X-linked dystonia-parkinsonism/Lubag

Alternate names

DYT3; Dystonia-Parkinsonism, X-linked; XDP; Torsion dystonia-Parkinsonism, Filipino type; X-Linked Torsion Dystonia-Parkinsonism syndrome; X-Linked Dystonia-Parkinsonism syndrome; Lubag; DYT-TAF1; Dystonia 3, torsion, X-linked

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.

Cause

• XDP is due to mutations in the TAF1 gene (Xq13.1) .
• The TAF1 gene provides instructions for making part of a protein called transcription factor IID (TFIID).
• This protein is active in cells and tissues throughout the body, where it plays an essential role in regulating the activity of most genes.
• The TAF1 gene is part of a complex region of DNA known as the TAF1/DYT3 multiple transcript system.
• This region consists of short stretches of DNA from the TAF1 gene plus some extra segments of genetic material near the gene.
• These stretches of DNA can be combined in different ways to create various sets of instructions for making proteins. Researchers believe that some of these variations are critical for the normal function of nerve cells (neurons) in the brain.

Gene mutations

• Several changes in the TAF1/DYT3 multiple transcript system have been identified in people with X-linked dystonia-parkinsonism.
• Scientists are uncertain how these changes are related to the movement abnormalities characteristic of this disease. However, they suspect that the changes disrupt the regulation of critical genes in neurons.
• This defect leads to the eventual death of these cells, particularly in areas of the brain called the caudate nucleus and putamen.
• These regions are critical for normal movement, learning, and memory.
• It is unclear why the effects of changes in the TAF1/DYT3 multiple transcript system appear to be limited to dystonia and parkinsonism.

Inheritance

X-linked recessive inheritance

• 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.

Signs and symptoms

• 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.

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

30%-79% of people have these symptoms

• Blepharospasm(Eyelid spasm)
• Bradykinesia(Slow movements)
• Chorea
• Hand tremor(Tremor of hand)
• Myoclonus
• Parkinsonism with favorable response to dopaminergic medication
• Postural instability(Balance impairment)
• Progressive extrapyramidal muscular rigidity
• Resting tremor(Tremor at rest)
• Shuffling gait(Shuffled walk)
• Torsion dystonia

5%-29% of people have these symptoms

• Aspiration pneumonia
• Difficulty walking(Difficulty in walking)
• Frequent falls
• Impaired oropharyngeal swallow response
• Laryngeal stridor
• Limb dystonia
• Protruding tongue(Prominent tongue)

Diagnosis

• 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.

Antenatal diagnosis Prenatal diagnosis is possible in families with a known TAF1 mutation.

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.

NIH genetic and rare disease info

• NIH info on X-linked dystonia-parkinsonism/Lubag

X-linked dystonia-parkinsonism/Lubag is a rare disease.

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