X-Linked Dystonia-Parkinsonism

Clinical characteristics.

Individuals with X-linked dystonia-parkinsonism (XDP) have dystonia of varying severity and parkinsonism. XDP afflicts primarily Filipino men and, rarely, women. The mean age of onset in men is 39 years; the clinical course is highly variable with parkinsonism as the initial presenting sign, overshadowed by dystonia as the disease progresses. Features of parkinsonism include resting tremor, bradykinesia, rigidity, postural instability, and severe shuffling gait. The dystonia develops focally, most commonly in the jaw, neck, trunk, and eyes, and less commonly in the limbs, tongue, pharynx, and larynx, the most characteristic being jaw dystonia often progressing to neck dystonia. Individuals with pure parkinsonism have non-disabling symptoms that are only slowly progressive; those who develop a combination of parkinsonism and dystonia can develop multifocal or generalized symptoms within a few years and die prematurely from pneumonia or intercurrent infections. Female carriers are mostly asymptomatic, though a small minority may manifest dystonia, parkinsonism, or chorea.

Diagnosis/testing.

The diagnosis of XDP is suspected in a male with typical clinical findings, family history consistent with X-linked inheritance, and maternal ancestral roots from the Panay Islands in the Philippines. Molecular genetic testing for variants that tag a disease-associated haplotype of the multilocus transcript system termed TAF/DYT3 is required to confirm the diagnosis in those with no known family history of XDP, very early symptoms, and/or a phenotype of pure parkinsonism, pure tremor, or chorea without dystonia. Olfactory testing indicates olfactory dysfunction early in the disease and may be used to support the diagnosis when molecular genetic testing is not available.

Management.

Treatment of manifestations: Pharmacologic agents are used to treat dystonia or parkinsonism or both. Anticholinergic agents, benzodiazepines, and sometimes neuroleptics are used in the early stages of dystonia; zolpidem and tetrabenazine are used after dystonia becomes multifocal or generalized. Botulinum toxin injections improve focal dystonia but may worsen swallowing in individuals with preexisting dysphagia. Parkinsonism is treated with levodopa and dopamine agonists to control tremor. Bilateral pallidal deep brain stimulation may be used to treat advanced disease and medically refractory dystonia, although it may have less effect on parkinsonism.

Prevention of secondary complications: Swallowing evaluation to guide diet modification and swallowing techniques to minimize risk of aspiration. Physical therapy, coupled with maximal medical and surgical therapy, may help delay immobility and its complications.

Surveillance: Annual clinical evaluations in males with the disease-related haplotype who are not yet symptomatic, biannual evaluation for symptomatic males to monitor medications, and periodic swallowing evaluation, especially in those with subjective dysphagia.

Genetic counseling.

XDP is inherited in an X-linked manner. Approximately 94% of affected individuals have a known family history of the condition. De novo occurrence of the disease-related haplotype associated with the disorder has not been observed to date. Males with XDP pass the TAF1/DYT3 disease-associated haplotype to all of their daughters and none of their sons. Women who are carriers have a 50% chance of transmitting the TAF1/DYT3 disease-associated haplotype in each pregnancy: males who inherit the TAF1/DYT3 disease-associated haplotype will be affected; females who inherit the TAF1/DYT3 disease-associated haplotype are mostly asymptomatic, although a small percentage may manifest symptoms. Carrier evaluation of at-risk female relatives is possible if the TAF1/DYT3 disease-associated haplotype has been identified in the family. Once the TAF1/DYT3 disease-associated haplotype has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for XDP are possible. Caution should be exercised in interpreting the results of prenatal testing as the c.94C>T (p.Arg32Cys) variant that marks the disease haplotype has not been proven to be the molecular cause of XDP.

Clinical Diagnosis

The diagnosis of X-linked dystonia-parkinsonism (XDP) should be suspected in an individual with the following clinical findings, neuroimaging results, and neurophysiologic test results.

Clinical findings

• Dystonia of varying severity, ranging from focal to generalized typically starting in early adulthood
• Parkinsonism
• Family history consistent with X-linked inheritance
• Maternal ancestral roots from the Panay Islands in the Philippines where XDP originated as a genetic founder effect. All known affected individuals to date are of Filipino descent.

Neuroimaging. CT and brain MRI in 20 individuals with symptomatic XDP did not reveal significant striatal or brain stem atrophy [Evidente, personal observation]. Generalized cerebral atrophy (usually mild) may be seen in some individuals. Caudate atrophy on brain imaging can be seen in individuals with more advanced disease similar to that seen in Huntington disease, though this is not a consistent finding.

Neurophysiologic testing

• Olfactory. The degree of olfactory impairment in XDP can be as severe as that seen in Parkinson disease. Evidente et al [2004a] administered a culturally corrected University of Pennsylvania Smell Identification Test (ccUPSIT) consisting of 25 odor items to 20 symptomatic males with XDP and 20 controls. The mean ccUPSIT score of individuals with XDP (18±3.19) was significantly lower (p=0.003) than that of controls (20.5±3.02). The olfactory scores did not correlate with phenotype, severity of dystonia, or duration of disease. Nine of 20 individuals with XDP (45%) had ccUPSIT scores below the mean, with the lowest score being 11, suggesting that olfactory dysfunction may occur in individuals with XDP even early in the disease.
  As genetic testing is often not available in the endemic rural areas in the Philippines, olfactory testing may support the diagnosis in symptomatic (and possibly presymptomatic) individuals with XDP, though this possibility needs to be studied further.
• Other. Nerve conduction studies, somatosensory evoked potential studies, electroencephalography, blink reflex studies, and brain stem evoked potential studies in ten symptomatic males with XDP with dystonia and parkinsonism have revealed no abnormalities [Evidente, personal observation].

Establishing the Diagnosis

Male proband. The diagnosis of XDP is established in a male proband with typical clinical and neuroimaging findings. In those with no known family history of XDP, very early symptoms, and/or a phenotype of pure parkinsonism, pure tremor, or chorea without dystonia, molecular genetic testing is required to confirm the diagnosis. A single haplotype of the multilocus transcript system termed TAF1/DYT3 is the only locus associated with XDP. The molecular cause of XDP has not been determined; therefore, variants on the TAF1/DYT3 disease-associated haplotype are used as a marker for XDP (see Table 1).

Female proband. The diagnosis of XDP is usually established in a symptomatic female proband with a family history of XDP who presents with either chorea, pure parkinsonism, focal dystonia, or (rarely) generalized dystonia; it is confirmed by identification of a TAF1/DYT3 disease-associated haplotype (see Male proband and Table 1).

Molecular genetic testing. Approaches can include targeted analysis for a TAF1/DYT3 disease-associated haplotype and use of a multigene panel:

• Targeted analysis for the XDP-disease-specific sequence variant c.94C>T (p.Arg32Cys) is consistent with the diagnosis in all affected males; however, this is an indirect test. See Note (1).
  Note: (1) Although detection of c.94C>T (p.Arg32Cys) in a symptomatic individual is considered diagnostic, this is an indirect finding. Variants at this locus not previously associated with XDP cannot be interpreted as disease associated (see Genetically Related Disorders). (2) This variant has only been associated with XDP in individuals of Filipino ancestry. (3) Recent data suggest that a haplotype-tagging SVA (short interspersed nuclear element, variable number of tandem repeats, and Alu composite) retrotransposon insertion in TAF1, which contains an unstable repeat expansion, may be the causative variant. Note that due to the context of the sequence, testing for this SVA and repeat expansion poses a technical challenge for molecular testing [Makino et al 2007, Bragg et al 2017].
• A multigene panel that includes XDP-specific sequence variants and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

X-linked dystonia-parkinsonism (XDP) or lubag afflicts primarily adult Filipino men and, rarely, women. The male-to-female ratio is 99:1. The mean age of onset in men is 39 years, with a range of 12 to 64 years. The mean age of onset in women is 52 years, with a range of 26 to 75 years [Evidente et al 2004b]. The time from onset of dystonia to generalization ranges from one to 23 years, with a mean of 3.8 years.

The clinical course in men with XDP is highly variable. Although the presenting finding was traditionally thought to be dystonia in most cases [Lee et al 2002], a longitudinal follow up of asymptomatic or early symptomatic individuals with genetically confirmed XDP revealed that the initial presenting sign is almost universally parkinsonism [Evidente et al 2002c]. In particular, abnormality of rapid alternating limb movements (which can be asymmetric) can often be appreciated on neurologic examination in early symptomatic (or soon to be symptomatic) individuals.

Parkinsonism. Individuals with XDP may present predominantly with one or more of the cardinal features of Parkinson disease, including resting tremor, bradykinesia, rigidity, and postural instability. Shuffling gait, in the absence of lower-limb dystonia, can be severe enough to cause recurrent falls and significant impairment of walking.

Some individuals may have pure parkinsonism and no dystonia for many years [Evidente et al 2002c]. In some of these individuals, the dystonia develops very late in the course and is usually focal or segmental. When the dystonia becomes advanced (i.e., multifocal or generalized in distribution), the parkinsonism remains, although it is overshadowed by the dystonia.

Some individuals with XDP (both male and female) may have all the cardinal features of parkinsonism, asymmetric findings, and levodopa responsiveness. These individuals may initially be misdiagnosed as having Parkinson disease [Evidente et al 2002c, Domingo et al 2014].

Dystonia. The dystonia develops focally, most commonly in the jaw, neck, trunk, and eyes, and less commonly in the limbs, tongue, pharynx, and larynx.

The most characteristic dystonia seen in males with XDP is jaw dystonia, more commonly presenting as more difficulty with jaw opening than jaw closing. Jaw dystonia often progresses to neck dystonia, with retrocollis being more common than torticollis. Retrocollis can be so severe that the neck is extended more than 90 degrees, and the trunk is hyperextended. Cervical dystonia may be accompanied by a dystonic head tremor. Extension dystonia of the trunk is far more common than flexion or lateral dystonia of the trunk.

Blepharospasm is only rarely the initial symptom of XDP. It tends to be more common as the disease progresses. It can coexist with mid- or lower-facial dystonia.

Limb dystonia, rarely an initial presenting finding, is more commonly seen as disease advances. It affects the upper limbs as often as the lower limbs and is usually bilateral, although severity can be greater on one side of the body than the other. Unlike DYT1 torsion dystonia, XDP only rarely presents with dystonia of the foot.

Tongue dystonia may also be seen, manifesting as either involuntary tongue protrusion or limitation in tongue protrusion. Pharyngeal dystonia, manifesting as difficulty swallowing, usually affects those with orolingual dystonia. Pharyngeal dystonia often leads to significant weight loss, aspiration pneumonia, and early death.

Laryngeal dystonia leading to stridor (a rare finding) can also lead to sudden death. Individuals with orolingual, pharyngeal, or laryngeal dystonia may present with respiratory sounds [Evidente et al 2002a]. Such vocalizations can be observed during both inspiration and expiration.

Sensory tricks (improvement in dystonia by touching certain areas) have been observed in individuals with XDP with dystonia, particularly those with cervical dystonia.

Other neurologic findings. Traditionally, XDP was thought to be a combination of dystonia and parkinsonism only [Evidente et al 2002a]; however, with genotypic correlation, other neurologic findings including pure tremor, chorea, athetosis, and myoclonus have been recognized:

• Resting tremor or action tremor can be seen in either the early or later stages of disease. In some individuals, an asymmetric resting tremor of a limb with an oscillation of 3-6 Hz (similar to that seen in Parkinson disease) can be observed. Some individuals may also have a coarse, relatively symmetric upper-limb tremor or head tremor similar to that in individuals with essential tremor. The tremor can involve not only the limbs and head, but also the trunk, craniofacial region (lips, jaw, or facial muscles), and voice. Distal limb tremor can sometimes be of slow frequency (1-3 Hz), reminiscent of myorhythmia [Evidente et al 2002a].
• Chorea usually occurs in the distal upper limbs in the early stages and is combined with subtle dystonia, thus resulting in athetotic movements. Chorea can also be seen with the generalized dystonic movements.
• Action myoclonus can be present in the limbs or even in the craniofacial region. Myoclonus is characterized by a combination of rapid, brief, lightning-like muscle contractions and is often mistaken for tremor.
  Electrophysiologic studies show muscle bursts ≤50-100 milliseconds in duration. Back-averaging may show a jerk-locked pre-movement surface-positive cortical electroencephalographic potential in the contralateral sensorimotor area, supporting the cortical origin of the myoclonus.

General cognition often remains intact although there may be problems with frontal executive functions [Domingo et al 2011].

Depression is also a common feature, most likely related to the profound disability and loss of employment that XDP causes, especially in more advanced cases [Morigaki et al 2013]. Impulse control disorder in the form of pathological gambling has been described in XDP [Gillian 2013].

Disease progression. Those with pure parkinsonism with little or no dystonia have the best prognosis; they have non-disabling symptoms that are slowly progressive or non-progressive.

Those who develop a combination of parkinsonism and orobuccolingual dystonia and cervical dystonia in the first year or two of the disease have the worst prognosis. Such individuals develop multifocal or generalized symptoms from the second to fifth year after onset, rapidly become bedridden, and die prematurely from aspiration pneumonia, laryngeal stridor, and/or intercurrent infections resulting from immobility.

Phenotype in women. Female XDP carriers are mostly asymptomatic, although a small percentage may manifest symptoms. Compared to men, women with XDP often do not present with dystonia, or if they do, the dystonia is usually focal, non-progressive, and non-disabling [Evidente et al 2004b]. The dystonia can subtly manifest in the neck or limbs. However, there have been rare cases of women with XDP who have generalized dystonia similar to that seen in affected men [Lee et al 2011].

Other manifestations in women include chorea (which can be in a hemi-distribution), focal tremor (usually limb), or parkinsonism. The parkinsonism is usually mild, non-progressive, and non-disabling. Rarely, levodopa-responsive parkinsonism very similar to Parkinson disease can be observed.

Neuroimaging studies have revealed the following:

• Normal findings on CT and brain MRI in the majority of patients, although generalized cerebral atrophy (usually mild) may be seen in some individuals and caudate atrophy in more advanced disease [Evidente, personal observation]
• Evidence for strong involvement of the white matter and putamen based on diffusion-weighted imaging [Brüggemann et al 2016]
• Evidence of both postsynaptic [Eidelberg et al 1993] and presynaptic nigrostriatal involvement [Waters et al 1993] on [¹⁸F] fluorodopa PET scan studies
• Putaminal abnormalities on flurodeoxyglucose (FDG) PET scan in affected men with early or mild symptomatic lubag despite normal brain CT or MRIs [Evidente et al 2002d]
• Results on presynaptic single-photon emission computed tomography (SPECT) studies using either [¹²³I]-β-carbomethoxy-iodophenyl-nortropane (CIT) or ioflupane I-123 dopamine transporter (DaT scan) which can be similar to those seen in individuals with Parkinson disease, with the putamina involved more severely than the caudate, and one side more affected than the other [Tackenberg et al 2007; Evidente, personal observation]. DAT scan abnormalities are noted even in early XDP with pure parkinsonism, or with only mild dystonia.
• Functional decline of postsynaptic dopaminergic transmission related to disease duration and ongoing degeneration function on [¹²³I] (IBZM)-SPECT studies [Brüggemann et al 2017].
• Hyperechogenicity of the substantia nigra in 79% and of the lenticular nuclei in 81% of individuals with XDP on transcranial brain sonography studies [Walter et al 2017]. Abnormal substantia nigra hyperechogenicity was more frequent in individuals with prominent parkinsonism (100%) compared to those without (68%). Thus, substantia nigra hyperechogenicity may be regarded as a preclinical risk marker of parkinsonism-predominant XDP.

Thus, it appears that by functional imaging, individuals with XDP may have one of the following:

• Postsynaptic striatal involvement. Affected individuals may represent the majority of XDP, with pure dystonia or combined dystonia-parkinsonism from the early stages; this group does not respond to levodopa.
• Presynaptic nigrostriatal involvement. Affected individuals may represent those few who have pure parkinsonism for a considerable number of years, with dystonia setting in late in the course; this group appears to be more responsive to levodopa.

Neuropathology. Little information is available on the neuropathology of XDP.

The earliest neuropathology report on XDP, from one Filipino male with dystonia-parkinsonism, showed neuronal loss and a multifocal mosaic pattern of astrocytosis in the caudate and lateral putamen [Waters et al 1993]. This information has been updated by Pasco et al [2011], who report that "[i]n the neostriatum, the dystonic phase of XDP shows the involvement of striosomes and matrix sparing, while the later, i.e., parkinsonian phase, shows matrix involvement as well. In the dystonic phase, the loss of striosomal inhibitory projections lead to disinhibition of nigral dopaminergic neurons, perhaps resulting in a hyperkinetic state; while in the parkinsonian phase, severe and critical reduction of matrix-based projection may result in extranigral parkinsonism."

Neuropathologic examination on an individual with severe generalized dystonia and parkinsonism confirmed the mosaic pattern of striatal gliosis as reported earlier, but also noted that the gliotic patches showed gradients that were dorsal to ventral, rostral to caudal, and medial to lateral [Evidente et al 2002b]. The caudate was more affected than the putamen, and the accumbens was largely spared. The head of the caudate was more affected than the tail. The patchy areas of striatal gliosis were not associated with microglial activation. The more marked involvement of caudate and putamen than of the ventral, limbic striatum (i.e., nucleus accumbens) suggests that striatal synaptic input from the limbic lobe is less affected than the synaptic input from the sensorimotor and association cortices. With synaptic immunostaining, it was noted that the patchy areas of gliosis corresponded to the areas of poor synaptophysin staining, suggesting that the basis for the patchy gliosis is synaptic loss rather than neuronal loss. The synaptic loss and gliosis were also observed in the globus pallidus interna and externa. Some focal gliosis was also noted in the substantia nigra pars reticularis, but not in the pars compacta.

Postmortem analyses of the basal ganglia based on striatal compartments (i.e., the striosomes and the matrix compartment) showed that in the neostriatum of individuals with XDP, the striosomes are severely depleted while the matrix component is relatively spared [Goto et al 2005]. Thus, the disproportionate involvement of the neostriatum compartments and their efferent projections may be responsible for dystonia in XDP and possibly in other neurodegenerative disorders.

Neuropathologic studies have shown a neostriatal defect of the neuropeptide Y system in individuals with XDP, suggesting that the neuropeptide Y system may play a role in the progressive loss of striatal neurons [Goto et al 2013].

Genotype-Phenotype Correlations

All symptomatic individuals have the same disease-associated TAF1/DYT3 haplotype regardless of phenotype [Nolte et al 2003], which comprises a spectrum including pure parkinsonism, focal dystonia, segmental dystonia, multifocal dystonia, and generalized dystonia in symptomatic men and chorea, pure parkinsonism, and focal or multifocal dystonia in symptomatic women.

Recently, Bragg et al [2017] have further analyzed the sequence of the SVA in TAF1 and detected polymorphic variation in the length of a hexanucleotide repeat domain, (CCCTCT)n, which varies from 35 to 52 repeats. The length of the repeat correlates inversely with age at disease onset [Bragg et al 2017].

Anticipation

Anticipation is not observed in XDP.

Nomenclature

XDP was first described by Lee et al [1976] as "dystonia musculorum deformans."

In the local Filipino dialect, lubag describes intermittent twisting or posturing. Other terms used include wa-eg (sustained postures) and sud-sud (shuffling gait), which are commonly seen in persons with XDP.

Prevalence

The first epidemiologic study was by Lee et al [1976]. More than 500 cases of XDP have been described in the literature. XDP is believed to have originated ancestrally in the Philippines, particularly in the Panay Islands through a founder variant some 50 meiotic generations (~1,000 years) ago. The prevalence rate is 5.24:100,000 in the Panay Islands, with the highest rate of 18.9:100,000 in the province of Capiz, where it is endemic [Lee et al 2002].

The prevalence in the general population in the Philippines is estimated at 0.34:100,000.

Although maternal ancestry can be traced to the Panay Islands in most cases, some individuals have no such traceable ancestry.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with X-linked dystonia-parkinsonism (XDP) syndrome, the following evaluations are recommended if they have not already been completed:

• Neurologic examination
• Assessment of speech
• Assessment of swallowing
• Nutritional assessment
• Surface electromyography study
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Prevention of Primary Manifestations

See Treatment of Manifestations.

Prevention of Secondary Complications

The secondary complications of significant dysphagia and immobility are usually related to progression of dystonia.

Swallowing evaluation, especially in those with subjective dysphagia, can guide diet modification and use of swallowing techniques that minimize the risk for aspiration pneumonia.

Physical therapy, coupled with maximal medical and surgical therapy, may help delay the bedridden state and its complications.

Although traditional neuroleptics may initially help focal or segmental dystonia, they may eventually exacerbate the underlying parkinsonism in individuals with XDP and also lead to tardive dystonia with chronic use. Thus, it may be difficult to determine with chronic therapy if traditional neuroleptics actually help or worsen dystonia in individuals with XDP.

Surveillance

Presymptomatic males known to have the disease-associated haplotype may need yearly clinical evaluations after age 30 years to identify the onset of symptoms in order to institute appropriate therapy as early as possible.

Once an individual is symptomatic, biannual follow ups are recommended in order to adjust medications to assure best management of dystonia and/or parkinsonism.

Periodic swallowing evaluation, especially in those with subjective dysphagia, is appropriate.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Other sleep medications such as zaleplon (Sonata™) have had no beneficial effect on dystonia in individuals with XDP.

Drugs that have been used anecdotally with poor or inconsistent effects on dystonia in individuals with XDP include gabapentin, topiramate, baclofen, and tizanidine.

Brain surgeries for advanced dystonia in individuals with XDP that have failed in the past include four thalamotomies, two pallidotomies, and one cerebellar implantation [Lee et al 2002].