Clinical manifestations

Presentation and course

Typically, dopa-responsive dystonia presents in children between infancy and adolescence, with an average age at onset of 6 years (38; 128; 04; 40). Rarely, evidence of dystonia may be noted at birth (152). Its 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 (131) or become manifest with exercise (21). Frequent daily falling has also been reported (150). Although over 75% of childhood-onset dopa-responsive dystonia becomes generalized between 1 year and 1 decade from the disease onset (112), limb involvement remains asymmetrical throughout its course. 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 (28). Table 1 lists the clinical features found in a review of 86 cases and other series (111; 108; 109). With childhood onset, other characteristics of the disorder are 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.

The manifestations of dopa-responsive dystonia vary with patient age and, if left untreated, its symptoms worsen over time (112) 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 crural (leg) dystonia that is postural and worsens late in the day. With advancing age, dystonia may become more prominent in the arms and be accompanied by a postural tremor. In adulthood, tremor may be present with minimal or no dystonia, no diurnal variation, and normal deep tendon reflexes (131). Family members of patients with dopa-responsive dystonia may present with a phenotype mimicking otherwise typical idiopathic Parkinson disease (144). Rare GCH1 coding variants have been associated with an increased risk for Parkinson disease in family members of patients with dopa-responsive dystonia (102). 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.

Dopa-responsive dystonia is usually not 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 (154). A study of 23 dopa-responsive dystonia patients 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).

Research of families with dopa-responsive dystonia has reinforced that clinical variability is common (58; 152), but in a study correlating clinical phenotype with genotype within 1 family, the presence of parkinsonism or dystonia on examination was the most typical presentation (53). Most patients have dystonia and rigidity limited to limb muscles, although tremor, myoclonus, axial dystonia, cervical dystonia, and oromandibular dystonia may also be prominent clinical features (155; 78; 137; 92). Dopa-responsive dystonia is often wrongly diagnosed as cerebral palsy, juvenile parkinsonism, "foot-drop," or psychogenic gait disorder.

A possible association between dopa-responsive dystonia and Tourette syndrome has been reported in a study (123). Three family members across 3 generations had both a novel GCH1 gene mutation and Tourette syndrome. Although this combination may have been purely coincidental, we described 2 siblings with both Tourette syndrome and dopa-responsive dystonia, suggesting that GCH1 mutations may be associated with Tourette syndrome (163).

The clinical phenotype of genetically confirmed dopa-responsive dystonia has been expanded to include various forms of focal or segmental dystonia and dystonia with a relapsing and remitting course (21; 06; 137; 52; 99), as well as oculogyric crisis (131), ataxia (14), and hypotonic weakness (87; 96; 29). Patients who carry compound heterozygote mutations in the most common disease-causing gene (GCH1) may present with developmental motor delay and axial hypotonia in addition to more typical limb dystonia (44).

Mutations in the ATM gene have been shown to cause dopa-responsive dystonia. Detection of this mutation should be considered in the differential diagnosis of unexplained dopa-responsive dystonia, especially if the dystonia is cervical and if there is a recessive family history (15). A novel heterozygous synaptojanin-1 mutation was associated with a dopa-responsive dystonia-parkinsonism in 2 brothers of German descent (120). Also of note are patients with atypical presentations of dopa-responsive dystonia and no known gene mutation. These disorders, which include dopa-responsive cervical dystonia and dopa-responsive dystonic camptocormia, may be pathogenically distinct disorders (127; 153; 103).

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.

Table 1. Clinical Features in Dopa-Responsive Dystonia

Biological basis

Etiology and pathogenesis

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 (GTP cyclohydrolase1) and more rarely caused by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes (136; 16). The most common pattern of inheritance is autosomal dominant, and the majority of affected families have a mutation in the guanosine triphosphate cyclohydrolase I (GTP-CHI) gene GCH1, localized to chromosomal region 14q22.1-22.2. The encoded is responsible for the conversion of guanosine triphosphate to tetrahydrobiopterin.

Tetrahydrobiopterin is a cofactor for aromatic L-amino acid hydroxylases, including tyrosine hydroxylase, and, therefore, is essential to dopamine synthesis (72; 146). Low levels of GTP cyclohydrolase 1 activity remain in affected patients so that they can continue to synthesize tetrahydrobiopterin, but not in sufficient quantities to last all day, which results in diurnal fluctuations (71). Analysis of the genomic DNA from dopa-responsive dystonia patients has revealed over 100 different mutations in the GCH1 gene (49; 07; 44; 145; 68; 41; 134; 37; 147). In 1 study, the prevalence of GCH1 mutations was 1.9% (5 out of 268) among patients with Parkinson disease and 26.9% (7 out of 26) among patients with dopa-responsive dystonia (164).

Women are 2 to 4 times more frequently affected than men (110; 152), possibly due to the regulatory effect of estrogen on GCH1 expression (133). The penetrance of GCH1 mutations is over 2 times higher in women (about 45% to 90%) than in men (about 14% to 40%) (108; 46; 140), and affected women tend to display more severe symptoms (158; 94). 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 (157).

Because of the high number of mutations, genetic testing may not be practical, and the diagnosis is usually based on clinical criteria, occasionally supported by the phenylalanine loading test or spinal fluid analysis. In those patients without an identifiable GCH1 mutation, further genetic testing is usually not fruitful. Molecular analyses of other genes, including tyrosine hydroxylase and sepiapterin reductase, can be performed in patients without GCH1 mutation and in those dopa-responsive dystonia patients with other neurologic features (including mental retardation, oculogyric crises, psychiatric manifestations, axial hypotonia, and dysautonomia symptoms), particularly when onset occurs during the first year of life and before the age of 10 (16). Another autosomal dominant form of dopa-responsive dystonia was described in a family with a genetic locus mapping to 14q13 (54), but this kindred was found to actually have a misidentified GCH1 defect (30); 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 (84; 74; 162). 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 (63; 51). A study of 6 patients with tyrosine hydroxylase deficiency demonstrated levodopa-induced dyskinesias as a common finding (118). 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 (141). Also, compound heterozygous GCH1 mutations may produce a more severe dopa-responsive dystonia phenotype with developmental delay (44).

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 (130). Low cerebrospinal fluid homovanillic acid levels suggest impaired dopamine production (117; 90), 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 (125; 135; 151), indicating that the presynaptic nigrostriatal dopaminergic terminals are intact, and (2) increased D2 receptor density (83; 91; 122), which normalizes following treatment with levodopa (83), suggesting integrity of postsynaptic nigrostriatal pathways. D1 receptor levels are unchanged (122). SPECT using dopamine transporter ligand shows normal binding to striatal dopamine transporters (64; 67; 81). Thus, both PET and SPECT distinguish patients with dopa-responsive dystonia from those with dopamine depletion from Parkinson disease (144; 80; 67). 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 (65; 57).

Mutations in GCH1, the gene encoding guanosine triphosphate cyclohydrolase I (GTP-CHI), cause most cases of dopa-responsive dystonia. GTP-CHI is involved in the production of tetrahydrobiopterin, which is required by 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 (32; 72), which may be corrected by exogenous tetrahydrobiopterin (77) or levodopa. Identification of dopa-responsive dystonia causative genes has facilitated animal models for the disorder (69; 85). 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 (35). 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 (119; 47; 42; 54), 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 (42). 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 (34).

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 (61). The relationship between GTP-CHI enzyme activity and dopa-responsive dystonia is not completely understood. Unanswered questions (131) 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 (62; 76; 140; 131; 128).

Epidemiology

Although its exact prevalence remains unknown, it is estimated that 0.5 persons per million have dopa-responsive dystonia (109). The distribution of reported cases is worldwide, and unlike idiopathic torsion dystonias, dopa-responsive dystonia is not more common among Ashkenazi Jews. 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 (112), though gender variable penetrance is not seen in all kindreds (152). A report of dopa-responsive dystonia involving a family of 4 female siblings, including monozygotic triplets, highlights the discovery of a novel frameshift GCH1 mutation (142). 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) (113). 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.

Prevention

With the advent of gene localization, genetic counseling is an option for families considering reproductive choices.

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; 98). A literature review of 576 cases between 1952 and 2011 revealed an average delay in diagnosis of 13.5 years (143). 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 3 categories: classic dopa-responsive dystonia, dopa-responsive dystonia with parkinsonism, and early-onset atypical dopa-responsive dystonia (159). A metaanalysis 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 (82).

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; 161). Indeed, an empiric trial of levodopa should be considered in any child with dystonia (43). 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 (79). 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 (89). 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 (160).

Table 2. Differential Diagnosis of Dopa-Responsive Dystonia

Apart from guanosine triphosphate cyclohydrolase I deficiency (from GCH1 mutations), other less common disorders of neurotransmitter metabolism may cause dystonia responsive to levodopa. These disorders are often, but not always (104; 45; 138), accompanied by other neurologic deficits. Table 3 lists these diseases; all arise during infancy or childhood and are inherited in an autosomal recessive manner (141; 63; 38; 126; 20; 106; 01; 147).

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

A PubMed systemic literature review until 2020 that included 734 dopa-responsive dystonia patients and 151 asymptomatic GCH1 mutation carriers showed that pathogenic variants in the guanosine triphosphate cyclohydrolase-1 (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. In addition, recessive/biallelic mutations in GCH1 as well as in 4 other genes (tyrosine hydroxylase [TH], 6-pyruvoyl tetrahydrobiopterin synthase [PTS], sepiapterin reductase [SPR], and quinoid dihydropteridine reductase [QDPR]) have been frequently associated with monogenic dopa-responsive dystonia. Data of 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 (156).

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. 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” (97). However, this proposal has been challenged, and many clinicians still believe that an early trial of levodopa is potentially diagnostic and therapeutic (03).

The genotypic heterogeneity of dopa-responsive dystonia complicates the interpretation of gene testing (38). GCH1 is composed of 6 exons spanning approximately 30 kilobases (72; 73). 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 15% (43; 38; 56; 39). 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 (165) because comprehensive screening fails to identify the responsible mutation in 40% to 50% of the families (38). 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; 138). In those patients without GCH1 mutations and dopa-responsive dystonia plus other neurologic features, molecular analyses of tyrosine hydroxylase and sepiapterin reductase genes should be considered. Whole-exome sequencing was used to make a rapid genetic diagnosis for 2 atypical dopa-responsive dystonia pedigrees (139). With improvements in cost and availability, whole-exome sequencing may improve diagnosis in patients with suspected heterogeneous genetic conditions in the near future.

Routine diagnostic studies such as CT, MRI, EEG, and blood chemistries are normal, as is PET with fluorodopa. PET and SPECT seem to differentiate dopa-responsive dystonia patients from young-onset Parkinson disease patients and may have a diagnostic utility (12; 105; 67). ¹²³I-FP-CIT(DaTSCAN) SPECT studies demonstrate normal uptake in dopa-responsive dystonia and decreased uptake in young-onset Parkinson disease (10). A structural MRI study of 9 dopa-responsive dystonia patients and 37 controls using cortical thickness analysis demonstrated that dopa-responsive dystonia patients relative to controls had cortical thinning of right precentral gyrus, posterior cingulate cortex, supramarginal gyrus and left middle temporal gyrus, and posterior cingulate cortex. Dopa-responsive dystonia patients 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 (88).

Transcranial sonography of the midbrain (normal in dopa-responsive dystonia patients and hyperechogenic in those with early-onset Parkinson disease) may also serve to distinguish these populations (55). 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 (86).

Routine CSF parameters are normal, but CSF homovanillic acid levels (a dopamine metabolite) as well as biopterin and neopterin levels (tetrahydrobiopterin pathway metabolites) are all reduced (109). These findings are in contrast to early-onset parkinsonism, which exhibits low biopterin but normal neopterin levels (38). Serotonin is also synthesized via a tetrahydrobiopterin-dependent hydroxylase (tryptophan hydroxylase), but CSF levels of the serotonin metabolite 5-HIAA are inconsistently altered in patients with autosomal dominant dopa-responsive dystonia (109). Serum prolactin levels are normal in patients with dopa-responsive dystonia associated with GCH1 gene mutations (37).

Differentiation of juvenile Parkinson disease from dopa-responsive dystonia has been demonstrated by measurement of guanosine triphosphate cyclohydrolase I activity in mononuclear blood cells of affected individuals (73; 60; 50), 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 (59; 17). A study of 509 Parkinson disease patients did not identify any pathogenic GCH1 mutations (121). 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).

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 (70; 05), but the method is not yet standardized to minimize false-negative test results (124). This test is based on the fact that patients with GCH1 deficiency cannot adequately convert phenylalanine into tyrosine because tetrahydrobiopterin is a cofactor for phenylalanine hydroxylase. Treatment with tetrahydrobiopterin should be avoided during the oral phenylalanine loading test due to the possibility of misinterpretation of the results (115). Simultaneous measurements of the phenylalanine/tyrosine ratio and biopterin in plasma or dried spot blood may be important in pediatric patients (116).

Management

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. Initially, carbidopa/levodopa is given as 12.5/50 mg (half tablet) once or twice daily. A quarter tablet may be given to patients under 5 years of age. An excellent response is usually seen within several days of drug initiation. The dose may be increased gradually, but patients rarely require more than several hundred milligrams of levodopa per day. An optimal response at 10 mg/kg has been suggested (155). Even individuals whose treatment is delayed for years may experience a full resolution of their dystonia. 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 (66). 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 (149). Treatment limiting dyskinesias in a family with a prominent brachial dystonia and a novel GCH1 mutation has been described (95). Overall, drug-induced dyskinesias have been described in a minority of patients (19; 66), 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. 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 (112). Some patients with dopa-responsive dystonia respond to tetrahydrobiopterin, but the effect is variable (33), and others may require combination therapy using levodopa and tetrahydrobiopterin for optimum improvement (46). The cost of tetrahydrobiopterin probably precludes its use as a monotherapy. 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 (66). Patients with associated depression or obsessive compulsive disorder (perhaps attributable to defective serotonin synthesis) usually respond well to selective serotonin reuptake inhibitors. The serotonin precursor 5-hydroxytryptophan also may prove useful in treating depression in some individuals with dopa-responsive dystonia (154). Of note, 1 case report demonstrated normal concentration of serotonin in the striatum of a patient with dopa-responsive dystonia (48).

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 (36). Neuroleptic malignant syndrome has been described in 1 patient with comorbid psychiatric illness (75). Although selective serotonin reuptake inhibitors are generally well tolerated by patients with dopa-responsive dystonia, 1 report associated these drugs with a reversal of levodopa benefit (100).

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 (148; 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 (27).

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 (131). 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 (93). 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 (112), 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).

Special considerations

Pregnancy

In a series of 12 pregnant women with genetically proven dopa-responsive dystonia cases, remission occurred in 3 patients and a mild deterioration occurred in 2 patients (149). In the majority of patients, levodopa was continued at a stable dose. Levodopa was used safely, and no fetal abnormalities were reported in 20 pregnancies. In another study, transient worsening of dystonia was reported in 3 of 12 women during pregnancies occurring prior to levodopa therapy (112). No lasting problems emerged postpartum. Levodopa treatment appears safe during pregnancy (114). Fluctuations of estrogen and progesterone may be associated with symptom exacerbation (112).

Anesthesia

Dopamine receptor blocking agents, including neuroleptic medications for agitation and phenothiazines for nausea, should be avoided in the perioperative period for the reasons noted above.