Dopa-reactive dystonia: causes, symptoms, diagnosis, and treatment

Dopa-reactive dystonia (DRD) is a less common movement disorder without specific clinical manifestations, and easily confused with other diseases. However, levodopa has good effect in treatment of DRD. Therefore, patients need timely diagnosis and treatment.


Causes

Guanosine triphosphate cyclase hydrolase (GTPCH) and sepiapterin reductase (SR) are essential enzymes for the synthesis of tetrahydrobiopterin (BH4), and important cofactors in dopamine and serotonin synthesis pathways. In addition, BH4 is an essential cofactor for phenylalanine hydroxylase and tyrosine hydroxylase (TH). GTPCH, SR, or TH deficiency can lead to synaptic dopamine deficiency, resulting in both motor and non-motor symptoms (mood swings, depression, memory and attention problems).


Signs and Symptoms

Different subtypes of DRD have different onset, clinical manifestations, and treatment responses.

Guanosine triphosphate cyclase hydrolase deficiency syndrome (GTPCH-DRD): This is the most common and most typical type of DRD. Onset is generally in childhood. Symptoms are local or staged lower limb dystonia, accompanied by difficulty walking (Figure 1). These symptoms may worsen in nightfall (intraday fluctuations), and may be associated with family history (autosomal dominant inheritance). Dystonia can be segmental, systemic, or axial, but usually involving lower limbs.

In young patients, DRD is easily misdiagnosed as bilateral cerebral palsy or hereditary spastic paraplegia, and epilepsy if patients with myoclonus. GTPCH-DRD is less common in adult patients (average age of onset is 37 years old). Symptoms are characterized mainly by Parkinson's syndrome or dystonic tremor.

Sepiapterin reductase deficiency syndrome (SR-DRD): mainly seen in infants and young children, most of patients have dystonia, developmental delay, axial muscle tension reduction, oculogyric crisis, and intraday fluctuations of symptoms. Due to movement and cognitive disorders, SR-DRD is also easily misdiagnosed as cerebral palsy. Patients with SR-DRD may also have other dyskinesia, including chorea or static tremor.

Tyrosine hydroxylase deficiency syndrome (TH-DRD): This is the most serious DRD, mainly seen in infants, manifested as Parkinson's syndrome, spastic paraplegia, or progressive infantile encephalopathy. SR-DRD and TH-DRD are sometimes referred to as DRD overlap syndrome.


Diagnosis

DRD is a treatable disease that requires a timely administration of levodopa tested at least 300 mg per day for 2 months. If treatment with levodopa has poor response, DRD cannot be ruled out. In this case, it is necessary to determine whether there are other biochemical defects or related genetic mutations. 

Examinations

Levodopa test: in children patients, dose of levodopa (combined with dopadecarboxylase inhibitors) is initially 1 mg/kg/day, and increases gradually according to toleration and treatment responses to 4 - 5 mg/kg/day in most patients. In adult patients, dose of levodopa (in combination with dopadecarboxylase inhibitors) is initially 100 mg/day, and increases gradually to 300 - 400 mg/day.

Phenylalanine load test: If effect of levodopa treatment is not clear, phenylalanine load test is necessary. Patients are asked to have a low-protein diet 2 hours before test. Baseline blood samples are taken for detection of phenylalanine and tyrosine concentrations. After patients take 100 mg / kg of L-phenylalanine (dissolved in 100ml of water), detections of plasma amino acid are taken in 1, 2, 4 hours. Ratio of plasma phenylalanine to tyrosine in 4 hours > 7.5 suggests DRD.

Genetic test: If phenylalanine load test results are negative, but DRD is still strongly suspected, genetic test is needed, including GCH1 gene caused GTPCH-DRD, SRR gene encoding SR, and TH gene. 

SPECT Imaging: FP-CIT SPECT examination is required to identify other neurodegenerative diseases, such as Parkinson's disease and DRD in Parkinson's syndrome in young patients. Results of SPECT examination are generally normal in patients with DRD.

Cerebrospinal fluid pterin analysis: different DRD syndromes have different cerebrospinal fluid metabolites, depending on different enzyme deficiency. Detection of pterin in cerebrospinal fluid is helpful in identifying different DRDs.


Treatment

Levodopa helps to relieve symptoms of DRD patients, but cannot change the course of disease, nor can improve DRD-related non-motor symptoms (cognitive dysfunction). Treatment response of levodopa is usually sustained and long-term. Few patients may have dyskinesia. In general, if patients have motor fluctuations or obvious dyskinesias, other diagnoses are needed to consider.