Limb‐girdle muscular dystrophies (LGMD) are a group of genetically heterogeneous disorders characterized by predominantly proximal muscle weakness. We aimed to characterize epidemiological, clinical and molecular data of patients with autosomal recessive LGMD2/LGMD‐R in Brazil. A multicenter historical cohort study was performed at 13 centers, in which index cases and their affected relatives' data from consecutive families with genetic or pathological diagnosis of LGMD2/LGMD‐R were reviewed from July 2017 to August 2018. Survival curves to major handicap for LGMD2A/LGMD‐R1‐calpain3‐related, LGMD2B/LGMD‐R2‐dysferlin‐related and sarcoglycanopathies were built and progressions according to sex and genotype were estimated. In 370 patients (305 families) with LGMD2/LGMD‐R, most frequent subtypes were LGMD2A/LGMD‐R1‐calpain3‐related and LGMD2B/LGMD‐R2‐dysferlin‐related, each representing around 30% of families. Sarcoglycanopathies were the most frequent childhood‐onset subtype, representing 21% of families. Five percent of families had LGMD2G/LGMD‐R7‐telethonin‐related, an ultra‐rare subtype worldwide. Females with LGMD2B/LGMD‐R2‐dysferlin‐related had less severe progression to handicap than males and LGMD2A/LGMD‐R1‐calpain3‐related patients with truncating variants had earlier disease onset and more severe progression to handicap than patients without truncating variants. We have provided paramount epidemiological data of LGMD2/LGMD‐R in Brazil that might help on differential diagnosis, better patient care and guiding future collaborative clinical trials and natural history studies in the field.

Transthyretin familial amyloid polyneuropathy is an autosomal dominant inherited sensorimotor and autonomic polyneuropathy, which if untreated, leads to death in approximately 10 years. In Brazil, liver transplant and tafamidis are the only disease-modifying treatments available. This review consists of a consensus for the diagnosis, management and treatment for transthyretin familial amyloid polyneuropathy from the Peripheral Neuropathy Scientific Department of the Brazilian Academy of Neurology. The first and last authors produced a draft summarizing the main views on the subject and emailed the text to 10 other specialists. Relevant literature on this subject was reviewed by each participant and used for the individual review of the whole text. Each participant was expected to review the text and send a feedback review by e-mail. Thereafter, the 12 panelists got together at the city of Fortaleza, discussed the controversial points, and reached a consensus for the final text.

Pompe disease (glycogen storage disease type II or acid maltase deficiency) is an inherited autosomal recessive deficiency of acid alpha-glucosidase (GAA), with predominant manifestations of skeletal muscle weakness. A broad range of studies have been published focusing on Pompe patients from different countries, but none from Brazil. We investigated 41 patients with either infantile-onset (21 cases) or late-onset (20 cases) disease by muscle pathology, enzyme activity and GAA gene mutation screening. Molecular analyses identified 71 mutant alleles from the probands, nine of which are novel (five missense mutations c.136T> G, c.650C > T, c.1456G > C, c.1834C > T, and c.1905C > A, a splice-site mutation c.1195-2A > G, two deletions c.18_25del and c.2185delC, and one nonsense mutation c.643G > T). Interestingly, the c.1905C > A variant was detected in four unrelated patients and may represent a common Brazilian Pompe mutation. The c.2560C > T severe mutation was frequent in our population suggesting a high prevalence in Brazil. Also, eight out of the 21 infantile-onset patients have two truncating mutations predicted to abrogate protein expression. Of the ten late-onset patients who do not carry the common late-onset intronic mutation c.-32-13T > G, five (from three separate families) carry the recently described intronic mutation, c.-32-3C > A, and one sibpair carries the novel missense mutation c.1781G > C in combination with known severe mutation c.1941C > G. The association of these variants (c.1781G > C and c.-32-3C > A) with late-onset disease suggests that they allow for some residual activity in these patients. Our findings help to characterize Pompe disease in Brazil and support the need for additional studies to define the wide clinical and pathological spectrum observed in this disease.

Objective: To determine the prevalence of amyotrophic lateral sclerosis (ALS) in the city of Porto Alegre, Brazil. Method: We conducted an extensive investigation in clinics and hospitals that provide specialized assistance to these patients, contacted neurologists and the regional association of people with ALS. Results: On July 31, 2010, 70 patients were alive and diagnosed with amyotrophic lateral sclerosis. Considering the population living in the city in the same period (1,409,351), the estimated prevalence was 5.0 cases per 100,000 people (95% CI, 3.9-6.2), being higher for men (5.2/100,000 95% CI, 3.6-7.2) than for women (4.8/100,000 95% CI, 3.4-6.5). The prevalence increased with age peaking in the age group 70-79 years in both genders. Conclusion: The prevalence of ALS in the city of Porto Alegre is similar to that reported in other parts of the world.

Different types of mutations in the DMD gene underlie Duchenne muscular dystrophies (DMD) and Becker muscular dystrophies (BMD). Large deletions and duplications are the most frequent causative genetic alterations worldwide, but little is known about DMD/BMD genetic profile in Brazil. Hence, we recruited patients with DMD and BMD from 8 neuromuscular reference centers along the country, and performed a comprehensive molecular investigation that included Multiplex Ligation-dependent Probe Amplification and Next generation sequencing (NGS) analyses. We evaluated 199 patients from 177 unrelated families: 166 with DMD, 32 with BMD and 1 1.5 years old asymptomatic patient with persistent hiperCKemia. Overall, large deletions (58.2%) followed by nonsense mutations (12.4%) and large duplications (11.3%) were the most frequent variants in Brazilian families. Large deletions were less frequent in BMD than in DMD (44.8% vs 60.8%). We identified 19 new DMD variants. Nonsense mutations were significantly more frequent in patients from northeastern region than from southern/southeastern regions of Brazil (27.7% vs 8.5%, P < .05). Genetic profile of Brazilian patients with DMD/BMD is similar to previously reported cohorts, but it is not uniform across the country. This information is important to plan rational clinical care for patients in face of the new coming mutation-specific therapies.

RESUMO -

No abstract

A patogênese da Esclerose Lateral Amiotrófica (ELA) não está definida, tendo como principais possibilidades, a excitotoxicidade glutamatérgica sobre os neurônios motores, a disfunção mitocondrial, o estresse oxidativo, a agregação proteica, o déficit de transporte axonal, aliado a inflamação peri-neuronal, sinalização aberrante de fatores de crescimento e, provavelmente outras causas ainda não aventadas ou menos "votadas". Portanto, com inúmeras hipóteses, a ciência neurológica não sabe, verdadeiramente, a(s) causa(s) da ELA.Para uma adequada terapêutica, o conhecimento das causas da enfermidade seria fundamental. Como visto acima, a etiologia não está definida, assim, está sendo necessário lançar mão de algumas estratégias para tentar novas terapêuticas. Entre estas estratégicas está a indução de animais mutantes com características clínicas semelhantes às da ELA humana, em especial a deficiência da enzima superóxido dismutase I, encontrada em uma forma de ELA familiar. Desta forma pode-se realizar estudos pré-clínicos na tentativa de desenvolver medicamentos com base nas teorias etiológicas acima expostas.Outra estratégia para se encontrar outras drogas é a de, após escolhido o mecanismo causador a ser estudado, geralmente de forma prévia por estudos em animais, verifica-se no mercado se já há drogas existentes e licenciadas que se enquadrem no perfil de combate a possível etiologia em estudo. Desta forma pode-se iniciar testes clínicos com maior rapidez e grande economia.Para exemplificar tal estratégia, pode-se tomar como base a seguinte premissa: a redução do nível de glutamamto ns sinpases se deveria ao aumento da captação dessa substância por células nervosas (astrócitos e gliócitos). Isso é mediado pela expressão de um transportador de glutamamto (EAAT2). Assim, foram avaliados 1040 compostos aprovados