Dystonia 3, Torsion, X-Linked (DYT3)

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Disease Ontology 12 DOID:0090057 OMIM 56 314250 OMIM Phenotypic Series 56 PS128100 MeSH 43 D004421 ICD10 32 G24.1 ICD10 via Orphanet 33 G24.1

UMLS via Orphanet 72 C1839130 Orphanet 58 ORPHA53351 MedGen 41 C1839130 SNOMED-CT via HPO 68 127324008 17450006 22451001 228158008 249872000 25082004 26079004 271700006 285503005 399317006 406444002 41432000 422588002 43005009 431034009 53787002 59026006 more UMLS 71 C0013423 C1839130

NIH Rare Diseases : ⁵² The following summary is from Orphanet , a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 53351 Definition X-linked dystonia -parkinsonism (XDP) is a neurodegenerative movement disorder characterized by adult-onset parkinsonism that is frequently accompanied by focal dystonia, which becomes generalized over time, and that has a highly variable clinical course. Epidemiology Over 500 cases of XDP have been reported in the literature to date, all occurring in the Philippines (Panay Island). The estimated prevalence in the Philippines is 1/322,000 and in the Province of Capiz it is at its highest with a prevalence of 1/4,000 in the male population. Clinical description XDP affects mainly males, most female carriers are asymptomatic. The disease typically presents in adulthood (mean: 39 years) with either focal dystonia or, more commonly, parkinsonism. Focal dystonia affects mainly the jaw, neck, eyes and trunk, but also rarely the limbs, pharynx, larynx and tongue, leading to various manifestations such as difficulty with jaw opening and closing, blepharospasm, involuntary tongue protrusion, difficulty swallowing, retrocollis, trunk hyperextension, leg spasms, foot flexion, and foot inversion. Within 2-5 years after onset, 50% of patients have generalized dystonia. Parkinsonism manifests with bradykinesia, rigidity, resting tremor, shuffling gait and postural instability, which may be severe and can lead to walking impairment and frequent stumbling. Less common findings include sensory tricks, myoclonus, chorea and myorhythmia. In those with pure parkinsonism, the disease progresses slowly and is usually non-disabling. Most who develop orobuccolingual and cervical dystonia suffer from lethal complications such as infections, aspiration pneumonia and laryngeal stridor, leading to premature death. Mean duration of illness is 13-16 years. Etiology XDP is due to mutations in the TAF1 gene (Xq13.1) encoding the TAF1 RNA polymerase II, TATA box-binding protein -associated factor, 250kDa. Diagnostic methods Diagnosis is based on clinical and neuroimaging findings (of postsynaptic striatal and presynaptic nigrostriatal involvement), as well as having a positive family history compatible with X-linked inheritance and maternal Panay Island ancestral roots. MRI usually shows no abnormalities. Molecular genetic testing can confirm the diagnosis by identifying a TAF1 mutation. Preliminary results from a pilot study indicate olfactory dysfunction in XDP, therefore olfactory testing may also support diagnosis. Differential diagnosis Differential diagnoses include Parkinson's disease, hereditary essential tremor, dopa-responsive dystonia and Parkinson-plus syndromes . Antenatal diagnosis Prenatal diagnosis is possible in families with a known TAF1 mutation. Genetic counseling XDP is inherited in an X-linked recessive manner and genetic counseling is recommended. Males with XDP pass the mutation to all of their daughters and none of their sons, whereas female carriers have a 50% chance of passing the mutation to their offspring. Rare de novo mutations have been reported. Management and treatment There is no cure for XDP. Treatment involves the use of pharmacological agents and offers only temporary or partial relief. In the early stages of dystonia, benzodiazepines and anticholinergic agents may be effective, especially in combination. Botulinum toxin injections may relieve focal dystonia. Tetrabenazine and zolpidem can improve dystonia once it becomes generalized or multifocal. Those with pure parkinsonism may be responsive to levodopa. Deep brain stimulation has shown promise in a few cases with advanced disease refractory to medication. Periodic swallowing evaluation is recommended, especially in those with dysphagia . Physical therapy may be helpful. Psychological counseling should be offered to patients and their families. Prognosis Prognosis is phenotype -dependent. Those with pure parkinsonism have the best prognosis, while those with a combination of parkinsonism followed by the development of orobuccolingual and cervical dystonia, 1-2 years after disease onset, have the worst prognosis, usually becoming bedridden with a reduced life expectancy. Visit the Orphanet disease page for more resources.

MalaCards based summary : Dystonia 3, Torsion, X-Linked, also known as x-linked dystonia-parkinsonism, is related to dystonia 12 and dystonia 1, torsion, autosomal dominant, and has symptoms including tremor, myoclonus and dystonia. An important gene associated with Dystonia 3, Torsion, X-Linked is TAF1 (TATA-Box Binding Protein Associated Factor 1). The drugs Acetylcholine and Acetylcholine Release Inhibitors have been mentioned in the context of this disorder. Affiliated tissues include eye, brain and tongue, and related phenotypes are chorea and myoclonus

Disease Ontology : ¹² A focal dystonia that is characterized by parkinsonism that is frequently accompanied by focal dystonia and progresses to generalized dystonia that has material basis in X-linked recessive inheritance of SVA retrotransposon insertion in the intron of the TATA-box binding protein associated factor 1 gene (TAF1) on chromosome Xq13.1.

Genetics Home Reference : ²⁵ X-linked dystonia-parkinsonism is a movement disorder that has been found only in people of Filipino descent. This condition affects men much more often than women. Parkinsonism is usually the first sign of X-linked dystonia-parkinsonism. Parkinsonism is a group of movement abnormalities including tremors, unusually slow movement (bradykinesia), rigidity, an inability to hold the body upright and balanced (postural instability), and a shuffling gait that can cause recurrent falls. Later in life, many affected individuals also develop a pattern of involuntary, sustained muscle contractions known as dystonia. The dystonia associated with X-linked dystonia-parkinsonism typically starts in one area, most often the eyes, jaw, or neck, and later spreads to other parts of the body. The continuous muscle cramping and spasms can be disabling. Depending on which muscles are affected, widespread (generalized) dystonia can cause difficulty with speaking, swallowing, coordination, and walking. The signs and symptoms of X-linked dystonia-parkinsonism vary widely. In the mildest cases, affected individuals have slowly progressive parkinsonism with little or no dystonia. More severe cases involve dystonia that rapidly becomes generalized. These individuals become dependent on others for care within a few years after signs and symptoms appear, and they may die prematurely from breathing difficulties, infections (such as aspiration pneumonia), or other complications.

UniProtKB/Swiss-Prot : ⁷³ Dystonia 3, torsion, X-linked: A X-linked dystonia-parkinsonism disorder. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DYT3 is characterized by severe progressive torsion dystonia followed by parkinsonism. It has a well-defined pathology of extensive neuronal loss and mosaic gliosis in the striatum (caudate nucleus and putamen) which appears to resemble that in Huntington disease.

More information from OMIM: 314250 PS128100

GeneReviews: NBK1489

Clinical features from OMIM:

314250

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