X-linked dystonia-parkinsonism (Lubag syndrome, DYT3)
This is a 35 year old right-handed man whose mother originated from the Panay Islands in the Philippines. He now presents with akathisia which progressed to focal dystonia of the left upper extremity, followed by generalized dystonia within approximately 18 months. He was treated initially as having symptoms of anxiety and a conversion disorder. By the time he was evaluated by neurology, he had not responded to diazepam 10mg four times daily. His exam was significant for spastic and strained speech, dystonic grimacing, opisthotonic posturing, sustained bilateral plantar flexion and inversion with contractures, sustained bilateral wrist and finger flexion, and bilateral upper extremity cogwheel rigidity (R>L). Given his presentation of severe dystonia with mild features of parkinsonism, there was concern for a generalized dystonia syndrome of adult onset (i.e., DYT1 or DYT3) vs. secondary dystonia (i.e., Wilson's disease, tardive dystonia, etc.). Taking into account his gender, adult age of onset, and his mother's country of origin, DYT3 was very high on the differential. This was further supported by the relatively classic presentation of an initial focal dystonia, followed by generalized dystonia. Also notable was his initial presentation of dystonia which was then followed by parkinsonism. Ultimately, the patient's genetic testing was positive for mutation in the disease locus DYT3.
Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer disease, afflicting 1-2 million Americans. Parkinson's disease has an age-adjusted prevalence rate between 100-200 cases per 100,000. Age is the strongest risk factor and tremor is the most common presenting symptom, reported in 50-70% of cases. A diagnosis requires the presence of bradykinesia and at least one of the following: muscular rigidity, tremor, and postural instability. Three or more of the following features, when present, are further supportive of this diagnosis: unilateral onset, tremor at rest, progression in time, asymmetry of motor symptoms, response to levodopa for at least five years, clinical course of at least ten years and appearance of dyskinesias induced by the intake of excessive levodopa. Notably, over 70% of patients of Parkinson's disease will show an initial response to levodopa.
PARK2 mutation should also be considered since it is a common cause of autosomal recessive, levodopa responsive, and "young onset" Parkinson's disease. PARK2 mutation accounts for approximately half of the familial cases with onset before the age of 40, and 75% of those with onset before the age of 20.
This disease should be within consideration when confronted with a patient showing mixed movement features. It is an autosomal recessive genetic disorder of the ATP7B gene leading to copper accumulation in tissues, particularly the basal ganglia and liver. Symptoms usually start in the first decade of life and can incorporate varying combinations of dystonia, parkinsonism, subcortical dementia, and ataxia along with liver disease (i.e., cirrhosis, portal hypertension, and hepatic encephalopathy). Copper studies including serum ceruloplasmin, urine copper, and slit lamp examination can be used as screening tests, with subsequent confirmation by liver biopsy and genetic testing.
This diagnosis should be considered in patients with a mixed dystonia and parkinsonism phenotype. This disease is in actuality a group of mutations in the dopamine synthesis pathway leading to dopamine deficiency. There are both autosomal dominant and recessive forms. Onset of dopa-responsive dystonia is during childhood (around age five) in 90% of patients and a characteristic feature is the presence of diurnal fluctuations, with worsening of the symptoms as the day progresses and improvement upon rest. The disease usually starts in the lower limb with focal dystonia, followed by generalization by the teenage years. There is also an exquisite and sustained response to low doses of levodopa.
Lubag syndrome, or X-linked dystonia-parkinsonism, is an adult onset, male predominant, progressive neurodegenerative movement disorder with a high rate of penetrance and a high predilection toward generalization of dystonia symptoms. Lubag syndrome was first described in 1975 among inhabitants from the island of Panay, Philippines. The island is located in the western part of the middle division to the Philippine islands and spans approximately 4,637 square miles in area with a population of just under four million. In the local dialect, the term Lubag translates to "twisted." Lubag syndrome is believed to have originated on the island through a founder mutation some 1-2,000 years ago. The prevalence of the disease throughout the combined population of the country is 0.34 per 100,000. The prevalence on the Panay Island, however, is estimated through registry information at 5.24 per 100,000 and is highest in the providence of Capiz at 18.88 per 100,000. By comparison, prevalence rates for amyotrophic lateral sclerosis in Europe and North America ranges between 2.7 and 7.4 per 100,000 and the prevalence of myasthenia gravis is estimated at 15-20 per 100,000. According to registry data, 92% of cases have a positive family history and 99% of the cases are males. The mean age of onset for males is 39 years, ranging from 12 to 64 years, and the initial presenting feature in 94% of patients is focal dystonia, while only 6% present with parkinsonism.
Common initial sites of focal dystonia include the lower extremities (33%), craniofacial and oromandibular (27%), cervical and shoulder (25%), upper extremities (14%), and trunk (1%). Facial dystonia can entail blepharospasm associated with apraxia of eye opening, or Meige syndrome (a.k.a. oral facial dystonia) manifesting lip pursing, jaw opening or closing, and tongue protrusion. Patients with Lubag syndrome may also demonstrate laryngopharyngeal dystonia, which can be associated with dysphagia, dysphonia, or respiratory difficulties. If the trunk is affected, then truncal hyperextension or arching, rotation, flexion, or lateral bending can be present.
Once focal dystonia sets in, the dystonia progresses in 98% of patients and generalizes within five years in 84%, albeit the rate of progression is highly variable between patients. With disease progression, parkinsonism can emerge, involving asymmetric resting tremor, bradykinesia, postural instability, and festinating gait. The mean duration of illness is 12.95 years. Among patients afflicted with this condition, only 4% are still able to work, 72% are not working but ambulant and can care for themselves, while 23% are wheelchair or bed bound.
Since Lubag syndrome is an X-linked recessive disorder, almost all affected individuals are male and inherited their disease from their carrier mothers. There are case studies of affected women, albeit limited in number. In one particular case study of eight women (seven heterozygous and one homozygous) from five families, the average age of onset was 52 years (26-75 years) and six out of eight had parkinsonism initially, whereas one had dystonia. Seven of these eight female patients demonstrated slow or no progression of their symptoms and required no treatment. One patient with disabling parkinsonism was responsive to carbidopa and levodopa. This perceived phenotypic difference in males vs. females (with milder disease—older age of onset, slow or non-progressive course, and predominance of early parkinsonism) is theorized to be due to an extreme X-inactivation mosaic, with the mutated X-active in a significant number of neurons within the basal ganglia.
Routine laboratory and electrophysiological testing do not reveal any particular abnormality. Magnetic resonance imaging of patients with early disease demonstrate minimal atrophy of the caudate and putamen, or only subtle putaminal signal abnormalities. Later in the clinical course, when the parkinsonism dominates, brain imaging may show more significant atrophy of the striatum, which correlates to previously documented autopsy reports. Limited positron emission tomography (PET) data on three patients demonstrated a selective reduction in normalized striatal glucose metabolism compared to fifteen normal volunteer adults. Findings from PET studies utilizing fluorodopa have been inconclusive.
Genetic studies have assigned the disease locus (DYT3), approximately 300-350 kb in length, to the proximal long arm of the X chromosome (Xq13.1). The exact pathophysiology is unclear, but recent data suggest a reduction in neuron-specific expression of the TATA-binding protein-associated factor-1 (TAF1—a promoter region for gene transcription).
No effective therapy has been established for patients with Lubag syndrome. Anecdotal treatment with a benzodiazepine (i.e., clonazepam or diazepam) plus an anticholinergic agent, trihexyphenidyl or biperiden, has been documented to offer some relief. There are also reports of limited success with zolpidem and tetrabenazine along with botulinum toxin for focal dystonia. Levodopa can improve the parkinsonism, but is ineffective for the dystonia (and may even occasionally exacerbate it).
Data regarding surgical experience and long-term outcomes are also limited. Previous to 2007, intracranial surgical procedures with four thalamotomies and two pallidotomies were largely unsuccessful, with some patients dying in the postoperative period. The first published successful case with surgical intervention was by Evidente et al. after a 45 year-old Filipino male was implanted with bilateral pallidal deep brain stimulators (DBS). At one year follow-up, with stimulation alone, the Burke-Fahn-Marsden dystonia score and motor Unified Parkinson's Disease Rating Scale were improved by 71% and 62%, respectively. By 2009, there was a report by Martinez-Torres et al. of a 34 year-old male patient exhibiting clinical benefit from bilateral DBS implantation to the posteroventral globus pallidus interna.
Because of phenotypic overlap, Lubag syndrome can often be misdiagnosed. This quandary is further magnified by the fact that some patients describe equivocal family histories, have families born outside the endemic areas, or fail to recall any maternal ancestral roots from the Philippine Islands. Therefore it is imperative to elicit an exhaustive family history and consider genetic testing in any male with Filipino ancestry who presents with a progressive movement disorder.
The patient underwent a carbidopa/levodopa trial for seven days (25/100 0.5 tabs b.i.d.) without any clinical improvement. He also tried varying forms of muscle relaxants and benzodiazepines, including diazepam up to 15 mg t.i.d., baclofen up to 140 mg/day, zolpidem 10 mg q.h.s., citalopram 40 mg daily, tizanidine up to 8 mg q.i.d., levetiracetam 500 mg b.i.d., lorazepam p.r.n., and diphenhydramine p.r.n. All of these trials did not yield appreciable benefit. He received a trial baclofen infusion first of 50 mcg (1 mL of 50 mcg/mL) and then of 100 mcg (2 mL of 50 mcg/mL), yielding notable improvement of symptoms. Thereafter, a baclofen pump was implanted with the tip of the catheter at C2 and the infusion rate was gradually increased to 1622 mcg/day. He also underwent botulinum toxin injections to the left hamstring 200 U, posterior tibialis 100 U, and right flexor carpi radialis 100 U from which he received some benefit. Later botulinum toxin injections also included the gastrocs, flexor hallicus longus, and flexor digitorum longus in the lower extremities as well as flexor digitorum profundus and the lumbricals in the upper extremities. He also underwent tendon release due to persistent contractures. While his response to the baclofen pump was better than with oral medications in terms of relieving the dystonic spasms, disabling symptoms persisted as he continued to be dependent on most of his activities of daily living (ADLs). Subsequently, he underwent bilateral Gpi DBS placement and experienced significant reduction in his symptoms and improvement in his mobility and ADLs. Four years after his initial presentation, he remained in a rehabilitation facility but was able to perform most ADLs and was mobile with assistive devices. He also remained on the baclofen pump at 1622 mcg/day, citalopram 40 mg/day, clonazepam 0.5 mg b.i.d., and tizanidine 2 mg q.8.h.
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