Diagnosing Dopamine-Responsive Dystonias
Diagnosing Dopamine-Responsive Dystonias
When a child or adult presents with what appears to be a primary dystonia, mainly affecting the lower limbs, clinicians must consider and exclude a reversible or treatable DRD. This is the case even without an autosomal-dominant family history and/or diurnal variation (with symptoms worsening towards the end of the day). Such features suggest guanosine triphosphate cyclohydrolase deficiency syndrome (GTPCH-DRD), but may be absent, and the diagnosis cannot rely on their presence. In contrast, tyrosine hydroxylase deficiency syndrome (TH-DRD) and sepiapterin reductase deficiency syndrome (SR-DRD)—considered to be 'DRD-plus' syndromes—usually present to paediatric neurologists in the first year of life with dystonia, hypotonia, hypersomnia, encephalopathy, oculogyric crisis or parkinsonism.
GTPCH and SR are enzymes required in the synthesis of tetrahydrobiopterin (BH4), which is an essential cofactor within the biosynthetic pathways for dopamine and serotonin. For dopamine synthesis, BH4 is a necessary cofactor for phenylalanine hydroxylase and TH enzymes (see figure 1).
Deficiency of any of these three enzymes (GTPCH, SR or TH) leads to dopamine depletion at the synaptic terminals within the basal ganglia, causing both motor and non-motor dysfunction (mood swings, depression, verbal memory deficits and concentration problems). There is pathological and biochemical evidence of striatal dopamine deficiency in DRDs to support this hypothesis.
The age of onset, clinical phenotype and response to treatment vary with the different DRD syndromes, although there is some overlap. Distinguishing between the DRD syndromes on clinical grounds alone may be difficult due to this phenotypic overlap, and diagnostic tests become valuable adjuncts in this setting. Identifying the specific molecular defect helps to inform accurate prognosis and obviates the risk of blind treatment.
This is by far the most common and typical form of DRD. Usually, there is onset of focal or segmental lower limb dystonia with walking difficulties in childhood (figure 2). The symptoms may deteriorate towards the end of the day (diurnal fluctuation), and there may be a family history consistent with autosomal-dominant inheritance. Even with the same mutation, the age of onset and clinical severity may vary. A difference in gene penetrance probably accounts for the variation in age of onset between sexes (mean age 4.5 years for males and 7 years for females) and within families. Dystonia in DRD can also be segmental, axial or generalised, but typically affects the lower limbs. There is some evidence of impulsivity in GTPCH-DRD.
(Enlarge Image)
Figure 2.
Affected adult male before treatment. (A) Typically clothed and seated in wheelchair. (B) Unclothed and extended with assistance to display torso and extremities. Note, there are kyphoscoliosis and contractures of hands and feet.
In young people, it is easy to misdiagnose DRD as diplegic cerebral palsy or hereditary spastic paraplegia; brisk lower limb reflexes, increased lower limb tone and spurious 'striatal' plantar responses may contribute to this diagnostic error. It is even possible for dystonic spasms to be mistaken for seizures. Delays in diagnosis miss an opportunity to treat symptoms effectively, and can result in unnecessary orthopaedic interventions.
GTPCH-DRD can rarely present in adulthood (mean age at onset 37 years). People in this age group may present with parkinsonian or dystonic tremor phenotype. While GTPCH-DRD is usually inherited as an autosomal-dominant disorder with reduced penetrance, autosomal recessive transmission with neonatal and infantile onset can also occur with a more severe phenotype. Females outnumber males by approximately three to one.
SR-DRD is very rare, and presents in infancy or early childhood. Most cases present with a combination of dystonia (generalised, segmental or focal), developmental delay, axial hypotonia, oculogyric crisis and diurnal fluctuation of symptoms. Again, cases can be misdiagnosed as cerebral palsy due to the presence of motor and cognitive delay. The average age of onset is 7 months, with reported delays in diagnosis of up to 9 years. SR-DRD can also present with other movement disorders such as chorea or rest tremor. There is a dramatic improvement in motor symptoms with l-dopa treatment, and 5-hydroxytryptophan may give further benefits.
TH-DRD is the most severe phenotype of DRD spectrum presenting with infantile parkinsonism, spastic paraplegia or progressive infantile encephalopathy. The onset is usually in infancy, but there are case reports of delayed diagnosis in patients with milder phenotypes. More severe phenotypes are less likely to be l-dopa responsive.
SR-DRD and TH-DRD are sometimes classified together under the rubric DRD-plus syndromes.
DRDs are potentially treatable disorders. Starting treatment with L-dopa early can give dramatic and sustained relief of symptoms, improving performance of activities of daily living and quality of life. It is important to give an adequate therapeutic trial of l-dopa—at least 300 mg daily for 3 months. This is usually decisive. Rarely, however, a limited or uncertain l-dopa response may not confirm or exclude the diagnosis of DRD. In this situation, identifying a biochemical defect or relevant genetic mutation may secure the diagnosis of a possible DRD syndrome. We now suggest a protocol to investigate suspected DRD cases (figure 3).
(Enlarge Image)
Figure 3.
An algorithm for approaching adult patients with dopamine-responsive dystonia. DRD, dopamine-responsive dystonia; GTPCH1, guanosine triphosphate cyclohydrolase.
Trial of L-dopa. In children, L-dopa (in combination with a dopa-decarboxylase inhibitor) should be started at 1 mg/kg/day in divided doses. This can be increased gradually according to tolerability and response, with most children requiring 4–5 mg/kg/day. For adult patients, L-dopa (with dopa-decarboxylase inhibitor) should be started at 100 mg/day in divided doses. L-dopa can be gradually increased, and most patients will respond to 300–400 mg/day.
In a case series of 58 patients with DRD, the average L-dopa requirement of 29 patients with identified GCH1 mutations was 166 mg/day (range 25–400 mg/day). L-dopa requirements in those without GCH1 mutations were higher at 232 mg/day (range 12.5–600 mg/day).
Occasionally, higher L-dopa doses are required in adults (up to 1000 mg/day) and children (up to 20 mg/kg/day), but biochemical or genetic diagnostic confirmation should be attempted before escalating L-dopa doses further to avoid dopaminergic side effects and prolonged blind treatment.
Phenylalanine Loading Test. If the L-dopa response is ambiguous, the next diagnostic step is the phenylalanine loading test. In this test, patients drink an oral phenylalanine solution and then provide blood samples at baseline and prespecified time intervals thereafter to determine plasma levels of amino acids, phenylalanine and tyrosine. Patients with DRD syndromes have impaired conversion of phenylalanine to tyrosine because of BH4 deficiency (see figure 1).
Adult Protocol: Patients can have a low-protein breakfast (cereal) approximately 2 h before the test. Blood samples are collected in lithium heparin tubes and transferred to the analysing laboratory on dry ice (–70°C), although protocols may vary by laboratory. Patients give a baseline blood sample for plasma phenylalanine and tyrosine concentrations. They then take 100 mg/kg l-phenylalanine, diluted in 100 mL of water or lemonade to drink. Blood samples are then collected at 1, 2 and 4 h post dose for plasma amino acid analysis.
Interpretation: A plasma phenylalanine:tyrosine ratio of >7.5 at 4 h in adults strongly suggests a DRD syndrome, but importantly, this test does not help to distinguish between the various DRD syndromes.
Genetic Testing. If the phenylalanine loading test is negative or indeterminate (plasma phenylalanine to reach a minimum level of 600 μmol/L for the test to be valid), but there is still a clinical suspicion of a DRD syndrome then the patient may need genetic testing. There are over 200 different mutations described in the GCH1 gene located on chromosome 14q22.1–q22.2 that result in GTPCH-DRD. Whole gene sequencing should be performed due to the high number of pathogenic mutations described. In adults and children aged older than 1 year, this is the most likely gene to be mutated. In infancy, the causative genetic mutation most likely resides in either the SPR or TH genes. There are about 15 different known mutations in the SPR gene, which codes for the SR enzyme, located on chromosome 2p14–p12 and over 50 different known mutations in the TH gene located on chromosome 11p15.5. Several laboratories now offer multigene panel testing (using DNA microarray) for all three genes (GTPCH, SR and TH). Patients and their families should have access to appropriate prediagnostic and postdiagnostic genetic counselling.
SPECT Imaging. FP-CIT ((123)I-N-omega-fluoropropyl-2β-carboxymethoxy-3β(4-iodophenyl) nortropane) single-photon emission CT (SPECT) may occasionally be required to distinguish neurodegenerative diseases, such as young-onset Parkinson disease due to PARKIN mutations from GTPCH-DRD with a parkinsonian phenotype. Patients with DRD have a normal scan.
Cerebrospinal Fluid Pterin Analysis. Several different inherited neurotransmitter defects can manifest with predominant hyperkinetic movement disorder phenotypes in infancy and early childhood. The manifestations of dopamine, serotonin and folate metabolic pathway defects can overlap clinically. Cerebrospinal fluid (CSF) pterin metabolites analysis by high-pressure liquid chromatography is an inexpensive way to distinguish these classes of neurotransmitter disorders, allowing for focused confirmatory genetic testing to establish the exact cause. Each DRD syndrome has a recognised CSF metabolite profile, depending upon the deficient enzyme (Table 1). This technique rarely helps for those with adult presentations, although it may be relevant for adolescents with undiagnosed hyperkinetic disorders who are in transition from paediatric neurology services.
L-dopa helps the symptoms without altering the disease course. However, the non-motor manifestations within DRD-plus syndromes (eg, cognitive dysfunction) are not L-dopa responsive. The clinical assessment of the response to treatment is based on improvement in motor symptoms. However, there is no validated scale to measure this response reliably, and the clinical heterogeneity of DRD syndromes would make it challenging to develop such a scale.
The response to L-dopa in DRD is usually sustained and prolonged. It is very uncommon for patients to develop dyskinesia, but this occasionally happens. In one series of 20 patients with DRD, one-fifth of patients developed dyskinesias after a mean disease duration of 28.9±14.8 years (range 5–54 years) with a mean daily dose of 343 mg/day of L-dopa (range 100–600 mg/day). There was a relationship between the development of dyskinesias and the prescribed dose of L-dopa. In general, however, the appearance of motor fluctuations and/or significant dyskinesia should prompt a review of the diagnosis of DRD and consideration of early-onset Parkinson disease, in which lower limb dystonia can be a prominent and early feature.
When to Suspect DRD?
When a child or adult presents with what appears to be a primary dystonia, mainly affecting the lower limbs, clinicians must consider and exclude a reversible or treatable DRD. This is the case even without an autosomal-dominant family history and/or diurnal variation (with symptoms worsening towards the end of the day). Such features suggest guanosine triphosphate cyclohydrolase deficiency syndrome (GTPCH-DRD), but may be absent, and the diagnosis cannot rely on their presence. In contrast, tyrosine hydroxylase deficiency syndrome (TH-DRD) and sepiapterin reductase deficiency syndrome (SR-DRD)—considered to be 'DRD-plus' syndromes—usually present to paediatric neurologists in the first year of life with dystonia, hypotonia, hypersomnia, encephalopathy, oculogyric crisis or parkinsonism.
Pathophysiology
GTPCH and SR are enzymes required in the synthesis of tetrahydrobiopterin (BH4), which is an essential cofactor within the biosynthetic pathways for dopamine and serotonin. For dopamine synthesis, BH4 is a necessary cofactor for phenylalanine hydroxylase and TH enzymes (see figure 1).
Deficiency of any of these three enzymes (GTPCH, SR or TH) leads to dopamine depletion at the synaptic terminals within the basal ganglia, causing both motor and non-motor dysfunction (mood swings, depression, verbal memory deficits and concentration problems). There is pathological and biochemical evidence of striatal dopamine deficiency in DRDs to support this hypothesis.
Clinical Phenotypes
The age of onset, clinical phenotype and response to treatment vary with the different DRD syndromes, although there is some overlap. Distinguishing between the DRD syndromes on clinical grounds alone may be difficult due to this phenotypic overlap, and diagnostic tests become valuable adjuncts in this setting. Identifying the specific molecular defect helps to inform accurate prognosis and obviates the risk of blind treatment.
Guanosine Triphosphate Cyclohydrolase Dopamine-Responsive Dystonia
This is by far the most common and typical form of DRD. Usually, there is onset of focal or segmental lower limb dystonia with walking difficulties in childhood (figure 2). The symptoms may deteriorate towards the end of the day (diurnal fluctuation), and there may be a family history consistent with autosomal-dominant inheritance. Even with the same mutation, the age of onset and clinical severity may vary. A difference in gene penetrance probably accounts for the variation in age of onset between sexes (mean age 4.5 years for males and 7 years for females) and within families. Dystonia in DRD can also be segmental, axial or generalised, but typically affects the lower limbs. There is some evidence of impulsivity in GTPCH-DRD.
(Enlarge Image)
Figure 2.
Affected adult male before treatment. (A) Typically clothed and seated in wheelchair. (B) Unclothed and extended with assistance to display torso and extremities. Note, there are kyphoscoliosis and contractures of hands and feet.
In young people, it is easy to misdiagnose DRD as diplegic cerebral palsy or hereditary spastic paraplegia; brisk lower limb reflexes, increased lower limb tone and spurious 'striatal' plantar responses may contribute to this diagnostic error. It is even possible for dystonic spasms to be mistaken for seizures. Delays in diagnosis miss an opportunity to treat symptoms effectively, and can result in unnecessary orthopaedic interventions.
GTPCH-DRD can rarely present in adulthood (mean age at onset 37 years). People in this age group may present with parkinsonian or dystonic tremor phenotype. While GTPCH-DRD is usually inherited as an autosomal-dominant disorder with reduced penetrance, autosomal recessive transmission with neonatal and infantile onset can also occur with a more severe phenotype. Females outnumber males by approximately three to one.
Sepiapterin Reductase Dopamine-Responsive Dystonia
SR-DRD is very rare, and presents in infancy or early childhood. Most cases present with a combination of dystonia (generalised, segmental or focal), developmental delay, axial hypotonia, oculogyric crisis and diurnal fluctuation of symptoms. Again, cases can be misdiagnosed as cerebral palsy due to the presence of motor and cognitive delay. The average age of onset is 7 months, with reported delays in diagnosis of up to 9 years. SR-DRD can also present with other movement disorders such as chorea or rest tremor. There is a dramatic improvement in motor symptoms with l-dopa treatment, and 5-hydroxytryptophan may give further benefits.
Tyrosine Hydroxylase Dopamine-Responsive Dystonia
TH-DRD is the most severe phenotype of DRD spectrum presenting with infantile parkinsonism, spastic paraplegia or progressive infantile encephalopathy. The onset is usually in infancy, but there are case reports of delayed diagnosis in patients with milder phenotypes. More severe phenotypes are less likely to be l-dopa responsive.
SR-DRD and TH-DRD are sometimes classified together under the rubric DRD-plus syndromes.
When to Test?
DRDs are potentially treatable disorders. Starting treatment with L-dopa early can give dramatic and sustained relief of symptoms, improving performance of activities of daily living and quality of life. It is important to give an adequate therapeutic trial of l-dopa—at least 300 mg daily for 3 months. This is usually decisive. Rarely, however, a limited or uncertain l-dopa response may not confirm or exclude the diagnosis of DRD. In this situation, identifying a biochemical defect or relevant genetic mutation may secure the diagnosis of a possible DRD syndrome. We now suggest a protocol to investigate suspected DRD cases (figure 3).
(Enlarge Image)
Figure 3.
An algorithm for approaching adult patients with dopamine-responsive dystonia. DRD, dopamine-responsive dystonia; GTPCH1, guanosine triphosphate cyclohydrolase.
How to Test?
Trial of L-dopa. In children, L-dopa (in combination with a dopa-decarboxylase inhibitor) should be started at 1 mg/kg/day in divided doses. This can be increased gradually according to tolerability and response, with most children requiring 4–5 mg/kg/day. For adult patients, L-dopa (with dopa-decarboxylase inhibitor) should be started at 100 mg/day in divided doses. L-dopa can be gradually increased, and most patients will respond to 300–400 mg/day.
In a case series of 58 patients with DRD, the average L-dopa requirement of 29 patients with identified GCH1 mutations was 166 mg/day (range 25–400 mg/day). L-dopa requirements in those without GCH1 mutations were higher at 232 mg/day (range 12.5–600 mg/day).
Occasionally, higher L-dopa doses are required in adults (up to 1000 mg/day) and children (up to 20 mg/kg/day), but biochemical or genetic diagnostic confirmation should be attempted before escalating L-dopa doses further to avoid dopaminergic side effects and prolonged blind treatment.
Phenylalanine Loading Test. If the L-dopa response is ambiguous, the next diagnostic step is the phenylalanine loading test. In this test, patients drink an oral phenylalanine solution and then provide blood samples at baseline and prespecified time intervals thereafter to determine plasma levels of amino acids, phenylalanine and tyrosine. Patients with DRD syndromes have impaired conversion of phenylalanine to tyrosine because of BH4 deficiency (see figure 1).
Adult Protocol: Patients can have a low-protein breakfast (cereal) approximately 2 h before the test. Blood samples are collected in lithium heparin tubes and transferred to the analysing laboratory on dry ice (–70°C), although protocols may vary by laboratory. Patients give a baseline blood sample for plasma phenylalanine and tyrosine concentrations. They then take 100 mg/kg l-phenylalanine, diluted in 100 mL of water or lemonade to drink. Blood samples are then collected at 1, 2 and 4 h post dose for plasma amino acid analysis.
Interpretation: A plasma phenylalanine:tyrosine ratio of >7.5 at 4 h in adults strongly suggests a DRD syndrome, but importantly, this test does not help to distinguish between the various DRD syndromes.
Genetic Testing. If the phenylalanine loading test is negative or indeterminate (plasma phenylalanine to reach a minimum level of 600 μmol/L for the test to be valid), but there is still a clinical suspicion of a DRD syndrome then the patient may need genetic testing. There are over 200 different mutations described in the GCH1 gene located on chromosome 14q22.1–q22.2 that result in GTPCH-DRD. Whole gene sequencing should be performed due to the high number of pathogenic mutations described. In adults and children aged older than 1 year, this is the most likely gene to be mutated. In infancy, the causative genetic mutation most likely resides in either the SPR or TH genes. There are about 15 different known mutations in the SPR gene, which codes for the SR enzyme, located on chromosome 2p14–p12 and over 50 different known mutations in the TH gene located on chromosome 11p15.5. Several laboratories now offer multigene panel testing (using DNA microarray) for all three genes (GTPCH, SR and TH). Patients and their families should have access to appropriate prediagnostic and postdiagnostic genetic counselling.
SPECT Imaging. FP-CIT ((123)I-N-omega-fluoropropyl-2β-carboxymethoxy-3β(4-iodophenyl) nortropane) single-photon emission CT (SPECT) may occasionally be required to distinguish neurodegenerative diseases, such as young-onset Parkinson disease due to PARKIN mutations from GTPCH-DRD with a parkinsonian phenotype. Patients with DRD have a normal scan.
Cerebrospinal Fluid Pterin Analysis. Several different inherited neurotransmitter defects can manifest with predominant hyperkinetic movement disorder phenotypes in infancy and early childhood. The manifestations of dopamine, serotonin and folate metabolic pathway defects can overlap clinically. Cerebrospinal fluid (CSF) pterin metabolites analysis by high-pressure liquid chromatography is an inexpensive way to distinguish these classes of neurotransmitter disorders, allowing for focused confirmatory genetic testing to establish the exact cause. Each DRD syndrome has a recognised CSF metabolite profile, depending upon the deficient enzyme (Table 1). This technique rarely helps for those with adult presentations, although it may be relevant for adolescents with undiagnosed hyperkinetic disorders who are in transition from paediatric neurology services.
Treatment of Motor Symptoms
L-dopa helps the symptoms without altering the disease course. However, the non-motor manifestations within DRD-plus syndromes (eg, cognitive dysfunction) are not L-dopa responsive. The clinical assessment of the response to treatment is based on improvement in motor symptoms. However, there is no validated scale to measure this response reliably, and the clinical heterogeneity of DRD syndromes would make it challenging to develop such a scale.
Long-term Response and Complications
The response to L-dopa in DRD is usually sustained and prolonged. It is very uncommon for patients to develop dyskinesia, but this occasionally happens. In one series of 20 patients with DRD, one-fifth of patients developed dyskinesias after a mean disease duration of 28.9±14.8 years (range 5–54 years) with a mean daily dose of 343 mg/day of L-dopa (range 100–600 mg/day). There was a relationship between the development of dyskinesias and the prescribed dose of L-dopa. In general, however, the appearance of motor fluctuations and/or significant dyskinesia should prompt a review of the diagnosis of DRD and consideration of early-onset Parkinson disease, in which lower limb dystonia can be a prominent and early feature.
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