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LAMA2‐related dystrophies (LAMA2‐RD) constitute a rare neuromuscular disorder with a broad spectrum of phenotypic severity. Our understanding of the genotype–phenotype correlations in this condition remains incomplete, and reliable clinical data for clinical trial readiness is limited. In this retrospective study, we reviewed the genetic data and medical records of 114 LAMA2‐RD patients enrolled at seven research centers in Brazil. We identified 58 different pathogenic variants, including 21 novel ones. Six variants were more prevalent and were present in 81.5% of the patients. Notably, the c.1255del, c.2049_2050del, c.3976 C>T, c.5234+1G>A, and c.4739dup variants were found in patients unable to walk and without cortical malformation. In contrast, the c.2461A>C variant was present in patients who could walk unassisted. Among ambulatory patients, missense variants were more prevalent (p < 0.0001). Although no specific hotspot regions existed in the LAMA2, 51% of point mutations were in the LN domain, and 88% of the missense variants were found within this domain. Functional analysis was performed in one intronic variant (c.4960‐17C>A) and revealed an out‐of‐frame transcript, indicating that the variant creates a cryptic splicing site (AG). Our study has shed light on crucial phenotype–genotype correlations and provided valuable insights, particularly regarding the Latin American population. [ABSTRACT FROM AUTHOR]

Background: LAMA2-muscular dystrophy (LAMA2-MD) is an autosomal recessive disease, and the most common form of congenital muscular dystrophy (CMD). Most of the patients develop a form of disease characterized by inability to achieve walking capacity, multiple joint deformities, respiratory insufficiency, and some degree of dysphagia. However, there is a gravity spectrum, and some patients never achieve sitting position, while others can walk unassisted. There are still no adequate biomarkers to assess disease progression, and muscle ultrasound can be a useful tool, and also complement the assessment of respiratory and swallowing function. Objective: Evaluate, through muscular ultrasound, the function of the respiratory muscles, tongue muscles and correlate them with respiratory function, degree of dysphagia, disease severity and age. Methods: Ten patients with genetically confirmed LAMA2-MD were divided according to motor severity and evaluated. Muscle ultrasound of tongue, respiratory and paravertebral muscles were made. For muscles comparable to bone echo, the 4-point Heckmatt scale was used, for the others the classifications were hypoechoic, slightly hyperechoic, or very hyperechoic. Patients underwent respiratory function assessment and underwent neuromuscular disease swallowing status scale (NdSSS). Results: 2 patients had severe presentation and were not able to sit without support. They presented geniohyoid and genioglossus muscles very hyperechoic, had level 3 NdSSS dysphagia and required gastrostomy. They both had very affected external oblique, internal oblique and transverse muscles, but presented normal diaphragm, with normal thickening. They had altered polysomnography. 4 patients had maximum motor ability to sit without support and were under six years old. They presented geniohyoid and genioglossus muscles slightly hyperechoic, affected external oblique muscle with normal internal oblique and transverse muscles and normal diaphragm, with normal thickening. They all had total lung capacity (TLC) above 50% and level 7 NdSSS. 3 patients had classic disease presentation but were older than twelve years old. They presented geniohyoid and genioglossus muscles highly hyperechoic, affected external oblique, internal oblique and transverse muscles, with normal diaphragm, with normal thickening. They all had TLC below 35% and level 7 NdSSS. Conclusions: US can be used as a tool to evaluate disease progression and contribute to the assessment of respiratory function and dysphagia in LAMA2-MD. [ABSTRACT FROM AUTHOR]

Background: Patients with LAMA2-congenital muscular dystrophy (CMD) usually present with a severe phenotype characterized by inability to achieve walking capacity, multiple joint deformities, and respiratory insufficiency. However, there is a gravity spectrum, and some patients can walk unassisted. Characteristically, the patients have white matter changes in T2-WI and FLAIR in brain magnetic resonance. More rarely, cortical changes like polymicrogyria in the temporo-occipital regions can be observed and some of these patients can manifest epilepsy and intellectual disabilities. Objective: The aim of this study was to characterize central nervous system manifestations in a large cohort of CMD-LAMA2 and correlate them to genotype and motor function. Methods: In this observational study, 52 patients with genetically confirmed CMD-LAMA2 were included. All patients had brain MRI, and the presence of cortical malformations, epilepsy, intellectual disability was correlated to the motor function. The type and location of the LAMA2 variants were correlated to the motor function and central nervous system manifestations. Results: All patients had white matter abnormalities in brain MRI, and ten of them (19.2%) presented cortical malformations (i.e. polymicrogyria, lissencephaly-pachygyria, cobblestone), seven had cerebellar cysts and white matter changes and three had temporal cysts. In addition, ten patients (19.2%) presented epilepsy and six (11.5%) had intellectual disability. Central nervous system manifestations correlated with motor function severity, and to the variants located at LG-domain (p= 0.029). The presence of cortical malformations correlated to the occurrence of epilepsy and intellectual disability (p= 0.016 and p= 0.0017). A higher frequency of missense, in comparison to null variants, was observed in patients able to walk (p= 0.037) and null variants in both alleles were observed in 90% of the patients with cortical malformations. Conclusions: Central nervous system manifestations are frequent among the CMD-LAMA2 patients and correlate with motor function severity and the presence of LG-domain variants in LAMA2. [ABSTRACT FROM AUTHOR]

Desmin (DES) is the main intermediate muscle filament that connects myofibrils individually and with the nucleus, sarcolemma, and organelles. Pathogenic variants of DES cause desminopathy, a disorder affecting the heart and skeletal muscles. We aimed to analyze the clinical features, morphology, and distribution of desmin aggregates in skeletal muscle biopsies of patients with desminopathy and to correlate these findings with the type and location of disease-causing DES variants. This retrospective study included 30 patients from 20 families with molecularly confirmed desminopathy from 2 neuromuscular referral centers. We identified 2 distinct patterns of desmin aggregates: well-demarcated subsarcolemmal aggregates and diffuse aggregates with poorly delimited borders. Pathogenic variants located in the 1B segment and the tail domain of the desmin molecule are more likely to present with early-onset cardiomyopathy compared to patients with variants in other segments. All patients with mutations in the 1B segment had well-demarcated subsarcolemmal aggregates, but none of the patients with variants in other desmin segments showed such histological features. We suggest that variants located in the 1B segment lead to well-shaped subsarcolemmal desmin aggregation and cause disease with more frequent cardiac manifestations. These findings will facilitate early identification of patients with potentially severe cardiac syndromes., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The COVID-19 pandemic has brought substantial challenges for current practices in treating hereditary neuromuscular disorders (hNMDs). However, this infection has not been the only concern for these patients. Social distancing has compromised multidisciplinary assistance and physical activity, and has brought about several mental health issues. We presented a follow-up on 363 patients with hNMDs at a Brazilian tertiary center during the peak of the COVID-19 pandemic., Objective: We aimed to show the frequency and severity of SARS-CoV-2 infection among hNMD patients and to demonstrate the effects of the pandemic on life habits, disease progression and multidisciplinary supportive care status., Methods: Three hundred and sixty-three patients (58% male and 42% female) were followed for three months through three teleconsultations during the peak of the COVID-19 pandemic in Brazil., Results: There were decreases in the numbers of patients who underwent physical, respiratory and speech therapies. For several patients, their appetite (33%) and sleep habits (25%) changed. Physical exercises and therapies were interrupted for most of the patients. They reported new onset/worsening of fatigue (17%), pain (17%), contractions (14%) and scoliosis (7%). Irritability and sleep, weight and appetite changes, and especially diminished appetite and weight loss, were more frequent in the group that reported disease worsening. There was a low COVID-19 contamination rate (0.8%), and all infected patients had a mild presentation., Conclusion: The isolation by itself was protective from a COVID-19 infection perspective. However, this isolation might also trigger a complex scenario with life habit changes that are associated with an unfavorable course for the NMD.

Peripheral nerve hyperexcitability syndrome comprises a heterogeneous group of diseases, clinically characterised by myokymia, fasciculation, muscle cramps and stiffness. The causes are either immune mediated or non-immune mediated. Non-immune-mediated forms are mostly genetic, relating to two main genes: KCNQ2 and KCNA1 Patients with KCNQ2 gene mutations typically present with epileptic encephalopathy, benign familial neonatal seizures and myokymia, though occasionally with purely peripheral nerve hyperexcitability. We report a woman with marked facial myokymia and distal upper limb contractures whose mother also had subtle facial myokymia; both had the c.G620A (p.R207Q) variant in the KCNQ2 gene. Patients with familial myokymia and peripheral nerve hyperexcitability syndrome should be investigated for KCNQ2 variants. This autosomal dominant condition may respond to antiepileptic medications acting at potassium channels., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)