For medical and health professionals
Biological Basis
Primary source: Arasaratnam et al., 2021 🌐 https://pubmed.ncbi.nlm.nih.gov/33227492/
Epidemiology
The disease has a relatively high prevalence in the province of Capiz in the Philippine Island of Panay. The prevalence in the province is 23.66 per 100,000 compared to 5.74 per 100,000 in the island of Panay and 0.31 per 100,000 in the country. In fact, careful genealogical studies have traced almost all cases to mothers with roots in Panay Island (Lee et al., 2011b).
X-linked Transmission
Males with XDP pass the TAF1/DYT3 disease-associated haplotype to all of their daughters and none of their sons . Women who are carriers have a 50% chance of transmitting the TAF1/DYT3 disease-associated haplotype in each pregnancy: males who inherit the TAF1/DYT3 disease-associated haplotype will be affected; females who inherit the TAF1/DYT3 disease-associated haplotype are mostly asymptomatic, although a small percentage may manifest symptoms. Carrier evaluation of at-risk female relatives is possible if the TAF1/DYT3 disease-associated haplotype has been identified in the family. Once the TAF1/DYT3 disease-associated haplotype has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for XDP are possible.
Neuropathology
Neuropathology studies in XDP generally report atrophy of basal ganglia structures, namely the caudate nucleus and putamen. These observations have been determined through MRI studies, in addition to post-mortem tissue examination (Goto et al., 2005, 2013; Hanssen et al., 2018). The degree of atrophy is almost in direct correlation with symptom duration, with virtually unnoticeable changes in the striatum in patients with a short illness duration, to grave atrophy of the striatum in patients with a lengthy illness duration. (Goto et al., 2005).
Genetics
It is believed that XDP originated through a founder mutation in the Panay Islands of the Philippines (Lee et al., 2002). The X-linked pattern of distribution was confirmed in 1990 with an analysis of 36 males from 21 families (Kupke et al., 1990). Specifically, the founder haplotype was mapped to a disease locus (DYT3) on chromosome Xq13.1 through a series of linkage analyses (Graeber & Müller, 1992; Haberhausen et al., 1995; Wilhelmsen et al., 1991). The disease locus contains five genes, of which TAF1 (TATA-Box Binding Protein Associated Factor 1) has been most studied and assumed to be the gene of interest.
In addition to the disease locus, an intergenic multiple transcript system that consists of five unconventional exons exists within 260 kb of the DYT3 region (Domingo et al., 2015; Nolte et al., 2003). The sequencing of the DYT3 region using genomic DNA from an XDP patient revealed five different disease-specific single nucleotide changes: a 48- bp deletion, and a Short interspersed nuclear element, Variable num ber of tandem repeats, and Alu composite retrotransposon insertion (SVA) in intron 32 of the TAF1 gene (Makino et al., 2007).
The genetic basis of XDP is thought to be the SVA insertion within the TAF1 gene (Aneichyk et al., 2018). The insertion typically contains a hexameric repeat (CCCTCT), where a strong inverse correlation between the number of hexameric repeats and the age of onset of XDP symptoms has been found (Bragg et al., 2017; Westenberger et al., 2019a). In particular, a linear regression analysis conducted by Westenberger and colleagues has shown that the age of onset for XDP symptoms reduces by approximately 1.41 years for every additional increase in the hexameric repeat copy number. Furthermore, for every additional increase in repeat number, the likelihood that parkinsonian characteristics manifest first as opposed to dystonia are reduced by 0.12 fold (Westenberger et al., 2019). However, it is postulated that the predominance of dystonia as an initial symptom in XDP patients is related to early age at onset, rather than a higher hexameric repeat number. Additionally, the increase of the hexameric repeat number demonstrates a significant correlation with reduced TAF1 gene expression. Moreover, the repeats have shown a tendency to increase over generations (Westenberger et al., 2019b). Thus, Westenberger and colleagues surmise that the size of the hexameric repeat within the SVA insertion of the TAF1 gene acts as a genetic modifier of XDP age-related disease penetrance (Westenberger et al., 2019b). It is proposed that this genetic hexameric repeat mutation may initiate XDP by altering the expressions of TAF1 isoforms through potential DNA methylation changes (Makino et al., 2007).
The TAF1 gene is part of the transcription factor IID (TFIID) complex, which is involved in RNA polymerase 2 mediated transcription (Kandiah et al., 2014).The TAF1 gene, located on the long arm of the human X chromosome (Xq13.1) consists of 38 highly conserved exons (Herzfeld et al., 2013). The exons 1–38 are part of a TAF1/DYT3 multiple tran script system that includes 5 additional exons. These additional exons lie downstream of exon 38 (Müller et al., 2007) and are commonly referred to as exons d1- d5. An extronic XDP-specifc nucleotide change (DSC3) is located in exon d4. In turn, DSC3 is able to affect the expression of a large number of other genes (Herzfeld et al., 2013). Many of these genes are involved in vesicular transport and dopamine function, including DDC which encodes DOPA decarboxylase, an enzyme responsible for converting L-dopa into dopamine. The dysfunction of these dopamine-centric genes could thus lead to the characteristic parkinsonian symptoms of XDP. It is postulated that the DSC3-mediated dysregulation of the dopamine-centric genes could be the molecular pathological mechanism in XDP (Herzfeld et al., 2013).
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