Dopa-responsive dystonia …

Arushi Gahlot Saini MD DM MNAMS

Movement Disorders

Updated 04.03.2025
Released 07.16.1993
Expires For CME 04.03.2028

Dopa-responsive dystonia

Author: Arushi Gahlot Saini MD DM MNAMS

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Editor: Robert Fekete MD

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Dopa-responsive dystonia

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Introduction

Overview

Dopa-responsive dystonia is a genetically heterogeneous syndrome that typically presents in children as leg dystonia and parkinsonism. Similar to juvenile-onset Parkinson disease, dopa-responsive dystonia is due to dopamine depletion, but unlike Parkinson disease, dopamine deficiency arises secondary to a defect in neurotransmitter synthesis rather than a loss of dopaminergic neurons.

Monogenic dopa-responsive dystonia comprises a group of rare, treatable, monogenic dystonias that dramatically respond to small doses of levodopa (L-dopa). The genes involved in dopa-responsive dystonia encode enzymes involved in tetrahydrobiopterin (BH4) and dopamine biosynthesis or recycling, and they include the following: (1) the autosomal dominant form of guanosine triphosphate cyclohydrolase-1 (GCH1) deficiency, the most common cause; and (2) autosomal recessive/biallelic forms involving the GCH1 gene, tyrosine hydroxylase (TH) gene, 5 6-pyruvoyl tetrahydrobiopterin synthase (PTS) gene, 6-sepiapterin reductase (SPR) gene, and quinoid dihydropteridine reductase (QDPR) gene (105; 168).

As early-onset dystonia in combination with parkinsonism has been described as one of the phenotypic hallmarks of dopa-responsive dystonia, the Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders recommends the use of the prefix DYT/PARK preceding the specific gene name to classify the different dopa-responsive dystonia syndromes (ie, DYT/PARK-GCH1, DYT/PARK-TH, DYT/PARK-PTS, DYT/PARK-SPR, and DYT/PARK-QDPR) (105).

In this article, the author reviews the cardinal features, diagnosis, pathophysiology, treatment, and differential diagnosis of autosomal dominant GTPCH1-deficient dopa-responsive dystonia (DYT-GCH1, DYT5a), the major form of dopa-responsive dystonia.

Key points

	• Dopa-responsive dystonia is a syndrome that typically presents in children as leg dystonia and parkinsonism.
	• Dopa-responsive dystonia is a genetically heterogeneous disorder that can be inherited in either an autosomal dominant or autosomal recessive fashion.
	• The autosomal dominant form is the most common pattern of dopa-responsive dystonia associated with dominant mutation in GCH1.
	• Dopa-responsive dystonia responds dramatically to low-dose levodopa therapy, independent of patient age or disease duration.

Historical note and terminology

The first description of dystonia specifically responsive to levodopa was provided in 1971 by Segawa (139). In the midst of the excitement of Parkinson disease treatment with levodopa, Segawa reported several young girls with prominent diurnal variation of dystonia whose symptoms were ameliorated with low-dose levodopa (136). Subsequent reports described families whose members had dystonia and parkinsonism that improved markedly following levodopa treatment. Further studies have distinguished dopa-responsive dystonia from young-onset Parkinson disease with dystonia and have clarified the genetic basis of the disorder (107; 113).

Among the inherited forms of secondary dystonia, dopa-responsive dystonia or hereditary progressive dystonia with diurnal variation (HPD) is classified as DYT5, a “dystonia-plus syndrome,” because of its association with other neurologic features (ie, parkinsonism), although evidence of neurodegeneration is lacking (32; 41).

Clinical manifestations

Presentation and course

Age of onset. Typically, all dopa-responsive dystonia subgroups show an early age of onset between infancy and childhood, with a median age of onset across all groups of 6 years (range 0–68 years) (39; 41; 135; 04; 168). Rarely, evidence of dystonia may be noted at birth (164).

Clinical features (Table 1). The most common feature is action dystonia, affecting the lower extremities during ambulation and producing equinovarus foot posturing with gait difficulty and postural instability. The clinical presentation of dopa-responsive dystonia may be heterogeneous; for example, it may be paroxysmal (138) or become manifest with exercise (21). Frequent daily falling has also been reported (162). Although over 75% of childhood-onset dopa-responsive dystonia becomes generalized between 1 year and 1 decade from the disease onset (119), limb involvement remains asymmetrical throughout its course.

Research on dopa-responsive dystonia families highlights significant clinical variability (60; 164). In one family, parkinsonism or dystonia was the most common presentation (55). Most patients exhibit limb dystonia and rigidity, although tremor, myoclonus, and axial, cervical, and oromandibular dystonia may also occur (167; 81; 144; 97). Dopa-responsive dystonia is often misdiagnosed as cerebral palsy, juvenile parkinsonism, footdrop, or psychogenic gait disorder.

The phenotype of genetically confirmed dopa-responsive dystonia has also included focal or segmental dystonia, relapsing-remitting dystonia (21; 06; 144; 54; 105), oculogyric crisis (138), ataxia (14), and hypotonic weakness (91; 102; 30). Compound heterozygous mutations in GCH1 may cause developmental motor delay and axial hypotonia alongside limb dystonia (46).

Diurnal fluctuations. Diurnal fluctuation of dystonia may be present, especially in the form of "sleep benefit," but this feature, although characteristic of dopa-responsive dystonia, is reported in only about 50% to 75% of cases. Furthermore, diurnal variation is not specific for dopa-responsive dystonia and may be seen in some forms of early-onset parkinsonism (29; 118; 115; 116).

Associated motor and systemic features. With childhood onset, other characteristics of the disorder may be seen, including short stature and hyperactive deep tendon reflexes without an associated extensor plantar response. Because of stiff gait, hyperreflexia, and marked postural instability (particularly retropulsion), many patients with dopa-responsive dystonia are initially misdiagnosed with cerebral palsy. Some patients exhibit a striatal toe deformity, which may be mistaken for a Babinski sign. In general, intellectual and cognitive function is normal, and there is no evidence of cerebellar, sensory, and autonomic disturbances in individuals with GTPCH1-deficient dopa-responsive dystonia.

Non-motor features. Dopa-responsive dystonia is not usually associated with neuropsychiatric problems, although some data suggest that obsessive compulsive disorder, depression, and sleep disturbances are overrepresented in persons with dopa-responsive dystonia compared with the general population (166). A study of 23 patients with dopa-responsive dystonia and 26 age-matched controls indicated quality-of-life scores were specifically impaired in the physical health domain, but psychological, environmental, and social relationships were not significantly affected (11).

A possible association between dopa-responsive dystonia and Tourette syndrome has been reported in a study (130). Three family members across three generations had both a novel GCH1 gene mutation and Tourette syndrome. Although this combination may have been purely coincidental, two siblings with both Tourette syndrome and dopa-responsive dystonia have also been described, suggesting that GCH1 mutations may be associated with Tourette syndrome (175). A higher lifetime prevalence of psychiatric disorders and daytime sleepiness has been noted in adults but not in children with GTPCH1-deficient dopa-responsive dystonia (159).

Table 1. Clinical Features in Autosomal Dominant GCH1 Deficiency-Related Dopa-Responsive Dystonia

	• Childhood-onset focal dystonia following normal early motor development
	• Typically foot dystonia (equinovarus posture) resulting in gait disturbance
	• Underlying normal intellectual and cognitive function and absence of cerebellar, sensory, and autonomic disturbances
	• Diurnal fluctuation
	• Female predominance
	• Gradual progression of generalized dystonia, typically more pronounced dystonia in the legs throughout the disease course
	• Striatal toe (dystonic extension of the big toe)
	• Flexion inversion (equinovarus posture) of the foot
	• Scoliosis
	• Later development of parkinsonism with rest or postural tremor, bradykinesia, rigidity, and marked postural instability
	• Hyperreflexia, ankle clonus, increased muscle tone
	• A dramatic and sustained response to low doses of levodopa
	• Absence of adverse motor effects of long-term levodopa therapy

Prognosis and complications

Course of disease. The manifestations of dopa-responsive dystonia vary with patient age and, if left untreated, its symptoms worsen over time (119) although its clinical course does not reflect a progressive neurodegenerative process. Patients less than 10 years of age are most likely to have a typical presentation with hyperreflexia and leg dystonia that is postural and worsens late in the day.

Gradually, arm dystonia, postural tremors of the hands, slowness of movements, fatigability with repetitive motor tasks, and lumbar lordosis secondary to standing with equinovarus feet may appear. In adulthood, tremor may be present with minimal or no dystonia, no diurnal variation, and normal deep tendon reflexes (138).

Family members of patients with dopa-responsive dystonia may present with a phenotype mimicking otherwise typical idiopathic Parkinson disease (154). Rare GCH1 coding variants have been associated with an increased risk for Parkinson disease in family members of patients with dopa-responsive dystonia (108). Unlike patients with dopamine-responsive parkinsonism, even longstanding dopa-responsive dystonia is unaccompanied by autonomic dysfunction, cognitive decline, “freezing,” and the motor complications (eg, dyskinesias) commonly associated with long-term dopamine replacement therapy.

Clinical vignette

A 9-year-old girl was referred to a neurology clinic by her pediatrician because of an abnormal gait. She had been diagnosed with cerebral palsy at 3 years of age, but her family and physical therapist felt that there were atypical features. She had demonstrated normal developmental milestones, but exhibited worsening coordination, gait, and fine motor dexterity over the past few years. Most striking was the fluctuation of her abilities, with clear deterioration over the course of the day. In her family history, she had a maternal cousin with cerebral palsy and a maternal grandfather with Parkinson disease. Examination revealed that she was an intelligent child with dystonic lower limb posturing, impaired gait, and brisk deep tendon reflexes. A trial of low-dose carbidopa/levodopa resulted in dramatic improvement of all motor difficulties within 10 days. Excellent long-term benefit continued at 13 years of age.

Biological basis

Etiology and pathogenesis

Genetic basis. Dopa-responsive dystonia is a genetically heterogeneous disorder that can be inherited in either an autosomal dominant or autosomal recessive fashion. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene localized to chromosomal region 14q22.1-22.2. Rarely, dopa-responsive dystonia may be caused by autosomal recessive mutations in the GCH1, TH, PTS, QDPR, or SPR genes (143; 16). The encoded enzyme guanosine triphosphate cyclohydrolase 1 (GTPCH1) is responsible for the conversion of guanosine triphosphate to BH4, which is required as a cofactor for aromatic L-amino acid hydroxylases, including tyrosine hydroxylase. The function of tyrosine hydroxylase is to convert tyrosine into the dopamine precursor levodopa; therefore, loss of enzyme activity leads to a dopamine-deficient state (33; 74), which may be corrected by exogenous BH4 (80) or levodopa (156). Low levels of GTPCH1 activity remain in affected patients so that they can continue to synthesize BH4, but not in sufficient quantities to last all day, which results in diurnal fluctuations (73).

GCH1 biochemical structures and metabolic pathway

Biochemical structures and metabolic pathway of GTP cyclohydrolase I. (Contributed by Dr. Joseph Ferrara.)

Analysis of the genomic DNA from patients with dopa-responsive dystonia has revealed over 100 different mutations in the GCH1 gene (51; 07; 46; 155; 70; 42; 141; 38; 158). In a study, the prevalence of GCH1 mutations was 1.9% (5 of 268) among patients with Parkinson disease and 26.9% (7 of 26) among patients with dopa-responsive dystonia (176).

Women are two to four times more frequently affected than men (117; 164), possibly due to the regulatory effect of estrogen on GCH1 expression (140). The penetrance of GCH1 mutations is over two times higher in women (about 45% to 90%) than in men (about 14% to 40%) (115; 48; 150), and affected women tend to display more severe symptoms (170; 100). Although it has been hypothesized that differences may stem from lower basal GCH1 expression in women, no gender-specific differences in GCH1 mRNA expression were found in series of cerebellar brain samples from healthy men and women (169).

In patients without an identifiable GCH1 mutation on specific gene testing, molecular analyses of other genes, including TH and SPR, can be performed. Looking at the genetic heterogeneity of dopa-responsive dystonia and dopa-responsive dystonia–like conditions, whole-exome testing may be more fruitful than selective gene testing (16). Biochemical testing may help in cases in which genetic testing is inconclusive and is best done in consultation with a biochemical specialist and geneticist.

Another autosomal dominant form of dopa-responsive dystonia was described in a family with a genetic locus mapping to 14q13 (56), but this kindred was found to actually have a misidentified GCH1 defect (31); therefore, GCH1 remains the only identified form autosomal dominant dopa-responsive dystonia. An autosomal recessive form has been reported in families with mutations of the tyrosine hydroxylase gene (88; 76; 174). When compared to autosomal dominant dopa-responsive dystonia, tyrosine hydroxylase deficiency appears as a more severe condition, with earlier onset and a wider clinical spectrum (65; 53). A study of six patients with tyrosine hydroxylase deficiency demonstrated levodopa-induced dyskinesias as a common finding (125). Inherited deficiencies in other enzymes involved in the synthesis of tetrahydrobiopterin and dopamine may also produce dystonia responsive to levodopa, often in conjunction with more widespread neurologic dysfunction (151). Also, compound heterozygous GCH1 mutations may produce a more severe dopa-responsive dystonia phenotype with developmental delay (46).

Biochemical basis. Dopa-responsive dystonia is characterized by dopamine deficiency without loss of nigrostriatal dopaminergic neurons, which suggests a metabolic defect in neurotransmitter synthesis. An autopsy of a 90-year-old woman with dopa-responsive dystonia indicated the cause of the disease was deficiency of the activities of the nigrostriatal dopamine neuron that modulates dopamine transmission with high tyrosine hydroxylase activities in the terminals of the neuron. This differs from the pathophysiology of Parkinson disease, which is caused by deficiency of dopamine in the substantia nigra pars compacta of the nigrostriatal dopamine neuron (137). Low cerebrospinal fluid homovanillic acid levels suggest impaired dopamine production (124; 94), whereas functional neuroimaging demonstrates an anatomically intact nigrostriatal system. PET studies of patients with dopa-responsive dystonia reveal (1) normal (or nearly normal) fluorodopa uptake (132; 142; 163), indicating that the presynaptic nigrostriatal dopaminergic terminals are intact, and (2) increased D2 receptor density (87; 95; 129), which normalizes following treatment with levodopa (87), suggesting integrity of postsynaptic nigrostriatal pathways. D1 receptor levels are unchanged (129). SPECT using dopamine transporter ligand shows normal binding to striatal dopamine transporters (66; 69; 84). Thus, both PET and SPECT distinguish patients with dopa-responsive dystonia from those with dopamine depletion from Parkinson disease (154; 83; 69). A study screening for dopa-responsive dystonia in 11 patients with parkinsonism who had Scans Without Evidence of Dopamine Deficiency (SWEDD) did not find GCH1 gene mutations in any of the patients (23).

Findings on fluorodeoxyglucose PET, which detects regional glucose metabolism, are also distinct and imply that the pathophysiology of dopa-responsive dystonia is different from idiopathic torsion dystonia. Dopa-responsive dystonia patients display increased glucose metabolism in the dorsal midbrain, cerebellum, and supplementary motor cortex and decreased metabolism in the basal ganglia as well as the motor and lateral premotor cortices (02). Likewise, electrophysiological studies of patients with dopa-responsive dystonia (using transcranial magnetic stimulation) also distinguish the condition from primary dystonias; however, these data remain preliminary (67; 59).

Identification of dopa-responsive dystonia causative genes has facilitated animal models for the disorder (71; 89). Mutant mice with GTP-CHI deficiency demonstrate a decrease in tetrahydrobiopterin as well as a therapeutic response to exogenously administered tetrahydrobiopterin (13). Tetrahydrobiopterin deficiency suppresses the activity of tyrosine hydroxylase and phenylalanine hydroxylase, causing a decrease in dopamine production and hyperphenylalaninemia (36). Patients with a homozygous mutation in the GCH1 gene are reported to show hyperphenylalaninemia, in addition to dopa-responsive dystonia. Patients with a heterozygous mutation in GCH1 also show symptoms of dopa-responsive dystonia, but they do not have hyperphenylalaninemia. Blood phenylalanine levels in patients with dopa-responsive dystonia have been demonstrated to be within the normal range, but higher than those in controls, suggesting that the activity of phenylalanine hydroxylase is partially affected by the decrease in tetrahydrobiopterin in dopa-responsive dystonia.

Autopsy studies of patients with known GCH1 mutations are scarce (126; 49; 43; 56), but available data confirm that such individuals have normal histopathology other than a reduction of neuromelanin within the substantia nigra. Lewy bodies are not a feature of dopa-responsive dystonia. In contrast to the paucity of structural findings, biochemical analysis of brain tissue reveals several changes: biopterin levels, tyrosine hydroxylase protein levels, tyrosine hydroxylase enzymatic activity, dopamine levels, and homovanillic acid levels are all reduced within the striatum. Interestingly, in an autopsy study of an asymptomatic GCH1 carrier, tetrahydrobiopterin levels were as low as patients affected by dystonia, but tyrosine hydroxylase levels were intermediate between controls and those with clinical disease (43). Accordingly, variability in how tetrahydrobiopterin concentrations affect tyrosine hydroxylase levels and activity may determine phenotypic expression. However, there is no evidence that variations or polymorphisms in the tyrosine hydroxylase gene account for the observed clinical variability of dopa-responsive dystonia (35).

Asymptomatic family members of patients with GCH1-related dopa-responsive dystonia (or those with adult-onset symptoms) may have lower ratios of normal to mutant alleles (63). The relationship between GTPCH1 enzyme activity and dopa-responsive dystonia is not completely understood. Unanswered questions (138) include: (1) why are heterozygous GCH1 mutations sufficient to produce symptoms; ie, what is the basis of the dominant negative effect?; (2) why does tetrahydrobiopterin deficiency disrupt tyrosine hydroxylase in excess of other aromatic L-amino acid hydroxylases?; (3) why does tetrahydrobiopterin deficiency lower striatal tyrosine hydroxylase protein levels in addition to enzymatic activity?; (4) what accounts for the variable phenotypic expression amongst family members sharing a common genotype? The reader is referred to review articles for a more complete discussion of these topics (64; 79; 150; 138; 135; 105; 168).

Epidemiology

Although its exact prevalence remains unknown, it is estimated that 0.5 persons per million have dopa-responsive dystonia (116). The distribution of reported cases is worldwide, and unlike idiopathic torsion dystonia, dopa-responsive dystonia is not more common among Ashkenazi Jews. The prevalence of GTPCH1-deficient dopa-responsive dystonia in Serbia has been reported as 2.96 per million based on 21 symptomatic individuals with pathogenic GCH1 variants in a population of 7.1 million (27). Although no single common founder was identified, haplotype analysis suggested that certain affected individuals shared ancestral origins. When inherited as an autosomal dominant disorder, dopa-responsive dystonia affects females approximately twice as often as males, suggesting reduced penetrance of GCH1 mutations in males (119), though gender variable penetrance is not seen in all kindreds (164). A report of dopa-responsive dystonia involving a family of four female siblings, including monozygotic triplets, highlights the discovery of a novel frameshift GCH1 mutation (152). Family members of patients with dopa-responsive dystonia may, on occasion, present with a Parkinson disease phenotype with normal fluorodopa-PET (in contrast to idiopathic Parkinson disease) (120). Thus, the true incidence of dopa-responsive dystonia may be obscured by clinical overlap with familial parkinsonism, both the young-onset and more typical adult-onset varieties. A questionnaire-based epidemiological survey on pediatric-onset dystonia from Japan categorized 736 patients based on etiological factors and diagnostic names (147). Inherited causes (63%) were most common, with the DYT series being the most common (68%), followed by the NBIA series (8%) and other genetic disorders (24%). Within the DYT series, DYT10 (21%), followed by DYT5 (DYT/PARK-GCH1) (8%), were most commonly reported (147). Penetrance in individuals with GTPCH1-deficient dopa-responsive dystonia has been reported to be higher in females than in males: 87% versus 38% (48), 100% versus 55% (146), and 87% versus 35% (138). The reported female-to-male ratios range from 1.3:1 to 8.3:1 (48; 138; 161; 171; 27).

Differential diagnosis

Patients frequently are given a variety of erroneous diagnoses before dopa-responsive dystonia is confirmed, including hereditary spastic paraplegia, cerebral palsy, intractable epilepsy, juvenile parkinsonism, "foot-drop," and a psychogenic gait disorder (06; 104). A literature review of 576 cases between 1952 and 2011 revealed an average delay in diagnosis of 13.5 years (153). Interestingly, the delay in diagnosis was even longer after the availability of the GCH1 genetic test in 1994. The mean delay in diagnosis before 1994 was 9.1 years, and after 1994 it was 15.2 years. A recommendation to help narrow the differential diagnosis is to group the clinical presentations into three categories: classic dopa-responsive dystonia, dopa-responsive dystonia with parkinsonism, and early-onset atypical dopa-responsive dystonia (171). A meta-analysis of articles in the PubMed database on early-onset autosomal dominant GCH1 deficiency published from 1995 to 2019 identified 137 patients and found that the mean duration of diagnostic delay was 14.6 years (85).

A PubMed systemic literature review until 2020 that included 734 patients with dopa-responsive dystonia and 151 asymptomatic GCH1 mutation carriers showed that pathogenic variants in the GCH1 gene are the most frequent causes of monogenic dopa-responsive dystonia, with the autosomal dominant form with heterozygous variants being the most common subgroup (168). Data from 734 patients (488 autosomal dominant DYT/PARK-GCH1, 25 autosomal recessive DYT/PARK-GCH1, 104 DYT/PARK-TH, 64 DYT/PARK-PTS, 42 DYT/PARK-SPR, and 11 DYT/PARK-QDPR) and an additional 151 heterozygous asymptomatic GCH1 mutation carriers were extracted. Dystonia, L-dopa responsiveness, early age at onset, and diurnal fluctuations were identified as red flags; parkinsonism without dystonia was rarely reported (11%) and was combined with dystonia in only 18% of patients (168).

A pharmacologic challenge with low-dose levodopa usually readily separates dopa-responsive dystonia from idiopathic torsion dystonia and from most secondary dystonias, although occasionally patients with other forms of dystonia may respond at least partially to dopaminergic medications (06; 173). Indeed, an empiric trial of levodopa should be considered in any child with dystonia (44). An unusually robust response to small doses of anticholinergic medications in a child with presumptive idiopathic torsion dystonia should also prompt consideration of dopa-responsive dystonia (82). An uncommon condition, rapid-onset dystonia-parkinsonism, may be differentiated by the emergence of symptoms over a period of hours and failure to progress afterward (93). A case report demonstrated that hereditary spastic paraplegia resulting from SPG11 mutations should be considered in the differential diagnosis of a patient presenting with dopa-responsive dystonia, parkinsonism, and spasticity (172). ATM gene mutations can cause dopa-responsive dystonia, particularly cervical dystonia with a recessive family history (15). A heterozygous SYNJ1 mutation was linked to dopa-responsive dystonia-parkinsonism in two German brothers (127). Some cases with atypical dopa-responsive dystonia and no known mutation, such as dopa-responsive cervical dystonia or dystonic camptocormia, may represent distinct disorders (134; 165; 109).

Table 2. Differential Diagnosis of Dopa-Responsive Dystonia

• Other neurotransmitter disorders
• Dopamine receptor agonist-responsive dystonia (from aromatic L-amino acid decarboxylase deficiency)
• Idiopathic torsion dystonia
• Early-onset Parkinson disease (PINK1 and PRKN genes)
• Rapid-onset dystonia-parkinsonism
• Juvenile Huntington disease
• Wilson disease
• X-linked dystonia-parkinsonism ("Lubag")
• Idiopathic kyphoscoliosis (109)

Apart from GTPCH1 deficiency (from GCH1 mutations), other less common disorders of neurotransmitter metabolism may cause dystonia responsive to levodopa. These disorders are often, but not always (110; 39; 145), accompanied by other neurologic deficits. Table 3 lists these diseases; all arise during infancy or childhood and are inherited in an autosomal recessive manner (151; 65; 39; 133; 20; 112; 01; 158).

Table 3. Disorders of Neurotransmitter Metabolism That May Cause Dystonia Responsive to Levodopa

Deficient enzyme	Gene and locus	Plasma phenylalanine	CSF Studies	Other neurologic manifestations
Autosomal recessive GTPCH1 deficiency (tetrahydrobiopterin [BH4]-deficient hyperphenylalaninemia)	GCH1 gene on 14q22.1-22.2	elevated	• Low HVA, 5-HIAA, neopterin and biopterin	All may display a variable degree of: •cognitive impairment •behavior disturbances •seizures •axial hypotonia •appendicular spasticity •myoclonus •autonomic dysfunction (eg, paroxysmal sweating) •ptosis and bulbar dysfunction •ataxia •extrapyramidal signs (eg, oculogyric crisis, parkinsonism, chorea)
6-pyruvoyl tetra-hydropterin synthase-deficient dopa-responsive dystonia (DYT-PTPS)	11q22.3-23.3	elevated	• Low HVA, 5-HIAA • High neopterin, biopterin
Sepiapterin reductase-deficient dopa-responsive dystonia (DYT-SPR)	SPR gene on 2p14-p12	normal	• Low HVA, 5-HIAA • High biopterin, dihydrobiopterin
Tyrosine hydroxylase–deficient dopa-responsive dystonia (DYT5b; DYT-TH)	TH gene on 11p15.5	normal	• Low HVA • Normal 5-HIAA, neopterin, biopterin
Dihydropteridine reductase (DHPR)	DHPR gene on 4p15.31	elevated	• Low HVA, 5-HIAA • Low or normal tetra-hydrobiopterin • High dihydrobiopterin
Aromatic L-amino acid decarboxylase (AADC)	AADC or DDC gene on 7p11	normal	• Low HVA, 5-HIAA • Normal neopterin, biopterin • Elevated 3-O-methyldopa, 5-hydroxy-tryptophan and L-dopa
Adapted from: (151).

Diagnostic workup

Although substantial testing may be part of an idiopathic torsion dystonia evaluation, dopa-responsive dystonia requires less testing once clinical suspicions are confirmed by levodopa responsiveness. Routine diagnostic studies, such as CT, MRI, EEG, and blood chemistries, are normal, as is PET with fluorodopa.

Levodopa trial. A levodopa trial has long been used as a first step in the approach of early-onset dystonia, but Maas and colleagues suggested that this time-tested strategy is “outdated” and should only be used “after biochemical corroboration of a defect in dopamine biosynthesis, in genetically confirmed [dopa-responsive dystonia], or if nigrostriatal degeneration has been demonstrated by nuclear imaging in adult patients presenting with lower limb dystonia” (103). However, this proposal has been challenged, and many clinicians still believe that an early trial of levodopa is potentially diagnostic and therapeutic (03).

Genetic testing. The diagnosis of GTPCH1-deficient dopa-responsive dystonia is established in a proband by identification of a heterozygous pathogenic variant in GCH1 by molecular genetic testing. The genotypic heterogeneity of dopa-responsive dystonia complicates the interpretation of gene testing (39). GCH1 is composed of six exons spanning approximately 30 kilobases (74; 75). A sizable minority (about 40%) of families with dopa-responsive dystonia have no detectable sequence alteration in the GCH1 gene’s coding region, and even with the addition of quantitative polymerase chain reaction, the percentage of patients without an identifiable mutation remains approximately 13% to 15% (44; 58; 40). In patients without GCH1 mutations and dopa-responsive dystonia plus other neurologic features, molecular analyses of TH and sepiapterin reductase genes should be considered. Whole-exome sequencing was used to make a rapid genetic diagnosis for two atypical dopa-responsive dystonia pedigrees (149). With improvements in cost and availability, whole-exome sequencing may improve diagnosis in patients with suspected heterogeneous genetic conditions in the near future, with a yield of up to 90%.

Gene-targeted deletion/duplication analysis. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Most mutations described in GCH1 are single base changes. If a point mutation is excluded, it has been recommended that GCH1 deletion analysis should be performed (177) because comprehensive screening fails to identify the responsible mutation in 40% to 50% of the families (39). As mutations mostly occur in the heterozygous state, deletions are not detected by sequencing. Special methods are required for deletion detection, and multiple ligation-dependent probe amplification techniques may offer a reliable and less tedious method of deletion analysis than quantitative polymerase chain reaction (26; 145).

If molecular testing does not identify a pathogenic variant, biochemical testing should be performed.

CSF. The enzyme GTPCH1 catalyzes the first step in the biosynthesis of tetrahydrobiopterin (BH4), which is the cofactor for tryptophan hydroxylase, and phenylalanine hydroxylase. Routine CSF parameters are normal, but CSF homovanillic acid levels (a dopamine metabolite) as well as biopterin and neopterin levels (BH4 pathway metabolites) are all reduced (116). These findings are in contrast to early-onset parkinsonism, which exhibits low biopterin but normal neopterin levels (39).

Serotonin is also synthesized via a BH4-dependent hydroxylase (tryptophan hydroxylase), but CSF levels of the serotonin metabolite 5-HIAA are inconsistently altered in patients with autosomal dominant dopa-responsive dystonia (116). Serum prolactin levels are normal in patients with dopa-responsive dystonia associated with GCH1 gene mutations (38).

GTPCH1 enzyme activity. Differentiation of juvenile Parkinson disease from dopa-responsive dystonia has been demonstrated by measurement of GTPCH1 enzyme activity in mononuclear blood cells or cytokine-stimulated fibroblasts of affected individuals (75; 62; 52), yet some GCH1 mutations may not alter enzyme activity (08). Although evidence suggests GCH1 is a strong biological candidate as a potential Parkinson disease gene, GCH1 mutations are not common in early-onset Parkinson disease (61; 17). A study of 509 patients with Parkinson disease did not identify any pathogenic GCH1 mutations (128). Mutations in the PARK2 gene (parkin) that causes autosomal recessive juvenile parkinsonism may present as dopa-responsive dystonia. Dopa-responsive dystonia presentation of juvenile parkinsonism should be carefully ruled out by testing patients for PARK2 mutations and by performing 123I-FP-CIT SPECT or [18F]dopa PET scans (16).

Other biochemical tests. It has been reported that quantitative analysis of biopterin metabolites in fibroblasts is useful as a diagnostic marker of dopa-responsive dystonia (09). A relatively simple oral phenylalanine loading test has been reported to demonstrate good specificity (95%) for dopa-responsive dystonia compared to other focal and generalized types of dystonia (72; 05), but the method is not yet standardized to minimize false-negative test results (131). This test is based on the fact that patients with GCH1 deficiency cannot adequately convert phenylalanine into tyrosine because BH4 is a cofactor for phenylalanine hydroxylase. Treatment with BH4 should be avoided during the oral phenylalanine loading test due to the possibility of misinterpretation of the results (122). Simultaneous measurements of the phenylalanine/tyrosine ratio and biopterin in plasma or dried spot blood may be important in pediatric patients (123).

Neuroimaging. A structural MRI study of nine patients with dopa-responsive dystonia and 37 controls using cortical thickness analysis demonstrated that patients with dopa-responsive dystonia relative to controls had cortical thinning of right precentral gyrus, posterior cingulate cortex, supramarginal gyrus and left middle temporal gyrus, and posterior cingulate cortex. Patients with dopa-responsive dystonia compared with controls also showed an increased volume of right putamen and pallidum. Dopa-responsive dystonia subjects showed a widespread right-sided white matter damage of the corticospinal tract, corona radiata, superior longitudinal fasciculus, anterior limb of the internal capsule, external capsule, genu of the corpus callosum, temporal and orbitofrontal working memory, and cerebral peduncle (92).

Positron emission tomography (PET) and single-photon emission computed tomography (SPECT). PET and SPECT using presynaptic dopaminergic markers have demonstrated normal results in the striatum of dopa-responsive dystonia and "benign" parkinsonism due to GCH1 pathogenic variants; thus, both are helpful in the differentiation of patients with dopa-responsive dystonia from patients with young-onset Parkinson disease (12; 111; 69; 157; 98). 123I-FP-CIT(DaTSCAN) SPECT studies demonstrate normal uptake in dopa-responsive dystonia and decreased uptake in young-onset Parkinson disease (10). These findings are supported by normal striatal levels of dopa decarboxylase, dopamine transporter, and vesicular monoamine transporter at autopsy of individuals with GTPCH1-deficient dopa-responsive dystonia, indicating that striatal dopamine nerve terminals are preserved in this disorder (49; 43).

GTPCH1-deficient dopa-responsive dystonia has been associated with a specific metabolic topography. Increases in the dorsal midbrain, cerebellar vermis, and supplementary motor area and decreases in the putamen as well as lateral premotor and motor cortical regions on [18F]-fluorodeoxyglucose PET images (02), and elevated D2-receptor binding in the striatum on [11C]-raclopride PET has been found in GTPCH1 (87). Some reports suggest dopaminergic impairments in primary dystonia but need further evaluation (78).

Transcranial sonography. Transcranial sonography of the midbrain (normal in patients with dopa-responsive dystonia and hyperechogenic in those with early-onset Parkinson disease) may also serve to distinguish these populations (57).

Electrophysiology. EMG and nerve conduction velocities are normal with the exception of nonspecific muscle overactivity in the dystonic limbs. H-reflex abnormalities may be present in some individuals with dopa-responsive dystonia, although the finding is not specific to this disorder (90).

Dopa-responsive dystonia neuropathology. Dopa-responsive dystonia neuropathology has shown a normal population of cells with reduced melanin and no evidence of Lewy body formation in the substantia nigra of four individuals with GTPCH1-deficient dopa-responsive dystonia and one asymptomatic individual with a GCH1 pathogenic variant (126; 49; 43; 56; 170; 137).

At autopsy, biopterin and neopterin levels in the putamen were significantly reduced in two affected individuals (-84% and -62%) compared to controls. The caudal putamen had the most dopamine loss (-88%). Although dopa decarboxylase, dopamine transporter, and vesicular monoamine transporter levels were normal, tyrosine hydroxylase (TH) protein was severely reduced (> -97%). This suggests dopamine loss in GTPCH1-deficient dopa-responsive dystonia results from both decreased tyrosine hydroxylase activity due to low BH4 and tyrosine hydroxylase protein loss without nerve terminal degeneration (43; 38; 39; 148).

In an asymptomatic individual with a GCH1 variant, biopterin and neopterin reductions (-82% and -57%) were similar to symptomatic cases, but tyrosine hydroxylase protein and dopamine levels in the caudal putamen (-52% and -44%) were less affected. As motor symptoms require less than 60% to 80% dopamine loss, the 44% reduction was insufficient to cause symptoms. Striatal serotonin markers remained normal (86; 50).

Management

Levodopa supplementation. Because aromatic L-amino acid decarboxylase (the enzyme that converts levodopa into dopamine) does not require tetrahydrobiopterin, levodopa supplementation is an effective treatment for dopa-responsive dystonia. Levodopa is usually given in combination with the peripheral dopa-decarboxylase inhibitor carbidopa to minimize side effects. The initial suggested dose for a levodopa trial is as follows (119; 42; 172):

	• For children under 6 years: 1 to 10 mg/kg levodopa/decarboxylase inhibitor daily, administered in multiple doses
	• For children 6 years and older: 25 to 50 mg levodopa/decarboxylase inhibitor one to three times daily
	• For adults: 50 mg levodopa/decarboxylase inhibitor one to three times daiily

Changes to the dose should be slow and in small increments. Motor benefit can be recognized immediately or within a few days of starting levodopa therapy. Full benefit occurs within several days to a few months. Maximum benefit (complete or near-complete responsiveness of symptoms) is generally achieved by less than 300 to 400 mg/day of levodopa/decarboxylase inhibitor; optimal response at 10 mg/kg has been suggested (167). Even individuals whose treatment is delayed for years may experience a full resolution of their dystonia. Transient dyskinesias seen at the onset of treatment generally do not reappear with later gradual increments in dose. The typical adverse motor effects of chronic levodopa therapy (motor response fluctuations and dopa-induced dyskinesias) do not occur.

Older family members with a Parkinson disease phenotype also seem to do well with modest doses of levodopa, whereas adults who present with focal dystonia respond less consistently (06). In a study of 20 patients with dopa-responsive dystonia, 20% of the patients exhibited mild levodopa-induced dyskinesias (68). However, in another study involving a cohort of 27 patients with dopa-responsive dystonia treated with levodopa for an average of 11.7 years, none of the patients developed long-term levodopa side effects such as motor fluctuations or disabling dyskinesias (161). Treatment limiting dyskinesias in a family with a prominent brachial dystonia and a novel GCH1 mutation has been described (101). Overall, drug-induced dyskinesias have been described in a minority of patients (19; 68) but usually are mild and only arise immediately following an increase in levodopa dosage. If choreatic movements develop, they typically remit after a reduction in levodopa dosage and do not recur when a slower dose titration is initiated. In terms of duration of therapy, few studies have been reported, but it has been observed that levodopa dose requirements seem to lessen with age (68).

BH4. Some patients with dopa-responsive dystonia respond to BH4, but the effect is variable (34), and others may require combination therapy using levodopa and BH4 for optimum improvement (48). The cost of BH4 probably precludes its use as a monotherapy.

Selective serotonin reuptake inhibitors (SSRIs). Patients with associated depression or obsessive compulsive disorder (perhaps attributable to defective serotonin synthesis) usually respond well to SSRIs. The serotonin precursor 5-hydroxytryptophan may also prove useful in treating depression in some individuals with dopa-responsive dystonia (166). Of note, one case report demonstrated normal concentration of serotonin in the striatum of a patient with dopa-responsive dystonia (50). Although SSRIs are generally well tolerated by patients with dopa-responsive dystonia, one report associated these drugs with a reversal of levodopa benefit (106).

Other drugs. Anticholinergics, dopamine receptor agonists, tricyclic agents, and carbamazepine have all been employed with some success but are less effective than levodopa and generally not indicated (119).

Drugs to avoid. Dopamine receptor antagonist drugs (eg, neuroleptic and some antiemetic medications) should be avoided by patients with dopa-responsive dystonia, as small doses of these medications may markedly worsen dystonia and parkinsonism (22). A case report of dystonic crisis in a patient with dopa-responsive dystonia, diagnosed by a phenylalanine challenge test, who consumed sugar-free energy drinks, advocates that these drinks and similar products that are high in aspartame should be avoided as aspartame is metabolized 50% to phenylalanine (37). Neuroleptic malignant syndrome has been described in one patient with comorbid psychiatric illness (77).

Deep brain stimulation. Bilateral subthalamic nuclei deep brain stimulation surgery in a 6-year-old boy with tyrosine hydroxylase deficiency and a 66-year-old woman with a GCH1 variant, both presenting with dopa-responsive dystonia, suggest that surgical treatment may be beneficial in medication refractory cases (160; 18). There was also improvement after bilateral globus pallidus internus deep brain stimulation surgery in a 27-year-old woman with a 22-year history of dopa-responsive dystonia (28).

Outcomes

Dopa-responsive dystonia responds dramatically to low-dose levodopa therapy independent of patient age or disease duration. The long-term outcome is universally good. Anecdotal case reports also suggest that nonmotor defects (eg, short stature and disrupted sleep architecture) also respond to levodopa (138). A case report of a patient with a novel GCH1 gene mutation suggested a possible link between growth hormone deficiency and dopa-responsive dystonia that resulted in an increase in height when treated with levodopa (99). Remarkably, in contrast to juvenile parkinsonism, escalation of levodopa dose does not appear necessary over many years, and drug-related motor fluctuations do not occur. In the literature, some individuals with “wearing-off” phenomena are thought to be misclassified patients with juvenile parkinsonism (119), but even some patients with a stable motor response to levodopa describe an alteration in mood consistent with a form of “wearing-off” phenomena (24). Although dopa-responsive dystonia may remit in some individuals, it is typically a lifelong condition (25).

In families with GTPCH1-deficient dopa-responsive dystonia, two types of adult-onset parkinsonism have been described (45). “Benign” parkinsonism has been described in adults who do not exhibit dystonia before developing parkinsonian symptoms in mid-to-late adulthood, have normal PET and SPECT imaging with presynaptic dopaminergic markers, show a significant response to low doses of levodopa, and, with appropriate treatment, maintain normal functional status for an extended period without experiencing motor fluctuations or levodopa-induced dyskinesias (120; 98). The second type is “neurodegenerative” parkinsonism, including Parkinson disease with abnormal 18F-fluorodopa PET or dopamine transporter SPECT imaging (108; 157; 98).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Arushi Gahlot Saini MD DM MNAMS

Dr. Saini of Postgraduate Institute of Medical Education and Research, Chandigarh, India, has no relevant financial relationships to disclose.
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Editor

Robert Fekete MD

Dr. Fekete of New York Medical College received consultation fees from Acadia Pharmaceutical, Acorda, Adamas/Supernus Pharmaceuticals, Amneal/Impax, Kyowa Kirin, Lundbeck Inc., Neurocrine Inc., and Teva Pharmaceutical, Inc.
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Former Authors

Christopher F O'Brien MD
Leon Dure MD
Joseph M Ferrara Jr MD
Toby C Yaltho MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: female>male, >2:1
Heredity: heredity may be a factor

autosomal dominant

autosomal recessive
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Dopa-responsive dystonia: G24.13
ICD-11: Dystonia-plus: 8A02.11
OMIM: Dystonia, progressive, with diurnal variation: #128230

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Dopa-responsive dystonia

Associated Disorders

Parkinson disease

Differential Diagnosis

hereditary spastic paraplegia
cerebral palsy
intractable epilepsy
juvenile parkinsonism
"foot-drop" and a psychogenic gait disorder
- idiopathic torsion dystonia
- other secondary dystonias
- rapid-onset dystonia-parkinsonism
- hereditary spastic paraplegia resulting from SPG11 mutations
- atypical varieties of dopa-responsive dystonia
- dopamine receptor agonist-responsive dystonia (from aromatic L-amino acid decarboxylase deficiency)
- juvenile Huntington disease
- Wilson disease
- X-linked dystonia-parkinsonism ("Lubag")
- idiopathic kyphoscoliosis

Also Relevant

Abnormalities of tetrahydrobiopterin metabolism
Blepharospasm
Childhood movement disorders
Levodopa
Limb dystonia
- Oromandibular dystonia
- Parkinson disease
- Periodic limb movements
- Primary dystonia

Dopa-responsive dystonia

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Clinical Features in Autosomal Dominant GCH1 Deficiency-Related Dopa-Responsive Dystonia

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Table 2. Differential Diagnosis of Dopa-Responsive Dystonia

Table 3. Disorders of Neurotransmitter Metabolism That May Cause Dystonia Responsive to Levodopa

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

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Oromandibular dystonia

Blepharospasm

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