Ovarioleukodystrophy Due to EIF2B Genes: Systematic Review and Case Report.

Leukodystrophies comprise a spectrum of genetic disorders affecting white matter (WM) formation in the central nervous system (CNS), of which vanishing white matter disease (VWMD) is one. VWMD presents with progressive neurological deterioration and a variety of manifestations. Ovarioleukodystrophy, a subtype of VWMD, exhibits a distinctive clinical profile encompassing both CNS WM alterations and ovarian dysfunction. Variants in genes of the eukaryotic translation initiation factor 2B (EIF2B) complex affect the full form and are implicated in VWMD, including ovarioleukodystrophy. This work aimed to systematically review all published cases of ovarioleukodystrophy associated with variants in the EIF2B1-5 gene complex based on the first case identified in a Mexican population. We performed a systematic review according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines of published cases of ovarioleukodystrophy associated with the EIF2B gene complex, including a newly identified case from Mexico. We identified 207 publications using PUBMED, SCOPUS, and PMC databases. One hundred fifty-one publications were eliminated due to duplicates, titles, abstracts, or other reasons, while 56 publications were revised, of which 29 were eliminated because they dealt with other genes or non-human research, and 27 reports were assessed for eligibility. Finally, 14 reports describing ovarian involvement, neuroimaging, and molecular variants were included. Our review identified 20 cases worldwide, with a median age of onset of 19 years. Clinical features included WM involvement, ovarian abnormalities, gait disturbances, epilepsy, cognitive and language impairment, and other neurological manifestations. Neuroimaging showed characteristic WM changes, highlighting the importance of MRI in diagnosis. Missense variants predominated among the identified genetic mutations, especially in the EIF2B4 and EIF2B5 genes. Ovarioleukodystrophy is an ultra-rare disorder with a wide range of clinical manifestations and ovarian changes. Gynecological evaluation is crucial in suspected cases of ovarioleukodystrophy, as ovarian manifestations may precede neurological symptoms. The role of MRI is crucial in the diagnostic approach to this entity. Continued collaborative efforts are essential to elucidate genotype-phenotype correlations, improve clinical management, and promote therapeutic advances for this rare disorder.

Factors Influencing Feeding Decisions in Children With Bronchiolitis on High-Flow Nasal Cannula.

BACKGROUND AND OBJECTIVES: High-flow nasal cannula (HFNC) is used in up to 50% of children admitted with bronchiolitis. Consensus recommendations for feeding these children have not been established, and there is variability in practice. We sought to identify factors influencing feeding decisions for general care patients admitted with bronchiolitis on HFNC from a national sample of interdisciplinary care team members. METHODS: In this qualitative study, we conducted semi-structured virtual interviews with care team members involved in making feeding decisions at 10 US hospitals from June 2022 to March 2023. Eligible participants included 1 nurse, respiratory therapist, speech language pathologist, and physician from each site. Interviews were audio-recorded, transcribed, and conducted until reaching sufficiency. Three researchers analyzed transcript data using content analysis guided by the Systems Engineering Initiative for Patient Safety 2.0 model. RESULTS: We interviewed 29 participants, including 19 nurses, respiratory therapists, and speech language pathologists and 10 physicians. Participants identified 11 factors influencing feeding decisions related to hospital work systems and processes outlined in the Systems Engineering Initiative for Patient Safety model, including people (child and parent characteristics, care team experience), tools and technology (guideline, protocol, ordersets), organization (institutional culture, education), environment (time of day, care location), task (interventions to optimize feeding), and process (clinical assessment, feeding trial, communication). CONCLUSIONS: Our findings suggest that feeding decisions are driven by factors related to the child, care team experience, institutional tools, and culture. These key factors may inform local improvement efforts to decrease variation in feeding children with bronchiolitis requiring HFNC.

Social Media Use, Emotional Investment, Self-Control Failure, and Addiction in Relation to Mental and Sleep Health in Hispanic University Emerging Adults.

The number of social media users has increased dramatically in recent years. Common correlates of social media use may be poor mental and sleep health which are pressing issues among emerging adults and Hispanic groups. This study investigated the relationships between five different forms of social media use and mental and sleep health in Hispanic university emerging adults. Hispanic university emerging adults (n = 358) completed a survey assessing sociodemographics, overall social media use frequency, nighttime in-bed social media use, social media addiction, social media self-control failure, emotional investment in social media, depression, anxiety, stress, and sleep quality. Findings demonstrated that social media addiction and social media self-control failure were positively associated with stress and poor sleep quality. Emotional investment in social media was positively associated with depression. Findings may suggest that Hispanic university emerging adults may use social media emotionally and problematically to cope with negative affect and poor sleep quality, or that negative affect and poor sleep quality stem from using social media emotionally and problematically. The clinical implications of these results are discussed. Prospective studies are warranted to assess temporality.

Antibacterial activity of gallic acid and methyl gallate against emerging non-fermenting bacilli.

Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia cenocepacia are considered emerging pathogens classified as a public health problem due to extensive antimicrobial resistance. Therefore, the discovery of new therapeutic strategies has become crucial. This study aimed to evaluate the antimicrobial activity of gallic acid and methyl gallate against non-fermenting bacteria. The study included five clinical isolates of Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia cenocepacia. The minimum inhibitory concentrations of gallic acid and methyl gallate were determined by the broth microdilution method. Growth curves, metabolic activity, and biofilm formation of each bacterial strain in the presence or absence of phenolic compounds were performed. Finally, the therapeutic efficacy of the compounds was evaluated using an in vivo model. Gallic acid and methyl gallate showed antibacterial activity against bacterial strains in a concentration range of 64 to 256 µg/mL, both compounds reduced bacterial growth and metabolic activity of the strains, even at subinhibitory concentrations. Only, methyl gallate exhibited activity to inhibit the formation of bacterial biofilms. Moreover, gallic acid and methyl gallate increased larval survival by up to 60% compared to 30% survival of untreated larvae in a bacterial infection model in Galleria mellonella. Our results highlight the potential of gallic acid and methyl gallate as therapeutic alternatives for infections by emerging non-fermentative bacteria.

Epilepsy in Duchenne and Becker muscular dystrophies.

OBJECTIVE: Duchenne and Becker muscular dystrophies (DMD and BMD) are dystrophinopathies caused by variants in DMD gene, resulting in reduced or absent dystrophin. These conditions, characterized by muscle weakness, also manifest central nervous system (CNS) comorbidities due to dystrophin expression in the CNS. Prior studies have indicated a higher prevalence of epilepsy in individuals with dystrophinopathy compared to the general population. Our research aimed to investigate epilepsy prevalence in dystrophinopathies and characterize associated electroencephalograms (EEGs) and seizures. METHODS: We reviewed 416 individuals with dystrophinopathy, followed up at three centers between 2010 and 2023, to investigate the lifetime epilepsy prevalence and characterize EEGs and seizures in those individuals diagnosed with epilepsy. Associations between epilepsy and type of dystrophinopathy, genotype, and cognitive involvement were studied. RESULTS: Our study revealed a higher epilepsy prevalence than the general population (1.4%; 95% confidence interval: 0.7-3.2%), but notably lower than previously reported in smaller dystrophinopathy cohorts. No significant differences were found in epilepsy prevalence between DMD and BMD or based on underlying genotypes. Cognitive impairment was not found to be linked to higher epilepsy rates. The most prevalent epilepsy types in dystrophinopathies resembled those observed in the broader pediatric population, with most individuals effectively controlled through monotherapy. INTERPRETATION: The actual epilepsy prevalence in dystrophinopathies may be markedly lower than previously estimated, possibly half or even less. Our study provides valuable insights into the epilepsy landscape in individuals with dystrophinopathy, impacting medical care, especially for those with concurrent epilepsy.

The relationships between fear of missing out and psychological and sociocultural factors in Latinx emerging adult college students.

OBJECTIVES: The proliferation of social media has resulted in negative consequences such as fear of missing out (FoMO), the anxious feelings one has when others are having rewarding experiences. Few studies have assessed FoMO in Latinx emerging adult college students, none utilizing the socioecological framework. This study assessed the relationships between FoMO and psychological and sociocultural risk and protective factors. METHOD: Latinx college students (n = 452; Mage = 19.97 years, SD = 1.89; 77.2% female) completed an online survey assessing demographics, FoMO, social media addiction, depression, anxiety, stress, Machiavellianism, narcissism, psychopathy, familism, and acculturation. Two multiple linear regressions assessed the associations between FoMO and psychological and sociocultural factors. RESULTS: Both regressions were statistically significant. First, FoMO was positively associated with social media addiction, depression, and Machiavellianism. Second, FoMO was positively associated with familial honor and negatively associated with familial interconnectedness and ethnic social relations. CONCLUSIONS: Associations between FoMO and psychological factors are consistent with past literature, yet they highlight the need for prospective studies to assess temporality. The fact that FoMO was related uniquely to familistic attitudes suggests the importance of family in FoMO perceptions and the need to assess these associations in a more nuanced manner. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Relative Age Effect Analysis in the History of the Ballon d'Or (1956-2023).

Ballon d'Or is the most important individual award in football, and is a significant measure of excellence. From our knowledge, this is the first study that explored the relative age effect (RAE) throughout the history of the Ballon d'Or. A total of 1899 football players nominated for the award from the first edition in 1956 to the most recent edition (2023) were analyzed. To assess the RAE, the birthdate distributions were categorized into four trimesters. The comparison involved correcting for the uniform distribution using chi-square analysis, with Cramer's V serving as a measure of effect size. Standardized residuals were computed to identify quarters that exhibited significant deviation from the expected values. Odds Ratio and 95% confidence intervals were used to identify discrepancies between trimesters. The results indicated a pronounced presence of an RAE at the global level. However, the longitudinal analysis revealed variations in the behavior of the RAE over time. In the initial decades, there is an overrepresentation of players born in the last months of the year. Subsequently, there is no discernible RAE. In the most recent decades, there has been a clear resurgence of RAE, with an overrepresentation of players born in the first quarters of the year.

Coherent Electron-Vibron Interactions in Surface-Enhanced Raman Scattering (SERS).

In this Letter we identify coherent electron-vibron interactions between near-resonant and nonresonant electronic levels that contribute beyond standard optomechanical models for off-resonant or resonance surface-enhanced Raman scattering (SERS). By developing an open-system quantum model using first molecular interaction principles, we show how the Raman interference of both resonant and nonresonant contributions can provide several orders of magnitude modifications of the SERS peaks with respect to former optomechanical models and over the fluorescence backgrounds. This cooperative optomechanical mechanism allows for generating an enhancement of nonclassical photon pair correlations between Stokes and anti-Stokes photons, which can be detected by photon-counting measurements. Our results demonstrate Raman enhancements and suppressions of coherent nature that significantly impact the standard estimations of the optomechanical contribution from SERS spectra and their quantum mechanical observable effects.

Increased Proteolytic Activity of Serratia marcescens Clinical Isolate HU1848 Is Associated with Higher eepR Expression.

Serratia marcescens is a global opportunistic pathogen. In vitro cytotoxicity of this bacterium is mainly related to metalloprotease serralysin (PrtS) activity. Proteolytic capability varies among the different isolates. Here, we characterized protease production and transcriptional regulators at 37°C of two S. marcescens isolates from bronchial expectorations, HU1848 and SmUNAM836. As a reference strain the insect pathogen S. marcescens Db10 was included. Zymography of supernatant cultures revealed a single (SmUNAM836) or double proteolytic zones (HU1848 and Db10). Mass spectrometry confirmed the identity of PrtS and the serralysin-like protease SlpB from supernatant samples. Elevated proteolytic activity and prtS expression were evidenced in the HU1848 strain through azocasein degradation and qRT-PCR, respectively. Evaluation of transcriptional regulators revealed higher eepR expression in HU1848, whereas cpxR and hexS transcriptional levels were similar between studied strains. Higher eepR expression in HU1848 was further confirmed through an in vivo transcriptional assay. Moreover, two putative CpxR binding motifs were identified within the eepR regulatory region. EMSA validated the interaction of CpxR with both motifs. The evaluation of eepR transcription in a cpxR deletion strain indicated that CpxR negatively regulates eepR. Sequence conservation suggests that regulation of eepR by CpxR is common along S. marcescens species. Overall, our data incorporates CpxR to the complex regulatory mechanisms governing eepR expression and associates the increased proteolytic activity of the HU1848 strain with higher eepR transcription. Based on the global impact of EepR in secondary metabolites production, our work contributes to understanding virulence factors variances across S. marcescens isolates.

SRF transcriptionally regulates the oligodendrocyte cytoskeleton during CNS myelination.

Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)-a transcription factor known to regulate expression of actin and actin regulators in other cell types-as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the mechanistic role of SRF in oligodendrocyte lineage cells. Here, we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in oligodendrocyte precursor cells and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Surprisingly, oligodendrocyte-restricted loss of SRF results in upregulation of gene signatures associated with aging and neurodegenerative diseases. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies an essential pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease.

Effectiveness of a Peer Mentoring on University Dropout and Academic Performance / La eficacia de un programa de mentoría en el abandono y el rendimiento académico

Mentoring programs have been proposed to reduce dropout and increase academic performance. We analyzed the effect of peer mentoring on university dropout and academic performance in the context of Spain. We applied a quasi-experimental posttest-only control group design with 3,774 students (mentees, n = 1,887; control, n = 1,887). Mentees had participated in a peer mentoring program. We apply the student’s t-test, Cohen’s d, phi statistic, and chi-square statistic. Mentees exhibited lower dropout than controls and showed higher academic performance regardless of the area of knowledge. Results support the implementation of mentoring programs in Spanish universities with the goal of reducing student dropout and increasing academic performance. The research provides empirical evidence for theory building in higher education studies, developmental relationships, and integration programs. (AU)

Se ha propuesto la aplicación de programas de mentoría para reducir la deserción universitaria y aumentar el rendimiento académico. En el artículo analizamos el efecto de la mentoría entre pares sobre el abandono universitario y el rendimiento académico en España. Aplicamos un diseño de grupo de control cuasiexperimental con medida post en una muestra de 3.774 estudiantes (mentorados, n = 1,887; control, n = 1,887). Los mentorados habían participado en un programa de mentoría entre pares. Aplicamos la prueba t de Student, la d de Cohen, el estadístico phi y el chi-cuadrado. Los mentorados presentaban un menor abandono que los controles y un mayor rendimiento académico independientemente del área de conocimiento. Los resultados avalan la implementación de programas de mentoría en las universidades españolas con el objetivo de reducir el abandono universitario y aumentar el rendimiento académico. La investigación proporciona evidencia empírica para la elaboración de teorías en estudios de educación superior, relaciones de desarrollo y programas de integración. (AU)

Efficacy and safety of onasemnogene abeparvovec in children with spinal muscular atrophy type 1: real-world evidence from 6 infusion centres in the United Kingdom.

Background: Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg. Methods: This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements. Findings: Ninety-nine patients (45 SMA therapy-naïve) were treated with OA (median age at infusion: 10 [range, 0.6-89] months; median weight: 7.86 [range, 3.2-20.2] kg; duration of follow-up: 3-22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged <6 months had a 13.9 points higher gain in CHOP-INTEND score than patients ≥2 years (95% CI, 6.8-21.0; P < 0.001). Asymptomatic thrombocytopenia (71/99 patients; 71.7%), asymptomatic troponin-I elevation (30/89 patients; 33.7%) and transaminitis (87/99 patients; 87.9%) were reported. No thrombotic microangiopathy was observed. Median steroid treatment duration was 97 (range, 28-548) days with dose doubled in 35/99 patients (35.4%). There were 22.5-fold increased odds of having a transaminase peak >100 U/L (95% CI, 2.3-223.7; P = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2-209.2; P = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; P < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported. Interpretation: OA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients. Funding: Novartis Innovative Therapies AG provided a grant for independent medical writing services.

Recurrent atraumatic compartment syndrome as a manifestation of genetic neuromuscular disease.

Compartment syndrome (CS) is a medical emergency that occurs secondary to excessively high pressures within a confined fibro-osseous space, resulting in reduced perfusion and subsequent tissue injury. CS can be divided into acute forms, most commonly due to trauma and considered an orthopaedic emergency, and chronic forms, most commonly presenting in athletes with recurrent exercise-induced pain. Downstream pathophysiological mechanisms are complex but do share commonalities with mechanisms implicated in genetic neuromuscular disorders. Here we present 3 patients with recurrent CS in the context of a RYR1-related disorder (n = 1) and PYGM-related McArdle disease (n = 2), two of whom presented many years before the diagnosis of an underlying neuromuscular disorder was suspected. We also summarize the literature on previously published cases with CS in the context of a genetically confirmed neuromuscular disorder and outline how the calcium signalling alterations in RYR1-related disorders and the metabolic abnormalities in McArdle disease may feed into CS-causative mechanisms. These findings expand the phenotypical spectrum of RYR1-related disorders and McArdle disease; whilst most forms of recurrent CS will be sporadic, above and other genetic backgrounds ought to be considered in particular in patients where other suggestive clinical features are present.

Los Músculos Isquiosurales y su Capacidad Profiláctica sobre la Translación Tibial Anterior en Lesión de Ligamento Cruzado Anterior: Una Revisión Sistemática / The Hamstrings Muscles and their Prophylactic Capacity on Anterior Tibial Translation in Anterior Cruciate Ligament Injury: A Systematic Review

La ruptura de ligamento cruzado anterior (LCA) es la lesión de rodilla más común que se trata de una reconstruc- ción quirúrgica. El objetivo principal de esta revisión fue analizar la importancia de la función de los músculos isquiosurales como factor de riesgo de posibles lesiones de LCA. Se llevó a cabo siguiendo las normas Preferred Reported Item for Systematic Reviews and Meta- analyses (PRISMA). La fuente de la recopilación de datos fue la consulta directa de las bases de datos Pubmed, Sportdiscus, Web of Science y Scopus. Para la recuperación documental, se utilizaron varias palabras clave y se evaluó la calidad de los estudios que fueron seleccionados mediante la escala PEDro. Los déficits de la función muscular en los músculos isquiosurales se han relacionado con una mayor translación tibial anterior y, como consecuencia, un incremento del estrés tensional sobre el LCA entre los 10° y 45° de flexión de rodilla. Una co-activación de los músculos isquiosurales con el músculo cuádriceps femoral puede ser de gran ayuda para reducir los factores de riesgo de la lesión LCA.

SUMMARY: Anterior cruciate ligament (ACL) rupture is the most common knee injury to undergo surgery in the sports setting. The main objective of this review was to analyze the importance of hamstring function as a risk factor for potential ACL injury. It was conducted following the Preferred Reported Item for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The source of data collection was direct consultation of the Pubmed, Sportdiscus, Web of Science and Scopus databases. For documentary retrieval, several key words were used and the quality of the studies that were selected was assessed using the PEDro scale. Muscle function deficits in the hamstrings have been related to increased anterior tibial translation and, as a consequence, increased tensional stress on the ACL between 10° and 45° of knee flexion. A co-activation of the hamstrings with the quadriceps may be helpful in reducing the risk factors for ACL injury.

Parent Experiences with the Process of Sharing Inpatient Safety Concerns for Children with Medical Complexity: A Qualitative Analysis.

OBJECTIVE: To describe the process of identifying and reporting inpatient safety concerns from the perspective of parents of children with medical complexity (CMC). METHODS: We conducted a secondary analysis of qualitative data from semi-structured interviews with 31 English and Spanish-speaking parents of CMC at two tertiary children's hospitals. Interviews lasted 45-60 minutes and were audio-recorded, translated, and transcribed. Three researchers inductively and deductively coded transcripts using an iteratively refined codebook with validation by a fourth researcher. Thematic analysis was used to develop a conceptual model of the process of inpatient parent safety reporting. RESULTS: We identified four steps illustrating the process of inpatient parent safety concern reporting 1) parent recognizing concern, 2) parent reporting concern, 3) staff/hospital response continuum, and 4) parent feelings of validation/invalidation. Many parents endorsed that they were the first to catch a safety concern and were identified as unique reporters of safety information. Parents typically described reporting their concerns verbally and in real-time to the person they felt could quickly remedy the situation. There was a spectrum of validation. Some parents reported their concerns were not acknowledged and addressed, which led them to feel overlooked, disregarded, or judged. Others reported their concerns were acknowledged and addressed, resulting in parents feeling heard and seen and often leading to changes in clinical care. CONCLUSIONS: Parents described a multi-step process of reporting safety concerns during hospitalization and a spectrum of staff response and validation. These findings can inform family-centered interventions that support safety concern reporting in the inpatient setting.

Psychosocial and personality trait associates of phubbing and being phubbed in hispanic emerging adult college students.

Phubbing is when one uses their smartphone in a social interaction instead of interacting with the other individual(s) in their presence. Phubbing and being phubbed are growing concerns as the number of smartphones and frequency of smartphone use increases. This study assessed the relationships between phubbing, being phubbed, psychosocial constructs, and socially adverse personality traits among Hispanic emerging adult college students. Hispanic college students (n = 452) completed a survey assessing: sociodemographics, phubbing, being phubbed, depression, anxiety, stress, Machiavellianism, narcissism, psychopathy, and need for drama (interpersonal manipulation, impulsive outspokenness, persistent perceived victimhood). Hispanic emerging adult college students reported low-to-moderate levels of phubbing and being phubbed. Regarding phubbing findings, nomophobia (fear of separation from one's phone), interpersonal conflict, and problem acknowledgement were positively associated with negative affect. Moreover, interpersonal conflict, self-isolation, and problem acknowledgement were positively associated with interpersonal manipulation. Regarding being phubbed findings, perceived norms, feeling ignored, and interpersonal conflict were positively associated with persistent perceived victimhood. Findings indicate that Hispanic college students may use their smartphones in social settings to alleviate negative affect. Moreover, a virtual environment on a smartphone may be easier to manipulate and can be used to continue garnering attention and portraying oneself as the victim, fulfilling one's need for drama. Regarding exploratory mediations, phubbing and being phubbed mediated the relationships between multiple socially adverse personality traits and negative affect. The clinical implications of these results are discussed. Prospective studies are warranted to determine temporality. Supplementary information: The online version contains supplementary material available at 10.1007/s12144-023-04767-y.

Muscle Ultrasound Abnormalities in Individuals with RYR1-Related Malignant Hyperthermia Susceptibility.

BACKGROUND: Variants in RYR1, the gene encoding the ryanodine receptor-1, can give rise to a wide spectrum of neuromuscular conditions. Muscle imaging abnormalities have been demonstrated in isolated cases of patients with a history of RYR1-related malignant hyperthermia (MH) susceptibility. OBJECTIVE: To provide insights into the type and prevalence of muscle ultrasound abnormalities and muscle hypertrophy in patients carrying gain-of-function RYR1 variants associated with MH susceptibility and to contribute to delineating the wider phenotype, optimizing the diagnostic work-up and care for MH susceptible patients. METHODS: We performed a prospective cross-sectional observational muscle ultrasound study in patients with a history of RYR1-related MH susceptibility (n = 40). Study procedures included a standardized history of neuromuscular symptoms and a muscle ultrasound assessment. Muscle ultrasound images were analyzed using a quantitative and qualitative approach and compared to reference values and subsequently subjected to a screening protocol for neuromuscular disorders. RESULTS: A total of 15 (38%) patients had an abnormal muscle ultrasound result, 4 (10%) had a borderline muscle ultrasound screening result, and 21 (53%) had a normal muscle ultrasound screening result. The proportion of symptomatic patients with an abnormal result (11 of 24; 46%) was not significantly higher compared to the proportion of asymptomatic patients with an abnormal ultrasound result (4 of 16; 25%) (P = 0.182). The mean z-scores of the biceps brachii (z = 1.45; P < 0.001), biceps femoris (z = 0.43; P = 0.002), deltoid (z = 0.31; P = 0.009), trapezius (z = 0.38; P = 0.010) and the sum of all muscles (z = 0.40; P < 0.001) were significantly higher compared to 0, indicating hypertrophy. CONCLUSIONS: Patients with RYR1 variants resulting in MH susceptibility often have muscle ultrasound abnormalities. Frequently observed muscle ultrasound abnormalities include muscle hypertrophy and increased echogenicity.

The emerging spectrum of fetal acetylcholine receptor antibody-related disorders (FARAD).

In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex congenita (AMC). Fetal AChR antibodies have also been implicated in apparently rare, milder myopathic presentations termed fetal acetylcholine receptor inactivation syndrome (FARIS). The full spectrum associated with fAChR antibodies is still poorly understood. Moreover, since some mothers have no myasthenic symptoms, the condition is likely underreported, resulting in failure to implement effective preventive strategies. Here we report clinical and immunological data from a multicentre cohort (n = 46 cases) associated with maternal fAChR antibodies, including 29 novel and 17 previously reported with novel follow-up data. Remarkably, in 50% of mothers there was no previously established myasthenia gravis (MG) diagnosis. All mothers (n = 30) had AChR antibodies and, when tested, binding to fAChR was often much greater than that to the adult AChR isoform. Offspring death occurred in 11/46 (23.9%) cases, mainly antenatally due to termination of pregnancy prompted by severe AMC (7/46, 15.2%), or during early infancy, mainly from respiratory failure (4/46, 8.7%). Weakness, contractures, bulbar and respiratory involvement were prominent early in life, but improved gradually over time. Facial (25/34; 73.5%) and variable peripheral weakness (14/32; 43.8%), velopharyngeal insufficiency (18/24; 75%) and feeding difficulties (16/36; 44.4%) were the most common sequelae in long-term survivors. Other unexpected features included hearing loss (12/32; 37.5%), diaphragmatic paresis (5/35; 14.3%), CNS involvement (7/40; 17.5%) and pyloric stenosis (3/37; 8.1%). Oral salbutamol used empirically in 16/37 (43.2%) offspring resulted in symptom improvement in 13/16 (81.3%). Combining our series with all previously published cases, we identified 21/85 mothers treated with variable combinations of immunotherapies (corticosteroids/intravenous immunoglobulin/plasmapheresis) during pregnancy either for maternal MG symptom control (12/21 cases) or for fetal protection (9/21 cases). Compared to untreated pregnancies (64/85), maternal treatment resulted in a significant reduction in offspring deaths (P < 0.05) and other complications, with treatment approaches involving intravenous immunoglobulin/ plasmapheresis administered early in pregnancy most effective. We conclude that presentations due to in utero exposure to maternal (fetal) AChR antibodies are more common than currently recognized and may mimic a wide range of neuromuscular disorders. Considering the wide clinical spectrum and likely diversity of underlying mechanisms, we propose 'fetal acetylcholine receptor antibody-related disorders' (FARAD) as the most accurate term for these presentations. FARAD is vitally important to recognize, to institute appropriate management strategies for affected offspring and to improve outcomes in future pregnancies. Oral salbutamol is a symptomatic treatment option in survivors.