Dystonia is a neurological syndrome of typically patterned, often repetitive twitching movements or abnormal postures, associated with sustained or intermittent muscle contractions (23649720). These symptoms usually worsen by voluntary action of the muscle. (24978640).
It can be classified in multiple ways based on, the age of onset (early or late); the topographical involvement of regions (focal – single region, segmental – two or more adjacent regions, multifocal – two or more non-adjacent regions, generalised – leg/legs and trunk with one other region, hemidystonia – ipsilateral arm and leg); the loci of gene involved; primary or secondary (drugs and neurological disorders) (14509661).
Still being primitive in understanding the physiology of dystonia, synchronized contraction of agonistic and antagonistic muscle groups due to cortical over excitability and loss of inhibition at a required level of the nervous system is considered to be the possible pathophysiology of dystonia. (8752405) Amongst the early onset dystonia’s, Dopa-Responsive Dystonia (DRD) has a particular importance in that, even a minimal dosage of levodopa can show a dramatic improvement in symptoms (3041760) with long-term benefits.
DRD also known as Segawa disease or autosomal dominant GTP Cyclohydroxylase 1 (GCH 1) deficiency disorder, which involves a complex of motor symptoms with a varying range of severity, is caused by the heterogeneous mutation in GCH 1 gene on chromosome 14. (12891652). A total of 60 different mutations (11553975) (nonsense, missense, and frameshift) in the GCH1 gene have been reported with Autosomal Dominant DRD. Deficiency of the enzyme GCH 1, results in low tetrahydrobiopterin (BH4), in turn, leading to dystonic symptoms due to decreased dopamine levels (1).
Although, the standard age of presentation of the symptoms in DRD is in the childhood, usually 6 years, there are some patients who presented in their early fifties. (12891652). In a classic phenotype of DRD, the symptoms begin with lower limb progressing to a segmental or a generalized dystonia (26100751). Dystonic symptoms, gait abnormalities or any unexplained paraparesis in a child or a young adult should raise a suspicion for DRD and promptly treated with levodopa.
Despite the dramatic improvement of symptoms with levodopa, the drug is associated with a spectrum of side effects from mild symptoms like nausea, fatigue, constipation and lightheadedness to a severe form, dyskinesia. Though dyskinesia is unusual in DRD with L-dopa therapy (1899474), we report a young female who was genetically diagnosed (GCH1 exon 3 deletion) with DRD, showed improvement in the dystonic symptoms but later, developed dyskinesia.
Discussion: Molecular Genetics: Tetrahydrobiopterin (BH4) plays a key role in the synthesis of catecholamine’s (dopamine, epinephrine, and norepinephrine) and serotonin by acting as a co-factor for the enzymes phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase. GCH 1 is one among the important enzymes required for the denovo synthesis of BH4. The decrease in GCH 1 enzyme due to the mutation of GCH 1 gene, results in lowering the BH4, in turn, declining the serotonin and catecholamine’s levels (1). Figure:
DRD due to TH or BH4 deficiency can manifest as a recessive form (7814018) but cannot be called Segawa’s disease (17971156). Mutation of TH gene on 11 p15. 5 (16541791) and def in the enzymes dihydropteridine reductase, sepiapterin reductase, and 6-pyruvoyl-tetrahydropterin synthase, which play an important role in the synthesis of BH4 along with GCH1, can cause TH and BH4 deficiency respectively (1). Differentials: Parkinson disease, idiopathic torsion dystonia, hereditary spastic paraplegia and cerebral palsy are the most common misdiagnosis of DRD (19332422).
30 % of the people with DRD have a deletion of parkin gene on the 6th chromosome (10825351). Several types of dystonia may also respond to levodopa but these can be differentiated from Segawa disease in that, the other types have normal GCH 1 activity when compared to latter. (9182249) Both DRD and Parkinson disease have impaired dopamine synthesis and respond to levodopa treatment. However, DRD differs from PD in that, dopamine storage is intact in the former (10496263) and markedly reduced in the latter (2123623).
The autopsy of the patients with Segawa disease showed the deficiency of dopamine in the nigrostriatal dopamine neuronal terminals but preserved dopamine in pars compacta of substantia nigra (23468278). The short-duration response to levodopa can occur in cases of DRD with preserved dopamine function but, when compared to PD, it is slower and persists longer (11405805). Clinical features: Depending on the loci of mutation, DRD is divided into two types; postural type and action type.
Postural type starts in early childhood (usually 6 years) involving dystonic posture of the leg that progresses to other extremities and trunk with the age. It can be associated with postural tremor of an upper extremity, which progresses to other extremities and neck muscles. In action type, dystonia is seen in the late childhood (usually 8-10 years) and is mainly focal or segmental involving upper extremities (writer’s cramp) and neck muscles (action torticollis). Craniocervical dystonia is extremely rare at disease onset; however, it can occur during the disease progression (23946315).
Both the types are similar in asymmetrical involvement and exaggerated deep tendon reflexes without any positive pyramidal tract signs. The rigidity symptoms in postural type appear contralateral to the involvement of striatal dopamine neuron which differs it from action type, in which ipsilateral involvement is seen (23468278). Oromandibular dystonia, blepharospasm, severe spasmodic dysphonia (19332422), atypical symptoms like hypersalivation and swallowing difficulties (8647336) have been noted in some patients with DRD.
Mutation carriers, over the age of twenty, are known to show symptoms of recurrent depression and obsessive compulsive disorder. Defective melatonin metabolism due to decreased serotonin synthesis (a precursor of melatonin) is the major cause of sleep disturbances like difficulty in falling asleep, nightmares, excessive sleepiness (16361586). Although rigid muscular dystonic symptoms are known to show diurnal fluctuation it is not the essential criteria for diagnosis. 35% of the cases in a pediatric study conducted by Deonna.
T were positive for dystonic symptoms without any diurnal fluctuation (3724992). Lack of sufficient BH4 levels to last all day, due to low GCH1, might be the probable cause for the diurnal fluctuation of symptoms (10984669) in DRD. Diagnosis: CSF analyses for neurotransmitter metabolites along with total biopterin and neopterin appears to be useful in diagnosing GCH1-deicient and TH-deficient DRD (16541791). Treatment: Levodopa is known to show a dramatic improvement of symptoms in DRD patients (3041760).
In most cases, before the levodopa era, DRD had progressed to the generalized form of dystonia within a few years (1899474) (7582048). The required dose of levodopa varies with time as the disease progresses initially and becomes stable. The recommended initial dose of carbidopa/levodopa is 6. 25/25 mg, 2 to 3 times a day, and can gradually be titrated to 25/100 mg; improvement in the symptoms is usually appreciated in the first few days of the initiation of treatment, but failure to do so at this high dosage is probably satisfactory to exclude the DRD diagnosis (1899474).
Though the levodopa is the mainstay in treating DRD, several cases have been reported where the symptoms being unresponsive. These cases showed improvement by a combination therapy of levodopa and selegiline (20399390) (10753262). With dopamine reuptake inhibition and monoamine reuptake inhibition properties, Trihexyphenidyl and Amitriptyline have benefited some patients in improving the symptoms with DRD respectively (2). Deep Brain Stimulation (DBS) is known to show great benefits than medical therapy in advanced Parkinson disease (19126811) but its importance in DRD is less clear.
However, DBS of the bilateral subthalamic nucleus in a 6-year-old child, who was diagnosed with THdeficient DRD, had shown significant global improvement in the symptoms (21631204). Though unusual (1899474), the major limiting factor for the levodopa treatment is dyskinesia. A study conducted in 66 DRD patients, the prevalence of LevodopaInduced Dyskinesia (LID) is only 15% (1899474). In another study, 60 percent of the subjects were known to show dyskinesia when they were treated with doses that are normally used in Parkinson disease (10442251).
LID due to chronic levodopa treatment is usually seen in juvenile parkinsonism (9120424) but are less prevalent in DRD, (8292676) suggesting the nigrostriatal dopamine nerve involvement as a possible pathology than the striatal dopamine depletion. WJ Hwang et. al conducted a study in 20 pts with DRD in which 20% of them who have shown mild dyskinesia were on relatively higher doses of L-dopa compared to the rest of the study group; decreasing the dosage of dopamine in these patients showed the improvement in dyskinesia without any motor deterioration, suggesting dopamine over dosage as the cause for dyskinesia.
The decrease in the turnover of dopamine determining the low requirement of levodopa to control the symptoms, with the progression of the disease, would probably be the precipitating factor for LID in long-term users (11472874). Though LID is usually seen in the later stages of treatment, several cases have been reported to develop in the early stage (1449240). Surprisingly, Nygaard TG reported a case who developed dyskinesia with a single dose of levodopa (3762960).
The pathogenesis of LID remains uncertain. A study conducted in 11 individuals with positive genetic mutations for DRD, irrespective of symptoms, are known to show dopamine receptor upregulation (9566390). This upregulation may be explained by a true increase in the number of receptors, as a compensation to the low dopamine levels or due to decreased competition to bind the receptors at synaptic level (8059335). The upregulation of D2 receptors has been implicated in the pathogenesis for LID (2774488).
Some studies have shown that striatal dopamine deficiency (9566407) plays a major in dyskinesia pathogenesis on par with dopamine receptor supersensitivity, as the latter is seen in early stages (2136932) on contrary to the development of dyskinesia which is usually seen in the later stages. To my understanding, depletion of striatal dopamine with an increase in the sensitivity of D2 receptors due to their rise in the number at striatum appears to be the most likely pathogenesis for the LID. Despite the complications of levodopa, it is justifiable to treat with it, in any child who presents with dystonia.