Understanding XDP through imaging,pathology,and genetics

The X-linked dystonia-parkinsonism (XDP) is a severe progressive, adult-onset X-linked endemic disorder in Filipinos, which is characterized by dystonic movements that start in the third of fourth decade, and replaced by parkinsonism beyond the 10th year of illness. Understanding the pathophysiology of XDP and development of rational therapies will depend on observations from imaging pathological and genetic studies. In this paper we summarize the results of these studies on patients with XDP. The cranial magnetic resonance imaging shows hy-perintense putaminal rim in both dystonic and parkinsonian stages, and atrophy of the caudate head or putamen in the parkinsonian stage. Neuropathological findings show atrophy of the caudate nucleus and putamen, with mild to severe neuronal loss and gliosis. In the neostriatum, the dystonic phase of XDP shows the involvement of striosomes and matrix sparing, while the later, i.e., p[arkinsonian 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. Genetic sequencing of the XDP critical region in Xq13.1 has revealed an SVA retronsposon insertion in an intron of TAF1. This may reduce neuron-specific expression of the TAF1 isoform in the caudade nucleus, and subsequently interfere with the transcription of many neuronal genes, including DRD2. Findings from imaging, pahtology, and genetics studies are gradually shedding light on the pathophysiology of XDP, which hopefully will lead to mare rational and directed therapies.

Botulinum toxin-A targeted for focal/ multifocal dystonias- An open- label application in X-linked Dystonia-Parkinsonism

Targeted for relief of spasms, posturing, pain, impaired function and disfigurement, botulinum toxin type-A (BoNT-A) was injected in dystonias of X-linked dystonia-parkinsonism (XDP). From 1992-2012, focal/ multifocal dystonia combinations were injected in XDP at the following regions: Peri-ocular (21 cases), oromandibular (50 cases), ligual (35 cases), laryngeal (5 cases), cervical (56 cases), truncalaxil (24 cases) upper limbs (13 cases) and lower limbs (18 cases). Pain was frequently reported in 40/50 cases with oromandibular dystonia, 28/56 cases with cervical dystonia, 18/24 cases with truncal-axil dystonia and 16/31 cases with limb dystonia. Outcomes were assessment through the global dystonia rating scale (DRS) at week 4, VAS pain reduction at week 4, duration of BoNT-A effects and safety. Cranial, laryngeal and cervical dystonia showed substantial improvement (DRS median score of 3-4), whereas truncal-axil and limb dystonias showed moderate improvement (DRS median score of 2), following BoNT-A. Pain reduction ranged from 30-100% (VAS), for those dystonias that reported co-morbid pain. BoNT-A effects had a duration ranging from 8-20 weeks. Procedures were generally well tolerated, and the adverse events were most significant in laryngeal injections (voice breathiness, but was eventually followed by a strong voice). The other events were mouth dryness, dysphagia and weekness in oromandibular, cervical and limb dystonias, respectively. Therefore, BoNT-A is a safe and valuable therapeutic option for the dystonias of XDP, especially the disabling and painful dystonias. BoNT-A injection working protocols could be adopted in dystonia that adheres to cost minimization (e.g. lower dose end per selected muscles), yet achieving a substantial benefit, and a reduced adverse event profile. Futhermore, this present study allowed us to recommend a "high potency, low dillution" of BoNT-A in oromandibular, linual, laryngeal, cervical and distal limb dystonias. In dystonias of the abdominal, paraspinal and proximal limb muscles, the "low potency, high dilution" BoNT-A injection protocol could be adopted.

The unique phenomenology of sex-linked dystonia parkinsonism (XDP, DYT3, "Lubag")

Sex-linked dystonia parkinsonism (XDP, DYT3, "Lubag") is an adult-onset, progressive, debilitating movement disorder first described in Filipino males from Panay Island in 1975. XDP manifests predominantly as torsion dystonia, later combined with or sometimes replaced with parkinsonism. Within the Island of Panay, the preva-lence rate is highest in the province of Capiz, where 1:4000 men suffer from the disorder. There is a high degree of penetrance and generalization. While women often serve as carriers, XDP is not limited to men. An updated XDP Philippine registry (as of January 2010) has identified 505 cases, with 500 males and 5 females. While some report that females may carry a milder form of the disorder, in our experience, both sexes generally follow a similar progressive clinical course.