Dystonia is a movement disorder characterised by persistent and intermittent muscle contractions that cause involuntary repetitive movements, and that can lead to abnormal posture in affected parts of the body (1 ). Classic dopa-responsive dystonia typically begins in childhood or adolescence, most often with walking difficulties. Symptoms worsen towards the evening and improve in the morning after sleep, and show a highly positive and sustained response to levodopa (2 –4 ).
The aim of this article is to provide general practitioners, neurologists, paediatricians and other interested parties with a basic knowledge of this diagnostic group, with an emphasis on clinical aspects.
Method
We searched the Ovid database (Medline) for the period 1 January 1946–2 December 2016 with the following search strings: ((dopa* or levodopa* or hereditary) adj3 (respon* or progressive*) adj (parkinson* or dystoni* or extrapyramid*)).tw or (segawa* adj5 (disease or dystoni* or syndrome)).tw or (dystoni* and ((infantile or juvenile or young)) adj2 parkinson*).mp or (GTP adj (Cyclohydrolase or CH) adj3 deficien*).tw or (sepiapterin reductase adj3 deficien*).mp or sr deficien*.mp or (tyrosine hydroxylase adj3 deficien*).mp.
We included only those articles that were written in English or a Scandinavian language and that related to humans.
The database search yielded 812 hits, and we identified an additional four references from our own archive. A total of 747 articles were excluded on the basis of the title and abstract or because they were duplicates, while 65 publications were considered in full text. Only original articles describing two or more patients, and describing diagnosis and treatment, were included. We also included all individual case reports based on Norwegian patients. Older review articles that had been superseded by newer reviews were excluded. A total of 39 articles were included in the current review, one of which was a review article from our own literature archive (5 ). A textbook (6 ) and the websites ‘Gene Reviews’ (7 ) and ‘OMIM’ (8 ) were also included. The search strategy is shown in Figure 1.
Figure 1 Flowchart summarising the article search
Background
Segawa et al . published the first patient dataset with nine patients in 1976 (9 ). The disorder has been referred to by several names: Segawa’s disease, hereditary progressive dystonia/diurnal dystonia and infantile parkinsonism. The term ‘dopa-responsive dystonia’ was introduced by Nygaard in 1988 (10 ) and is now the most widely used.
From the 1990s onwards, studies have been conducted to characterise the underlying genetic causes and associated biochemical deficiencies and pathophysiology. This has led to changes in the names of the disorders and has formed the basis for a more targeted clinical approach. To date, patients have been shown to have pathogenic variants in one of three genes: guanosine triphosphate (GTP) cyclohydrolase 1 , sepiapterin reductase , and tyrosine hydroxylase (3 , 11 , 12 ). There is a lack of high quality epidemiological data on the disorders, and underdiagnosis is likely (6 , 12 , 13 ). A prevalence in the general population of 0.5 per million is often reported in the literature (12 , 13 ). Only a few articles based on Norwegian data have been published (14 –16 ).
Pathophysiology and inheritance
Dopamine, noradrenaline and serotonin are monoamine transmitters that play a crucial role in motor control, sleep, emotions, and in cognitive and autonomic functions (6 ). GTP cyclohydrolase 1 and sepiapterin reductase are key enzymes in the formation of tetrahydrobiopterin, an essential cofactor for tyrosine, tryptophan and phenylalanine hydroxylase. Tyrosine and tryptophan hydroxylase are rate-limiting enzymes in the formation of dopamine and serotonin, respectively (6 ) (Figure 2). Impaired phenylalanine hydroxylase function gives rise to Følling’s disease/phenylalaninaemia, a better known disorder that may be detected during neonatal screening. Dopa-responsive dystonia with pathogenic variants in the genes GTP cyclohydrolase 1 , sepiapterin reductase or tyrosine hydroxylase generally goes undetected in neonatal screening, as patients usually have normal levels of phenylalanine in the blood (6 ). Phenylalanine hydroxylase, like tyrosine hydroxylase, is dependent on the cofactor tetrahydrobiopterin.
Figure 2 The figure shows the pathways by which dopamine and serotonin are synthesised, and the various enzymes and metabolites involved. Most of the intermediates and end products can be measured in the cerebrospinal fluid, providing information on which enzyme has reduced activity. Phenylalanine, tryptophan and tyrosine are all dependent on BH4 as a cofactor. The arrows/enzymes in red are the enzymes affected in cases of dopa-responsive dystonia. Dashed lines indicate that there are multiple steps in the reaction path. AADC = aromatic L-amino acid decarboxylase, BH2 = dihydrobiopterin, BH4 = tetrahydrobiopterin, GTP = guanosine triphosphate, GTPCH1 = GTP cyclohydrolase 1, HO-BH4 = hydroxy-BH4 , 5-HIAA = 5-hydroxyindoleacetic acid, 5-HT = 5-hydroxytryptophan, HVA = homovanillic acid, NH2 TP = dihydroneopterin triphosphate, PAH = phenylalanine hydroxylase, PTP = 6-pyruvoyltetrahydropterin, PTPS = PTP synthase, SR = sepiapterin reductase, TH = tyrosine hydroxylase, TPH = tryptophan hydroxylase, VMA = vanillylmandelic acid.
Dopa-responsive dystonia may show autosomal recessive or dominant inheritance. However, many patients are the only family member to be affected, as de novo mutations, reduced penetrance and variable expressivity are common (3 , 6 ).
Clinical presentation
Dopa-responsive dystonia is primarily described as a motor disorder (6 , 11 , 12 ). Nevertheless, many patients have cognitive and psychiatric symptoms (17 –19 ), and variation in the clinical picture has been reported (7 , 12 , 20 –22 ).
School-age children and adolescents with dystonia or increased tonus in their legs that shows diurnal variation must always be assessed for the condition (12 ). Infants and young children with dystonia or other movement disorders, possibly accompanied by other neurological symptoms such as hypotonia, hypersomnia and/or autonomic dysfunction, should also be assessed for dopa-responsive dystonia. Oculogyric crises, which are episodes of dystonic, bilateral movements of the eyes, should raise suspicion of these disorders (2 , 3 , 6 , 12 , 23 , 24 ).
The term ‘dopa-responsive dystonia-plus’ is used to refer to patients with earlier disease onset, more severe motor symptoms and more prominent non-motor symptoms compared to the classic form (6 , 11 , 25 ).
Patients often experience a delay between symptom onset and a correct diagnosis; Box 1 lists common misdiagnoses received by patients (3 , 6 , 13 , 19 , 22 , 26 –28 ).
Box 1 Misdiagnoses commonly received by patients with dopa-responsive dystonia (3, 6, 13, 19, 22, 26–28)
Cerebral palsy
Hereditary spastic paraplegia
Idiopathic dystonia/isolated dystonia
Juvenile Parkinson’s disease
Muscular dystrophy
Psychosomatic disorder
Neurodegenerative disease
Congenital metabolic disease of unknown origin
Subgroups
Autosomal dominant GTP cyclohydrolase 1 deficiency
This is the most common form of dopa-responsive dystonia (25 ). The typical patient is a previously healthy child who, at the age of 6–12 years, begins to show asymmetric gait abnormalities (see video). Parents often report worsening of symptoms in the afternoon and evening. Physical activity typically exacerbates symptoms, while symptoms may fully resolve at rest. The dystonia progresses over time if left untreated, and gradually spreads asymmetrically to other extremities and the trunk. It can easily be mistaken for increased tonus with alternative aetiology. A number of patients develop parkinsonian symptoms with bradykinesia, rigidity, postural tremor or postural instability (9 , 13 , 18 , 19 , 26 , 29 ). Clinical examination typically reveals lively deep tendon reflexes. Many patients have a so-called ‘striatal toe’; i.e. a dystonic extension of the big toe. Autosomal dominant GTP cyclohydrolase 1 deficiency may also have onset in adulthood with dystonia, tremor and/or parkinsonism (3 , 29 ).
Autosomal recessive GTP cyclohydrolase 1 deficiency
This disease gives rise to complex and severe neurological symptoms, and is sometimes diagnosed following the discovery of hyperphenylalaninaemia during neonatal screening (23 , 30 ). Symptoms usually begin during the first few months of life and may be present from birth.
Prominent signs are severe psychomotor retardation, bradykinesia, truncal hypotonia, autonomic dysfunction and often epilepsy (23 , 28 , 31 ).
Autosomal recessive tyrosine hydroxylase deficiency
This disease is associated with a broad clinical picture consistent with catecholamine deficiency (32 ). The enzyme deficiency can give rise to classic dopa-responsive dystonia, hypokinesia, rigidity and severe progressive encephalopathy (33 ). Willemsen et al . described 36 patients with the disorder and divided them into two main clinical groups (32 ). Type A has onset in the first year of life with a progressive hypokinetic-rigid syndrome (infantile parkinsonism) and dystonia, with cognitive function usually within the normal range. These patients respond well to levodopa. Type B is described as a severe encephalopathy with neonatal onset. Type B typically features truncal hypotonia, possibly combined with extremity hypertonia, and vegetative symptoms with episodes of sweating and drooling, as well as periods of irritability.
Autosomal recessive sepiapterin reductase deficiency
This is described as a ‘dopa-responsive dystonia-plus’ disease, and patients present with symptoms of both dopamine and serotonin deficiency (14 , 22 , 34 ). The most common symptoms are psychomotor development retardation, axial hypotonia, dystonia, muscle weakness and oculogyric crises. In addition, many patients have behavioural disorders, autonomic dysfunction and sleep disorders (22 , 35 ).
Other conditions
Up to 20 % of patients with dopa-responsive dystonia test negative for pathogenic variants in the three known genes (25 ). Other genes are also likely to be involved in the pathogenesis of this disease group (5 , 6 , 25 ). Pathogenic variants in other known genes can give rise to a similar clinical picture, with a partial response to levodopa (5 , 25 ). There are reports of patients with hereditary ataxias or spastic paraplegias, or with early-onset familial Parkinson’s disease/infantile parkinsonism with dystonia/increased tonus, responding to levodopa (5 , 25 ). Based on their clinical presentation and treatment response, the latter diseases have not typically been regarded as dopa-responsive dystonia (2 , 3 , 6 , 11 ).
Assessment
Given the good therapeutic response and broad clinical picture of dopa-responsive dystonia, it is important that patients are thoroughly assessed (3 , 6 , 24 ). Many patients first undergo a negative round of testing in the form of brain magnetic resonance imaging, electroencephalography and routine cerebrospinal fluid analyses (cells, protein, glucose, amino acid quantification, lactate) as well as metabolic screening of urine and blood.
After this preliminary testing, several publications recommend attempting treatment with levodopa as part of the diagnostic work-up (2 , 3 , 6 , 12 ). Treatment should be continued for at least one month. It is important to emphasise that dystonia is not always the main symptom in these patients and an immediate treatment response is not always achieved. In other words, the term ‘dopa-responsive dystonia’ must not limit the diagnostic testing of these patients (2 ).
It is recommended that treatment should be continued for a minimum of 2–3 months in patients with oculogyric crises, focal or generalised dystonia, parkinsonism and encephalopathy, as time to treatment response is expected to be longer in this group (3 , 6 , 24 ). Quantification of pterins, biogenic monoamines and their metabolites (often referred to simply as neurotransmitter substances) in the cerebrospinal fluid is a key part of the work-up, along with molecular genetic testing (6 ). Biochemical changes in the cerebrospinal fluid in the various disorders are shown in Table 1 (36 ). It should be noted that ongoing treatment with levodopa may affect the results. Lumbar puncture should thus be performed prior to treatment initiation and the sample frozen for later analysis (6 , 12 ). In most patients, genetic testing will confirm the precise diagnosis (12 , 25 ).
Table 1
Biochemical changes in cerebrospinal fluid in the various dopa-responsive dystonias. N = normal, ↓ = values lower than reference range, ↓↓ = values much lower than reference range, ↑ = values higher than reference range. Reference ranges are age-dependent. GTPCH1 = guanosine triphosphate cyclohydrolase 1, TH = tyrosine hydroxylase, SR = sepiapterin reductase.
Biochemical marker in cerebrospinal fluid
GTPCH1 deficiency1
SR deficiency
TH deficiency
Total neopterin
↓
N/↑
N
Total biopterin
↓
↑
N
Tetrahydrobiopterin (BH4 )
↓
N
N
Dihydrobiopterin (BH2 )
N
↑
N
Sepiapterin
N
↑
N
Homovanillic acid (HVA)
↓
↓
↓/↓↓
5-hydroxyindoleacetic acid (5-HIAA)
N/↓
↓
N
HVA/5-HIAA-ratio
-
-
↓/↓↓
Dopamine transporter scintigraphy (DaTSCAN) usually shows normal results in the various conditions, but may reveal pathology in cases of early-onset familial Parkinson’s disease/juvenile parkinsonism, a neurodegenerative disorder with a distinct genetic aetiology (3 ).
The serum concentration of prolactin may be elevated in cases of sepiapterin reductase or tyrosine hydroxylase deficiency owing to a lack of dopaminergic inhibition (6 , 14 , 37 ), while prolactin levels are usually normal in cases of autosomal dominant GTP cyclohydrolase 1 deficiency (38 ).
Although dopa-responsive dystonia does not usually give rise to hyperphenylalaninaemia, a bolus dose of phenylalanine followed by serum concentration measurements after one and two hours often reveals an elevated phenylalanine/tyrosine ratio in patients with pathogenic variants of the genes GTP cyclohydrolase 1 and sepiapterin reductase (6 , 36 , 39 ). This is due to a lack of tetrahydrobiopterin. The test will yield normal results in cases of tyrosine hydroxylase deficiency.
Treatment
Levodopa is the cornerstone of the treatment of dopa-responsive dystonia. However, the dosage, regimen, expected response and need for additional treatment depend on the underlying aetiology, disease severity, and adverse effects (2 , 6 , 28 , 40 ).
Treatment must be tailored to the individual in collaboration with a doctor with experience in the field. The recommended starting dose of levodopa is 0.5–1 mg/kg/day (2 , 6 , 24 , 28 , 32 , 35 ). If no response is seen but the diagnosis is still suspected, the dose should be gradually increased. In addition, tablets containing 5-hydroxytryptophan and/or tetrahydrobiopterin may be appropriate for patients with ‘dopa-responsive dystonia-plus’ (6 , 24 ). The response to levodopa treatment is not always satisfactory in complex forms of tyrosine hydroxylase deficiency (33 , 41 ).
Discussion
‘Dopa-response dystonia’ was named in line with the symptoms shown by most patients and the treatment to which they respond. However, the term encompasses various genetic disorders, with varying clinical presentation and therapeutic requirements, in addition to patients for whom no genetic diagnosis has been established. Identifying the underlying enzyme deficiency and precise genetic diagnosis is advantageous both in the clinic and in research (3 ).
Several different assessment strategies have been proposed in the literature (6 , 12 ). The optimal order of testing will depend on clinical findings, the results of previous tests, the response to attempted treatment and the availability of the various tests.
Molecular genetic testing is becoming increasingly important in neurological diseases. Gene panels are now available for neurological diseases with motor symptoms and for metabolic disorders; such panels include the genes implicated in dopa-responsive dystonia (42 ). Nevertheless, it is important to also take advantage of the information offered by concentrations of pterins, biogenic monoamines and their metabolites in cerebrospinal fluid. This information can be of assistance in reaching an exact diagnosis, revealing the significance of a genetic variant and selecting drugs as adjuvants to levodopa. Cerebrospinal fluid analysis will often be indicated as part of the initial work-up for movement disorders as well as in cases of dopa-responsive dystonia.
It must be emphasised that even if the exact diagnosis cannot be confirmed biochemically and/or genetically, this should not preclude a diagnosis of dopa-responsive dystonia or treatment attempts on the basis of clinical indication.
International networks and increased expertise will be essential for gathering and disseminating information about this patient population (43 ).
