Series of Dopa Responsive Dystonia Masquerading as Other Diseases with Short Review

ABSTRACT

Dopa-responsive dystonia (DRD) encompasses a group of clinically and genetically heterogeneous disorders that typically manifest as limb-onset, diurnally fluctuating dystonia presenting in early life and exhibits a robust and sustained response to levodopa treatment. DRD is one of the treatable dystonia syndromes of childhood. It starts with the involvement of lower limb and associated with characteristic diurnal variation. Many times it is misdiagnosed as cerebral palsy due to selective lower limb preference. We report a series of three cases of DRD which were previously misdiagnosed. The first case presented as myelopathy and other two were diagnosed as cerebral palsy. It is a treatable condition with very good response to drugs. Early diagnosis and adequate therapy can prevent from catastrophic complications.

INTRODUCTION

The term dopa-responsive dystonia (DRD) encompasses an array of clinically and genetically heterogeneous disorders, and was coined in 1988 to draw attention to the fact that the hyperkinetic and hypokinetic movements seen in the condition markedly improve with levodopa treatment.[1] The typical phenotype is childhood onset of limb dystonia, mainly in the lower limbs, that can progress to generalized dystonia. Symptoms fluctuate diurnally, and the response to levodopa treatment is excellent and sustained. The most extensively studied disorder that manifests as DRD is Segawa disease (also known as DYT5a). Typical picture of DRD was first described by Segawa et al.[2] with the name of “hereditary progressive basal ganglia disease with marked diurnal fluctuation” and later “hereditary progressive dystonia with marked diurnal fluctuation.” This condition is caused by an autosomal dominant deficiency of GTP cyclohydrolase 1 (GTP‑CH‑I), which is encoded by GCH1.[2] GTP‑CH‑I is involved in the production of an essential cofactor for biosynthesis of monoamine neurotransmitters.[3] Nowadays the DRD is considered as a spectrum of several diseases. Several enzyme deficiencies can present with similar features. The exact prevalence is not known in Indian population. But worldwide incidence is reported to be of 0.5 per million.[4]

CASE HISTORY

Case 1

A 15-year-old female presented with right limb onset dystonia associated with mild tightness of both lower limbs for 7 years. It progressed day by day with involvement of neck and trunk. It was associated with marked diurnal variation. Previously she was diagnosed with cervical myelopathy and was being treated for that by anti-spasticity drugs and cervical collar. On examination, she had mild weakness and spasticity with brisk reflexes without sensory and bladder involvement. She had action-induced foot dystonia, neck dystonia in form of retro, latero, and torticollis. Left lateropulsion in trunk was associated with it. She had marked diurnal variation and sleep benefit. She was evaluated by doing MRI of brain and cervical spine. Other blood tests were normal. She was given trial of levodopa and she improved significantly on the third day of therapy. She was asymptomatic after 15 days of follow-up.

Case 2

A 10-year-old boy presented with history of mild developmental delay with twisting of right foot and severe tightness of both limbs. He was facing extreme difficulty to walk and do his daily activities. He was complete bed bound at the evening time. Previously he was diagnosed as a case of spastic cerebral palsy. On examination he was having normal intelligence according to age. Motor examinations revealed gross spasticity with brisk reflexes. It was associated with fixed contracture in the right ankle and hand twisting while eating food. Occasionally he was suffering from left laterocollis at the evening. He was evaluated by imaging. It was found to be normal. Then he was given levodopa trial according to his weight in low dose. He improved significantly. His contracture relieved. He could play and run like normal children.

Case 3

A 6-year-old boy without any history of birth asphyxia presented with tightness of both lower limbs while walking and delay in motor milestones. He was walking with a spastic gait just like a robot. It was associated with marked diurnal variation and sleep benefit. He was previously treated as a case of cerebral palsy by paediatricians. On examination his intelligence was normal according to his age. Motor examinations revealed gross spasticity with brisk reflexes. Action-induced hand dystonia and foot dystonia were prominent. He was evaluated by imaging. It was found to be normal. Then he was given levodopa trial according to his weight in low dose. He improved significantly. He was completely spasticity and dystonia free on day 3 of levodopa trial. All three cases are summarized in Table 1.

Table 1.

Case summary

Sl no.	Age, sex	Presentation	Previous diagnosis	Outcome
1	17, F	Lower limb weakness, twisting of foot, tightness of both upper limb and lower limb	Cervical myelopathy	Complete recovery
2	10, M	Lower limb weakness, contracture of foot, tightness of both upper limb and lower limb, delayed motor milestone	Cerebral palsy	Complete recovery
3	6, M	Tightness of limbs, contracture of foot, tightness of both upper limb and lower limb, delayed motor milestone	Cerebral palsy	Complete recovery

DISCUSSION

Biochemically DRD spectrum is a disease of Dopamine biosynthetic pathway. The etiology is deficiency in enzymes in that pathway [Table 2]. Phenotypical pleomorphism is encountered in several different enzyme deficiencies with varied response to levodopa therapy. Typical clinical features of DRD are childhood or adolescent onset dystonia sometimes associated with mild parkinsonism, marked diurnal fluctuations, and improvement with sleep or rest, and a dramatic and sustained response to low doses of Levodopa without motor fluctuations or dyskinesias as the hallmark of the disease.[10] Several additional features may be encountered depending on the enzyme deficiency.

Table 2.

Types of enzyme deficiency in DRD

Enzyme deficiency	Inheritance	Age at onset	Additional features	Response to levodopa
GTP‑CH‑I deficiency[5]	AD	Mean 8.5 years, range 0.2–48 years	Parkinsonism, Pyramidal features, scoliosis, anxiety, depression, OCD	Excellent and sustained response, Dyskinesia occasional
GTP‑CH‑I deficiency[6]	AR	Can manifest at <6 months	Spasticity, excessive drooling, oculogyric crises, poor sleep	Excellent sustained response, but high dose
Tyrosine hydroxylase deficiency[7]	AR	Between a few weeks after birth and 5 years	Progressive hypokinetic-rigid syndrome with dystonia (type A), complex encephalopathy (type B), tremor, ptosis, autonomic disturbance, spasticity, hypotonia, delayed motor developmental milestones, intellectual disability	Good response, frequent dyskinesia
Sepiapterin reductase deficiency[8]	AR	Between birth and 6 years	Oculogyric crisis, symptoms of dysautonomia symptoms (such as hypersalivation), developmental delay, microcephaly or growth retardation, hypotonia, intellectual disability, sleep disorders, parkinsonism, hyper-reflexia	Good response, frequent dyskinesia
PTP synthase deficiency[9]	AR	Birth to early childhood	Early childhood seizure, spasticity, mild cognitive deficits	Marked and sustained positive response

GTP = guanosine triphosphate, CH = cyclohydrolase, PTP = pyruvoyltetrahydropterin, OCD = Obsessive compulsive disease, AD = Autosomal dominant, AR = Autosomal recessive

Due to varieties of atypical features in some children, three syndromic groups are made. DRD was defined as a syndrome of selective nigrostriatal dopamine deficiency caused by genetic defects in the dopamine synthetic pathway without nigral cell loss; DRD-plus shares same etiologic background with DRD, with more severe features and differential response to therapy. Some other dystonias are responsive to dopaminergic drugs but do not fit into DRD or DRD-plus (genetic defects in the dopamine synthetic pathway without nigral cell loss). It was termed as DRD look-alike to include the additional cases with similar presentation but with dissimilar pathology [Table 3].[11,12,13,14,15] This classification helps to differentiate the DRD spectrum from other groups presenting like DRD.

Table 3.

Expanding spectrum of DRD

Syndromic classification[11,12,13,14,15]	Definition
DRD	A group of non-neurodegenerative disorders by genetic defects involving nigrostriatal dopaminergic system with cardinal manifestations like dystonia and/or parkinsonism, and dramatic response to levodopa without long-term motor complications.	DRD Spectrum
DRD-plus	A group of non-neurodegenerative disorders by genetic defects involving nigrostriatal dopaminergic system with dopa-responsiveness plus additional features like infantile onset, developmental delay, psychomotor retardation, seizure, hypotonia, drowsiness, recurrent hyperthermia, ptosis, cerebellar dysfunction, poor responsiveness to levodopa or other dopaminergic drugs that are not seen in DRD	Dopaminergic system, non-neurodegenerative.
		1) Enzymatic deficiency in dopamine synthetic pathway
		2) Transportopathy
		DAT deficiency
		VMAT deficiency
		3) Developmental disorder affecting dopamine system: SOX mutation
DRD look-alike	A group of	Dopaminergic system, neurodegenerative
	1) neurodegenerative or non-neurodegenerative disorders without involving the nigrostriatal dopaminergic system or	Juvenile Parkinson’s disease
	2) neurodegenerative disorders with involving nigrostriatal dopaminergic system, that could present with dystonia responsive to dopaminergic drugs	Pallidopyramidal syndrome
		Spinocerebellar ataxia type III.
		Others
		Non-neurodegenerative disorder
		DYT 1
		GLUT deficiency syndrome
		Myoclonus-dystonia
		Neurodegenerative disorder
		Ataxia telangiectasia
		Undetermined disorder
		Levodopa-responsive camptocormia

DAT = dopamine transporter, VMAT2 = vesicular monoamine transporter 2, GLUT: glucose transporter

DIAGNOSIS

Levodopa trial

The first step in the diagnosis of DRD is to establish the levodopa responsiveness of the dystonia by means of a levodopa trial.[16] A low-dose levodopa challenge readily separates DRD from idiopathic torsion dystonia, as the latter condition does not respond to levodopa. For children aged <6 years with classic limb-onset dystonia, 1–10mg/kg levodopa daily was administered in multiple doses, in combination with a peripheral decarboxylase inhibitor. For children aged >6 years, teenagers, a trial of 12.5mg carbidopa and 50mg levodopa one to three times daily was administered with meals for 1 week, increasing to 25mg carbidopa and 50mg levodopa three times daily for 1 week, followed by 50mg carbidopa and 200mg levidopa three times daily. If no response is seen after 1 month, the trial should be aborted. For infants and children who present with episodes of oculogyric crisis, focal or generalized dystonia, parkinsonism, and encephalopathy, a trial of 0.5–10.0mg/kg levodopa daily was administered in multiple doses and combined with a peripheral decarboxylase inhibitor, and continued for at least 2–3 months.

Imaging

The value of PET and SPECT studies is limited in the diagnosis of DRD, but they might enable differentiation between DRD and juvenile PD. In juvenile PD, fluorodopa uptake and dopamine transporter density are reduced, whereas abnormalities in these parameters are minimal in DRD.[17]

Cerebrospinal fluid and blood analysis

One of the most important diagnostic tests in children with encephalopathy and/or unexplained early-onset neurological disorders is analysis of the levels of neurotransmitters and metabolites (such as homovanillic acid, 5‑hydroxyindoleacetic acid, neopterin, and biopterin) in cerebrospinal fluid (CSF), and phenylalanine in blood. In GTP‑CH‑I deficiency, all the values of metabolites are low, whereas the blood phenylalanine level is normal.[18]

Others

Other tests like phenylalanine loading tests, GTP‑CH‑1 activity tests, and Genomic screenings are also done for definite diagnosis and genetic counseling.

TREATMENT

DRD is usually treated with levodopa, but the exact doses, regimens, and resulting response depend on the precise nature and severity of the condition. Some patients have residual symptoms, and some can develop levodopa-induced dyskinesia. Levodopa treatment in patients with GCH1 mutations typically produces a dramatic response. A daily dose of 50–200mg of levodopa, usually combined with a peripheral decarboxylase inhibitor (carbidopa), is often sufficient for almost complete resolution of neurological deficits. Even if levodopa therapy is delayed for many years, most patients still respond to low doses of this agent. Controlled-release levodopa, dopamine agonists, and anticholinergic drugs, such as trihexyphenidyl, can also be effective.[19,20] Autosomal recessive GTP‑CH‑I deficiency also responds well to levodopa therapy. In early childhood, treatment of this condition usually requires higher doses (~6–10mg/kg daily) than does treatment of the autosomal dominant form.[20] In some individuals, especially those with spasmodic dysphonia, even doses of up to 600mg daily might produce an incomplete response.[19,21] Levodopa-related motor complications, which frequently occur in patients with PD, are uncommon in patients with GTP‑CH‑I deficiency. Even after long-term use of levodopa, wearing off rarely occurs in these patients.[21] When levodopa-induced dyskinesia does occur, it usually presents at the initiation of treatment and is the result of unusually high doses.[22] As in patients with PD, amantadine can suppress levodopa-induced dyskinesia in GTP‑CH‑I deficiency.[23,24] Patients with type A tyrosine hydroxylase deficiency exhibit an excellent response to low doses of levodopa therapy. Often, the resolution of symptoms, including oculogyric crisis, is complete, but some patients have mild residual motor or cognitive impairment. In pediatric patients with type A tyrosine hydroxylase deficiency, levodopa is frequently used at 3–10mg/kg daily, divided into three doses. Patients with the type B condition can be extremely sensitive to levodopa, so initial doses must be below 0.5mg/kg daily, administered in multiple doses.[25]

CONCLUSIONS

The most common cause of DRD is GTP‑CH‑I deficiency; consequently, the term DRD has become synonymous with this enzyme deficiency and its constellation of clinical features, which include lower-limb onset of action dystonia that fluctuates diurnally, can generalize over time, and shows a dramatic and sustained response to low-dose levodopa therapy. It very often mimics cerebral palsy, hereditary spastic paraplegia, and idiopathic dystonia. Good history taking, early suspicion, and proper diagnosis can help the child with very good outcome.

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Conflicts of interest

There are no conflicts of interest.