DiagnosisClinical DiagnosisThe diagnosis of X-linked dystonia-parkinsonism (XDP) is suspected in individuals with the following:Dystonia of varying severity, ranging from focal to generalizedParkinsonismFamily history consistent with X-linked inheritanceMaternal 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. TestingNeuroimaging. 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].Molecular Genetic TestingGene. TAF1 has 38 exons. A multilocus transcript system termed TAF1/DYT3 is the only locus in which mutations are known to cause XDP. Five disease-specific single-nucleotide changes (DSC) and a 48-bp deletion that were unique to XDP were identified [Nolte et al 2003]. DSC3 is the only DSC embedded in a coding region, specifically exon d4 resulting in p.Arg32Cys; see Table 2). See Molecular Genetics for details on the multilocus transcript. Clinical testing Table 1. Summary of Molecular Genetic Testing Used in X-Linked Dystonia-ParkinsonismView in own windowGene/Locus SymbolProportion of XDP Attributed to Variants in This Gene/LocusTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test Availability Affected MalesCarrier FemalesTAF1/DYT3100% in affected individuals of Filipino descent 2Targeted mutation analysisXPD-disease-specific sequence variant c.94C>T 3100% for the targeted variant 4, 5100% for the targeted variant 4, 5Clinical TAF1100% in affected individuals of Filipino descent 2Sequence analysisSequence variants 4, 6Unknown 7Unknown 81. The ability of the test method used to detect a mutation that is present in the indicated gene2. Proportion in other populations is unknown.3. Also termed disease-specific single-nucleotide change 3 (DSC3), which is embedded in downstream (d) exon ‘d4’ (see Molecular Genetics)4. Of note, all individuals reported by Nolte et al [2003] with these sequence changes were of Filipino origin. To date, XDP is known only in persons of Filipino descent; however, testing for these molecular genetic changes has been limited in individuals from other ethnic backgrounds presenting with phenotypes similar to XDP.5. Detection frequency in affected individuals other than Filipino is unknown; all known cases to date are in individuals of Filipino descent.6. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.7. Lack of amplification by PCR prior to sequence analysis can suggest a putative exon(s) or whole gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis. 8. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a probandIn most cases, the diagnosis of XDP is established in a symptomatic male who has:Florid multifocal or generalized dystonia with parkinsonismA family history of other affected males that is consistent with an X-linked recessive pattern of inheritanceMaternal origins in the Panay Islands (Philippines) Molecular genetic testingTargeted 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) DisordersNo other phenotypes are known to be associated with mutations in TAF1.}

Natural HistoryX-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 CorrelationsAll symptomatic individuals have the same mutation, regardless of phenotype [Nolte et al 2003].

Differential DiagnosisParkinson disease multi-gene panels may include testing for a number of the genes associated with disorders discussed in this section. See Dystonia Overview.Individuals with X-linked dystonia-parkinsonism (XDP) with tremor can be misdiagnosed as having Parkinson disease or essential tremor, especially in the early stages in which dystonia may be absent or subtle. Individuals with XPD with all the cardinal features of parkinsonism, asymmetric findings, and levodopa responsiveness are often diagnosed as having Parkinson disease or Parkinson-plus syndrome.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with X-linked dystonia-parkinsonism (XDP) syndrome, the following evaluations are recommended:Neurologic examinationAssessment of speechAssessment of swallowingNutritional assessmentSurface electromyography (EMG) study Medical genetics consultationTreatment of ManifestationsPharmacologic Treatment of DystoniaAnticholinergic agents and benzodiazepines. In the early stages of the disease when dystonia is focal or segmental in distribution, individuals may respond significantly to anti-dystonia medications, particularly to anticholinergic agents and benzodiazepines.The two most commonly prescribed anticholinergic drugs are trihexyphenidyl (Artane™) and biperiden (Akineton™). Trihexyphenidyl appears to have a more consistent and beneficial effect than biperiden, especially in the moderate-to-advanced stages.The benzodiazepine associated with the best response is clonazepam.Even greater improvement in dystonia is noted when anticholinergic drugs are combined with clonazepam.Zolpidem. Once the dystonia is multifocal or generalized in distribution, even polypharmacy offers only partial relief of the dystonic symptoms. In such states, zolpidem has been observed to be potentially effective [Evidente 2002].Zolpidem is particularly useful in individuals with a predominantly phasic type of generalized dystonic movements and no contractures. In such cases dramatic improvement can occur: some individuals experience nearly 100% improvement of dystonia for a few hours.The clinical effect of zolpidem may last six to eight hours per 10 mg dose in the first few weeks. Subsequently, the effect becomes progressively shorter, decreasing to two to three hours.Although zolpidem was previously reported to have modest effects on parkinsonism in some individuals with progressive supranuclear palsy (PSP) [Daniele et al 1999] and Parkinson disease [Daniele et al 1997], its effect on dystonia in individuals with XDP is more robust than its effect on parkinsonism.Individuals with XDP who take frequent doses of zolpidem either overcome its soporific effects rapidly or develop tolerable daytime sleepiness.Neuroleptics, particularly those with strong dopamine D₂ antagonistic properties, are often prescribed because they are relatively cheap and widely available.Haloperidol is often used by primary care physicians who see individuals with XDP de novo in the Panay Islands. Although haloperidol may be effective initially for mild-to-moderate dystonia, its effect in more advanced dystonia remains dubious, as it is unclear if the progression of the dystonia is caused by the disease alone or partially caused by the extrapyramidal side effects (EPS) of haloperidol.Risperidone seems less effective than haloperidol in controlling dystonia. At doses of 6 mg/day or higher, risperidone may also be associated with EPS including tardive dyskinesias and parkinsonism. Of the atypical neuroleptics, clozapine has the greatest potential to be effective, at least for a limited period. However, its clinical use is limited by its potential to cause aplastic anemia and the need to do frequent complete blood counts, which is impractical in the rural areas of the Panay Islands where XDP is most prevalent.Tetrabenazine also benefits some individuals with clinically advanced dystonia [Evidente et al 2002a]. Similar to zolpidem, tetrabenazine (a non-neuroleptic presynaptic dopamine depleter) best helps individuals with phasic dystonia and no contractures.Botulinum toxin injections improve focal dystonia, particularly cervical dystonia, blepharospasm, tongue dystonia, and jaw dystonia. It can, however, dramatically worsen swallowing in individuals with preexisting dysphagia if injected in the cervical or tongue area. The prohibitive cost of botulinum toxin also limits its use in individuals with XDP in rural areas. Rosales et al [2011] using botulinum toxin-A injections in 109 persons with XDP found substantial improvement for oromandibular and lingual dystonias and moderate improvement for truncal-axial dystonias as well as a significant reduction in associated pain.Injections of ethanol and lidocaine for afferent blocking of muscle are far less costly than botulinum toxin and have been attempted in individuals with XDP with cervical dystonia. They only offer clinical benefits for one to two weeks and are associated with undesirable side effects including severe pain during injections and muscle fibrosis and contractures with repeated use.Pharmacologic Treatment of ParkinsonismLevodopa. Individuals with XDP, particularly those with pure parkinsonism, may be responsive to levodopa. Persons with parkinsonism who develop dystonia may become increasingly less responsive to levodopa as the dystonia progresses. Of note, long-term use of levodopa does not lead to development of levodopa-associated dyskinesias.Dopamine agonists are also effective in controlling tremor in individuals with XDP but are less effective than levodopa in controlling bradykinesia or shuffling gait. Rarely, levodopa or dopamine agonists may exacerbate the dystonia in persons with XDP.Surgical Treatment of Dystonia and ParkinsonismDeep brain stimulation (DBS). Recently XDP was successfully treated in one individual using DBS of the globus pallidus interna (GPi) bilaterally [Evidente et al 2007]. The individual had parkinsonism and generalized dystonia, with severe disabling jaw-opening dystonia, drooling, dysphagia, and dysarthria (speech was unintelligible). He received only partial relief of his symptoms with a combination of levodopa, piribedil (a dopamine agonist), trihexyphenidyl, and zolpidem. His generalized dystonia and parkinsonism improved markedly within the first week after surgery, with sustained benefits at one-year follow-up. Thus, it appears that bilateral pallidal stimulation may be the best option for symptomatic improvement in individuals with XDP with advanced disease and medically refractory dystonia [Wadia et al 2010, Aguilar et al 2011].Prevention of Primary ManifestationsSee Treatment of Manifestations.Prevention of Secondary ComplicationsThe 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.SurveillancePresymptomatic 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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.OtherOther 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].

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. X-Linked Dystonia-Parkinsonism Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTAF1Xq13​.1Transcription initiation factor TFIID subunit 1TAF1 @ LOVDTAF1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for X-Linked Dystonia-Parkinsonism Syndrome (View All in OMIM) View in own window 313650TAF1 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 250-KD; TAF1 314250DYSTONIA 3, TORSION, X-LINKED; DYT3Molecular Genetic PathogenesisThough 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.XDP Critical RegionNormal allelic variants. Normal variants in the XDP critical region have been reported [Nolte et al 2003]. TAF1 (reference sequences: NM_004606.3, NP_004597.2) has 38 exons.Pathologic allelic variants. Nolte et al [2003] described five XDP-disease-specific changes (DSC), specifically DSC 1, 2, 3, 10, and 12, as well as a 48-bp deletion in the XDP critical region. These DSCs as well as the 48-bp deletion were found in all XDP affected Filipino individuals, but not in normal controls with no family history of XDP. None of the DSCs was located within a structural or regulatory region of a known gene. Rather, most changes occurred within repetitive DNA: DSC1 is located within an Alu repeat, DSC2 within a LINE2 repeat, and DSC10 within a LIMB2 repeat in intron 32 of TAF1. DSC12 is located in intron 18 of TAF1, whereas the 48-bp deletion is located in intron 2 of TAF1. Only DSC3 (c.94C>T, p.Arg32Cys) is embedded in an exonic DNA sequence, located in exon “d4”. The DSC3 variant was not detected in in unaffected Filipino or other non-Filipino populations and is the only molecular alteration detected in a mature transcript within the XDP core haplotype. Nolte et al [2003] concluded that it is likely that DSC3 plays a pathogenic role in XDP, although other XDP-specific sequence changes may also contribute to the disease (e.g., by influencing splicing of transcripts). To date, XDP is known only in persons of Filipino descent, suggesting genetic homogeneity. More recently, using genomic sequencing analysis followed by expression analysis of XDP in brain tissues, Makino et al [2007] reported a disease-specific short interspersed nuclear element, variable number of tandem repeats, and Alu composite (SVA) retrotransposon insertion in intron 32 of TAF1, with significantly reduced expression of TAF1 and the dopamine receptor D₂ gene (DDR2) in the caudate nucleus of individuals with XDP [Makino et al 2007]. The individual or combined roles of DSC3, the other DSCs, or the SVA retrotransposon in pathogenesis of XDP remain to be determined. Table 2. Selected Allelic Variants within the XDP Critical RegionView in own windowGene / Locus SymbolClass of Variant AlleleDNA Nucleotide Change Protein Amino Acid Change
(Alias ¹)Reference Sequences TAF1/DYT3Pathologic / markerc.94C>Tp.Arg32Cys
(DSC3)AJ549245​.1
CAD70488​.1See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventions Normal gene product. UnknownAbnormal gene product. Whether an abnormal protein product results from the DSC3 (c.94C>T) variant in TAF1/DYT3 is unknown. Nolte et al [2003] hypothesized that the DYT3-specific sequence changes could contribute to the disease by influencing splicing of transcripts. However, Makino et al [2007] suggested that the SVA retrotransposon insertion into TAF1 may cause XDP by altering expression of TAF1 isoforms (including the neuron-specific TA14-391), possibly through DNA methylation alterations. The decreased expression of the TA14-391 isoform (and possibly other TAF1 isoforms) in XDP brains may result in transcriptional dysregulation of many neuronal genes, including DRD2.