Genetic profile of Brazilian patients with LAMA2-related dystrophies.

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.

Marked neuropsychiatric involvement and dysmorphic features in nemaline myopathy.

BACKGROUND: Inherited nemaline myopathy is one of the most common congenital myopathies. This genetically heterogeneous disease is defined by the presence of nemaline bodies in muscle biopsy. The phenotypic spectrum is wide and cognitive involvement has been reported, although not extensively evaluated. METHODS: We report two nemaline myopathy patients presenting pronounced central nervous system involvement leading to functional compromise and novel facial and skeletal dysmorphic findings, possibly expanding the disease phenotype. RESULTS: One patient had two likely pathogenic NEB variants, c.2943G > A and c.8889 + 1G > A, and presented cognitive impairment and dysmorphic features, and the other had one pathogenic variant in ACTA1, c.169G > C (p.Gly57Arg), presenting autism spectrum disorder and corpus callosum atrophy. Both patients had severe cognitive involvement despite milder motor dysfunction. CONCLUSION: We raise the need for further studies regarding the role of thin filament proteins in the central nervous system and for a systematic cognitive assessment of congenital myopathy patients.

Brain MRI Abnormalities, Epilepsy and Intellectual Disability in LAMA2 Related Dystrophy - a Genotype/Phenotype Correlation.

BACKGROUND: LAMA2-related muscular dystrophy is a disorder that causes muscle weakness and varies in severity, from a severe, congenital type to a milder, late-onset form. However, the disease does not only affect the muscles, but has systemic involvement and can lead to alterations such as brain malformation, epilepsy and intellectual disability. OBJECTIVE: Describe the frequency of cortical malformations, epilepsy and intellectual disability in LAMA2-RD in a Brazilian cohort and correlate the neurological findings to genetic and motor function. METHODS: This is an observational study of 52 LAMA2-RD patients, who were divided into motor function subgroups and compared based on brain MRI findings, epilepsy, intellectual disability, and type of variants and variant domains. RESULTS: 44 patients (84.6%) were only able to sit, and 8 patients (15.4%) were able to walk. 10 patients (19.2%) presented with cortical malformations (polymicrogyria, lissencephaly-pachygyria, and cobblestone),10 patients (19.2%) presented with epilepsy, and 8 (15.4%) had intellectual disability. CNS manifestations correlated with a more severe motor phenotype and none of the patients able to walk presented with cortical malformation or epilepsy. There was a relation between gene variants affecting the laminin-α2 LG-domain and the presence of brain malformation (P = 0.016). There was also a relation between the presence of null variants and central nervous system involvement. A new brazilian possible founder variant was found in 11 patients (21,15%) (c.1255del; p. Ile419Leufs*4). CONCLUSION: Cortical malformations, epilepsy and intellectual disability are more frequent among LAMA2-RD patients than previously reported and correlate with motor function severity and the presence of variants affecting the laminin-α2 LG domain. This brings more insight fore phenotype-genotype correlations, shows the importance of reviewing the brain MRI of patients with LAMA2-RD and allows greater attention to the risk of brain malformation, epilepsy, and intellectual disability in those patients with variants that affect the LG domain.

Hypoglycemia in Patients With LAMA2-CMD.

BACKGROUND: Hypoglycemia has been reported in patients with LAMA2-CMD, but the frequency, risk factors, and correlation to genotype/phenotype have not been systematically assessed to date. METHODS: A retrospective cohort study was performed on 48 patients with LAMA2-CMD. Patients were divided into two groups: a hypoglycemic group, with at least one episode of hypoglycemia, and a nonhypoglycemic group. The groups were compared according to gait function, epilepsy, intellectual disability, constipation, gastroesophageal reflux, gastrostomy, weight percentile, scoliosis, the use of a ventilator device, the use of a feeding device, neuromuscular disease swallowing status scale, and type of mutation. RESULTS: Fifteen patients (31.2%) presented with at least one episode of symptomatic hypoglycemia and eight (16.6% of the cohort) had two or more episodes. All patients who had hypoglycemia were in the nonambulant group. We observed a correlation between gait, the use of ventilator and feeding devices, and swallow function with hypoglycemia. Patients with extremely low weight were five times more likely to have recurrent episodes of hypoglycemia. The presence of at least one missense variant appears to be associated with a lower risk of hypoglycemia. CONCLUSION: Patients with LAMA2-CMD are at risk of hypoglycemia. The risk is more relevant in patients with severe phenotype and patients with loss-of-function variants. For patients with extremely low weight, the risk is higher. Blood glucose should be actively measured in patients who are fasting or have infections, and health care providers should be prepared to identify and treat these patients.

Clinical Manifestation of Nebulin-Associated Nemaline Myopathy.

Background and Objectives: Nemaline myopathy (NM) is a genetically heterogeneous inherited myopathy related with at least 12 genes, whereas pathogenic variants in NEB gene are the most common genetic cause. The clinical spectrum of NM caused by NEB pathogenic variants (NM-NEB) is very broad, ranging from mild to severe presentations manifesting with generalized weakness, as well as respiratory and bulbar involvement. There is currently not enough data regarding the progression of the disease. In this study, we present a genotypic and phenotypic spectrum of 33 patients with NM caused by NEB variants (NM-NEB) classified according to age groups and the use of ventilatory support. We focused on interventional support, genotype-phenotype correlation, and association between respiratory, bulbar, and motor systems in groups of patients stratified by age and by the use of ventilatory support (VS). Methods: Clinical and genetic data from patients with NM-NEB followed up in one specialized center were collected through regular consultations. Patients were evaluated regarding motor, bulbar, and respiratory functions. Results: Thirty-three patients with NM-NEB were evaluated consisting of 15 females and 18 males with an average age of 18 (±12) years and a median of 17 (±11) years. 32% of patients with NM-NEB used a G tube, 35% were not able to walk without support, and 55% needed VS. Scoliosis and dysphagia were more common among patients who used VS. Described for the first time, half of the patients presented tongue atrophy in a triple furrow pattern, and the presence of the atrophy was associated with dysphagia. Comparing the patients grouped by age, we found that, proportionally, older patients had more scoliosis and respiratory dysfunction than younger groups, suggesting the progression of the disease in these domains. In addition to that, we showed that VS use was associated with scoliosis and dysphagia. Discussion: NM-NEB is a very debilitating disease. There is an association between scoliosis and respiratory dysfunction while patients using VS have more often scoliosis than the no-VS group. Triple furrow tongue atrophy is a novel and frequent finding, which is directly associated with dysphagia. Grouping patients by age suggested disease stability in motor and swallow function, but a progression in respiratory dysfunction and skeletal deformities. All observations are relevant in the management care of patients with NM.

Effect of the COVID-19 pandemic on patients with inherited neuromuscular disorders.

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.

The Location of Disease-Causing DES Variants Determines the Severity of Phenotype and the Morphology of Sarcoplasmic Aggregates.

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.

Effect of the COVID-19 pandemic on patients with inherited neuromuscular disorders / Efeito da pandemia do COVID-19 em pacientes com doenças neuromusculares hereditárias

ABSTRACT 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.

RESUMO Antecedentes: A Pandemia por COVID-19 tem trazido desafios subtanciais para a prática clínica no tratamento das doenças neuromusculares hereditárias (DNMh). A infecção não tem sido a única preocupação para os pacientes. O distanciamento social tem comprometido a assistência multidisciplinar, atividade física e tem trazido problemas mentais em decorrência do próprio isolamento. Nós apresentamos aqui um seguimento de 363 pacientes com DNMh de um centro terciário Brasileiro durante o pico da Pandemia de Covid-19. Objetivos: Mostrar a frequência e gravidade da infecção por Sars-Cov-2 em pacientes com DNMh e demonstrar os efeitos da pandemia nos hábitos de vida, na progressão da doença e no cuidado multidisciplinary. Métodos Trezentos e sessenta e três pacientes (58% homens and 42% mulheres) foram acompanhados por 3 meses através de 3 teleconsultas durante o pico da Pandemia de Covid-19 no Brasil. Resultados Houve um decréscimo no número de pacientes que faziam terapia física, respiratória e fonoaudiológica. Em muitos pacientes, o apetite (33%) e hábitos do sono (25%) se alteraram. Exercícios físicos e terapias foram interrompidas pela maioria dos pacientes. Physical exercises and therapies were interrupted for most of the patients. Eles relataram piora ou aparecimento de fadiga (17%), dor (17%), retrações (14%), e escoliose (7%). Irritabilidade, mudanças no sono, peso e apetite, sendo principalmente diminuição do apetite e peso foram mais frequentemente encontrados em pacientes que apresentaram piora clinica da doença. Houve uma baixa taxa de contaminação por Covid-19 (0.8%), e todos os pacientes infectado apresentaram quadro clinico leve. Conclusão O isolamento por si só se mostrou protetor na perspectiva de infecção por Covid-19, mas pode desencadear um cenário complexo com mudanças nos hábitos de vida e curso desfavorável da doença de base.

Facial myokymia in inherited peripheral nerve hyperexcitability syndrome.

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.

Clinical features of collagen VI-related dystrophies: A large Brazilian cohort.

OBJECTIVES: Collagen VI-related dystrophies (COL6-RDs) have a broad clinical spectrum and are caused by mutations in the COL6A1, COL6A2 and COL6A3 genes. Despite the clinical variability, two phenotypes are classically recognized: Bethlem myopathy (BM, milder form) and Ullrich congenital muscular dystrophy (UCMD, more severe form), with many patients presenting an intermediate phenotype. In this work, we present clinical and genetic data from 28 patients (27 families), aged 6-38 years (mean of 16.96 years), with COL6-RDs. PATIENTS AND METHODS: Clinical, muscle histology and genetic data are presented. COL6A1, COL6A2 and COL6A3 genes were analyzed by next-generation sequencing (NGS). RESULTS: Homozygous or heterozygous variants were found in COL6A1 (12 families), COL6A2 (12 families) and COL6A3 (3 families). Patients with the severe UCMD phenotype (three cases) had a homogeneous clinical picture characterized by neonatal onset of manifestations, no gait acquisition and a stable course, but with severe respiratory involvement. Most of the patients with the mild UCMD phenotype had neonatal onset of manifestations (88.8 %), delayed motor development (66.6 %), slowly progressive course, pulmonary involvement (55.5 %) and loss of the walking capacity before the age of 10 (66.6 %). In the intermediate group (nine patients), some children had neonatal onset of manifestations (44.5 %) and delayed motor development (88.9 %); but all of them achieved the ability to walk and were still ambulatory. Some patients that had the BM phenotype presented neonatal manifestations (57.1 %); however, all of them had normal motor development and normal pulmonary function. Only one patient from the group of BM lost the walking capacity during the evolution of the disease. Other frequent findings observed in all groups were joint retractions, spinal deformities, distal hyperextensibility, congenital hip dislocation and keloid formation. CONCLUSION: COL6-RDs present variable clinical manifestations, but common findings are helpful for the clinical suspicion. NGS is a valuable approach for diagnosis, providing useful information for the genetic counseling of families.

Nonalcoholic fatty liver disease: a cohort study focusing on treatment response to nutritional counseling / A doença hepática gordurosa não-alcoólica: um estudo de coorte com foco na resposta ao tratamento com orientação nutricional

BACKGROUND: Nonalcoholic fatty liver disease is the leading cause of liver pathology. The mainstay of management is weight loss. Our aim was to evaluate responses to nutritional counseling in long-term patients with this condition. METHODS: A prospective cohort study with consecutive inclusion of 105 subjects with nonalcoholic fatty liver disease who received individualized low-calories diet counseling (1400 to 1600 kcal/day according to gender) every three months for 24 months. Weight loss of 5% or more was considered as a therapeutic response. RESULTS: Out of 105 patients, 45 (42.9%) did not return for a second evaluation. Mean age was 55 ± 9 years, 81.6% were women and mean body mass index was 31.9 (23.8-44.9) kg/m2. Follow-up time was 6.5 (3.2-26.9) months and median appointment number was 3 (2-11). Metabolic syndrome and hypercholesterolemia were more common in women. The number of subjects who lost more than 5% weight was: 5/20 (25%) at 6-months; 3/15 (33%) at 12 months; 3/18 (17%) at 18 months and 4/13 (31%) at the end of follow up. The median body weight loss at 6, 12, 18 and 24 months decreased significantly. CONCLUSIONS: Adherence to nutritional counseling is poor in patients with nonalcoholic fatty liver disease. Only a very small proportion of patients reached the targeted body loss of weight on long term.

RESUMO OBJETIVOS: A doença hepática gordurosa não alcoólica éa principal causa de patologia hepática. Essencial para seu manejo éa perda de peso. Nosso objetivo foi avaliar as respostas a aconselhamento nutricional em pacientes crônicos com esta condição. METODOS: Estudo prospectivo de coorte com inclusão consecutiva de 105 indivíduos com doenca hepática gordurosa não alcoólica que receberam dieta individualizada de baixa caloria (1400-1600kcal/dia, de acordo com o sexo) e aconselhamento a cada 3 meses, durante 24 meses. A perda de peso de 5% ou mais foi considerada como resposta terapêutica adequada. RESULTADOS: Dos 105 pacientes, 45 (42,9%) não voltaram para uma segunda avaliação. A média de idade foi de 55 ± 9 anos, 81,6% eram mulheres e o índice de massa corporal foi de 31,9 (23,8-44,9) kg/m2. O tempo de seguimento foi de 6,5 (3,2-26,9) meses e número médio de entrevistas foi de 3 (2-11). A síndrome metabólica e a hipercolesterolemia foram mais comuns em mulheres. O número de indivíduos que perderam mais de 5% em peso foi: 5/20 (25%) em 6 meses; 3/15 (33%) aos 12 meses; 3/18 (17%) e aos 18 meses 4/13 (31%) no final do seguimento. A perda de peso corporal média aos 6, 12, 18 e 24 meses diminuiu significativamente. CONCLUSÕES: A adesão ao aconselhamento nutricional épobre em pacientes com doenca hepática gordurosa não alcoólica. Apenas uma pequena proporcão de pacientes que atingiu a perda de peso corporal programada a longo prazo.