Factors influencing reduced penetrance and variable expressivity in X-linked dystonia-parkinsonism

Abstract

X-linked dystonia-parkinsonism (XDP) is a neurodegenerative movement disorder that primarily affects adult Filipino men. It is caused by a founder retrotransposon insertion in TAF1 that contains a hexanucleotide repeat, the number of which differs among the patients and correlates with the age at disease onset (AAO) and other clinical parameters. A recent work has identified additional genetic modifiers of age-associated penetrance in XDP, bringing to light the DNA mismatch repair genes MSH3 and PMS2. Despite X-linked recessive inheritance, a minor subset of patients are female, manifesting the disease via various mechanisms such as homozygosity, imbalanced X-chromosome inactivation, or aneuploidy. Here, we summarize and discuss clinical and genetic aspects of XDP, with a focus on variable disease expressivity as a consequence of subtle genetic differences within a seemingly homogenous population of patients.

Keywords: X-linked dystonia-parkinsonism (XDP); age-related penetrance; genetic modifiers; repeat-length polymorphism; retrotransposon insertion.

Figure 1

A Kaplan–Meier plot showing the increase in the age-related penetrance of XDP, i. e., a decrease in likelihood for men with the XDP haplotype to remain unaffected with increasing age.

Figure 2

A diagram showing the effect of the number of (CCCTCT)_n repeats, alone, on age at onset (AAO) of XDP patients (white circles) and the combined effect of the harmful alleles and the number of repeats (red circle) and protective alleles and number of repeats (green circle). The latter two decrease the AAO by 7 years and increase the AAO by 7.9 years, respectively.

Figure 3

Explanations for penetrance of XDP in women. A. A homozygous carrier of the XDP haplotype. B. A Bell curve showing the effect of X-chromosome inactivation (XCI) on the penetrance of XDP in heterozygous female XDP-haplotype carriers. Xm – affected X chromosome (i. e., X chromosome containing the XDPhaplotype), Xwt wildtype X chromosomes. The silenced X chromosome is shown in red and the one that is expressed in green. The percentages below the curve are the ratios of cells with silenced affected vs. unaffected X chromosome. White female figures – unaffected heterozygous carriers; light and dark red female figures, mildly or severely affected female XDP patients, respectively. C. A woman with X chromosome monosomy (45, X), harboring only the affected X chromosome in all her cells.