Clinical Diagnosis

The diagnosis of X-linked dystonia-parkinsonism (XDP) is suspected in individuals with the following:

• Dystonia of varying severity, ranging from focal to generalized
• 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 cases to date are in individuals of Filipino descent.

Testing

Neuroimaging. CT and 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.

Positron emission tomography (PET)

• [¹⁸F] fluorodopa PET scan
  • In three males with symptomatic XDP, PET revealed selective reduction in striatal glucose metabolism but normal [¹⁸F] fluorodopa uptake, suggesting that the extrapyramidal manifestations are metabolically localized postsynaptically to the striatum [Eidelberg et al 1993].
  • In a separate report, [¹⁸F] fluorodopa PET in an affected male with moderately severe parkinsonism and dystonia showed reduced striatal uptake, consistent with presynaptic nigrostriatal involvement [Waters et al 1993].
• Fluorodeoxyglucose (FDG) PET scans were performed in six men with molecularly confirmed XDP. In all four who were symptomatic (two with parkinsonism only and two with generalized dystonia-parkinsonism), the putamina could not be visualized bilaterally; both asymptomatic men had normal results [Evidente et al 2002d]. In the four symptomatic men, brain CT / MRI revealed mild generalized atrophy in three and normal results in one. Thus, men with early or mild symptomatic lubag may have putaminal abnormalities on FDG PET scan and normal brain CT or MRI.

Note: Other PET tracers such as raclopride, tetrabenazine, and methylphenidate have not been studied in XDP.

Single-photon emission computed tomography (SPECT)

• In an affected male with generalized dystonia and levodopa-responsive parkinsonism, SPECT using [¹²³I]β-carbomethoxy-iodophenyl-nortropane (CIT), which measures dopamine transporter density, showed reduced uptake in the putamen bilaterally that was more symmetric and less pronounced than that observed in Parkinson disease [Evidente, personal observation].
• Fluoropropyl-CIT (FP-CIT) SPECT scan in another male with multifocal dystonia and levodopa-responsive marked parkinsonism showed a moderate decrease of putaminal dopamine transporter activity, suggesting a presynaptic nigral abnormality in XDP [Tackenberg et al 2007]. This was further corroborated by evidence of hyperechogenic signals in both substantia nigrae on transcranial parenchymal sonography. On ¹²³I-iodobenzamide (IBZM)-SPECT scan the same man showed decreased dopamine D₂ receptor expression in both striata, suggestive of a dopamine postsynaptic defect.

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.

Olfactory testing. 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. The degree of olfactory impairment can be as severe as that seen in Parkinson disease.

As genetic testing often is not available in the endemic rural areas in the Philippines, olfactory testing may help support the diagnosis in symptomatic (and possibly presymptomatic) individuals with XDP, though this possibility needs to be studied further.

Neurophysiology. Nerve conduction studies, somatosensory evoked potential studies, electroencephalography (EEG), blink reflex studies, and brain stem evoked potential studies in ten symptomatic males with XDP with dystonia and parkinsonism revealed no abnormalities [Evidente, personal observation].

Testing Strategy

To confirm/establish the diagnosis in a proband

• In most cases, the diagnosis of XDP is established in a symptomatic male who has:
  • Florid multifocal or generalized dystonia with parkinsonism
  • A family history of other affected males that is consistent with an X-linked recessive pattern of inheritance
  • Maternal origins in the Panay Islands (Philippines)
• Molecular genetic testing
  • Targeted mutation analysis/sequence analysis of TAF1 is required to confirm the diagnosis in those with no known family history of XDP, no traceable maternal roots from the Panay Islands, very early symptoms, and/or a phenotype of pure parkinsonism, pure tremor, or chorea without dystonia.
  • Another strategy for molecular diagnosis of a proband suspected of having XDP is use of a multi-gene panel. See Differential Diagnosis.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family. Note: Carriers are heterozygotes for this X-linked disorder and rarely develop clinical findings related to XDP.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in TAF1.

Natural History

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 may have all the cardinal features of parkinsonism, asymmetric findings, and levodopa responsiveness.

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, although rare, 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 have been recognized including pure tremor, chorea, athetosis, and myoclonus.

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 of 50-100 milliseconds' duration or less. 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].

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. 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.

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 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 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.

Genotype-Phenotype Correlations

All symptomatic individuals have the same mutation, regardless of phenotype [Nolte et al 2003].

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 mutation some 50 meiotic generations (~1000 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 in an individual diagnosed with X-linked dystonia-parkinsonism (XDP) syndrome, the following evaluations are recommended:

• Neurologic examination
• Assessment of speech
• Assessment of swallowing
• Nutritional assessment
• Surface electromyography (EMG) study
• Medical genetics consultation

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 lubag 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 patients with lubag.

Surveillance

Presymptomatic males known to have the disease-causing mutation 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 for access to 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].

Mode of Inheritance

X-linked dystonia-parkinsonism (XDP) is inherited in an X-linked recessive manner.

Risk to Family Members

Parents of a proband

• The father of an affected male will not have the disease nor will he be a carrier of the mutation.
• In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
• The family history is positive in approximately 94% of cases.
• If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo gene mutation. However, there is no evidence of de novo mutations in TAF1 causing XDP.
• When an affected male is the only affected individual in the family; several possibilities regarding his mother's carrier status need to be considered:
  • He has a de novo disease-causing mutation and his mother is not a carrier. However, there is no evidence of de novo mutations in TAF1 causing XDP.
  • His mother has a de novo disease-causing mutation, either
    • As a "germline mutation" (i.e., occurring at the time of her conception and thus present in every cell in her body);
      
      or
    • As "germline mosaicism" (i.e., present in a certain percentage of her germ cells only).
  • His mother has a disease-causing mutation that she inherited from a maternal female ancestor.

Sibs of a proband

• The risk to sibs depends on the carrier status of the mother.
• Most often, the mother of the proband is a carrier and the chance of transmitting the mutation in each pregnancy is 50%. Male sibs who inherit the mutation will eventually develop symptoms; female sibs who inherit the mutation will be carriers and will usually not be affected.
• Although no evidence of de novo mutations in TAF1 causing XDP exists, it remains a possibility. In the unlikely circumstance that the mother of the proband is not a carrier, the risk to the sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Males with XDP will pass the disease-causing mutation to all of their daughters and none of their sons.

Other family members of a proband. The proband's maternal aunts may be at risk of being carriers and of being mildly affected and the aunt's offspring, depending on their gender, may be at risk of being carriers and/or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if molecular genetic testing has confirmed the diagnosis in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). The disease-causing mutation of an affected family member must be identified before prenatal testing can be performed. Usually fetal sex is determined first and molecular genetic testing is performed if the karyotype is 46,XY.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for typically adult-onset conditions such as XDP are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Molecular Genetic Pathogenesis

Though first described in 1976, it was only in 1990 that X-linked dystonia-parkinsonism (XDP) was formally shown to be inherited as an X-linked recessive trait through segregation and biochemical analyses [Kupke et al 1990b]. This dispelled previous theories that XDP may be caused by environmental factors (similar to the then-prevailing theory on the cause of Guamanian ALS-parkinsonism) or to metabolic defects. Confirmation of X-linked recessive inheritance of XDP came with the assignment of the disease locus to Xq21 by linkage analysis [Kupke et al 1990a].

The locus in which mutation causes lubag (DYT3) was proposed to be a multiple transcript system within the XDP critical region. In this complex transcriptional unit, different transcript isoforms share some of the 3’ TAF1 exons as well as additional exons downstream (termed exons d1-d5). These latter exons can also be transcribed independently [Nolte et al 2003, Herzfeld et al 2007]. The genomic and transcriptional structure of the XDP critical region is being refined; some conflicting results remain to be resolved [Muller et al 2007, Tamiya et al 2007].

Nolte et al [2003] suggested that it is likely that DSC3 plays a pathogenic role in XDP, although the other XDP-specific sequence changes may also contribute to the disease. None of the DSCs or the 48-bp deletion within DYT3 was found in normal Filipino controls or in other populations with similar phenotypes.

Literature Cited

1. Aguilar JA, Vesagas TS, Jamora RD, Teleg RA, Ledesma L, Rosales RL, Fernandez HH, Lee HV. The promise of deep brain stimulation in X-linked dystonia parkinsonism. Int J Neurosci. 2011;121 Suppl 1:57–63. [PubMed: 21244299]
2. Daniele A, Albanese A, Gainotti G, Gregori B, Bartolomeo P. Zolpidem in Parkinson's disease. Lancet. 1997;349:1222–3. [PubMed: 9130951]
3. Daniele A, Moro E, Bentivoglio AR. Zolpidem in progressive supranuclear palsy. N Engl J Med. 1999;341:543–4. [PubMed: 10447452]
4. Domingo AR, Ledesma LKD, Pasco PM, Jamora RDG, Lee LV. Neuropsychological profile of X-linked dystonia parkinsonism (XDP, DYT3). Mov Disord. 2011;26 Suppl 2:S264.
5. Eidelberg D, Takikawa S, Wilhelmsen K, Dhawan V, Chaly T, Robeson W, Dahl R, Margouleff D, Greene P, Hunt A. et al. Positron emission tomographic findings in Filipino X-linked dystonia-parkinsonism. Ann Neurol. 1993;34:185–91. [PubMed: 8338342]
6. Evidente VG. Zolpidem improves dystonia in "Lubag" or X-linked dystonia-parkinsonism syndrome. Neurology. 2002;58:662–3. [PubMed: 11865155]
7. Evidente VG, Advincula J, Esteban R, Pasco P, Alfon JA, Natividad FF, Cuanang J, Luis AS, Gwinn-Hardy K, Hardy J, Hernandez D, Singleton A. Phenomenology of "Lubag" or X-linked dystonia-parkinsonism. Mov Disord. 2002a;17:1271–7. [PubMed: 12465067]
8. Evidente VG, Dickson D, Singleton A, Natividad F, Hardy J, Hernandez D. Novel neuropathological findings in Lubag or x-linked dystonia-parkinsonism. Mov Disord. 2002b;17 Suppl 1:294.
9. Evidente VG, Esteban RP, Hernandez JL, Natividad FF, Advincula J, Gwinn-Hardy K, Hardy J, Singleton A, Singleton A. Smell testing is abnormal in 'lubag' or X-linked dystonia-parkinsonism: a pilot study. Parkinsonism Relat Disord. 2004a;10:407–10. [PubMed: 15465396]
10. Evidente VG, Gwinn-Hardy K, Hardy J, Hernandez D, Singleton A. X-linked dystonia ("Lubag") presenting predominantly with parkinsonism: a more benign phenotype? Mov Disord. 2002c;17:200–2. [PubMed: 11835466]
11. Evidente VG, Lyons MK, Wheeler M, Hillman R, Helepolelei L, Beynen F, Nolte D, Muller U, Starr PA. First case of X-linked dystonia-parkinsonism ('Lubag') to demonstrate a response to bilateral pallidal stimulation. Mov Disord. 2007;22:1790–3. [PubMed: 17579361]
12. Evidente VG, Nolte D, Niemann S, Advincula J, Mayo MC, Natividad FF, Muller U. Phenotypic and molecular analyses of X-linked dystonia-parkinsonism ('lubag') in women. Arch Neurol. 2004b;61:1956–9. [PubMed: 15596620]
13. Evidente VGH, Santiago J, Fugoso L, Natividad FF. Fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) brain imaging findings in symptomatic and asymptomatic carriers of X-linked dystonia-parkinsonism (“Lubag”). Mov Disord. 2002d;21 Suppl 15:626.
14. Goto S, Lee LV, Munoz EL, Tooyama I, Tamiya G, Makino S, Ando S, Dantes MB, Yamada K, Matsumoto S, Shimazu H, Kuratsu J, Hirano A, Kaji R. Functional anatomy of the basal ganglia in x-linked recessive dystonia-parkinsonism. Ann Neurol. 2005;58:7–17. [PubMed: 15912496]
15. Herzfeld T, Nolte D, Müller U. Structural and functional analysis of the human TAF1/DYT3 multiple transcript system. Mamm Genome. 2007;18:787–95. [PubMed: 17952504]
16. Kupke KG, Lee LV, Muller U. Assignment of the X-linked recessive torsion dystonia gene to Xq21 by linkage analysis. Neurology. 1990a;40:1438–42. [PubMed: 1975433]
17. Kupke KG, Lee LV, Viterbo GH, Arancillo J, Donlon T, Muller U. X-linked recessive torsion dystonia in the Philippines. Am J Med Genet. 1990b;36:237–42. [PubMed: 2368812]
18. Lee LV, Maranon E, Demaisip C, Peralta O, Borres-Icasiano R, Arancillo J, Rivera C, Munoz E, Tan K, Reyes MT. The natural history of sex-linked recessive dystonia parkinsonism of Panay, Philippines (XDP). Parkinsonism Relat Disord. 2002;9:29–38. [PubMed: 12217620]
19. Lee LV, Pascasio FM, Fuentes FD, Viterbo GH. Torsion dystonia in Panay, Philippines. Adv Neurol. 1976;14:137–51. [PubMed: 941767]
20. Makino S, Kaji R, Ando S, Tomizawa M, Yasuno K, Goto S, Matsumoto S, Tabuena MD, Maranon E, Dantes M, Lee LV, Ogasawara K, Tooyama I, Akatsu H, Nishimura M, Tamiya G. Reduced neuron-specific expression of the TAF1 gene is associated with x-linked dystonia-parkinsonism. Am J Hum Genet. 2007;80:393–406. [PMC free article: PMC1821114] [PubMed: 17273961]
21. Muller U, Herzfeld T, Nolte D. The TAF1/DYT3 multiple transcript system in X-linked dystonia-parkinsonism. Am J Hum Genet. 2007;81:415–7. [PMC free article: PMC1950800] [PubMed: 17668393]
22. Nolte D, Niemann S, Muller U. Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism. Proc Natl Acad Sci USA. 2003;100:10347–52. [PMC free article: PMC193564] [PubMed: 12928496]
23. Pasco PM, Ison CV, Muñoz EL, Magpusao NS, Cheng AE, Tan KT, Lo RW, Teleg RA, Dantes MB, Borres R, Maranon E, Demaisip C, Reyes MV, Lee LV. Understanding XDP through imaging, pathology, and genetics. Int J Neurosci. 2011;121 Suppl 1:12–17. [PubMed: 21034368]
24. Rosales RL, Ng AR, Santos MM, Fernandez HH. The broadening application of chemodenervation in X-linked dystonia-parkinsonism (Part II): an open-label experience with botulinum toxin-A (Dysport®) injections for oromandibular, lingual, and truncal-axial dystonias. Int J Neurosci. 2011;121 Suppl 1:44–56. [PubMed: 21348790]
25. Tackenberg B, Metz A, Unger M, Schimke N, Passow S. Nigrostriatal dysfunction in X-linked dystonia-parkinsonism. Mov Disord. 2007;22:900–2. [PubMed: 17377924]
26. Tamiya G, Makino S, Kaji R. TAF1 as the most plausible disease gene for XDP/DYT3. Am J Hum Genet. 2007;81:417–8.
27. Wadia PM, Lim SY, Lozano AM, Adams JR, Poon YY, Torres Diaz CV, Moro E. Bilateral pallidal stimulation for x-linked dystonia parkinsonism. Arch Neurol. 2010;67:1012–5. [PubMed: 20697054]
28. Waters CH, Takahashi H, Wilhelmsen KC, Shubin R, Snow BJ, Nygaard TG, Moskowitz CB, Fahn S, Calne DB. Phenotypic expression of X-linked dystonia-parkinsonism (lubag) in two women. Neurology. 1993;43:1555–8. [PubMed: 8351010]

Acknowledgments

Dr. Evidente has received research support from the Udall PD Research Center of Excellence Grant #P50 NS40256, Mayo Clinic Foundation, and St. Luke’s Medical Center Research & Biotechnology Division (Philippines).

Revision History

• 18 October 2012 (me) Comprehensive update posted live
• 22 June 2010 (cd) Revision: prenatal testing available
• 27 April 2010 (me) Comprehensive update posted live
• 6 January 2009 (me) Comprehensive update posted live
• 13 December 2005 (me) Review posted to live Web site
• 8 March 2005 (vge) Original submission