Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design.

BACKGROUND: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3 -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

LIVECHART Patient-Reported Outcome Tool for Botulinum Toxin Treatment in Cervical Dystonia.

BACKGROUND: Many tools used for recording the response to botulinum toxin treatment are disease-specific, observer-based and cumbersome to implement in service settings, especially where clinics treat a variety of disorders. Physicians, clinics, researchers, and patients themselves could benefit from a practical and generic patient-reported outcome tool. The Liverpool botulinum toxin effects chart (LIVECHART) is a patient-administered questionnaire developed and used informally over 25 years in a major UK botulinum toxin treatment clinic. In preparation for more formal validation studies, this cross-sectional study aimed to understand how well LIVECHART captures the effects of botulinum toxin treatment, using patients with cervical dystonia as exemplars. METHODS: LIVECHART questionnaires were completed by 90 patients with cervical dystonia who had each experienced at least three previous botulinum toxin injection cycles with completed LIVECHARTs. RESULTS: There were significant positive correlations between Likert scores (major deterioration-major benefit) for botulinum toxin treatment effects, and measures derived from weekly visual analog scale (VAS) scores (0-100), including (1) baseline to peak effect, (2) Area Under the benefit Curve (AUC) of current cycle, (3) peak effect duration, (4) duration of acceptable benefit, (5) time back to baseline. The AUC of the current cycle was positively correlated with (1) VAS change baseline to peak effect, and (2) week worn off completely. CONCLUSIONS: We conclude that LIVECHART has high internal consistency and reliability. It adequately reflects amplitude, duration and overall benefit of botulinum toxin treatment, and is worth further formal evaluation to determine its validity and reliability.

Botulinum neurotoxin injections for muscle-based (dystonia and spasticity) and non-muscle-based (neuropathic pain) pain disorders: a meta-analytic study.

Apart from the known efficacy of Botulinum Neurotoxin Type A (BoNT/A) in hyperactive striated and smooth muscles, different pain states have become potential targets of toxin effects. This present study determined the comparative toxin effectiveness in pain reduction among those patients injected with BoNT/A in muscle-based and in non-muscle-based conditions. Randomized controlled trials (RCTs) on the effect of BoNT/A on selected pain conditions were included. The conditions were spasticity and dystonia for muscle-based pain. For non-muscle-based pain, conditions included were painful diabetic neuropathy (PDN), post-herpetic neuralgia (PHN), trigeminal neuralgia (TN), complex regional pain syndrome (CRPS), and spinal cord injury (SCI). In view of possibly differing pathophysiology, myofascial pain, temporomandibular joint (TMJ), other joint or tendon pains, cervicogenic and lumbar pains, migraine and visceral pain syndromes were excluded. Standardized mean difference was used as the effect measure and computed with STATA. 25 RCTs were analyzed. Pooled estimates showed significantly lower pain score in the Treatment group (z = 5.23, p < 0.01, 95% CI = - 0.75, - 0.34). Subgroup analyses showed that BoNT/A significantly reduced both muscle-based (z = 3.78, p < 0.01, 95% CI = - 0.72, - 0.23) and non-muscle-based (z = 3.37, p = 0.001, 95% CI = - 1.00, - 0.27) pain. Meta-regression using four covariates namely dosage, route, frequency and duration was done which revealed that dosage significantly affects standardized mean differences, while the other three covariates were insignificant. The joint F-test was found to be insignificant (p value = 0.1182). The application of the model with these covariates does not significantly explain the derived heterogeneity of standardized mean differences. In conclusion, BoNT/A can be effectively used in muscle-based and non-muscle-based pain disorders. We detected no difference between the presence and magnitude of pain relief favoring muscle-based compared to non-muscle-based pain. Thus, we cannot say whether or not there might be independent mechanisms of toxin-induced pain relief for pain generated from either muscle or nerve hyperactivity.

Delayed onset of severe chronic pain in CASPR2 autoantibody-associated Morvan syndrome in a former UK swine abattoir worker.

INTRODUCTION: Autoantibody-mediated autoimmunity directed against targets within the voltage-gated potassium channel complex (VGKCC autoantibodies) has been implicated in causing neuropathic pain. METHODS: We report the case of a 76-year-old, United Kingdom male who was diagnosed with contactin-associated protein 2 (CASPR2) autoantibody-associated Morvan syndrome, a rare neurological condition. RESULTS: He had previously worked in a swine abattoir; exposure to aerosol within swine abattoirs has been reported to elicit an immune response resulting in the production of these autoantibodies; however, unusually, his manifestations emerged with several years' latency. Although this patient's Morvan syndrome-associated seizures were well-controlled with antiepileptic drugs, his neuropathic pain and painful muscle fasciculations did not respond to pharmacological interventions. He refused pain management program treatment, but high-dose immunoglobulin treatment or treatment with rituximab, reported to be sometimes effective in this group, was not initiated because of concerns regarding his general frailty. DISCUSSION AND CONCLUSION: This case highlights issues around the identification and treatment of rare patients with chronic pain who have voltage-gated potassium channel complex autoantibodies; it also emphasizes the possibility that former swine abattoir workers might be at risk of developing neuropathic pain even years after their vocational exposure.

Predictive analysis for identifying potentially undiagnosed post-stroke spasticity patients in United Kingdom.

PURPOSE OF THE RESEARCH: Spasticity is one of the well-recognized complications of stroke which may give rise to pain and limit patients' ability to perform daily activities. The predisposing factors and direct effects of post-stroke spasticity also involve high management costs in terms of healthcare resources, and case-control designs are required for establishing such differences. Using 'The Health Improvement Network' (THIN) database, such a study would not provide reliable estimates since the prevalence of post-stroke spasticity was found to be 2%, substantially below the most conservative previously reported estimates. The objective of this study was to use predictive analysis techniques to determine if there are a substantial number of potentially under-recorded patients with post-stroke spasticity. METHODS: This study used retrospective data from adult patients with a diagnostic code for stroke between 2007 and 2011 registered in THIN. Two algorithm approaches were developed and compared, a statistically validated data-trained algorithm and a clinician-trained algorithm. RESULTS: A data-trained algorithm using Random Forest showed better prediction performance than clinician-trained algorithm, with higher sensitivity and only marginally lower specificity. Overall accuracy was 75% and 72%, respectively. The data-trained algorithm predicted an additional 3912 records consistent with patients developing spasticity in the 12months following a stroke. CONCLUSIONS: Using machine learning techniques, additional unrecorded post-stroke spasticity patients were identified, increasing the condition's prevalence in THIN from 2% to 13%. This work shows the potential for under-reporting of PSS in primary care data, and provides a method for improved identification of cases and control records for future studies.