Basal ganglia and cerebellar pathology in X-linked dystonia-parkinsonism

Abstract

X-linked dystonia-parkinsonism is a neurodegenerative movement disorder characterized by adult-onset dystonia combined with parkinsonism over the disease course. Previous imaging and pathological findings indicate exclusive striatal atrophy with predominant pathology of the striosomal compartment in the dystonic phase of X-linked dystonia-parkinsonism. The striosome occupies 10-15% of the entire striatal volume and the density of striosomes follows a rostrocaudal gradient with the rostral striatum being considered striosome-rich. Recent quantitative MRI analyses provided evidence for an additional involvement of the white matter and the pallidum. In this study, we aimed to (i) disentangle the degree of atrophy in the different subdivisions of the striatum; (ii) investigate changes of cortical morphology; and (iii) elucidate the role of the cerebellum in X-linked dystonia-parkinsonism. T1-weighted MRI scans were acquired in 17 male X-linked dystonia-parkinsonism patients with predominant dystonia (40.1 ± 7.5 years) and 17 ethnicity-matched male healthy controls (35.2 ± 7.4 years). Voxel-based morphometry used a region of interest-based approach for the basal ganglia and primary motor cortex, whole brain analysis, and a separate analysis of the cerebellum. Cortical thickness and subcortical volume were measured. Volume loss in X-linked dystonia-parkinsonism affected all parts of the striatum (-29% voxel intensity) but was most pronounced in the associative subdivision (-41%; P < 0.001). The volume loss also involved the external and internal pallidum, albeit to a lesser extent than the striatum (-19% and -12%, P<0.001). Cortical thickness was reduced in the frontal (-4.3%) and temporal cortex (-6.1%). In addition, we found grey matter pathology in the associative part of the cerebellum and increased voxel intensities in the anterior sensorimotor part of the cerebellum and the dorsal ponto-mesencephalic brainstem. Taken together, our analysis of subcortical and cortical grey matter in the dystonic phase of X-linked dystonia-parkinsonism showed that (i) the striosome-enriched rostral striatum was most severely affected; and (ii) cortical thickness was only reduced in those regions that predominantly have anatomical connections to striosomes. Moreover, the cerebellum may be implicated in both disease-related and compensatory changes, highlighting the significance of the cerebellum in the pathophysiology of dystonia.

A hexanucleotide repeat modifies expressivity of X‐linked dystonia parkinsonism

“…One study proposed that transcriptional interference due to G-quadruplex formation might be one of the primary processes influencing the disease manifestation. [27][28][29] In conclusion, our study confirms that approximately half of the AAO difference in the XDP patient population can be explained by the (CCCTCT) n repeat element. 23 Instead, multiple loss-and gain-of-function mechanisms act in concert to fuel neurodegeneration.…”

“…Finally, further variability may be explained by interindividual differences of the brain to compensate for the advanced neurodegenerative changes that can be observed already in early disease stages. [27][28][29] In conclusion, our study confirms that approximately half of the AAO difference in the XDP patient population can be explained by the (CCCTCT) n repeat element. It also revealed a positive correlation with disease severity and cognitive dysfunction in XDP and an inverse correlation with TAF1 expression.…”

Differential response to pallidal deep brain stimulation among monogenic dystonias: systematic review and meta-analysis

“…Available data were insufficient for a meta-analysis in cases of DYT/PARK- TAF1 , associated with X-linked dystonia-parkinsonism (XDP or Lubag disease)30; DYT- SGCE , responsible for an early-onset form of myoclonus-dystonia predominantly involving the neck and arms3; CHOR/DYT- ADCY5 , which may cause a variable phenotype characterised by chorea, dystonia or myoclonus31 32; GNAO1 , associated with a form of childhood dystonia combined with other hyperkinetic movement disorders, cognitive impairment and seizures33; and ACTB , responsible for a clinical phenotype characterised by dystonia and deafness 34 35. However, outcomes may not be significantly different from those observed in DYT- TOR1A using age- and disease-duration-adjusted motor and disability outcomes, with the only exception of CHOR/DYT- ADCY5 that showed significantly lower benefits from GPi DBS than DYT- TOR1A .…”

“…While these outcomes are encouraging, it is important to note that the clinical picture associated with DYT/PARK- TAF1 (ie, XDP) may change over time. Focal dystonia tends to generalise within the first 5 years; after 10 years, dystonia becomes relatively less severe in the face of increasingly prominent parkinsonian signs 30. A recent observational study from 16 patients showed that GPi DBS may also improve the parkinsonian features associated with XDP 36.…”

Association of Pallidal Neurostimulation and Outcome Predictors With X-linked Dystonia Parkinsonism

“…3 Postmortem investigations identified a loss of striatal medium spiny neurons predominantly in the striosomal compartment, which resulted in striking striatal atrophy. [4][5][6][7] Dystonia in XDP is severe and results in immobility, pain, insufficient food intake, weight loss, and aspiration, and oral treatments with antidystonic drugs are largely ineffective. 8 Deep brain stimulation of the internal pallidum (GPi-DBS) is an established therapeutic option in patients with treatment-refractory generalized and segmental-isolated dystonia 9 and has successfully been used in individual patients with XDP, providing anecdotal evidence only.…”