Understanding XDP Through Imaging, Pathology, and Genetics

Abstract

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 or 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 hyperintense 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., parkinsonian 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 retrotransposon insertion in an intron of TAF1. This may reduce neuron-specific expression of the TAF1 isoform in the caudate nucleus, and subsequently interfere with the transcription of many neuronal genes, including DRD2. Findings from imaging, pathology, and genetics studies are gradually shedding light on the pathophysiology of XDP, which hopefully will lead to more rational and directed therapies.

JPH3 repeat expansions cause a progressive akinetic-rigid syndrome with severe dementia and putaminal rim in a five-generation African-American family

“…Putaminal rim is otherwise most typically associated with MSA. In addition, it has recently been described as a constant feature in the dystonic, combined, and Parkinsonian phases of X-linked dystonia Parkinsonism (Lubag), in which caudate atrophy was also present in the majority of patients [12]. The sign may thus be an imaging correlate of neurodegenerative cell loss with in the striatum.…”

X-Linked Dystonia Parkinsonism: Clinical Phenotype, Genetics and Therapeutics

“…Cranial MRI in XDP shows hyperintense putaminal rim during both dystonic and parkinsonian phases , and atrophy of the caudate head or putamen during the parkinsonian phase 11. Neuropathology confirms an atrophy of the caudate nucleus and putamen, with mild to severe neuronal loss and gliosis 12.…”

X-linked Dystonia-Parkinsonism patient cells exhibit altered signaling via nuclear factor-kappa B

“…Since the description of the first reported cases (Lee et al, 1976), most research into XDP has focused on detailed characterizations of the clinical phenotype (Aguilar et al, 2011; Evidente et al, 2002a; Evidente et al, 2002b; Evidente et al, 2004; Jamora et al, 2014; Lee et al, 1991; Lee et al, 2002; Lee et al, 2011; Pasco et al, 2011) and efforts to pinpoint the pathogenic gene lesion (Domingo et al, 2015; Graeber and Muller, 1992; Haberhausen et al, 1995; Herzfeld et al, 2007; Kupke et al, 1992; Makino et al, 2007; Muller et al, 1994; Nemeth et al, 1999; Nolte et al, 2003; Wilhelmsen et al, 1991). There have been limited analyses of post-mortem brain tissue which have described XDP-related neuropathology (Goto et al, 2013; Goto et al, 2005; Waters et al, 1993) and expression of certain transcripts within the striatum (Makino et al, 2007), but to date there has been little information about specific cellular defects which might contribute to disease pathogenesis.…”