ABSTRACT
Limb-girdle muscular dystrophy type 2G/R7 (LGMD2G/R7) is an ultra-rare condition initially identified within the Brazilian population. We aimed to expand clinical and genetic information about this disease, including its worldwide distribution. A multicenter historical cohort study was performed at 13 centers in Brazil in which data from index cases and their affected relatives from consecutive families with LGMD2G/R7 were reviewed from July 2017 to August 2023. Additionally, a systematic literature review was conducted to identify case reports and series of the disease worldwide. Forty-one LGMD2G/R7 cases were described in the Brazilian cohort, being all subjects homozygous for the c.157C>T/(p.Gln53*) variant in TCAP. Survival curves showed that the median disease duration before individuals required walking aids was 21 years. Notably, women exhibited a slower disease progression, requiring walking aids 13 years later than men. LGMD2G/R7 was frequently reported not only in Brazil but also in China and Bulgaria, with 119 cases identified globally, with possible founder effects in the Brazilian, Eastern European, and Asian populations. These findings are pivotal in raising awareness of LGMD2G/R7, understanding its progression, and identifying potential modifiers. This can significantly contribute to the development of future natural history studies and clinical trials for this disease.
ABSTRACT
BACKGROUND: Because MS-related fatigue could be associated with enhanced proinflammatory cytokine production, drugs with immunomodulatories properties, such as salbutamol, may represent an alternative treatment. We aimed to evaluate the effect of salbutamol on MS-related fatigue. METHODS: Thirty patients with relapsing-remitting MS who were between 18 and 69 years old, and suffering from fatigue, were evaluated with the Fatigue Severity Scale (FSS) and the Brazilian version of the neurological fatigue index for multiple sclerosis (NFI/MS-BR). They received salbutamol 2 mg twice a day or a placebo in a pilot randomized, double-masked placebo-controlled trial. The primary outcome was the change in the FSS score at the end of 90 days. The secondary outcome was the efficacy, represented by changes in their scores on the NFI/MS-BR subdomains (in the same period) and the Expanded Disability Status Scale (EDSS) at the end of 90 days. RESULTS: Thirty subjects were allocated to receive either salbutamol (14) or a placebo (16). There was no superiority of salbutamol over the placebo in the FSS outcome at 30 (p ==0.498), 60 (p = 0.854) and 90 (p = 0.240) days. There was no a significant decrease in the proportion of patients with severe or moderate fatigue in the salbutamol group at the end of the follow-up. The scores on the NFI/MS-BR and its subscales did not improve significantly with treatment. No significant difference was observed in the EDSS outcome (p = 0.313). No serious adverse events were found. An increase in heart rate was evident in the salbutamol group only in the first 30 days, but without statistical significance in relation to placebo (p = 0.077). CONCLUSION: Treatment with salbutamol does not improve fatigue in patients with relapsing-remitting MS.
Subject(s)
Multiple Sclerosis , Adolescent , Adult , Aged , Albuterol/therapeutic use , Brazil , Double-Blind Method , Fatigue/drug therapy , Fatigue/etiology , Humans , Middle Aged , Multiple Sclerosis/complications , Multiple Sclerosis/drug therapy , Multiple Sclerosis, Relapsing-Remitting/complications , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Young AdultABSTRACT
Among agents of chromoblastomycosis, Fonsecaea pugnacius presents a unique type of infection because of its secondary neurotropic dissemination from a chronic cutaneous case in an immunocompetent patient. Neurotropism occurs with remarkable frequency in the fungal family Herpotrichiellaceae, possibly associated with the ability of some species to metabolize aromatic hydrocarbons. In an attempt to understand this new disease pattern, were conducted genomic analysis of Fonsecaea pugnacius (CBS 139214) performed with de novo assembly, gene prediction, annotation and mitochondrial genome assembly, supplemented with animal infection models performed with Tenebrio molitor in Mus musculus lineages BALB/c and C57BL/6. The genome draft of 34.8 Mb was assembled with a total of 12,217 protein-coding genes. Several proteins, enzymes and metabolic pathways related to extremotolerance and virulence were recognized. The enzyme profiles of black fungi involved in chromoblastomycosis and brain infection were analyzed with the Carbohydrate-Active Enzymes (CAZY) and peptidases database (MEROPS). The capacity of the fungus to survive inside Tenebrio molitor animal model was confirmed by histopathological analysis and by presence of melanin and hyphae in host tissue. Although F. pugnacius was isolated from brain in a murine model following intraperitoneal infection, cytokine levels were not statistically significant, indicating a profile of an opportunistic agent. A dual ecological ability can be concluded from presence of metabolic pathways for nutrient scavenging and extremotolerance, combined with a capacity to infect human hosts.
ABSTRACT
Significant advances in the understanding and management of Duchenne muscular dystrophy (DMD) took place since international guidelines were published in 2010. Our objective was to provide an evidence-based national consensus statement for multidisciplinary care of DMD in Brazil. A combination of the Delphi technique with a systematic review of studies from 2010 to 2016 was employed to classify evidence levels and grade of recommendations. Our recommendations were divided in two parts. We present Part 1 here, where we describe the guideline methodology and overall disease concepts, and also provide recommendations on diagnosis, steroid therapy and new drug treatment perspectives for DMD. The main recommendations: 1) genetic testing in diagnostic suspicious cases should be the first line for diagnostic confirmation; 2) patients diagnosed with DMD should have steroids prescribed; 3) lack of published results for phase 3 clinical trials hinders, for now, the recommendation to use exon skipping or read-through agents.
Subject(s)
Evidence-Based Medicine , Glucocorticoids/therapeutic use , Muscular Dystrophy, Duchenne/diagnosis , Muscular Dystrophy, Duchenne/drug therapy , Brazil , Clinical Trials as Topic , Delphi Technique , Follow-Up Studies , Genetic Testing , Humans , Muscular Dystrophy, Duchenne/genetics , Patient Care Team , Review Literature as Topic , Treatment OutcomeABSTRACT
ABSTRACT Significant advances in the understanding and management of Duchenne muscular dystrophy (DMD) took place since international guidelines were published in 2010. Our objective was to provide an evidence-based national consensus statement for multidisciplinary care of DMD in Brazil. A combination of the Delphi technique with a systematic review of studies from 2010 to 2016 was employed to classify evidence levels and grade of recommendations. Our recommendations were divided in two parts. We present Part 1 here, where we describe the guideline methodology and overall disease concepts, and also provide recommendations on diagnosis, steroid therapy and new drug treatment perspectives for DMD. The main recommendations: 1) genetic testing in diagnostic suspicious cases should be the first line for diagnostic confirmation; 2) patients diagnosed with DMD should have steroids prescribed; 3) lack of published results for phase 3 clinical trials hinders, for now, the recommendation to use exon skipping or read-through agents.
RESUMO Avanços na compreensão e no manejo da distrofia muscular de Duchenne (DMD) ocorreram desde a publicação de diretrizes internacionais em 2010. Nosso objetivo foi elaborar um consenso nacional baseado em evidências de cuidado multidisciplinar dos pacientes com DMD no Brasil. Utilizamos a técnica de Delphi combinada com revisão sistemática da literatura de 2010 a 2016 classificando níveis de evidência e graus de recomendação. Nossas recomendações foram divididas em duas partes. Apresentamos aqui a parte 1, descrevendo a metodologia utilizada e conceitos gerais da doença, e fornecemos recomendações sobre diagnóstico, tratamento com corticosteroides e novas perspectivas de tratamentos medicamentosos. As principais recomendações: 1) testes genéticos deveriam ser a primeira linha para confirmação de casos suspeitos; 2) pacientes com diagnóstico de DMD devem receber corticosteroides; 3) por enquanto, a falta de publicações de resultados dos ensaios clínicos de fase 3, dificulta recomendações de uso medicamentos que "saltam exons" ou "passam" por código de parada prematura.
Subject(s)
Humans , Evidence-Based Medicine , Muscular Dystrophy, Duchenne/diagnosis , Muscular Dystrophy, Duchenne/drug therapy , Glucocorticoids/therapeutic use , Patient Care Team , Brazil , Review Literature as Topic , Genetic Testing , Clinical Trials as Topic , Follow-Up Studies , Delphi Technique , Treatment Outcome , Muscular Dystrophy, Duchenne/geneticsABSTRACT
This study aimed to analyze the outcome and impact of pregnancy in women with myasthenia gravis (MG). Obstetric and clinical data were retrospectively analyzed before, during and after pregnancy. Predictors of outcome were studied. We included 35 pregnancies from 21 MG patients. In the course of MG symptoms in 30 pregnancies with live births, 50% deteriorated (mainly during the second trimester, p = 0.028), 30% improved, and 20% remained unchanged. The deterioration group had more frequent abnormal repetitive nerve stimulation (RNS) (p = 0.028) and lower myasthenia gravis composite (MGC) scores (p = 0.045) before pregnancy. The improvement group was associated with higher MGC scores (p = 0.012) before pregnancy. The no-change group was associated with longer duration of MG (p = 0.026) and normal RNS (p = 0.008) before pregnancy. The course of MG in the second pregnancy was different from that in the previous pregnancy in 65.3% of cases. Obstetric complications were reported in 20 pregnancies; the most common was preterm premature rupture of membranes (PPROM) (25.8%), and the most severe were abortion (11.4%) and fetal death (2.9%). Most of the patients delivered via caesarean section (66.7%). Spinal anesthesia was performed in 73.3%. Transient neonatal myasthenia gravis occurred in 12.9% of live-born infants, and no predictors were found. In conclusion, severity and duration of MG, RNS and treatment influence MG and pregnancy. Pregnant MG patients have greater rates of PPROM and caesarean delivery. Our data suggest that duration of MG, MGC and RNS before pregnancy may be useful in helping to predict the course of MG during pregnancy.
Subject(s)
Myasthenia Gravis/diagnosis , Pregnancy Complications/diagnosis , Adult , Female , Fetal Membranes, Premature Rupture/diagnosis , Fetal Membranes, Premature Rupture/epidemiology , Follow-Up Studies , Humans , Myasthenia Gravis/epidemiology , Pregnancy , Pregnancy Complications/epidemiology , Young AdultABSTRACT
Serological diagnosis of flavivirus infection is a challenge, particularly in the context of a disease associated with immune response enhancement in a transplant patient, where aspects such as previous flavivirus infections may be involved with the outcome. We report a case of a pediatric patient who developed Guillain-Barré syndrome (GBS) after matched-unrelated hematopoietic stem cell transplantation (HSCT). The patient lives in a Brazilian region that is experiencing an epidemic of Zika virus (ZIKV) and dengue virus (DENV). Because an increasing number of cases of GBS, likely triggered by ZIKV infection, are being reported in Brazil, samples from the patient were tested for both ZIKV and DENV infection. Serological assays strongly suggested a recent ZIKV infection, although infection by DENV or co-infection with both viruses cannot be ruled out. The presence of anti-DENV immunoglobulin-G in donor serum led to the hypothesis that antibodies from the donor could have enhanced the severity of the ZIKV infection. This hypothesis is in agreement with the recent findings that DENV sero-cross-reactivity drives antibody-dependent enhancement of ZIKV infection. These findings highlight the need for discussion of the indication to perform previous flavivirus tests in HSCT donors, especially in areas where ZIKV and other flaviviruses co-circulate.
Subject(s)
Dengue Virus/immunology , Dengue/complications , Guillain-Barre Syndrome/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Zika Virus Infection/complications , Zika Virus/immunology , Antibodies, Viral/blood , Brazil , Child , Coinfection , Cross Reactions , Dengue/diagnosis , Dengue/virology , Female , Guillain-Barre Syndrome/diagnosis , Guillain-Barre Syndrome/immunology , Humans , Immunoglobulin M/blood , Serologic Tests , Zika Virus Infection/diagnosis , Zika Virus Infection/virologyABSTRACT
OBJECTIVE: To identify the molecular basis and elucidate the pathogenesis of a fatal congenital myasthenic syndrome. METHODS: We performed clinical electrophysiology studies, exome and Sanger sequencing, and analyzed functional consequences of the identified mutation. RESULTS: Clinical electrophysiology studies of the patient revealed several-fold potentiation of the evoked muscle action potential by high frequency nerve stimulation pointing to a presynaptic defect. Exome sequencing identified a homozygous c.340delA frameshift mutation in synaptobrevin 1 (SYB1), one of the three SNARE proteins essential for synaptic vesicle exocytosis. Analysis of both human spinal cord gray matter and normal human muscle revealed expression of the SYB1A and SYB1D isoforms, predicting expression of one or both isoforms in the motor nerve terminal. The identified mutation elongates the intravesicular C-terminus of the A isoform from 5 to 71, and of the D isoform from 4 to 31 residues. Transfection of either mutant isoform into bovine chromaffin cells markedly reduces depolarization-evoked exocytosis, and transfection of either mutant isoform into HEK cells significantly decreases expression of either mutant compared to wild type. INTERPRETATION: The mutation is pathogenic because elongation of the intravesicular C-terminus of the A and D isoforms increases the energy required to move their C-terminus into the synaptic vesicle membrane, a key step for fusion of the synaptic vesicle with the presynaptic membrane, and because it is predicted to reduce expression of either isoform in the nerve terminal.
ABSTRACT
UNLABELLED: The aim of the study was to analyze a series of Brazilian patients with Niemann-Pick disease type C (NP-C). METHOD: Correlations between clinical findings, laboratory data, molecular findings and treatment response are presented. RESULT: The sample consisted of 5 patients aged 8 to 26 years. Vertical supranuclear gaze palsy, cerebellar ataxia, dementia, dystonia and dysarthria were present in all cases. Filipin staining showed the "classical" pattern in two patients and a "variant" pattern in three patients. Molecular analysis found mutations in the NPC1 gene in all alleles. Miglustat treatment was administered to 4 patients. CONCLUSION: Although filipin staining should be used to confirm the diagnosis, bone marrow sea-blue histiocytes often help to diagnosis of NP-C. The p.P1007A mutation seems to be correlated with the "variant" pattern in filipin staining. Miglustat treatment response seems to be correlated with the age at disease onset and disability scale score at diagnosis.
Subject(s)
Niemann-Pick Disease, Type C/genetics , Niemann-Pick Disease, Type C/pathology , Adolescent , Adult , Age of Onset , Biopsy, Needle , Bone Marrow Cells/pathology , Brain/pathology , Brazil , Carrier Proteins/genetics , Cells, Cultured , Child , Female , Fibroblasts , Humans , Intracellular Signaling Peptides and Proteins , Magnetic Resonance Imaging , Male , Membrane Glycoproteins/genetics , Mutation , Niemann-Pick C1 Protein , Niemann-Pick Disease, Type C/drug therapy , Polymerase Chain Reaction , Retrospective Studies , Severity of Illness Index , Skin/pathology , Young AdultABSTRACT
The aim of the study was to analyze a series of Brazilian patients with Niemann-Pick disease type C (NP-C). Method Correlations between clinical findings, laboratory data, molecular findings and treatment response are presented. Result The sample consisted of 5 patients aged 8 to 26 years. Vertical supranuclear gaze palsy, cerebellar ataxia, dementia, dystonia and dysarthria were present in all cases. Filipin staining showed the “classical” pattern in two patients and a “variant” pattern in three patients. Molecular analysis found mutations in the NPC1 gene in all alleles. Miglustat treatment was administered to 4 patients. Conclusion Although filipin staining should be used to confirm the diagnosis, bone marrow sea-blue histiocytes often help to diagnosis of NP-C. The p.P1007A mutation seems to be correlated with the “variant” pattern in filipin staining. Miglustat treatment response seems to be correlated with the age at disease onset and disability scale score at diagnosis. .
O objetivo desse estudo foi analisar uma série de casos de pacientes brasileiros com doença de Niemann-Pick tipo C (NP-C). Método Correlação entre manifestações clínicas, alterações laboratoriais, estudo molecular e resposta ao tratamento foram realizadas. Resultado A amostra consiste de 5 pacientes com idade entre 8 e 26 anos. Paralisia do olhar vertical supranuclear, ataxia cerebelar, demência, distonia e disartria estavam presentes em todos os casos. Coloração de filipina na cultura de fibroblastos mostrou padrão “clássico” em dois pacientes e padrão “variante” em três casos. O estudo molecular encontrou mutações no gene NPC1 em todos os alelos. O tratamento com miglustate foi realizado em 4 pacientes. Conclusão Embora coloração de filipina seja utilizada para confirmar o diagnóstico, o histiócito azul-marinho no aspirado de medula óssea frequentemente auxilia a confirmar o diagnóstico de NP-C. A mutação p.P1007A está correlacionada com o padrão “ variante” na coloração de filipina. A resposta ao tratamento com miglustate parece estar correlacionada com a idade e escore de desabilidade no momento do diagnóstico. .
Subject(s)
Adolescent , Adult , Child , Female , Humans , Male , Young Adult , Niemann-Pick Disease, Type C/genetics , Niemann-Pick Disease, Type C/pathology , Age of Onset , Biopsy, Needle , Brazil , Bone Marrow Cells/pathology , Brain/pathology , Cells, Cultured , Carrier Proteins/genetics , Fibroblasts , Magnetic Resonance Imaging , Mutation , Membrane Glycoproteins/genetics , Niemann-Pick Disease, Type C/drug therapy , Polymerase Chain Reaction , Retrospective Studies , Severity of Illness Index , Skin/pathologyABSTRACT
INTRODUCTION: Salbutamol is a selective B2-adrenergic agonist, which has previously been described to be associated with partial improvement of myasthenia gravis and congenital myasthenic syndromes (CMS). In this study, we analyzed the effect of salbutamol in five patients with Dok-7 CMS. METHODS: We studied 5 patients (2 male and 3 female), with a mean age of 27±11.06 years, who harbored c.1124_1127dupTGCC, p.G64R and/or p.S45L mutations in DOK7 gene. Salbutamol was given at a dose of 2mg three times daily (6 mg/day) to all patients. The response was assessed by QMG score at baseline, 3, 6, 9 and 12 months; ADL-MG score and 6 minute walk test at baseline and after 12 months during follow-up clinic visits. Side effect profile of salbutamol was also evaluated. RESULTS: We noted an increasingly positive response as measured by the QMG score after 3 months of salbutamol treatment. Improvement in specific subcomponents of the QMG score such as leg outstretched in 45° supine was most marked. In ADL-MG scores and 6 minute walk test, comparison between baseline and after 12 months revealed a clear beneficial response. Salbutamol was well tolerated in all patients. CONCLUSIONS: Salbutamol is an effective treatment in Dok-7 CMS. This study provides class IV evidence that salbutamol given at a dose 6 mg/day improves function as measured by the QMG score, ADL-MG score and 6 minute walk test.
Subject(s)
Adrenergic beta-2 Receptor Agonists/therapeutic use , Albuterol/therapeutic use , Muscle Proteins/genetics , Mutation/genetics , Myasthenic Syndromes, Congenital/drug therapy , Myasthenic Syndromes, Congenital/genetics , Adolescent , Adult , Age Factors , Female , Follow-Up Studies , Humans , Male , Myasthenic Syndromes, Congenital/physiopathology , Neurologic Examination , Young AdultABSTRACT
PURPOSE: Phenytoin is known to be able to induce cerebellar atrophy in patients with epilepsy. It is also known that a CYP2C9 mutation (*2 or *3) reduces phenytoin metabolism by 25-50% and can increase the risk of phenytoin-related side effects. We examined the influence of CYP2C9 polymorphisms on total cerebellar volume and cerebellar gray and white matter volumes in patients with epilepsy taking phenytoin. METHODS: For the genotyping, 100 adult patients with documented epilepsy who had been taking phenytoin for >1 year were selected. From this group, we randomly selected 19 mutant individuals (MT group; CYP2C9*2 and *3) for a whole-brain volume measurement using MRI and 19 wild-type individuals (group WT; CYP2C9*1) with similar clinical and demographic characteristics to those in the MT group for comparison. Total intracranial volume measurements were used to normalize the acquired volumes, which were separated into gray matter volume, white matter volume, and total volume. RESULTS: The MT group exhibited a significant reduction in cerebellar white matter volume (p=0.002) but not in total cerebellar volume. CONCLUSION: Our study is the first to report evidence linking CYP2C9 polymorphism and a reduction in cerebellar volume in epileptic users of phenytoin.
Subject(s)
Anticonvulsants/adverse effects , Aryl Hydrocarbon Hydroxylases/genetics , Atrophy/genetics , Cerebellar Diseases/genetics , Epilepsy/genetics , Phenytoin/adverse effects , Polymorphism, Single Nucleotide , Adolescent , Adult , Aged , Alleles , Anticonvulsants/therapeutic use , Atrophy/chemically induced , Cerebellar Diseases/chemically induced , Cytochrome P-450 CYP2C9 , Epilepsy/drug therapy , Female , Gene-Environment Interaction , Genotype , Humans , Male , Middle Aged , Phenytoin/therapeutic useABSTRACT
Neurological disorders associated with glutamic acid decarboxylase (GAD) antibodies are rare pleomorphic diseases of uncertain cause, of which stiff-person syndrome (SPS) is the best-known. Here, we described nine consecutive cases of neurological disorders associated with anti-GAD, including nine patients with SPS and three cases with cerebellar ataxia. Additionally, four had hypothyroidism, three epilepsy, two diabetes mellitus and two axial myoclonus.