For medical and health professionals
Clinical Manifestations
X-linked dystonia parkinsonism (XDP, DYT3) is an adult-onset sex-linked neurodegenerative movement disorder with features of both dystonia and parkinsonism. It is endemic to the Panay Island in the Philippines and cases described elsewhere are all linked to Filipino ancestry. The national prevalence in the Philippines (in 2011) is 0.31/100,000.
Presentation and Course
There is evidence that XDP has a prodromal phase where neurodegeneration is already present but accompanied by only subtle motor and non-motor signs and symptoms. Balance and gait, and oculomotor disturbance (Mertin et al., 2023; Sprenger et al., 2019; Steinhardt et al., 2022) can be detected in XDP gene positive individuals who do not yet display overt symptoms. Olfactory abnormalities are also found (Evidente et al., 2004).
The true initial manifestation is likely a subtle form of parkinsonism, with mild rigidity and bradykinesia, often ignored or unnoticed for a long period of time. This appears to be more common in females, who may remain at this stage for years or may never progress at all (Domingo et al., 2014).
Most patients cite dystonia as the precipitating symptom for consult. The most prominent symptom of XDP, and the one most initially noticeable to the individual, is focal dystonia, in the neck, jaw, or limb, or as blepharospasm. There is progression to regional or generalized dystonia over time, but progression rate is highly variable. Regardless of the first site of regional involvement, the initial focal dystonia in XDP spreads 97% of the time and generalizes within 5 years in 84% (Lee et al., 2011a). This dystonic phase may also be milder in females, but can be fully expressed in both sexes.
Over time, an average of 7 to 10 years from time of diagnosis, there is gradual amelioration of the severity of the dystonia and progression of parkinsonian symptoms. By the 15th year from the initial dystonic symptoms, the predominant picture is one of parkinsonism manifesting as tremors, bradykinesia, and masked facies (Rosales, 2010). A natural history longitudinal study has a progression summary in data and graphical form (Acuna et al., 2023).
X-linked dystonia-parkinsonism (XDP) is associated with hexameric repeats in the TAF1 gene (Westenberger et al., 2019). The length and number of hexameric repeats has been tied to age of onset, phenotype, and severity (Bragg et al., 2017). It was concluded that the longer the hexameric repeats, the more prominent the dystonic component, and the shorter hexameric repeats were more parkinsonian.
Female XDP carriers can be mostly asymptomatic or only have subtle symptoms, primarily parkinsonian. Homozygosity and skewed X-inactivation can lead to women with XDP presenting with the classical dystonia (Domingo et al., 2014). Most of the symptomatic females may show focal dystonia, chorea, focal tremors and parkinsonian features. In most cases, symptoms are still less severe in females.
Prognosis and Complications
XDP often severely affects the capability to perform activities of daily living, and quality of life worsens. Depression and other mood changes are common. The severely symptomatic onset of XDP is in the 4th or 5th decade, and not surprisingly affects employment and work productivity. As much as 93% of patients exhibit depressive symptoms that are as severe as those found in other neurodegenerative diseases such as Alzheimer disease, Parkinson diseases, and Spinocerebellar degeneration (Morigaki et al., 2013).
Severely symptomatic XDP patients in the dystonic phase who are untreated have a shortened lifespan of 51 years on the average, and most do not go beyond the 10th year of the disease (Lee et al., 2011a). This may explain why only a few reach the parkinsonian phase. The cause of the demise is malnutrition, aspiration pneumonia, suicide. There is no extent data, but anecdotally, patients who reach the primarily parkinsonian phase do not appear to have a shortened lifespan.
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