Abstract Introduction Malignant Hyperthermia (MH) is a pharmacogenetic, hereditary and autosomal dominant syndrome triggered by halogenates/succinylcholine. The In Vitro Contracture Test (IVCT) is the gold standard diagnostic test for MH, and it evaluates abnormal skeletal muscle reactions of susceptible individuals (earlier/greater contracture) when exposed to caffeine/halothane. MH susceptibility episodes and IVCT seem to be related to individual features. Objective To assess variables that correlate with IVCT in Brazilian patients referred for MH investigation due to a history of personal/family MH. Methods We examined IVCTs of 80 patients investigated for MH between 2004‒2019. We recorded clinical data (age, sex, presence of muscle weakness or myopathy with muscle biopsy showing cores, genetic evaluation, IVCT result) and IVCT features (initial and final maximum contraction, caffeine/halothane concentration triggering contracture of 0.2g, contracture at caffeine concentration of 2 and 32 mmoL and at 2% halothane, and contraction after 100 Hz stimulation). Results Mean age of the sample was 35±13.3 years, and most of the subjects were female (n=43 or 54%) and MH susceptible (60%). Of the 20 subjects undergoing genetic investigation, 65% showed variants in RYR1/CACNA1S genes. We found no difference between the positive and negative IVCT groups regarding age, sex, number of probands, presence of muscle weakness or myopathy with muscle biopsy showing cores. Regression analysis revealed that the best predictors of positive IVCT were male sex (+12%), absence of muscle weakness (+20%), and personal MH background (+17%). Conclusions Positive IVCT results have been correlated to male probands, in accordance with early publications. Furthermore, normal muscle strength has been confirmed as a significant predictor of positive IVCT while investigating suspected MH cases. (MH pharmacogenetic halogenatessuccinylcholine halogenates succinylcholine halogenates/succinylcholine (IVCT earlier/greater earliergreater earlier greater caffeinehalothane halothane personalfamily family 8 20042019 2004 2019 2004‒2019 (age cores evaluation result initial 02g g 0 2g 0.2g 3 10 stimulation. stimulation . stimulation) 35133 35 13 35±13. years n=43 n43 n 43 (n=4 54% 54 60%. 60 60% (60%) 65 RYR1CACNA1S RYRCACNAS RYR1 CACNA1S RYR CACNA S genes probands +12%, 12 +12% , (+12%) +20%, +20% (+20%) +17%. 17 +17% (+17%) publications Furthermore cases 2004201 200 201 2004‒201 1 3513 35±13 n=4 n4 4 (n= 5 6 (60% CACNAS +12 (+12% +20 (+20% +17 (+17% 200420 2004‒20 351 35±1 n= (n (60 +1 (+12 +2 (+20 (+17 20042 2004‒2 35± (6 + (+1 (+2 2004‒ ( (+

Resumo Justificativa/objetivos Distrofia muscular de Duchenne/Becker afeta a musculatura esquelética e leva a fraqueza muscular progressiva e risco de reações atípicas anestésicas após exposição à succinilcolina ou halogenados. O objetivo do presente relato é descrever investigação e diagnóstico de paciente com distrofia muscular de Becker e revisar os cuidados necessários na anestesia. Relato de caso Paciente masculino, 14 anos, encaminhado por hiperCKemia (aumento crônico dos níveis séricos de creatinoquinase - CK), com valores de CK de 7.779-29.040 UI.L-1 (normal 174 UI.L-1). Apresentou discreto atraso da aquisição de marcos motores (sentou aos nove meses, andou aos 18). Antecedente de transplante hepático. No exame neurológico apresentava dificuldade para andar nos calcanhares, levantar miopático (apoiava mãos nas coxas para ficar de pé), palato arqueado alto, hipertrofia de panturrilhas, escápulas aladas, hipotonia muscular global e arreflexia. Havia insuficiência respiratória restritiva leve na espirometria (capacidade vital forçada: 77% do previsto). O teste de contratura muscular in vitro em resposta ao halotano e à cafeína foi normal. Estudo da distrofina muscular por técnica de Western blot mostrou redução da distrofina (20% do normal) para ambos os anticorpos (C e N-terminal), e permitiu o diagnóstico de distrofia muscular de Becker. Conclusão Na avaliação pré-anestésica, história de atraso do desenvolvimento motor, bem como sinais clínicos e/ou laboratoriais de miopatia, deve motivar avaliação neurológica, com o objetivo de diagnosticar miopatias subclínicas e planejar cuidados necessários para prevenir complicações anestésicas. Distrofia muscular de Duchenne/Becker, apesar de não conferir suscetibilidade aumentada à HM, pode levar a reações atípicas fatais na anestesia.

Abstract Background and objectives Duchenne/Becker muscular dystrophy affects skeletal muscles and leads to progressive muscle weakness and risk of atypical anesthetic reactions following exposure to succinylcholine or halogenated agents. The aim of this report is to describe the investigation and diagnosis of a patient with Becker muscular dystrophy and review the care required in anesthesia. Case report Male patient, 14 years old, referred for hyperCKemia (chronic increase of serum creatine kinase levels - CK), with CK values of 7,779-29,040 IU.L-1 (normal 174 IU.L-1). He presented with a discrete delay in motor milestones acquisition (sitting at 9 months, walking at 18 months). He had a history of liver transplantation. In the neurological examination, the patient showed difficulty in walking on one's heels, myopathic sign (hands supported on the thighs to stand), high arched palate, calf hypertrophy, winged scapulae, global muscle hypotonia and arreflexia. Spirometry showed mild restrictive respiratory insufficiency (forced vital capacity: 77% of predicted). The in vitro muscle contracture test in response to halothane and caffeine was normal. Muscular dystrophy analysis by Western blot showed reduced dystrophin (20% of normal) for both antibodies (C and N-terminal), allowing the diagnosis of Becker muscular dystrophy. Conclusion On preanesthetic assessment, the history of delayed motor development, as well as clinical and/or laboratory signs of myopathy, should encourage neurological evaluation, aiming at diagnosing subclinical myopathies and planning the necessary care to prevent anesthetic complications. Duchenne/Becker muscular dystrophy, although it does not increase susceptibility to MH, may lead to atypical fatal reactions in anesthesia.

Abstract Neuromuscular disorders (NMD) are a heterogeneous group of genetic conditions, with autosomal dominant, recessive, or X-linked inheritance. They are characterized by progressive muscle degeneration and weakness. Here, we are presenting our major contributions to the field during the past 30 years. We have mapped and identified several novel genes responsible for NMD. Genotype-phenotype correlations studies enhanced our comprehension on the effect of gene mutations on related proteins and their impact on clinical findings. The search for modifier factors allowed the identification of a novel "protective"; variant which may have important implication on therapeutic developments. Molecular diagnosis was introduced in the 1980s and new technologies have been incorporated since then. Next generation sequencing greatly improved our capacity to identify disease-causing mutations with important benefits for research and prevention through genetic counseling of patients' families. Stem cells researches, from and for patients, have been used as tools to study human genetic diseases mechanisms and for therapies development. The clinical effect of preclinical trials in mice and canine models for muscular dystrophies are under investigation. Finally, the integration of our researches and genetic services with our post-graduation program resulted in a significant output of new geneticists, spreading out this expertise to our large country.

Cramps and myalgias are frequent presentations of many disorders whose diagnosis is generally difficult. Among the unusual causes stand the milder phenotypes of dystrophinopathies, which are caused, just as Duchenne and Becker’s dystrophy, by mutations in the dystrophin gene. An 8 year-old boy presented severe muscle pain on exercise and serum rise in creatine kinase over 1000 U/l. He had normal muscle power and mild calf hypertrophy. The molecular analysis by polymerase chain reaction (PCR) of the dystrophin gene showed deletions of exons 45 to 51. Dystrophin analysis by Western blot revealed a dystrophin of reduced quantity and molecular weight. Emphasis is made to include dystrophinopathies in the differential diagnosis of myalgias and the usefulness of molecular genetic techniques in the identification of these disorders (Rev Méd Chile 2000; 128: 772-7).