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Abstract Background The nematode C. briggsae serves as a useful model organism for comparative analysis of developmental and behavioral processes. The amenability of C. briggsae to genetic manipulations and the availability of its genome sequence have prompted researchers to study evolutionary changes in gene function and signaling pathways. These studies rely on the availability of forward genetic tools such as mutants and mapping markers. Results We have computationally identified more than 30,000 polymorphisms (SNPs and indels) in C. briggsae strains AF16 and HK104. These include 1,363 SNPs that change restriction enzyme recognition sites (snip-SNPs) and 638 indels that range between 7 bp and 2 kb. We established bulk segregant and single animal-based PCR assay conditions and used these to test 107 polymorphisms. A total of 75 polymorphisms, consisting of 14 snip-SNPs and 61 indels, were experimentally confirmed with an overall success rate of 83%. The utility of polymorphisms in genetic studies was demonstrated by successful mapping of 12 mutations, including 5 that were localized to sub-chromosomal regions. Our mapping experiments have also revealed one case of a misassembled contig on chromosome 3. Conclusions We report a comprehensive set of polymorphisms in C. briggsae wild-type strains and demonstrate their use in mapping mutations. We also show that molecular markers can be useful tools to improve the C. briggsae genome sequence assembly. Our polymorphism resource promises to accelerate genetic and functional studies of C. briggsae genes.

Determining the genetic contributions to Parkinson's disease (PD) across diverse ancestries is a high priority as this work can guide therapeutic development in a global setting. The genetics of PD spans the etiological risk spectrum, from rare, highly deleterious variants linked to monogenic forms with Mendelian patterns of inheritance, to common variation involved in sporadic disease. A major limitation in PD genomics research is lack of racial and ethnic diversity. Enrollment disparities have detrimental consequences on the generalizability of results and exacerbate existing inequities in care. The Black and African American Connections to Parkinson's Disease (BLAAC PD) study is part of the Global Parkinson's Genetics Program, supported by the Aligning Science Across Parkinson's initiative. The goal of the study is to investigate the genetic architecture underlying PD risk and progression in the Black and/or African American populations. This cross-sectional multicenter study in the United States has a recruitment target of up to 2,000 individuals with PD and up to 2,000 controls, all of Black and/or African American ancestry. The study design incorporates several strategies to reduce barriers to research participation. The multifaceted recruitment strategy aims to involve individuals with and without PD in various settings, emphasizing community outreach and engagement. The BLAAC PD study is an important first step toward informing understanding of the genetics of PD in a more diverse population., (© 2024. The Author(s).)

Migraine has a relevant impact on pediatric health. Non-pharmacological modalities for its management are urgently needed. This study assessed the safety, feasibility, acceptance, and efficacy of repetitive neuromuscular magnetic stimulation (rNMS) in pediatric migraine. A total of 13 patients with migraine, ≥6 headache days during baseline, and ≥1 myofascial trigger point in the upper trapezius muscles (UTM) received six rNMS sessions within 3 weeks. Headache frequency, intensity, and medication intake were monitored using headache calendars; headache-related impairment and quality of life were measured using PedMIDAS and KINDL questionnaires. Muscular involvement was assessed using pressure pain thresholds (PPT). Adherence yielded 100%. In 82% of all rNMS sessions, no side effects occurred. All participants would recommend rNMS and would repeat it. Headache frequency, medication intake, and PedMIDAS scores decreased from baseline to follow-up (FU), trending towards statistical significance ( p = 0.089; p = 0.081, p = 0.055). A total of 7 patients were classified as responders, with a ≥25% relative reduction in headache frequency. PPT above the UTM significantly increased from pre- to post-assessment, which sustained until FU ( p = 0.015 and 0.026, respectively). rNMS was safe, feasible, well-accepted, and beneficial on the muscular level. The potential to reduce headache-related symptoms together with PPT changes of the targeted UTM may underscore the interplay of peripheral and central mechanisms conceptualized within the trigemino-cervical complex.

Repetitive neuromuscular magnetic stimulation (rNMS) for pediatric headache disorders is feasible, safe, and alleviates headache symptoms. This study assesses muscular effects and factors affecting response to rNMS. A retrospective chart review included children with headaches receiving six rNMS sessions targeting the upper trapezius muscles. Pressure pain thresholds (PPT) were measured before and after rNMS, and at 3-month follow-up (FU). Mean headache frequency, duration, and intensity within the last 3 months were documented. In 20 patients (14.1 ± 2.7 years), PPT significantly increased from pre- to post-treatment (p < 0.001) sustaining until FU. PPT changes significantly differed between primary headache and post-traumatic headache (PTH) (p = 0.019−0.026). Change in headache frequency was significantly higher in patients with than without neck pain (p = 0.032). A total of 60% of patients with neck pain responded to rNMS (≥25%), while 20% of patients without neck pain responded (p = 0.048). 60% of patients receiving rNMS twice a week were responders, while 33% of patients receiving rNMS less or more frequently responded to treatment, respectively. Alleviation of muscular hyperalgesia was demonstrated sustaining for 3 months, which was emphasized in PTH. The rNMS sessions may positively modulate headache symptoms regardless of headache diagnosis. Patients with neck pain profit explicitly well. Two rNMS sessions per week led to the highest reduction in headache frequency.

Introduction: Repetitive neuromuscular magnetic stimulation (rNMS) was previously applied in adult patients with episodic migraine, showing beneficial effects on headache characteristics, high safety, and convincing satisfaction. This study aims to assess rNMS as a personalized intervention in pediatric headache., Methods: Retrospective chart review including patients with migraine, TTH, mixed type headache, or PTH, who had received at least one test rNMS session targeting the upper trapezius muscles (UTM)., Results: 33 patients (13.9 ± 2.5 years; 61% females) were included in the primary analysis, resulting in a total of 182 rNMS sessions. 43 adverse events were documented for 40 of those sessions (22%). Most common side effects were tingling (32.6%), muscle sore (25.5%), shoulder (9.3%) and back pain (9.3%). Secondly, in patients (n = 20) undergoing the intervention, headache frequency (p = 0.017) and minimum and maximum intensities (p = 0.017; p = 0.023) significantly decreased from baseline to 3-month after intervention. 11 patients (44%) were classified as ≥25% responders, with 7 patients (28%) experiencing a ≥75% reduction of headache days. After 73% of interventions, patients reported rNMS helped very well or well. A majority of patients would repeat (88.5%) and recommend rNMS (96.2%) to other patients., Conclusion: rNMS seems to meet the criteria of safety, feasibility, and acceptance among children and adolescents with three age-typical headache disorders. A significant reduction in headache frequency and intensity during a 3 months follow-up was documented. Larger, prospective, randomized, sham-controlled studies are urgently needed to confirm if rNMS may become a new valuable non-invasive, non-pharmacological treatment option for pediatric headache disorders., (© 2022 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Despite a growing number of ion channel genes implicated in hereditary ataxia, it remains unclear how ion channel mutations lead to loss-of-function or death of cerebellar neurons. Mutations in the gene KCNMA1 , encoding the α-subunit of the BK channel have emerged as responsible for a variety of neurological phenotypes. We describe a mutation (BK G354S ) in KCNMA1 , in a child with congenital and progressive cerebellar ataxia with cognitive impairment. The mutation in the BK channel selectivity filter dramatically reduced single-channel conductance and ion selectivity. The BK G354S channel trafficked normally to plasma, nuclear, and mitochondrial membranes, but caused reduced neurite outgrowth, cell viability, and mitochondrial content. Small interfering RNA (siRNA) knockdown of endogenous BK channels had similar effects. The BK activator, NS1619, rescued BK G354S cells but not siRNA-treated cells, by selectively blocking the mutant channels. When expressed in cerebellum via adenoassociated virus (AAV) viral transfection in mice, the mutant BK G354S channel, but not the BK WT channel, caused progressive impairment of several gait parameters consistent with cerebellar dysfunction from 40- to 80-d-old mice. Finally, treatment of the patient with chlorzoxazone, a BK/SK channel activator, partially improved motor function, but ataxia continued to progress. These studies indicate that a loss-of-function BK channel mutation causes ataxia and acts by reducing mitochondrial and subsequently cellular viability., Competing Interests: The authors declare no competing interest.

Background: The nematode C. briggsae serves as a useful model organism for comparative analysis of developmental and behavioral processes. The amenability of C. briggsae to genetic manipulations and the availability of its genome sequence have prompted researchers to study evolutionary changes in gene function and signaling pathways. These studies rely on the availability of forward genetic tools such as mutants and mapping markers., Results: We have computationally identified more than 30,000 polymorphisms (SNPs and indels) in C. briggsae strains AF16 and HK104. These include 1,363 SNPs that change restriction enzyme recognition sites (snip-SNPs) and 638 indels that range between 7 bp and 2 kb. We established bulk segregant and single animal-based PCR assay conditions and used these to test 107 polymorphisms. A total of 75 polymorphisms, consisting of 14 snip-SNPs and 61 indels, were experimentally confirmed with an overall success rate of 83%. The utility of polymorphisms in genetic studies was demonstrated by successful mapping of 12 mutations, including 5 that were localized to sub-chromosomal regions. Our mapping experiments have also revealed one case of a misassembled contig on chromosome 3., Conclusions: We report a comprehensive set of polymorphisms in C. briggsae wild-type strains and demonstrate their use in mapping mutations. We also show that molecular markers can be useful tools to improve the C. briggsae genome sequence assembly. Our polymorphism resource promises to accelerate genetic and functional studies of C. briggsae genes.