Genome sequencing reanalysis increases the diagnostic yield in dystonia.

PURPOSE: We investigated the contribution of genomic data reanalysis to the diagnostic yield of dystonia patients who remained undiagnosed after prior genome sequencing. METHODS: Probands with heterogeneous dystonia phenotypes who underwent initial genome sequencing (GS) analysis in 2019 were included in the reanalysis, which was performed through gene-specific discovery collaborations and systematic genomic data reanalysis. RESULTS: Initial GS analysis in 2019 (n = 111) identified a molecular diagnosis in 11.7 % (13/111) of cases. Reanalysis between 2020 and 2023 increased the diagnostic yield by 7.2 % (8/111); 3.6 % (4/111) through focused gene-specific clinical correlation collaborative efforts [VPS16 (two probands), AOPEP and POLG], and 3.6 % (4/111) by systematic reanalysis completed in 2023 [NUS1 (two probands) and DDX3X variants, and a microdeletion encompassing VPS16]. Seven of these patients had a high phenotype-based dystonia score ≥3. Notable unverified findings in four additional cases included suspicious variants of uncertain significance in FBXL4 and EIF2AK2, and potential phenotypic expansion associated with SLC2A1 and TREX1 variants. CONCLUSION: GS data reanalysis increased the diagnostic yield from 11.7 % to 18.9 %, with potential extension up to 22.5 %. While optimal timing for diagnostic reanalysis remains to be determined, this study demonstrates that periodic re-interrogation of dystonia GS datasets can provide additional genetic diagnoses, which may have significant implications for patients and their families.

DHDDS and NUS1: A Converging Pathway and Common Phenotype.

BACKGROUND: Variants in dehydrodolichol diphosphate synthetase (DHDDS) and nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) cause a neurodevelopmental disorder, classically with prominent epilepsy. Recent reports suggest a complex movement disorder and an overlapping phenotype has been postulated due to their combined role in dolichol synthesis. CASES: We describe three patients with heterozygous variants in DHDDS and five with variants affecting NUS1. They bear a remarkably similar phenotype of a movement disorder dominated by multifocal myoclonus. Diagnostic clues include myoclonus exacerbated by action and facial involvement, and slowly progressive or stable, gait ataxia with disproportionately impaired tandem gait. Myoclonus is confirmed with neurophysiology, including EMG of facial muscles. LITERATURE REVIEW: Ninety-eight reports of heterozygous variants in DHDDS, NUS1 and chromosome 6q22.1 structural alterations spanning NUS1, confirm the convergent phenotype of hypotonia at birth, developmental delay, multifocal myoclonus, ataxia, dystonia and later parkinsonism with or without generalized epilepsy. Other features include periodic exacerbations, stereotypies, anxiety, and dysmorphisms. Although their gene products contribute to dolichol biosynthesis, a key step in N-glycosylation, transferrin isoform profiles are typically normal. Imaging is normal or non-specific. CONCLUSIONS: Recognition of their shared phenotype may expedite diagnosis through chromosomal microarray and by including DHDDS/NUS1 in movement disorder gene panels.

A single centre prospective study of three device-assisted therapies for Parkinson's disease.

Comparative studies assessing outcomes with the three device-assisted therapies could help to individualise treatment for patients living with Parkinson's disease. We designed a single-centre non-randomised prospective observational study assessing the quality of life (QoL), motor and non-motor outcomes at 6 and 12-months in patients treated with subcutaneous apomorphine continuous 16-hours infusion (APO), levodopa-carbidopa intestinal gel (LCIG) or subthalamic nucleus deep brain stimulation (STN-DBS). In this study, 66 patients were included (13 APO; 19 LCIG; 34 STN-DBS). At baseline, cognitive, non-motor and motor scores were significantly less severe in the STN-DBS group, whereas the LCIG group had a longer disease duration and higher non-motor scores. In the APO group, there were no statistically significant changes in non-motor, motor and QoL scales. The LCIG group had significant changes in QoL and motor scales that were significant after multiple comparison analysis at 6 and 12-months. The STN-DBS group showed improvement in QoL scores and non-motor and motor scores at 6 and 12-months after multiple comparison analysis. In this real-life prospective study, device-assisted therapies showed differences in their effects on QoL and motor and non-motor function at 12-months. However, there were also differences in baseline characteristics of the patient groups that were not based on pre-determined selection criteria. Differences in characteristics of patients offered and/or treatment with different device-assisted therapies may reflect within-centre biases that may, in turn, influence perceptions of treatment efficacy or outcomes. Treatment centres should be aware of this potential confounder when assessing and offering device-assisted treatment options to their patients and potential baseline differences need to be taken into consideration when comparing the results of non-randomised studies.

Subthalamic Nucleus Activity during Cognitive Load and Gait Dysfunction in Parkinson's Disease.

BACKGROUND: Gait freezing is a common, disabling symptom of Parkinson's disease characterized by sudden motor arrest during walking. Adaptive deep brain stimulation devices that detect freezing and deliver real-time, symptom-specific stimulation are a potential treatment strategy. Real-time alterations in subthalamic nucleus firing patterns have been demonstrated with lower limb freezing, however, whether similar abnormal signatures occur with freezing provoked by cognitive load, is unknown. METHODS: We obtained subthalamic nucleus microelectrode recordings from eight Parkinson's disease patients performing a validated virtual reality gait task, requiring responses to on-screen cognitive cues while maintaining motor output. RESULTS: Signal analysis during 15 trials containing freezing or significant motor output slowing precipitated by dual-tasking demonstrated reduced θ frequency (3-8 Hz) firing compared to 18 unaffected trials. CONCLUSIONS: These preliminary results reveal a potential neurobiological basis for the interplay between cognitive factors and gait disturbances including freezing in Parkinson's disease, informing development of adaptive deep brain stimulation protocols. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

SPG11 presenting with dystonic tremor in childhood.

This is a unique case of SPG11 mutation presenting as childhood onset dystonic tremor without weakness or spastic paraplegia. Hereditary spastic paraplegia is the most common phenotype of SPG11 mutation though there are reports of an extended phenotype of SPG11 including dopa-responsive dystonia and tremor.

Investigating the Precise Localization of the Grasping Action in the Mid-Cingulate Cortex and Future Directions.

Objective: To prospectively study the cingulate cortex for the localization and role of the grasping action in humans during electrical stimulation of depth electrodes. Methods: All the patients (n = 23) with intractable focal epilepsy and a depth electrode stereotactically placed in the cingulate cortex, as part of their pre-surgical epilepsy evaluation from 2015 to 2017, were included. Cortical stimulation was performed and examined for grasping actions. Post-implantation volumetric T1 MRIs were co-registered to determine the exact electrode position. Results: Five patients (male: female 4:1; median age 31) exhibited contralateral grasping actions during electrical stimulation. All patients had electrodes implanted in the ventral bank of the right cingulate sulcus adjacent to the vertical anterior commissure (VAC) line. Stimulation of other electrodes in adjacent regions did not elicit grasping. Conclusion: Grasping action elicited from a localized region in the mid-cingulate cortex (MCC) directly supports the concept of the cingulate cortex being crucially involved in the grasping network. This opens an opportunity to explore this region with deep brain stimulation as a motor neuromodulation target for treatment in specific movement disorders or neurorehabilitation.

Driving restrictions following deep brain stimulation surgery.

BACKGROUND: There are currently no Australian guidelines to assist clinicians performing deep brain stimulation (DBS) procedures in setting postoperative driving restrictions. PURPOSE: We aimed to provide recommendations for post-DBS driving restrictions to guide practice in Australia. METHODS: A review of current Australian and international driving guidelines, literature regarding the adverse effects of DBS and literature regarding the long-term effect of neurostimulation on driving was conducted using Elton B Stephens Company discovery service-linked databases. Australian neurologists and neurosurgeons who perform DBS were surveyed to gain insight into existing practice. RESULTS: No guidance on driving restrictions following DBS surgery was found, either in existing driving guidelines or in the literature. There was a wide difference seen in the rates of reported adverse effects from DBS surgery. The most serious adverse events (haemorrhage, seizure and neurological dysfunction) were uncommon. Longer term, there does not appear to be any adverse effect of DBS on driving ability. Survey of Australian practitioners revealed a universal acceptance of the need for and use of driving restrictions after DBS but significant heterogeneity in how return to driving is managed. CONCLUSION: We propose a 6-week driving restriction for private licences and 6-month driving restriction for commercial licences in uncomplicated DBS. We also highlight some of the potential pitfalls and pearls to assist clinicians to modify these recommendations where needed. Ultimately, we hope this will stimulate further examination of this issue in research and by regulatory bodies to provide more robust direction for practitioners performing DBS implantation.

Levodopa/dopa decarboxylase inhibitor associated microscopic colitis: An under-recognized drug reaction.

BACKGROUND: Microscopic colitis is a form of inflammatory bowel disease characterized by profuse non-bloody watery diarrhea. Macroscopic abnormality is not present on colonoscopy, and it requires biopsy for diagnosis. Few cases have been attributed to levodopa/dopa-decarboxylase inhibitor therapy. METHOD: A retrospective cohort study of 21 patients on levodopa/benserazide and one patient on levodopa-carbidopa intestinal gel with clinically suspected or biopsy proven microscopic colitis. RESULTS: All 21 patients on oral levodopa/benserazide had resolution of diarrhea with cessation of the medication. Four patients discontinued levodopa permanently. Two were rechallenged with levodopa/benserazide without symptom recurrence. One patient on oral levodopa/carbidopa developed diarrhea only with intermittent dispersible levodopa/benserazide. 14 were switched to levodopa/carbidopa with resolution of diarrhea in 9 but symptom recurrence in 5. One patient on oral levodopa/benserazide developed profuse diarrhea when switched to levodopa-carbidopa intestinal gel. Of 7/22 patients who had colonoscopy and biopsy, 5 had histopathological proven microscopic colitis. CONCLUSION: levodopa/dopa-decarboxylase inhibitor induced microscopic colitis may be more common than previously suspected, with the potential to affect treatment compliance and therapeutic options.

Rest tremor correlates with reduced contralateral striatal dopamine transporter binding in Parkinson's disease.

INTRODUCTION: In vivo dopamine transporter imaging is a useful tool for distinguishing nigrostriatal pathologies (e.g. Parkinson's disease) from other causes of tremor. However, while many of the motoric features of Parkinson's disease (e.g. bradykinesia, rigidity, hypomimia) correlate well with reduced striatal dopamine transporter binding, the same relationship has not been demonstrated for tremor. We investigated the relationship between striatal dopamine transporter binding and quantitative measures of tremor. METHODS: 23 participants with Parkinson's disease underwent standardised clinical assessment including structured, videotaped clinical examination, tremor neurophysiology study of both upper limbs using accelerometry and surface EMG, and Technitium-99 m TRODAT-1 brain SPECT imaging. Normalised striatal uptake values were calculated. Tremor EMG and accelerometry time series were processed with Fourier transformation to identify peak tremor power within a window of 3-10Hz and to calculate the tremor stability index (TSI). RESULTS: Spearman correlation analyses revealed an association between tremor power and contralaterally reduced striatal uptake in a number of recording conditions. This association was strongest for rest tremor, followed by postural tremor, with the weakest association observed for kinetic tremor. Lower TSI was also associated with lower contralateral striatal uptake in a number of rest and postural conditions. CONCLUSION: These data suggest a relationship between Parkinsonian rest tremor and contralateral reduction in striatal dopamine binding. Use of quantitative neurophysiology techniques may allow the demonstration of clinico-pathophysiological relationships in tremor that have remained occult to previous studies.

A survey of falls in people with dystonia.

OBJECTIVE: Dystonia is a chronic and sometimes progressive neurological disorder causing abnormalities in movement and function. We conducted a preliminary survey to investigate whether people with dystonia experience falls and to identify contributing factors to falls in this population. METHODS: An online survey of people with dystonia was conducted in November 2015. Respondents were asked to complete demographic information, three questionnaires (the Falls Self-Efficacy Scale International [FES-I], the Activities-based Balance Confidence Scale [ABC] and the Functional Disability Questionnaire [FDQ]), and to report any falls sustained during the previous 6 months. RESULTS: Thirty-nine percent of the 122 respondents reported falling in the previous 6 months and 65% of fallers were diagnosed with dystonia not affecting the lower limbs. Fallers reported lower falls self-efficacy and balance confidence with higher functional disability. Both falling scales correlated with self-reported functional disability. Linear regression analysis for falls prediction revealed the variables FES-I and FDQ accounted for almost 30% of the falls in this dystonia population. CONCLUSION: This survey indicates that fear of falling and balance confidence are impaired in people with dystonia, possibly impacting on function and falls. Further investigation into balance, function and falls in this population is required.

Cost-Effectiveness of IncobotulinumtoxinA in the Treatment of Sialorrhea in Patients with Various Neurological Conditions.

INTRODUCTION: Sialorrhea is a common and debilitating symptom associated with neurological conditions, which can result in considerable physical and psychosocial complications. In Australia, management options are limited and further impeded by the lack of approved treatments. Whilst there is emerging evidence for the efficacy and tolerability of botulinum toxin (BoNT) for the treatment of sialorrhea in patients with neurological conditions, the cost-effectiveness of the treatment is yet to be established. OBJECTIVES: To evaluate the cost-effectiveness of incobotulinumtoxinA for the treatment of chronic troublesome sialorrhea caused by various neurological conditions from the Australian healthcare perspective. METHODS: A Markov state transition model was developed to perform a cost-utility analysis comparing incobotulinumtoxinA with standard of care (SoC). The model consisted of a hypothetical cohort of patients transiting between three severity-based health states, defined according to the Drooling Severity and Frequency Scale (DSFS), in 16-weekly cycles over 5 years. All clinical and utility inputs were sourced from a single placebo-controlled randomised clinical trial. Only direct healthcare costs were considered, and potential indirect costs such as carer's time and lost productivity were ignored. The primary outcome measure was the incremental cost per quality-adjusted life-year (QALY). Univariate and probabilistic sensitivity analyses were conducted. RESULTS: The model demonstrated that proportionally more patients spent time in less severe sialorrhea health states in the incobotulinumtoxinA arm. For example, over the 5-year period, patients receiving incobotulinumtoxinA were estimated to spend 1.6 years with minimal or no sialorrhea, while no patients achieved this level of improvement under SoC. IncobotulinumtoxinA was shown to have an incremental cost per QALY gained of A$23,445 when compared with SoC. CONCLUSIONS: The quality of life (QoL) of patients with sialorrhea caused by neurological conditions was considerably compromised. IncobotulinumtoxinA was shown to successfully alleviate sialorrhea and it was demonstrated to be a cost-effective intervention when compared with SoC alone.

Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes.

INTRODUCTION: Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. METHODS: WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. RESULTS: A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). CONCLUSION: A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases.

Hitting the brakes: pathological subthalamic nucleus activity in Parkinson's disease gait freezing.

Gait freezing is a complex and devastating paroxysmal motor arrest commonly suffered in Parkinson's disease that causes significant impairment to mobility, commonly resulting in falls and subsequent injury. The neurobiological basis of gait freezing in Parkinson's disease is poorly understood and thus, currently available therapies are partially effective at best. We used a validated virtual reality gait paradigm to elicit freezing behaviour intraoperatively in eight patients undergoing subthalamic nucleus deep brain stimulation surgery while microelectrode recordings were obtained. This allowed us to directly test the hypothesis that increases in pathological multi-unit activity in the subthalamic nucleus are associated with freezing onset in real time, manifest as dysfunctional firing of lower limb muscles typical of freezing that were detected by EMG. We present evidence that freezing is related to transient increases in pathological subthalamic nucleus activity. We performed time-frequency analysis to characterize the oscillatory dynamics of subthalamic nucleus activity coincident with freezing onset, demonstrating an increase in pathological beta and theta rhythms that are followed by a temporal chain of activity culminating in characteristically abnormal lower limb muscle firing detected by EMG. Finally, we interrogate the potential clinical utility of our findings by contrasting the subthalamic nucleus activity signature during pathological freezing against purposeful stopping. These results advance our understanding of the neurobiological basis of gait freezing in Parkinson's disease, highlighting the role of the subthalamic nucleus and emergent synchronous activity in basal ganglia circuits in driving non-purposeful motor arrests in individuals with Parkinson's disease. Pathological subthalamic nucleus activity identified in association with freezing is discernible from that of volitional stopping, paving the way towards more effective therapeutics such as adaptive closed-loop deep brain stimulation protocols.