Stability of Mosaic Divergent Repeat Interruptions in X-Linked Dystonia-Parkinsonism.

BACKGROUND: X-Linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative disorder characterized by rapidly progressive dystonia and parkinsonism. Mosaic Divergent Repeat Interruptions affecting motif Length and Sequence (mDRILS) were recently found within the TAF1 SVA repeat tract and were shown to associate with repeat stability and age at onset in XDP, specifically the AGGG [5'-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n] mDRILS. OBJECTIVE: This study aimed to investigate the stability of mDRILS frequencies and stability of (AGAGGG)n repeat length during transmission in parent-offspring pairs. METHODS: Fifty-six families (n = 130) were investigated for generational transmission of repeat length and mDRILS. The mDRILS stability of 16 individuals was assessed at two sampling points 1 year apart. DNA was sequenced with long-read technologies after long-range polymerase chain reaction amplification of the TAF1 SVA. Repeat number and mDRILS were detected with Noise-Cancelling Repeat Finder (NCRF). RESULTS: When comparing the repeat domain, 51 of 65 children had either contractions or expansions of the repeat length. The AGGG frequency remained stable across generations at 0.074 (IQR: 0.069-0.078) (z = -0.526; P = 0.599). However, the median AGGG frequency in children with an expansion (0.072 [IQR: 0.066-0.076]) was lower compared with children with retention or contraction (0.080 [IQR: 0.073-0.083]) (z = -0.007; P = 0.003). In a logistic regression model, the AGGG frequency predicted the outcome of either expansion or retention/contraction when including repeat number and sex as covariates (ß = 80.7; z-score = 2.63; P = 0.0085). The AGGG frequency varied slightly over 1 year (0.070 [IQR: 0.063-0.080] to 0.073 [IQR: 0.069-0.078]). CONCLUSIONS: Our results show that a higher AGGG frequency may stabilize repeats across generations. This highlights the importance of further investigating mDRILS as a disease-modifying factor with generational differences. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Mosaic divergent repeat interruptions in XDP influence repeat stability and disease onset.

While many genetic causes of movement disorders have been identified, modifiers of disease expression are largely unknown. X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease caused by a SINE-VNTR-Alu(AGAGGG)n retrotransposon insertion in TAF1, with a polymorphic (AGAGGG)n repeat. Repeat length and variants in MSH3 and PMS2 explain ∼65% of the variance in age at onset (AAO) in XDP. However, additional genetic modifiers are conceivably at play in XDP, such as repeat interruptions. Long-read nanopore sequencing of PCR amplicons from XDP patients (n = 202) was performed to assess potential repeat interruption and instability. Repeat-primed PCR and Cas9-mediated targeted enrichment confirmed the presence of identified divergent repeat motifs. In addition to the canonical pure SINE-VNTR-Alu-5'-(AGAGGG)n, we observed a mosaic of divergent repeat motifs that polarized at the beginning of the tract, where the divergent repeat interruptions varied in motif length by having one, two, or three nucleotides fewer than the hexameric motif, distinct from interruptions in other disease-associated repeats, which match the lengths of the canonical motifs. All divergent configurations occurred mosaically and in two investigated brain regions (basal ganglia, cerebellum) and in blood-derived DNA from the same patient. The most common divergent interruption was AGG [5'-SINE-VNTR-Alu(AGAGGG)2AGG(AGAGGG)n], similar to the pure tract, followed by AGGG [5'-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n], at median frequencies of 0.425 (IQR: 0.42-0.43) and 0.128 (IQR: 0.12-0.13), respectively. The mosaic AGG motif was not associated with repeat number (estimate = -3.8342, P = 0.869). The mosaic pure tract frequency was associated with repeat number (estimate = 45.32, P = 0.0441) but not AAO (estimate = -41.486, P = 0.378). Importantly, the mosaic frequency of the AGGG negatively correlated with repeat number after adjusting for age at sampling (estimate = -161.09, P = 3.44 × 10-5). When including the XDP-relevant MSH3/PMS2 modifier single nucleotide polymorphisms into the model, the mosaic AGGG frequency was associated with AAO (estimate = 155.1063, P = 0.047); however, the association dissipated after including the repeat number (estimate = -92.46430, P = 0.079). We reveal novel mosaic divergent repeat interruptions affecting both motif length and sequence (DRILS) of the canonical motif polarized within the SINE-VNTR-Alu(AGAGGG)n repeat. Our study illustrates: (i) the importance of somatic mosaic genotypes; (ii) the biological plausibility of multiple modifiers (both germline and somatic) that can have additive effects on repeat instability; and (iii) that these variations may remain undetected without assessment of single molecules.

Movement disorders in hereditary spastic paraplegia (HSP): a systematic review and individual participant data meta-analysis.

BACKGROUND: Hereditary spastic paraplegia (HSP) is a rare genetic disorder associated with mutations in > 80 loci designated SPG (SPastic parapleGia). The phenotypic spectrum of HSP can extend to include other neurologic features, including movement disorders. Our aim was to investigate genotype-phenotype associations in HSP with a focus on movement disorders. METHODS: We performed a systematic review and individual participant data (IPD)-level meta-analysis by retrieving publications from Medline/EMBASE/Web of Science on HSP with a SPG genotype. Studies were included only if individual-level information was accessible and at least one patient with a movement disorder was reported for that genotype. Out of 21,957 hits, 192 manuscripts with a total of 1413 HSP cases were eligible. Data were compared between two HSP groups: manifested with (HSP-MD, n = 767) or without (HSP-nMD, n = 646) a movement disorder. RESULTS: The HSP-MD group had an older age of onset (20.5 ± 16.0 vs. 17.1 ± 14.2 yr, p < 0.001) and less frequent autosomal dominant inheritance (7.6% vs. 30.1%, p < 0.001) compared to HSP-nMD. SPG7 (31.2%) and SPG11 (23.8%) were the most frequent genotypes in the HSP-MD group. HSP-MD with SPG7 had higher frequency of later onset during adulthood (82.9% vs. 8.5%), ataxia (OR = 12.6), extraocular movement disturbances (OR = 3.4) and seizure (OR = 3.7) compared to HSP-MD with SPG11. Conversely, SPG11 mutations were more frequently associated with consanguinity (OR = 4.1), parkinsonism (OR = 7.8), dystonia (OR = 5.4), peripheral neuropathy (OR = 26.9), and cognitive dysfunction (OR = 34.5). CONCLUSION: This systematic IPD-level meta-analysis provides the largest data on genotype-phenotype associations in HSP-MD. Several clinically relevant phenotypic differences were found between various genotypes, which can possibly facilitate diagnosis in resource-limited settings.

Preferences for Communication About End-of-Life Care in Atypical Parkinsonism.

BACKGROUND: Studies on preferences regarding discussions on end-of-life care (EOLC), advance care planning (ACP), medical assistance in dying (MAiD), and brain donation have not yet been conducted in patients with atypical parkinsonism (AP). OBJECTIVE: The aim of this study was to know the preferences of patients with AP regarding discussions on EOLC, ACP, MAiD, and brain donation. METHODS: This cross-sectional study was conducted in patients clinically diagnosed with AP. An adapted questionnaire that assessed various potential factors that affect patients' preferences regarding EOLC and ACP was sent through postal mail to 278 patients. RESULTS: A total of 90 completed questionnaires were returned. Most patients preferred to discuss at the time of diagnosis information about the disease, its natural course, treatment options, and prognosis. In contrast, they preferred that EOLC and ACP be discussed when the disease has progressed. No demographic or disease-related factors were found to be predictors of the patient's preferences. Notably, most patients (63.3%) had previous actual discussions on these issues. Less than a third of patients were open to discussions about MAiD and brain donation; older age and the importance of spirituality and religion decreased the odds of discussing these. CONCLUSIONS: Our study demonstrates that patients with AP have preferences regarding the timing of the discussion of the different themes surrounding EOLC and ACP. A needs-based approach in initiating and conducting timely discussions on these difficult but essential issues is proposed. A thorough explanation and recognition of a patient's beliefs are recommended when initiating conversations about MAiD and brain donation. © 2021 International Parkinson and Movement Disorder Society.

Combined dystonias: clinical and genetic updates.

The genetic combined dystonias are a clinically and genetically heterogeneous group of neurologic disorders defined by the overlap of dystonia and other movement disorders such as parkinsonism or myoclonus. The number of genes associated with combined dystonia syndromes has been increasing due to the wider recognition of clinical features and broader use of genetic testing. Nevertheless, these diseases are still rare and represent only a small subgroup among all dystonias. Dopa-responsive dystonia (DYT/PARK-GCH1), rapid-onset dystonia-parkinsonism (DYT/PARK-ATP1A3), X-linked dystonia-parkinsonism (XDP, DYT/PARK-TAF1), and young-onset dystonia-parkinsonism (DYT/PARK-PRKRA) are monogenic combined dystonias accompanied by parkinsonian features. Meanwhile, MYC/DYT-SGCE and MYC/DYT-KCTD17 are characterized by dystonia in combination with myoclonus. In the past, common molecular pathways between these syndromes were the center of interest. Although the encoded proteins rather affect diverse cellular functions, recent neurophysiological evidence suggests similarities in the underlying mechanism in a subset. This review summarizes recent developments in the combined dystonias, focusing on clinico-genetic features and neurophysiologic findings. Disease-modifying therapies remain unavailable to date; an overview of symptomatic therapies for these disorders is also presented.

Botulinum Toxin-Associated Prolonged Remission of Idiopathic Cervical Dystonia.

Prolonged remission of dystonia occurs rarely; however, well-documented cases are lacking. We report the clinical characteristics and course of four patients with botulinum toxin (BoNT)-associated prolonged remission of idiopathic cervical dystonia. Mean age at onset was 40 years. All had a relatively short duration of symptoms (mean 10.3 months), and with remission occurring after ≤ 3 treatments with BoNT. At last examination, the remission duration was 2-5 years. In the two cases that subsequently relapsed after 4-5 years, there was an altered phenomenology and worsened severity than at the onset. Recognizing this rare phenomenon has valuable clinical implications.

A hexanucleotide repeat modifies expressivity of X-linked dystonia parkinsonism.

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. ANN NEUROL 2019;85:812-822.

Expanding Data Collection for the MDSGene Database: X-linked Dystonia-Parkinsonism as Use Case Example.

MDSGene is an online database on movement disorders that collates genetic and clinical knowledge using a standardized published literature abstraction strategy. This review is dedicated to X-linked dystonia-parkinsonism (XDP). We screened 233 citations and curated phenotypic and genotypic data for 414 cases. To reduce data missingness, we (1) contacted authors and engaged the research community to provide additional clinical and genetic information, and (2) revisited previously unpublished data from a cohort of XDP patients seen at our institution. Using these approaches, we expanded the cohort to 577 cases and increased information available for important clinical and genetic features such as age at onset, initial manifestation, predominant motor symptoms, functional impairments, and repeat size information. We established the use of mining unpublished data to expand the MDSGene workflow and present an up-to-date description of the phenomenology of XDP using an extensive collection of previously reported and unreported data. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Post-COVID-19 Unilateral Upper Lip Numbness: A Case Report.

This is a case of a 63-year-old female with post-COVID-19 unilateral upper lip pain and numbness. Neurologic examination did not reveal any deficits other than deficits on pinprick in the maxillary division (V2) of the left trigeminal nerve. Brain neuroimaging showed signs of acute inflammation of the left maxillary sinus. Neuropraxia of the infraorbital nerve, a branch of the trigeminal nerve, was the diagnosis considered. Reports on trigeminal neurosensory changes following acute sinusitis are few, and isolated trigeminal neuropathy is rare except in cases of dental disorders. Up to this writing, there have been no reports on post-COVID-19 unilateral upper lip numbness and pain. This study will also serve as a concise review on the correlative neuroanatomy of the trigeminal nerve.

Cross-cultural validation of the Cebuano version of a screening questionnaire for Parkinson's disease.

BACKGROUND: In the Philippines, the exact prevalence of Parkinson's disease (PD) has not yet been determined. Although cases can be extrapolated from medical registries, this method may undermine actual case rates. A reliable screening tool for PD is essential for a timely diagnosis and community-based epidemiological studies. The most widely used screening questionnaire for PD diagnosis was developed by Tanner et al., which consists of nine questions about the motor symptoms of PD. Although this questionnaire has been translated to several languages, the translated version must be validated for use in our local setting. OBJECTIVE: To determine the validity of the Cebuano version of a PD screening questionnaire. METHOD: The questionnaire was translated from English to Cebuano by a hired language specialist. Each item was supplied with a yes, no, or don't know answer. A total of 73 patients with PD and 244 control subjects completed the study. RESULTS: The overall Cronbach alpha for internal consistency of the questionnaire was 0.9410. The item on tremor had the highest sensitivity (97.26%), while the item on problems with buttoning had the highest specificity (100.00%). A cut-off score ≥ 3 obtained the best Youden index (99.18%), with a sensitivity of 100.00% and a specificity of 99.18%. The questionnaire had an almost perfect predictive ability to diagnose PD (AUC of 0.9994). CONCLUSION: The translated version of the Tanner questionnaire is a validated instrument to identify PD in a literate Cebuano population.

ANTEDECENTES: Nas Filipinas, a prevalência exata da doença de Parkinson (DP) ainda não foi determinada. Embora os casos possam ser extrapolados dos registros médicos, esse método pode prejudicar as taxas reais de casos. Uma ferramenta de triagem confiável para DP é essencial para um diagnóstico oportuno e estudos epidemiológicos baseados na comunidade. O questionário de triagem mais utilizado para o diagnóstico da DP foi desenvolvido por Tanner et al., que consiste em nove questões sobre os sintomas motores da DP. Embora este questionário tenha sido traduzido para vários idiomas, a versão traduzida deve ser validada para uso em nosso meio. OBJETIVO: Determinar a validade da versão Cebuano de um questionário de triagem de DP. MéTODOS: O questionário foi traduzido do inglês para o cebuano por um especialista em idiomas contratado. Cada item foi fornecido com uma resposta "sim", "não" ou "não sei". Um total de 73 pacientes com DP e 244 controles completaram o estudo. RESULTADOS: Em geral o alfa de Cronbach para consistência interna do questionário foi de 0,9410. O item "tremor" teve a maior sensibilidade (97,26%), enquanto o item "problemas com abotoamento" teve a maior especificidade (100,00%). Um escore de corte > 3 obteve o melhor índice de Youden (99,18%), com sensibilidade de 100,00% e especificidade de 99,18%. O questionário teve uma capacidade preditiva quase perfeita para diagnosticar DP (AUC de 0,9994). CONCLUSãO: A versão traduzida do questionário de Tanner é um instrumento validado para identificar a DP em uma população cebuana alfabetizada.

Longitudinal evaluations of somatosensory-motor inhibition in Dopa-responsive dystonia.

INTRODUCTION: GCH1 mutations have been linked to decreased striatal dopamine and development of dopa-responsive dystonia (DRD) and Parkinsonism. Sensory and sensorimotor integration impairments have been documented in various forms of dystonia. DRD patients with confirmed GCH1 mutations have demonstrated normal short-latency afferent inhibition (SAI), a measure of sensorimotor inhibition, under chronic dopaminergic replacement therapy (DRT), but reduced inhibition after a single l-dopa dose following 24 h withdrawal. Studies have revealed normal SAI in other forms of dystonia but reductions with DRT in Parkinson's disease. Longitudinal changes in sensorimotor inhibition are unknown. METHODS: We analyzed sensorimotor inhibition using two different measures: SAI and somatosensory-motor inhibition using dual-site transcranial magnetic stimulation (ds-TMS). SAI was measured using digit stimulation 25 ms prior to contralateral primary motor cortex (M1) TMS. DS-TMS was measured using TMS over the somatosensory cortex 1 or 2.5 ms prior to ipsilateral M1 stimulation. A total of 20 GCH1 mutation carriers and 20 age-matched controls were included in the study. SAI and ds-TMS were evaluated in GCH1 mutation carriers both OFF and ON DRT compared to controls. Furthermore, longitudinal changes of SAI were examined in a subset of the same individuals that were measured âˆ¼five years earlier. RESULTS: Neither SAI nor ds-TMS were significantly different in GCH1 mutation carriers relative to controls. No effects of DRT on SAI or ds-TMS were seen but SAI decreased over time in mutation carriers OFF DRT. CONCLUSION: Our longitudinal results suggest changes in SAI that could be associated with plasticity changes in sensorimotor networks.

Time estimation and arousal responses in dopa-responsive dystonia.

Dopa-responsive dystonia (DRD) is caused by an impaired dopamine biosynthesis due to a GTP-cyclohydrolase-1 (GCH1) deficiency, resulting in a combination of dystonia and parkinsonism. However, the effect of GCH1 mutations and levodopa treatment on motor control beyond simple movements, such as timing, action preparation and feedback processing, have not been investigated so far. In an active time estimation task with trial-by-trial feedback, participants indicated a target interval (1200 ms) by a motor response. We compared 12 patients tested (in fixed order) under their current levodopa medication ("ON") and after levodopa withdrawal ("OFF") to matched healthy controls (HC), measured twice to control for repetition effects. We assessed time estimation accuracy, trial-to-trial adjustment, as well as task- and feedback-related pupil-linked arousal responses. Patients showed comparable time estimation accuracy ON medication as HC but reduced performance OFF medication. Task-related pupil responses showed the reverse pattern. Trial-to-trial adjustments of response times were reduced in DRD, particularly OFF medication. Our results indicate differential alterations of time estimation accuracy and task-related arousal dynamics in DRD patients as a function of dopaminergic medication state. A medication-independent alteration of task repetition effects in DRD cannot be ruled out with certainty but is discussed as less likely.

Elucidating Hexanucleotide Repeat Number and Methylation within the X-Linked Dystonia-Parkinsonism (XDP)-Related SVA Retrotransposon in TAF1 with Nanopore Sequencing.

BACKGROUND: X-linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative disorder characterized by progressive dystonia and parkinsonism. It is caused by a SINE-VNTR-Alu (SVA) retrotransposon insertion in the TAF1 gene with a polymorphic (CCCTCT)n domain that acts as a genetic modifier of disease onset and expressivity. METHODS: Herein, we used Nanopore sequencing to investigate SVA genetic variability and methylation. We used blood-derived DNA from 96 XDP patients for amplicon-based deep Nanopore sequencing and validated it with fragment analysis which was performed using fluorescence-based PCR. To detect methylation from blood- and brain-derived DNA, we used a Cas9-targeted approach. RESULTS: High concordance was observed for hexanucleotide repeat numbers detected with Nanopore sequencing and fragment analysis. Within the SVA locus, there was no difference in genetic variability other than variations of the repeat motif between patients. We detected high CpG methylation frequency (MF) of the SVA and flanking regions (mean MF = 0.94, SD = ±0.12). Our preliminary results suggest only subtle differences between the XDP patient and the control in predicted enhancer sites directly flanking the SVA locus. CONCLUSIONS: Nanopore sequencing can reliably detect SVA hexanucleotide repeat numbers, methylation and, lastly, variation in the repeat motif.

Levodopa challenge test: indications, protocol, and guide.

A drug challenge test in Parkinson's disease, such as the levodopa challenge test (LCT), is an easy and generally safe procedure, which has been used by clinicians for various indications. The results of the test have significant implications in the management of patients, from preoperative evaluation for deep brain stimulation to providing the basis for medication adjustments to address motor or non-motor fluctuations and dyskinesias. This paper reviews the different indications and protocols commonly used in an acute LCT. Potential complications of the procedure and an overview of levodopa responsiveness and unresponsiveness are also discussed.