Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Quantitative Assessment of Response to Long‐Term Treatment with Intravenous Immunoglobulin in Patients with Stiff Person Syndrome

BACKGROUND: Stiff person syndrome (SPS) is an autoimmune condition involving antibodies against several components of the inhibitory synapse in the spinal cord, with glutamic acid decarboxylase antibodies being the predominant immune marker. SPS affects approximately 1 patient per million population per year. The effect of intravenous immunoglobulin (IVIG) has been established, but studies on the long‐term efficacy of regular IVIG are limited. OBJECTIVES: To review clinical details and long‐term treatment response using a patient‐reported questionnaire in SPS and related syndromes. METHODS: Patients were identified from a tertiary neuroimmunology clinic based on classical clinical symptoms, autoimmune profiles, and neurophysiological changes (Dalakas criteria). They were followed up after treatment to assess the response to IVIG. RESULTS: A total of 23 patients fulfilled the selection criteria. Patients' demographic profiles and clinical presentations were akin to that reported in literature. There was significant improvement in the functional ability (assessed by the modified Rankin scale [mRS]) and quality of life (QoL) following treatment with IVIG within 4 to 10 weeks (pre‐mRS vs. post‐mRS, P < 0.0001; pre‐QoL vs. post‐QoL, P = 0.0003) and sustained after 5 years of treatment (pre‐mRS vs. present mRS, P = 0.0003; pre‐QoL vs. present QoL, P = 0.0002). CONCLUSIONS: This article describes one of the largest single‐center experiences of 23 patients with SPS and related syndromes and is the first to establish the long‐term efficacy of regular IVIG using a patient‐reported scoring system (Birmingham Response to Immunomodulatory Therapy [BRIT]). Consistent improvement in QoL and functional scores were seen over nearly 5 years after regular use of IVIG. It is recommended to use BRIT scores to assess the initial response as well as to monitor continued improvement to immunomodulation in SPS

Deficits in social behavioral tests in a mouse model of alternating hemiplegia of childhood

Social behavioral deficits have been observed in patients diagnosed with alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism and CAPOS syndrome, in which specific missense mutations in ATP1A3, encoding the Na+, K+-ATPase α3 subunit, have been identified. To test the hypothesis that social behavioral deficits represent part of the phenotype of Na+, K+-ATPase α3 mutations, we assessed the social behavior of the Myshkin mouse model of AHC, which has an I810N mutation identical to that found in an AHC patient with co-morbid autism. Myshkin mice displayed deficits in three tests of social behavior: nest building, pup retrieval and the three-chamber social approach test. Chronic treatment with the mood stabilizer lithium enhanced nest building in wild-type but not Myshkin mice. In light of previous studies revealing a broad profile of neurobehavioral deficits in the Myshkin model – consistent with the complex clinical profile of AHC – our results suggest that Na+, K+-ATPase α3 dysfunction has a deleterious, but nonspecific, effect on social behavior. By better defining the behavioral profile of Myshkin mice, we identify additional ATP1A3-related symptoms for which the Myshkin model could be used as a tool to advance understanding of the underlying neural mechanisms and develop novel therapeutic strategies