Objective: To determine whether structural brain changes are present in female carriers (MC) of the TAF1 pathogenic change causing X-linked dystonia-parkinsonism (XDP).

Background: XDP is an X-linked hereditary neurodegenerative disease characterized by progressive adult-onset dystonia accompanied by parkinsonism. Male patients with manifest but also prodromal XDP show striatal and pallidal pathology and, in addition, structural changes of the cerebellum. In male prodromal MC, the predicted age at onset of motor symptoms can be estimated by combining genetic modifiers, including a hexanucleotide repeat within the (retrotransposon) mutation. Although the mode of inheritance is X-chromosomal, XDP has occasionally been observed in female MCs indicative of neurodegeneration.

Method: High-resolution T1-weighted images were acquired at 1.5T in 35 female MC without a diagnosis of a movement disorder and 44 female healthy controls not carrying the mutation (HC). Voxel-based morphometry was performedusing the CAT toolbox in SPM12. The online tool volbrain (https://volbrain.upv.es) was used for subcortical volumetry. The hypothesized age of motor manifestation derived from male carriers was calculated using the previously published modifiers.

Results: No women had a previous diagnosis of a movement disorder. Voxel-based morphometry revealed atrophy of the striatum and hypertrophy in the medial parts of the cerebellum in MC (Fig.1). Accordingly, volumes of the caudate (F(1,79)=46.7, -18.5%), putamen (F(1,79)=65.0, -19.6%), and pallidum (F(1,79)=29.5, -18.4%) were reduced in MC compared to HC (all p <0.001, Fig.2). Striatal atrophy as well as the volume of the caudate and the putamen correlated with age and with time from putative onset in MC (rho = -0.7162, p < 0.0001). In contrast, there was no correlation between striatal volume with age in HC.

Conclusion: Our findings suggest significant striatal neurodegeneration in female carriers of the underlying mutation in the TAF1gene despite X-chromosomal mode of inheritance. Future studies should therefore focus on potential subtle motor and non-motor phenotypes in female carriers to reveal the entire clinical spectrum of neurodegeneration in XDP.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/striatal-neurodegeneration-in-female-carriers-of-the-taf1-mutation-causing-x-linked-dystonia-parkinsonism/