Validation of the XDP–MDSP rating scale for the evaluation of patients with X-linked dystonia-parkinsonism

Pasco, Paul Matthew D.; Jamora, Roland Dominic G.; Rosales, Raymond L.; Diesta, Cid Czarina E.; Ng, Arlene R.; Teleg, Rosalia A.; Go, Criscely L.; Lee, Lillian; Fernández, Hubert H.

doi:10.1038/s41531-017-0026-0

Cited by 18 publications

(19 citation statements)

References 12 publications

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“…Of note, the recently published dedicated XDP rating scale 7 was not yet available at the time of patient examination. ), ensuring comparability of clinical scores across patients.…”

Section: Study Participants and Clinical Evaluationmentioning

confidence: 99%

A hexanucleotide repeat modifies expressivity of X‐linked dystonia parkinsonism

Westenberger

Reyes

Saranza

et al. 2019

Annals of Neurology

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114

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Objective: X-linked dystonia parkinsonism (XDP) is a neurodegenerative movement disorder caused by a single mutation: SINE-VNTR-Alu (SVA) retrotransposon insertion in TAF1. Recently, a (CCCTCT) n repeat within the SVA insertion has been reported as an age-at-onset (AAO) modifier in XDP. Here we investigate the role of this hexanucleotide repeat in modifying expressivity of XDP. Methods: We genotyped the hexanucleotide repeat in 355 XDP patients and correlated the repeat number (RN) with AAO (n = 295), initial clinical manifestation (n = 294), site of dystonia onset (n = 238), disease severity (n = 28), and cognitive function (n = 15). Furthermore, we investigated i) repeat instability by segregation analysis and Southern blotting using postmortem brain samples from two affected individuals and ii) relative TAF1 expression in blood RNA from 31 XDP patients. Results: RN showed significant inverse correlations with AAO and with TAF1 expression and a positive correlation with disease severity and cognitive dysfunction. Importantly, AAO (and not RN) was directly associated with whether dystonia or parkinsonism will manifest at onset. RN was lower in patients affected by mouth/tongue dystonia compared with blepharospasm. RN was unstable across germline transmissions with an overall tendency to increase in length and exhibited somatic mosaicism in brain. Interpretation: The hexanucleotide repeat within the SVA insertion acts as a genetic modifier of disease expressivity in XDP. RN-dependent TAF1 repression and subsequent differences in TAF1 mRNA levels in patients may be potentiated in the brain through somatic variability leading to the neurological phenotype.

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“…Of note, the recently published dedicated XDP rating scale 7 was not yet available at the time of patient examination. ), ensuring comparability of clinical scores across patients.…”

Section: Study Participants and Clinical Evaluationmentioning

confidence: 99%

A hexanucleotide repeat modifies expressivity of X‐linked dystonia parkinsonism

Westenberger

Reyes

Saranza

et al. 2019

Annals of Neurology

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114

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“…However, several studies indicate that early DBS in severe dystonia is a predictor for a beneficial postoperative outcome. 12,14,15…”

Section: Research Original Investigationmentioning

confidence: 99%

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

et al. 2019

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IMPORTANCE Anecdotal evidence suggests that deep brain stimulation (DBS) of the internal globus pallidus (GPi) is effective in ameliorating dystonia in X-linked dystonia parkinsonism (XDP), a disease that is usually refractive to medical therapy. OBJECTIVE To determine the efficacy of GPi-DBS in a cohort of patients with XDP in a prospective study and identify predictors of postoperative outcomes. DESIGN, SETTING, AND PARTICIPANTS This observational prospective cohort study enrolled patients in February 2013 and was completed in December 2014. The patients were followed up for up to 46 months. Patients from the Philippines were treated in a single center in Lübeck, Germany and followed up in the Philippines. Sixteen men with XDP (mean [SD] age, 40.9 [7.3] years; disease duration, 1-6 years) from the Philippines with predominant dystonia were selected. EXPOSURES All patients underwent bilateral GPi-DBS in Lübeck, Germany. MAIN OUTCOMES AND MEASURES Clinical assessment included the motor parts of the Burke-Fahn-Marsden scale (BFMDRS-M) and the Unified Parkinson's Disease Rating Scale (UPDRS-III). T1-based basal ganglia volumetry was performed and correlated with postoperative outcomes. RESULTSThe study participants included 16 Filipino men (mean age, 40.9 years). Masked video ratings revealed significant improvements of dystonia severity 1 week (−55%; range, −94% to 59%; P < .01) and 6 months (−59%; range, −100% to 22%; P < .001) after surgery. The UDPRS-III score also improved, albeit to a lesser extent (−19%; range, −54% to 95%; and −27%; range, −70% to 124%; respectively). Unmasked long-term follow-up confirmed the continued efficacy of GPi-DBS up to 46 months after surgery. Important secondary end points improved, including activities of daily living, pain severity, weight, and quality of life. Caudate atrophy was a predictor of a less beneficial outcome (r = 0.817, P = .004).CONCLUSIONS AND RELEVANCE Internal globus pallidus DBS had a positive association in XDP with predominant dystonia (the primary end point) and contributed to an improved quality of life (the secondary end point). The response to DBS occurred within 1 week. Given the inverse correlation of postoperative benefit and caudate atrophy, GPi-DBS should be considered early during the disease course. Close international collaboration, training, and funding from multiple sources enabled the sustainable follow-up of patients with XDP in the Philippines.

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“…Among others, new clinical rating scales may have to be developed to meet the requirements of a specific phenotype. Referring back to the example of XDP, the dedicated XDP‐MDSP rating scale covering both dystonia and parkinsonism has recently been developed and validated in 204 patients with XDP …”

Section: Analysis and Conclusionmentioning

confidence: 99%

“…Referring back to the example of XDP, the dedicated XDP-MDSP rating scale covering both dystonia and parkinsonism has recently been developed and validated in 204 patients with XDP. 28 In conclusion, (1) the response to established therapies can differ between genetic and nongenetic movement disorders. Hence, the genotype may predict treatment outcome and treatment choices.…”

Section: Analysis and Conclusionmentioning

confidence: 99%

Will genotype drive treatment options?

Brüggemann

Klein

2019

Movement Disorders

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Individual genetic variation can have a major impact on the clinical manifestation of a movement disorder and its response to treatment. Advances in gene discovery and increasing availability of diagnostic genetic testing have led to the identification of a growing number of patients with well‐defined hereditary movement disorders. Establishing a genetic diagnosis may greatly impact patient counseling and shape therapeutic decisions. Further, assignment of a movement disorder to a specific genetic defect holds promise for the development of causal treatment approaches and individualized therapies, especially as the first gene‐targeted approaches have recently entered clinical trials. However, important gaps remain, that is, genetic testing results are often inconclusive, gene‐specific treatment options are still exceedingly rare, and designing clinical trials to demonstrate disease modification continues to pose a major challenge. © 2019 International Parkinson and Movement Disorder Society

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Validation of the XDP–MDSP rating scale for the evaluation of patients with X-linked dystonia-parkinsonism

Cited by 18 publications

References 12 publications

A hexanucleotide repeat modifies expressivity of X‐linked dystonia parkinsonism

A hexanucleotide repeat modifies expressivity of X‐linked dystonia parkinsonism

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

Will genotype drive treatment options?

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