Dopamine-Responsive Dystonia

Updated: Oct 16, 2014
  • Author: Nirjal K Nikhar, MD, FRCP; Chief Editor: Amy Kao, MD  more...
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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]

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, [2, 3] 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.) [4]

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.)

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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. [5]

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, [6] 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. [7, 8]

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. [9] More than 50% of patients with autosomal-dominant inherited DRD have mutations in the GCH1 gene. [10, 11, 12, 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]

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. [16] Asymptomatic carriers of mutated genes also have been described, suggesting that neurologic function may be normal even when dopamine metabolism is altered. [17, 18]

Based on a mathematical model, it has been hypothesized that the diurnal fluctuations in motor function may be explained by presynaptic mechanisms. [19]

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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. [20]

Age-related demographics

As previously stated, the onset of DRD typically occurs in the first decade of life, [2, 3] 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. [4] Numerous cases of patients with late-onset parkinsonian features who responded to very low doses of levodopa have been reported.

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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.

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