What are the other Names for this Condition? (Also known as/Synonyms)

• Lubag Syndrome
• Torsion Dystonia-Parkinsonism, Filipino type
• X-Linked Torsion Dystonia-Parkinsonism Syndrome

What is X-Linked Dystonia-Parkinsonism? (Definition/Background Information)

• 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
• XDP affects mainly males, while most female carriers are asymptomatic. The disease typically presents in adulthood (mean age 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 of X-Linked Dystonia-Parkinsonism 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
• X-Linked Dystonia-Parkinsonism is inherited in an X-linked recessive manner and genetic counseling is recommended. Rare de novo mutations have been reported. Prenatal diagnosis is possible in families with a known TAF1 mutation

(Source: X-Linked Dystonia-Parkinsonism; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets X-Linked Dystonia-Parkinsonism? (Age and Sex Distribution)

• X-Linked Dystonia-Parkinsonism is a rare congenital disorder with over 500 cases reported in medical literature. However, all reported cases are from the Panay island in the Philippines
• The presentation of symptoms typically occur in adulthood
• The disorder predominantly affects males

What are the Risk Factors for X-Linked Dystonia-Parkinsonism? (Predisposing Factors)

• A positive family history may be an important risk factor, since X-Linked Dystonia-Parkinsonism can be inherited
• Currently, no other risk factors have been clearly identified for this disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of X-Linked Dystonia-Parkinsonism? (Etiology)

• X-Linked Dystonia-Parkinsonism is due to mutations in the TAF1 gene (Xq13.1) encoding the TAF1 RNA polymerase II, TATA box-binding protein-associated factor, 250kDa
• The disorder is inherited in an X-linked recessive manner
• In rare cases, de-novo mutation of TAF1 gene leading to X-Linked Dystonia-Parkinsonism are also reported

(Source: X-Linked Dystonia-Parkinsonism; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

X-linked recessive mode of inheritance: The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

What are the Signs and Symptoms of X-Linked Dystonia-Parkinsonism?

The signs and symptoms of X-Linked Dystonia-Parkinsonism may include:

• Chorea
• Myoclonus
• Parkinsonism with favorable response to dopaminergic medication
• Torsion dystonia
• Tremor

(Source: X-Linked Dystonia-Parkinsonism/Lubag; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

• Difficulty with jaw opening and closing
• Blepharospasm
• Involuntary tongue protrusion
• Difficulty swallowing
• Retrocollis 
• Trunk hyperextension
• Leg spasms, 
• Foot flexion
• Foot inversion

Within 2-5 years after onset, 50% of patients have generalized dystonia, whose signs and symptoms may include:

• Bradykinesia
• Rigidity
• Resting tremor
• Shuffling gait 
• Postural instability

(Source: X-Linked Dystonia-Parkinsonism; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

How is X-Linked Dystonia-Parkinsonism Diagnosed?

The diagnosis of X-Linked Dystonia-Parkinsonism 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

(Source: X-Linked Dystonia-Parkinsonism; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of X-Linked Dystonia-Parkinsonism?

The complications of X-Linked Dystonia-Parkinsonism may include:

• Injuries from stumbling/falling
• Swallowing difficulties may lead to significant weight loss
• Risk of infections 
• Aspiration pneumonia 
• Laryngeal stridor

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is X-Linked Dystonia-Parkinsonism Treated?

There is no cure for X-Linked Dystonia-Parkinsonism. 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 of patients and their families may be helpful

(Source: X-Linked Dystonia-Parkinsonism; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

How can X-Linked Dystonia-Parkinsonism be Prevented?

X-Linked Dystonia-Parkinsonism may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders
• Regular medical screening at periodic intervals with tests and physical examinations are recommended

What is the Prognosis of X-Linked Dystonia-Parkinsonism? (Outcomes/Resolutions)

• The prognosis of X-Linked Dystonia-Parkinsonism 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
• 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

(Source: X-Linked Dystonia-Parkinsonism/Lubag; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Additional and Relevant Useful Information for X-Linked Dystonia-Parkinsonism:

X-Linked Dystonia-Parkinsonism/Lubag is also known by the following additional synonyms:

• DYT3
• DYT-TAF1
• Torsion Dystonia-Parkinsonism, Filipino type
• X-Linked Dystonia-Parkinsonism Syndrome
• X-Linked Dystonia-Parkinsonism/Lubag
• X-Linked Torsion Dystonia 3

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/