskinesias have been reported that disappeared on reducing the dose of levodopa (de la Fuente-Fernandez, 1999).

Drug Category: Dopaminergic agents

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.

Drug Category: Anticholinergic agents

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.

Drug Category: Anticonvulsants

These agents are used to treat severe muscle spasms.

Drug Category: Toxins

This agent causes presynaptic paralysis of myoneural junction and reduces abnormal contractions. Therapeutic effects may last 3-6 months.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Outpatient Care

• Regular outpatient follow-up is required 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.

Complications

• Limb contractures can occur in untreated patients.
• Growth retardation occurs in untreated children.

Prognosis

• Good with adequate and early treatment

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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Article Last Updated: Apr 10, 2006