Dystonia represents a clinical syndrome characterized by involuntary sustained muscle contraction often resulting in twisting, repetitive movements and abnormal postures. Dystonia can be both primary (idiopathic) or symptomatic. Symptomatic or secondary dystonias are caused by varied structural or metabolic disturbances of the nervous system which may result from an underlying disease or drug treatment. Idiopathic dystonias are composed of a spectrum of disorders in which dystonia is the predominant clinical feature. X-linked dystonia parkinsonism is a recessively inherited, severe, adult-onset movement disorder. It is characterized by dystonia, predominantly focal at presentation, progressing to a generalized form with co-incidental parkinsonism in about 50% of cases. XDP is believed to originate from a common ancestor in the Philippine island of Panay. Linkage and allelic association studies have mapped the gene defect causing this disorder to a small interval in Xq13.1.
We aim to identify the disease causing mutation for X-linked dystonia parkinsonism. As part of this effort we have assisted in the collection of blood samples from >50 XDP patients and their immediate families in addition to samples from 100 male filipino controls. We have performed haplotype analysis on affected individuals, their nuclear families and controls. We have used an electronic database mining and positional cloning strategy to identify genes within the critical region and have constructed a physical map of the candidate region using a series of BACs, PACs and cosmids. We have sequenced all nine genes in 2 haplotype confirmed XDP cases and their mothers. Additionally, we have sequenced the coding exons of two genes 200kb centromeric to the candidate region. We have examined full-length gene transcripts from all nine genes amplified in adult and fetal cDNA libraries, lymphocyte DNA from an XDP case, his mother and an unrelated control. The lack of a coding mutation in all known genes suggests a non-coding regulatory region may harbor the pathogenic change. In an effort to identify this, or any mutation within the region we are constructing a genomic fosmid library from an affected individual. We intend to identify clones from the candidate region using a pooled PCR approach and sequence the entire segregating region (350kb) using a shotgun cloning methodology. In collaboration with Drs Virgiglio Evidente Dennis Dickson (mayo Clinic Scottsdale and Jacksonville respectively) we have further characterized the clinical and pathological aspects of this disorder in an attempt to better understand the disease process. This work is not only aimed at gaining insight into the pathogenesis and etiology of this disorder but also to that of dystonia and parkinsonism in general. Following the identification of this genetic defect and in conjunction with Dr Mark Cookson of LNG, NIA, we will construct both cellular and transgenic models of this disease in an attempt to gain insight into the mechanism of disease and to provide a model to test viable therapeutic strategies.
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