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Background: More than one-third of COVID-19 patients present neurological symptoms ranging from anosmia to stroke and encephalopathy. Furthermore, pre-existing neurological conditions may require special treatment and may be associated with worse outcomes. Notwithstanding, the role of neurologists in COVID-19 is probably underrecognized. Objective: The aim of this study was to report the reasons for requesting neurological consultations by internists and intensivists in a COVID-19-dedicated hospital. Methods: This retrospective study was carried out at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil, a 900-bed COVID-19 dedicated center (including 300 intensive care unit beds). COVID-19 diagnosis was confirmed by SARS-CoV-2-RT-PCR in nasal swabs. All inpatient neurology consultations between March 23rd and May 23rd, 2020 were analyzed. Neurologists performed the neurological exam, assessed all available data to diagnose the neurological condition, and requested additional tests deemed necessary. Difficult diagnoses were established in consensus meetings. After diagnosis, neurologists were involved in the treatment. Results: Neurological consultations were requested for 89 out of 1,208 (7.4%) inpatient COVID admissions during that period. Main neurological diagnoses included: encephalopathy (44.4%), stroke (16.7%), previous neurological diseases (9.0%), seizures (9.0%), neuromuscular disorders (5.6%), other acute brain lesions (3.4%), and other mild nonspecific symptoms (11.2%). Conclusions: Most neurological consultations in a COVID-19-dedicated hospital were requested for severe conditions that could have an impact on the outcome. First-line doctors should be able to recognize neurological symptoms; neurologists are important members of the medical team in COVID-19 hospital care.

Myasthenia gravis and thymoma are often presented in association with ∼10% of myasthenic cases having concomitant thymoma. Thymic carcinoma is one of the rarest/aggressive human epithelial tumors and has no correlation with myasthenia gravis hitherto. Here is provided a clinical case and review of literature on a very rare association of thymic carcinoma (with no sign of thymoma) and myasthenia gravis (antiacetylcholine receptor antibody positive). Two years after thymectomy, clinical evolution was satisfactory. This clinical case elicits hypothesis that thymic carcinoma may be related with myasthenia gravis, what may have good prognostic from oncologic and neurologic perspectives.

Congenital fiber type disproportion (CFTD) is a rare congenital myopathy subtype defined by slow type 1 hypotrophy in the absence of any other major structural findings such as rods, central nuclei or cores. Dominant missense changes in slow alpha-tropomyosin coded by TPM3 gene are the main cause of the CFTD. There are only a few reports of recessive loss-of-function mutations in TPM3 causing severe Nemaline Myopathy and CFTD. We present two patients harboring TPM3 mutations. The first is a novel homozygous missense variant with a mild CFTD clinical phenotype inherited in a recessive fashion. The second is a previously reported heterozygous mutation presenting within pronounced early axial involvement and dropped head. This report expands the genotype-phenotype correlation in the TPM3 myopathy showing a recessive mutation causing a mild clinical phenotype and also shows that TPM3 mutations should be part of the investigation in patients with dropped head.

Objectives To present phenotype features of a large cohort of congenital myasthenic syndromes (CMS) and correlate them with their molecular diagnosis. Methods Suspected CMS patients were divided into three groups: group A (limb, bulbar or axial weakness, with or without ocular impairment, and all the following: clinical fatigability, electrophysiology compatible with neuromuscular junction involvement and anticholinesterase agents response), group B (limb, bulbar or axial weakness, with or without ocular impairment, and at least one of additional characteristics noted in group A) and group C (pure ocular syndrome). Individual clinical findings and the clinical groups were compared between the group with a confirmed molecular diagnosis of CMS and the group without molecular diagnosis or with a non-CMS molecular diagnosis. Results Seventy-nine patients (68 families) were included in the cohort: 48 in group A, 23 in group B and 8 in group C. Fifty-one were considered confirmed CMS (30 CHRNE, 5 RAPSN, 4 COL13A1, 3 DOK7, 3 COLQ, 2 GFPT1, 1 CHAT, 1 SCN4A, 1 GMPPB, 1 CHRNA1), 7 probable CMS, 5 non-CMS and 16 unsolved. The chance of a confirmed molecular diagnosis of CMS was significantly higher for group A and lower for group C. Some individual clinical features, alterations on biopsy and electrophysiology enhanced specificity for CMS. Muscle imaging showed at least mild alterations in the majority of confirmed cases, with preferential involvement of soleus, especially in CHRNE CMS. Conclusions Stricter clinical criteria increase the chance of confirming a CMS diagnosis, but may lose sensitivity, especially for some specific genes.

Gene set-based signal detection analyses are used to detect an association between a trait and a set of genes by accumulating signals across the genes in the gene set. Since signal detection is concerned with identifying whether any of the genes in the gene set are non-null, a goodness-of-fit (GOF) test can be used to compare whether the observed distribution of gene-level tests within the gene set agrees with the theoretical null distribution. Here, we present a flexible gene set-based signal detection framework based on tail-focused GOF statistics. We show that the power of the various statistics in this framework depends critically on two parameters: the proportion of genes within the gene set that are non-null and the degree of separation between the null and alternative distributions of the gene-level tests. We give guidance on which statistic to choose for a given situation and implement the methods in a fast and user-friendly R package, wHC (https://github.com/mqzhanglab/wHC). Finally, we apply these methods to a whole exome sequencing study of amyotrophic lateral sclerosis.

Large-scale sequencing efforts in amyotrophic lateral sclerosis (ALS) have implicated novel genes using gene-based collapsing methods. However, pathogenic mutations may be concentrated in specific genic regions. To address this, we developed two collapsing strategies: One focuses rare variation collapsing on homology-based protein domains as the unit for collapsing, and the other is a gene-level approach that, unlike standard methods, leverages existing evidence of purifying selection against missense variation on said domains. The application of these two collapsing methods to 3093 ALS cases and 8186 controls of European ancestry, and also 3239 cases and 11,808 controls of diversified populations, pinpoints risk regions of ALS genes, including SOD1, NEK1, TARDBP, and FUS. While not clearly implicating novel ALS genes, the new analyses not only pinpoint risk regions in known genes but also highlight candidate genes as well.

A 2-month-old girl presented hypotonia, followed by progressive cognitive and motor deterioration, pyramidal signs, hearing loss, refractory epilepsy, and high serum lactate level. A biceps brachii biopsy presented cytochrome c oxidase negative fibers, and serial brain magnetic resonance imaging (MRI) showed progressive brain involvement (). Whole-exome sequencing showed the homozygous pathogenic variant c.542G>T (p.Arg181Leu) in TRMT10C. The nuclear gene TRMTC10C encodes RNase P protein responsible for mt-tRNA maturation and causes an autosomal recessive mitochondrial disease. To our knowledge, variants in [...]

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.

Background Nemaline myopathy is a rare congenital disease of skeletal muscle characterized by muscle weakness and hypotonia, as well as the diagnostic presence of nemaline rods in skeletal muscle fibers. Nemaline myopathy is genetically and phenotypically heterogeneous and, so far, mutations in 11 different genes have been associated with this disease. Dominant mutations in ACTA1 are the second most frequent genetic cause of nemaline myopathy and can lead to a variety of clinical and histologic phenotypes. Patients and Methods We present a series of ACTA1 -related cases from a Brazilian cohort of 23 patients with nemaline myopathy, diagnosed after Sanger sequencing the entire coding region of ACTA1 , and review the literature on ACTA1-related nemaline myopathy. Results The study confirmed ACTA1 mutations in four patients, including one with intranuclear rods, one with large intracytoplasmic aggregates, and two with nemaline intracytoplasmic rods. A repeat muscle biopsy in one patient did not show histological progression. Conclusion Despite the recognized phenotypic variability in ACTA1-related nemaline myopathy, clinical and histological presentations appear to correlate with the position of the mutation, which confirms emerging genotype/phenotype correlations and better predict the prognosis of affected patients.

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.

Mutations in RAPSN are an important cause of congenital myasthenic syndrome (CMS), leading to endplate acetylcholine receptor deficiency. We present three RAPSN early-onset CMS patients (from a Brazilian cohort of 61 CMS patients). Patient 1 and patient 2 harbor the mutation p.N88K in homozygosity, while patient 3 harbors p.N88K in compound heterozygosity with another pathogenic variant (p.V165M; c.493G ≥ A). At onset, patient 3 presented with more severe symptoms compared to the other two, showing generalized weakness and repeated episodes of respiratory failure in the first years of life. During adolescence, she became gradually less symptomatic and does not require medication anymore, presenting better long-term outcomes than patients 1 and 2. This case series illustrates the variability of RAPSN early-onset CMS, with patient 3, despite severe onset, revealing an almost complete reversal of myasthenic symptoms, not limited to apneic episodes. Moreover, it suggests that RAPSN CMS may be underdiagnosed in non-European countries.

Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease., Target ALS; European Union (European Union); Horizon 2020; European Research Council (ERC), European Union's Seventh Framework Programme (FP7/2007-2013); AFM Telethon; NIH; National Institute of Neurological Disorders and Stroke; NIH/NINDS; United Kingdom, Medical Research Council; Suna and İnan Kıraç Foundation; Legacy Heritage Fund; Bruno and Ilse Frick Foundation for Research on ALS; Teva Pharmaceutical Industries Ltd. as part of the Israeli National Network of Excellence in Neuroscience (NNE); Minna-James-Heineman Stiftung through Minerva; Israel Science Foundation; ALS-Therapy Alliance; Motor Neuron Disease Association (United Kingdom); Thierry Latran Foundation for ALS research; ERA-Net for Research Programmes on Rare Diseases (FP7); IsrALS, Yeda-Sela, Yeda-CEO, Israel Ministry of Trade and Industry; Y. Leon Benoziyo Institute for Molecular Medicine; Kekst Family Institute for Medical Genetics; David and Fela Shapell Family Center for Genetic Disorders Research; Crown Human Genome Center; Nathan, Shirley, Philip and Charlene Vener New Scientist Fund; Julius and Ray Charlestein Foundation; Fraida Foundation; Wolfson Family Charitable Trust; Adelis Foundation; Merck (United Kingdom); ALS Canada Tim E. Noel Postdoctoral Fellowship; Project5 for ALS; Robert Packard Center for ALS Research; University of Missouri Spinal Cord Injury/Disease Research Program; Hope Center for Neurological Disorders; ALS Association ; Biogen; ALS Finding a Cure; Angel Fund; ALS-One; Cellucci Fund; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Biomedical Research Centre

Large-scale sequencing efforts in amyotrophic lateral sclerosis (ALS) have implicated novel genes using gene-based collapsing methods. However, pathogenic mutations may be concentrated in specific genic regions. To address this, we developed two collapsing strategies, one focuses rare variation collapsing on homology-based protein domains as the unit for collapsing and another gene-level approach that, unlike standard methods, leverages existing evidence of purifying selection against missense variation on said domains. The application of these two collapsing methods to 3,093 ALS cases and 8,186 controls of European ancestry, and also 3,239 cases and 11,808 controls of diversified populations, pinpoints risk regions of ALS genes including SOD1, NEK1, TARDBP and FUS. While not clearly implicating novel ALS genes, the new analyses not only pinpoint risk regions in known genes but also highlight candidate genes as well.

International audience; Mutations in RYR1 give rise to diverse skeletal muscle phenotypes, ranging from classical central core disease to susceptibility to malignant hyperthermia. Next-generation sequencing has recently shown that RYR1 is implicated in a wide variety of additional myopathies, including centronuclear myopathy. In this work, we established an international cohort of 21 patients from 18 families with autosomal recessive RYR1-related centronuclear myopathy, to better define the clinical, imaging, and histological spectrum of this disorder. Early onset of symptoms with hypotonia, motor developmental delay, proximal muscle weakness, and a stable course were common clinical features in the cohort. Ptosis and/or ophthalmoparesis, facial weakness, thoracic deformities, and spinal involvement were also frequent but variable. A common imaging pattern consisted of selective involvement of the vastus lateralis, adductor magnus, and biceps brachii in Comparison to adjacent muscles. In addition to a variable prominence of central nuclei, muscle biopsy from 20 patients showed type 1 fiber predominance and a wide range of intermyofibrillary architecture abnormalities. All families harbored compound heterozygous mutations, most commonly a truncating mutation combined with a missense mutation. This work expands the phenotypic characterization of patients with recessive RYR1-related centronuclear myopathy by highlighting common and variable clinical, histological, and imaging findings in these patients. (C) 2017 Elsevier B.V. All rights reserved.

Skeletal muscle involvement as a neurologic manifestation in individuals with HIV is rare, especially as rod myopathy. We describe a 41-year-old male with HIV infection who presented progressive proximal muscle weakness and limb-girdle atrophy. A muscle magnetic resonance image showed bilateral fatty infiltration and post-contrast enhancement in the arm and thigh muscles. The muscle biopsy revealed intracytoplasmic aggregates with appearance of nemaline rod bodies with Gomori trichrome staining and electron microscopy in most fibers. The patient underwent six cycles of intravenous methylprednisolone pulses, presenting clinical improvement. Post-treatment muscle biopsy showed fewer nemaline bodies and muscle magnetic resonance image depicted a pronounced reduction of muscular edema. These findings corroborate that deposition of nemaline bodies in these patients might be related to an immune response triggered by the virus.

No abstract available

G N […] Muscle biopsy with dystrophic pattern and rimmed vacuoles: GNE myopathy in a Brazilian patient

INTRODUCTION MYH7 gene mutations are related to a heterogeneous group of skeletal and cardiac myopathies. METHODS We evaluated clinical and muscle MRI changes in patients with mutations in the rod domain of MYH7, including 1 with mosaicism and 3 with novel missense mutations. RESULTS Patients presented in childhood with a distal and axial phenotype. Biopsy findings were variable. Half of the cases displaying some type of core pathology, including minicores and eccentric cores. Most patients demonstrated internal bands of infiltration ("inverted-collagen-VI sign") in multiple muscles, particularly the soleus, and prominent atrophy and fatty infiltration of the tongue and the paraspinal, gluteus minimus, sartorius, gracilis, tibialis anterior, and extensor digitorum longus muscles. DISCUSSION Muscle imaging findings in patients with axial involvement provide significant clues permitting the distinction between MYH7-related myopathies and other axial myopathies such as those related to SEPN1 and LMNA genes. Muscle Nerve 58: 224-234, 2018.

INTRODUÇÃO: A ausência da distrofina na distrofia muscular de Duchenne (DMD) impacta múltiplos sistemas, como o sistema nervoso central e acarreta perda progressiva de força e capacidade funcional. Determinadas mutações genéticas podem apresentar quadros cognitivamente mais graves. Assim, é importante conhecer se tais genótipos interferem na função motora e cognitiva desses pacientes. OBJETIVO: Comparar o desempenho cognitivo, motor e funcional de crianças e adolescentes com DMD e típicas; comparar o desempenho de indivíduos com DMD com mutações genéticas anterior e posterior ao exon 44 (grupos upstream e downstream) e investigar possíveis correlações entre as variáveis de desempenho dos mesmos. MÉTODO: Foram aplicados os instrumentos: MFM e Vignos, teste de fluência verbal, teste de repetição de dígitos, vocabulário, cubos e o Inventário de Avaliação Pediátrica de Incapacidade (PEDI) em crianças com DMD e do grupo controle. RESULTADOS: Houve diferença significativa na Fluência Verbal, Cubos, Vocabulário e Repetição de dígitos em ordem direta (p 0,001) e na independência funcional (p 0,001). Quanto ao grupo DMD upstream e downstream, houve diferença entre os grupos nos testes de Fluência Verbal e Vocabulário e não houve diferença no desempenho motor e funcional. Foram encontradas correlações entre todas as variáveis motoras e de independência funcional. CONCLUSÃO: O desempenho cognitivo, motor e funcional mostrou-se deficiente nos indivíduos com DMD e pior quando a mutação era anterior ao exon 44 INTRODUCTION: The Duchenne muscular dystrophy (DMD) impacts multiple systems, such as the central nervous system, with progressive loss of strength and functional capacity. Certain genetic mutations can lead to cognitively more severe conditions. Thus, it is important to know whether such genotypes interfere in the motor and cognitive function of these patients. OBJECTIVE: Compare the cognitive, motor and functional performance of children and adolescents with DMD to typically children to compare the performance of individuals DMD with genetic mutations distal and proximal to exon 44 (downstream and upstream groups) and to investigate possible correlations between their performance variables. METHOD: we applied instruments: MFM and Vignos, verbal fluency test, digit repetition test, vocabulary, cubes and the Pediatric Assessment of Disability Inventory (PEDI) in children with DMD and in the control group RESULTS: There was a significant difference between the DMD and control groups in Verbal Fluency, Cubes, Vocabulary and Digit Repetition in direct order (p0.001) and in functional independence (p0.001). In upstream and downstream DMD group, there was a difference between the groups in the Verbal Fluency and Vocabulary tests and there was no difference in motor and functional performance. Correlations were found between all motor and functional independence variables. CONCLUSION: Cognitive, motor and functional performance proved to be deficient in individuals with DMD and worse when the mutation was prior to exon 44

As doenças neuromusculares (DNM) envolvem lesões ou disfunções nos neurônios motores superior e inferior, nervos periféricos, junção mioneural (miastenias) e/ou músculos (miopatias). Cursam com fraqueza muscular e baixa resistência muscular. A ACTIVLIM foi desenvolvida a partir do conceito de limitações nas atividades, proposto pela Classificação Internacional de Funcionalidade, Incapacidade e Saúde (CIF). É autorreferida, com 22 itens de atividades diárias, graduados em três níveis (fácil, difícil e impossível). O presente estudo observacional transversal visou realizar a tradução, adaptação transcultural e validação da versão em português do Brasil da ACTIVLIM. Incluiu a tradução do inglês para o português, síntese das traduções, retrotradução, avaliação por um comitê de especialistas e pré-teste para verificação das propriedades psicométricas. Em seguida, foram recrutadas 268 pessoas com diagnóstico de DNM para avaliação. Para a análise intra-examinador, 60 indivíduos foram avaliados um mesmo fisioterapeuta com intervalo de um mês, tendo como coeficiente (ICC) 0,95. A consistência interna avaliou o instrumento como um todo, o valor de alfa de Cronbach foi de 0,94 (classificado como alto). A correlação de Spearman foi utilizada para validar a consistência externa da escala. Houve forte correlação entre a ACTIVLIM e as escalas Vignos, Spencer & Archibald (r=-0,907), Brooke (r=-0,908) e Medida de Independência Funcional (r=0,864). Foram observadas correlações entre a força muscular (MRC) e a ACTIVLIM. Os coeficientes mais fortes entre força muscular e ACTIVLIM foram obtidos nos testes de correlação com a força proximal dos membros superiores (r=0,748) e com a força muscular proximal dos membros inferiores (r=0,793). Foi considerado p < 0,017 para todas as correlações citadas. Aspectos muito relevantes das atividades da ACTIVLIM, como autocuidado e mobilidade, correlacionaram-se com escalas de incapacidade, independência funcional e força muscular. A versão em português do Brasil foi concluída e é apresentada no presente estudo Neuromuscular diseases (NMD) involve lesions or dysfunctions in the upper and lower motor neurons, peripheral nerves, myoneural junction (myasthenia) and/or muscles (myopathies). NMD cause muscle weakness and low endurance. ACTIVLIM was developed based on the concept of activity limitations, proposed by the International Classification of Functionality, Disability and Health (ICF). It is self-reported, with 22 items of daily activities, graduated at three levels (easy, difficult, and impossible). This cross-sectional observational study aimed at translating, cross-cultural adapting and validating the Brazilian Portuguese version of ACTIVLIM. Translation from English to Portuguese, synthesis of translations, back-translation, evaluation by a committee of experts and pre-test to verify psychometric properties were the first steps. Then, 268 people with NMD were recruited for evaluation. For the intra-examiner analysis, 60 individuals were evaluated by the same physiotherapist, with an interval of one month, with a coefficient (ICC) of 0,95. The internal consistency evaluated the instrument, with a Cronbach\'s alpha of 0,94 (classified as high). Spearman\'s correlation was used to validate the external consistency. There was a strong correlation between ACTIVLIM and the Vignos, Spencer & Archibald staging (r=-0.907), Brooke classification (r=-0.908) and the Functional Independence Measure (r=0.864). Correlations between muscle strength measures (MRC) and ACTIVLIM were observed. The strongest correlation coefficient between muscle strength and ACTIVLIM was the upper limbs proximal strength (r=0.748) and lower limbs proximal (r=0.793); p < 0.016 for all the correlations. The activities of ACTIVLIM, such as self-care and mobility, correlated with disability, functional independence, and muscle strength measures. The Brazilian Portuguese version has been completed and presented in this study

A miopatia de Central Core (CCD) é uma doença neuromuscular hereditária, caracterizada pela presença de \"cores\" nas fibras musculares. Clinicamente, os o início dos sintomas nos pacientes é perinatal, com hipotonia, atrofia muscular, hiporreflexia e atraso no desenvolvimento motor. A CCD é causada predominantemente por mutações no gene RYR1.Este gene codifica o receptor de ryanodina, que é um canal de liberação de cálcio intracelular do retículo sarcoplasmático para ocitosol, em resposta a despolarização da membrana plasmática. Mutações nesse gene estão também associadas a suscetibilidade a Hipertermia Maligna (MHS). O objetivo deste trabalho consistiu em realizar estudo molecular para identificação de mutações primárias em pacientes com quadro clínico e histológico CCD, para diagnostico e aconselhamento genético da família. Foram avaliadas 21 famílias com pacientes CCD, e identificamos variantes no gene RYR1 em 20 famílias. Foi possível confirmar a patogenicidade molecular em 16 delas.A maioria destas variantes (23/24) são de sentido trocado, e únicas nas famílias. Duas mutações foram recorrentes em duas famílias. Identificamos 6 famílias (5nãoconsanguíneas)com variantes bialelicas resultando em 28% dos casos com possível herança AR. Identificamos 9 variantes não descritas na literatura, sendo cinco delas de significado patogênico.Identificamos uma família com duas mutações no exon 102, segregando em cis, sugerindo um efeito aditivo de duas mutações em um mesmo alelo. Este trabalho ressalta a importância da utilização da tecnologia de Sequenciamento de Nova Geração para o diagnóstico de doenças genéticas, e seu impacto na melhoria do aconselhamento genético adequado de famílias que possuem doenças genéticas raras e que ainda necessitam de estudos para serem melhor compreendidas Central Core myopathy is an inherited neuromuscular disease, characterized by the presence of Cores in muscle biopsy. The Clinical manifestation of symptoms is perinatal. Patients present hypotonia, muscle atrophy, hyporeflexia, and delayed motor development. CCD is predominantly cause by mutations in the RYR1 gene. This gene encodes the ryanodine receptor 1, which is an intracellular calcium release channel from the sarcoplasmic reticulum to the cytosol, in response to depolarization of the plasma membrane. Mutations in this gene are also associated with Malignant Hyperthermia susceptibility (MHS). The objective of this work was to carry out a molecular study to identify primary mutations in patients with clinical and histological characteristics of CCD, for diagnosis and genetic counseling of the family. We evaluated 21 families with CCD patients and identified RYR1 gene variants in 20 families. It was possible to confirm molecular pathogenicity in 16 of them. Most of these variants (23/24) are missenses and unique in families. Two variants were recurrent in two different families. We identified six families with biallelic mutations, five non-consanguineous, resulting in 28% of cases with possible AR inheritance. We identified nine variants not described in the literature, which five of them were classified as pathogenic. We identified a family with two mutations in exon 102, segregating in cis, suggesting an additive effect of two mutations in the same allele. This work highlights the importance of using New Generation Sequencing technologies for the diagnosis of genetic diseases and their impact on improving adequate genetic counseling for families that have rare genetic diseases, and that still need studies complementary to elucidate them