Lower extremity hypermobility, but not core muscle endurance influences balance in female collegiate dancers

Background Dance is a physically demanding activity, with almost 70% of all injuries in dancers occurring in the lower extremity (LE). Prior researchers report that muscle function (e.g. muscle endurance) and anatomical factors (e.g. hypermobility) affect physical performance (e.g. balance) and can subsequently influence LE injury risk. Specifically, lesser core muscle endurance, balance deficits, and greater hypermobility are related to increased LE injury risk. However, the potentials interrelationships among these factors in dancers remain unclear. Purpose The purposes of this study were to examine the relationships among core muscle endurance, balance, and LE hypermobility, and determine the relative contributions of core muscle endurance and LE hypermobility as predictors of balance in female collegiate dancers. Study Design Cross-sectional Methods Core muscle endurance was evaluated using the combined average anterior, left, and right lateral plank test time scores(s). LE hypermobility was measured using the LE-specific Beighton hypermobility measure, defining hypermobility if both legs had greater than 10 ° knee hyperextension. Balance was measured via the composite anterior, posterolateral, and posteromedial Star Excursion Balance Test (SEBT) reach distances (normalized to leg length) in 15 female healthy collegiate dancers (18.3 + 0.5yrs, 165.5 + 6.9cm, 63.7 + 12.1kg). Point-biserial-correlation-coefficients examined relationships and a linear regression examined whether core endurance and hypermobility predicted balance (p<.05). Results LE hypermobility (Yes; n = 3, No; n = 12) and balance (87.2 + 8.3% leg length) were positively correlated r(14)=.67, (p=.01). However, core endurance (103.9 + 50.6 s) and balance were not correlated r(14)=.32, (p=.26). LE hypermobility status predicted 36.9% of the variance in balance scores (p=.01). Conclusion LE hypermobility, but not core muscle endurance may be related to balance in female collegiate dancers. While LE hypermobility status influenced balance in the female collegiate dancers, how this LE hypermobility status affects their longitudinal injury risk as their careers progress needs further study. Overall, the current findings suggest that rather than using isolated core endurance-centric training, clinicians may encourage dancers to use training programs that incorporate multiple muscles - in order to improve their balance, and possibly reduce their LE injury risk

Risdiplam in Spinal Muscular Atrophy: Safety Profile and Use Through The Early Access to Medicine Scheme for the Paediatric Cohort in Great Britain

BACKGROUND: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by mutations in Survival motor neuron 1 (SMN1) gene, leading to reduction in survival motor neuron protein (SMN), key for motor neuron survival and function in the brainstem and spinal cord. Risdiplam is an orally administered SMN2-splicing modifier which increases production of functional SMN protein. Risdiplam was offered in the UK under early access to medicines scheme (EAMS) to SMA type 1 and 2 patients aged 2 months and older, not suitable for authorised treatments from September 2020 to December 2021. OBJECTIVE: To describe the largest paediatric European real-world set of data on patients' characteristics and short-term safety for risdiplam in Great Britain through EAMS. METHODS: We collated data from SMA REACH UK a national clinical and research network for all patients enrolled onto EAMS and assessed all submitted adverse events. RESULTS: Of the 92 patients; 78% were Type 2 SMA, mean age 10.9 years, range 0-17 years. 56 were treatment naïve, 33 previously treated; of these 25 had received nusinersen, 3 previous treatment unknown. Sixty adverse events (AEs) were reported occurring in 34 patients. The commonest were respiratory tract infections and gastrointestinal disturbance. Four life-threatening events were reported with 2 deaths and permanent cessation of risdiplam in 3 patients.Overall, 38/60 AEs were considered unrelated to risdiplam, 10/60 related to risdiplam and for 12/60 causality not specified. CONCLUSIONS: This study found a safety profile similar to clinical trials with no new safety concerns identified. With the restricted eligibility of onasemnogene abeparvovec and complications of nusinersen administration, EAMS allowed access or continued treatment to naïve patients or patients no longer suitable for approved medications. Collection of longitudinal data for this complex population is needed, to provide greater insights into risdiplam's role in addressing patients' needs into the future

Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy

Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics

Clinical and molecular characterisation of KCNT1-related severe early onset epilepsy

Objective: To characterise the phenotypic spectrum, molecular genetic findings and functional consequences of pathogenic variants in early onset KCNT1-epilepsy. Methods: We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple gene next generation sequencing panel and whole exome sequencing. Additional patients with non-EIMFS early onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. Where possible, we performed homology modelling to predict putative effects of variants on protein structure and function. We undertook electrophysiological assessment of mutant KCNT1 channels in a Xenopus oocyte model system. Results: We identified pathogenic variants in KCNT1 in 12 patients, four of which are novel. Most variants occurred de novo. Ten had a clinical diagnosis of EIMFS and the other two presented with early onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in one. Computational modelling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain-of-function, with significantly increased channel amplitude and variable blockade by quinidine. Conclusions: Gain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, though clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy

Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy.

Funder: Howard Hughes Medical InstituteMissense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics

Specific heterozygous frameshift variants hnRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy

RNA-binding proteins (RBPs) are essential for post-transcriptional regulation and processing of RNAs. Pathogenic missense variants in RBPs underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, inclusion body myopathy, distal myopathy, and Paget’s disease of the bone. Here, we present ten independent families with a severe, progressive, early-onset muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD), caused by heterozygous frameshift variants in the prion-like domain of hnRNPA2B1. We found that in contrast with the previously reported missense variants, the frameshift hnRNPA2B1 variants do not promote, but rather decelerate the fibrillization of the protein. Importantly, the frameshift variants harbor altered nuclear-localization sequences and exhibit reduced affinity for the nuclear-import receptor, Karyopherin-b2, which promotes their cytoplasmic accumulation in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with hnRNPA2B1 to include a severe, early-onset disease reminiscent of OPMD, caused by a distinct class of frameshift variants that alter its nucleocytoplasmic transport dynamics

Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy

none58: Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics.noneKim, Hong Joo; Mohassel, Payam; Donkervoort, Sandra; Guo, Lin; O'Donovan, Kevin; Coughlin, Maura; Lornage, Xaviere; Foulds, Nicola; Hammans, Simon R; Foley, A Reghan; Fare, Charlotte M; Ford, Alice F; Ogasawara, Masashi; Sato, Aki; Iida, Aritoshi; Munot, Pinki; Ambegaonkar, Gautam; Phadke, Rahul; O'Donovan, Dominic G; Buchert, Rebecca; Grimmel, Mona; Töpf, Ana; Zaharieva, Irina T; Brady, Lauren; Hu, Ying; Lloyd, Thomas E; Klein, Andrea; Steinlin, Maja; Kuster, Alice; Mercier, Sandra; Marcorelles, Pascale; Péréon, Yann; Fleurence, Emmanuelle; Manzur, Adnan; Ennis, Sarah; Upstill-Goddard, Rosanna; Bello, Luca; Bertolin, Cinzia; Pegoraro, Elena; Salviati, Leonardo; French, Courtney E; Shatillo, Andriy; Raymond, F Lucy; Haack, Tobias B; Quijano-Roy, Susana; Böhm, Johann; Nelson, Isabelle; Stojkovic, Tanya; Evangelista, Teresinha; Straub, Volker; Romero, Norma B; Laporte, Jocelyn; Muntoni, Francesco; Nishino, Ichizo; Tarnopolsky, Mark A; Shorter, James; Bönnemann, Carsten G; Taylor, J PaulKim, Hong Joo; Mohassel, Payam; Donkervoort, Sandra; Guo, Lin; O'Donovan, Kevin; Coughlin, Maura; Lornage, Xaviere; Foulds, Nicola; Hammans, Simon R; Foley, A Reghan; Fare, Charlotte M; Ford, Alice F; Ogasawara, Masashi; Sato, Aki; Iida, Aritoshi; Munot, Pinki; Ambegaonkar, Gautam; Phadke, Rahul; O'Donovan, Dominic G; Buchert, Rebecca; Grimmel, Mona; Töpf, Ana; Zaharieva, Irina T; Brady, Lauren; Hu, Ying; Lloyd, Thomas E; Klein, Andrea; Steinlin, Maja; Kuster, Alice; Mercier, Sandra; Marcorelles, Pascale; Péréon, Yann; Fleurence, Emmanuelle; Manzur, Adnan; Ennis, Sarah; Upstill-Goddard, Rosanna; Bello, Luca; Bertolin, Cinzia; Pegoraro, Elena; Salviati, Leonardo; French, Courtney E; Shatillo, Andriy; Raymond, F Lucy; Haack, Tobias B; Quijano-Roy, Susana; Böhm, Johann; Nelson, Isabelle; Stojkovic, Tanya; Evangelista, Teresinha; Straub, Volker; Romero, Norma B; Laporte, Jocelyn; Muntoni, Francesco; Nishino, Ichizo; Tarnopolsky, Mark A; Shorter, James; Bönnemann, Carsten G; Taylor, J Pau