RESUMO
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.
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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.
Assuntos
Vírus da Dengue/imunologia , Dengue/complicações , Síndrome de Guillain-Barré/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecção por Zika virus/complicações , Zika virus/imunologia , Anticorpos Antivirais/sangue , Brasil , Criança , Coinfecção , Reações Cruzadas , Dengue/diagnóstico , Dengue/virologia , Feminino , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/imunologia , Humanos , Imunoglobulina M/sangue , Testes Sorológicos , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/virologiaRESUMO
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.
Assuntos
Esclerose Múltipla , Adolescente , Adulto , Idoso , Albuterol/uso terapêutico , Brasil , Método Duplo-Cego , Fadiga/tratamento farmacológico , Fadiga/etiologia , Humanos , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/complicações , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto JovemRESUMO
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.
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Neurofibromatosis type 1, or von Recklinghausen disease, is a progressive, autosomal dominant, monogenic disease. Spinal muscular atrophy is a progressive, autosomal recessive, monogenic disease. Specific anti-polysaccharide antibody deficiency is an immune disorder suspected in any child older than 2 years who suffers from recurrent respiratory tract infections or in patients with unusually severe complications from infections under appropriate treatment. Reported here is the coinheritance of two monogenic syndromes in the same patient, a novel association with specific anti-polysaccharide antibody deficiency.
Assuntos
Síndromes de Imunodeficiência/complicações , Atrofia Muscular Espinal/complicações , Neurofibromatose 1/complicações , Criança , Humanos , Masculino , Atrofia Muscular Espinal/genética , Neurofibromatose 1/patologiaRESUMO
Here we report on a 44-year old woman presenting with both myasthenia gravis (MG) and neuromyelitis optica (NMO). MRI showed transverse myelitis extending from C2 to T4, multifocal demyelinating lesions in the supratentorial white matter, and left optic neuritis. Serological analysis demonstrated antibodies to acetylcholine receptors as well as NMO-IgG. To our knowledge, this is the first case of NMO-IgG positive NMO in a patient with MG but no history of thymectomy or immunosuppression.
Assuntos
Imunoglobulina G/metabolismo , Miastenia Gravis/complicações , Neuromielite Óptica/etiologia , Neuromielite Óptica/imunologia , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Neuromielite Óptica/patologia , Timectomia/métodosRESUMO
Lambert-Eaton myasthenic syndrome (LEMS) is an immune-mediated disorder of the neuromuscular junction that rarely is associated with cerebellar ataxia (CA). We describe two patients with non-paraneoplastic LEMS associated with CA who showed high levels of anti-P/Q-type voltage-gated calcium channels antibodies in the serum and cerebrospinal fluid, and reduced CMAP with increment after brief maximum voluntary contraction in electrophysiological studies. We suggest that LEMS should be considered in the differential diagnosis of patients with CA.
Assuntos
Ataxia Cerebelar/complicações , Síndrome Miastênica de Lambert-Eaton/complicações , Potenciais de Ação/fisiologia , Adulto , Anticorpos/sangue , Canais de Cálcio/imunologia , Ataxia Cerebelar/sangue , Ataxia Cerebelar/líquido cefalorraquidiano , Ataxia Cerebelar/tratamento farmacológico , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndrome Miastênica de Lambert-Eaton/sangue , Síndrome Miastênica de Lambert-Eaton/líquido cefalorraquidiano , Síndrome Miastênica de Lambert-Eaton/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Condução Nervosa/fisiologia , Síndromes Paraneoplásicas/sangue , Síndromes Paraneoplásicas/complicaçõesRESUMO
Scoliosis involves the central nervous system diseases, ligaments, articulations and skeletal muscles, but there is no consensus on its pathogeny and progression of muscle abnormalities. In this study, we investigate the morphologic changes in the muscle of rabbit submitted to experimental scoliosis, with special emphasis on abnormalities related to blood supply. We studied 26 rabbits subjected to costotransversectomy by pulling out six transverse processes at thoracic level and six rabbits were used as controls. All the animals operated upon developed scoliosis showing an average angle of 29.1 degrees on the 60th day, with its apices located at T4 and T12 when they were subjected to paraspinal muscle biopsy on both sides. The muscle biopsies were subjected to histological stains and histochemical reactions, as well as to a morphometric study. On the concave side, the changes were not statistically significant regarding the control group. On the convex side conjunctive tissue proliferation, infiltration by adipose tissue, central nucleus excess, inflammatory reaction, segmental fibrosis, type 1 fiber hypertrophy, type 2 fiber hypertrophy and atrophic angular dark fibers in the unspecific esterase were statistically significant. The segmental fibrosis reached a circumscribed muscle segment, compatible with an ischemic phenomenon. The histological diagnoses on the concave side of the animals had unspecific alterations (atrophy and hypertrophy) in 13, myopathy in 3, denervation in 3 and normal in 7. The convex side diagnoses were myopathy in 14, denervation in 8, mixed in 3 and normal in 1. The procedure determined morphologic changes on the convex side indicating possible denervation or myopathy of ischemic origin.
Assuntos
Isquemia/patologia , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Escoliose/patologia , Animais , Modelos Animais de Doenças , Humanos , Isquemia/etiologia , Coelhos , Escoliose/complicaçõesRESUMO
The Dandy-Walker syndrome (DWS) is a rare posterior fossa malformation. The DWS can occur associated with other brain or systemic malformations, but ocular abnormalities in this disease are rare and clinical findings mimicking myasthenia gravis have not been described to date. We report a 23-year-old woman who presented mild limitation of the ocular movements with progressive palpebral ptosis, which changed in intensity during the day. The investigation showed negative anti-acetylcholine receptor antibody, repetitive nerve stimulation and "Tensilon test", but the brain magnetic resonance image reveals DWS with hydrocephalus associated with callosal dysgenesis. The characteristic of disease, clinical manifestations and pathologic features, specially the clinical evaluation of ocular abnormalities in suspicion of DWS, including the MG in differential diagnosis are discussed.
Assuntos
Síndrome de Dandy-Walker/diagnóstico , Miastenia Gravis/diagnóstico , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Imageamento por Ressonância MagnéticaRESUMO
OBJECTIVE: To identify and quantify frontal sharp transients found in neonatal polysomnography of healthy full term newborns in each stage of the sleep-wake cycle within the first 48 hours of life. METHOD: The EEG from healthy term 32 newborns, legal age of two days and with adequate monitoring during pregnancy. Frontal sharp transients (FST) were quantified, according to synchronous or asynchronous, in each stage of the sleep-wake cycle. The results were compared by Kruskal-Wallis-test. RESULTS: FST were counted individually in each sleep phase, being present during quiet sleep (QS) in all tracings. FST bilateral and synchronous and lateralized FST were more frequent during QS (p<0.05). CONCLUSION: Lateralized FST were found mostly during quiet sleep. FST asynchronous in healthy full term newborns were normal and depended of FST density. FST unilateral appearance should not necessarily be considered abnormal as well.
Assuntos
Eletroencefalografia , Lobo Frontal/fisiologia , Recém-Nascido/fisiologia , Polissonografia/métodos , Sono/fisiologia , Índice de Apgar , Arritmias Cardíacas/diagnóstico , Peso Corporal , Feminino , Idade Gestacional , Humanos , Masculino , Fases do Sono/fisiologia , Estatísticas não ParamétricasRESUMO
Dopa-responsive dystonia (DRD) is an inherited metabolic disorder now classified as DYT5 with two different biochemical defects: autosomal dominant GTP cyclohydrolase 1 (GCH1) deficiency or autosomal recessive tyrosine hydroxylase deficiency. We report the case of a 10-years-old girl with progressive generalized dystonia and gait disorder who presented dramatic response to levodopa. The phenylalanine to tyrosine ratio was significantly higher after phenylalanine loading test. This condition had two different heterozygous mutations in the GCH1 gene: the previously reported P23L mutation and a new Q182E mutation. The characteristics of the DRD and the molecular genetic findings are discussed.
Assuntos
Dopaminérgicos/uso terapêutico , Distonia/tratamento farmacológico , Distonia/genética , GTP Cicloidrolase/genética , Levodopa/uso terapêutico , Mutação de Sentido Incorreto/genética , Criança , Distonia/sangue , Feminino , Heterozigoto , Humanos , Fenilalanina/sangue , Tirosina/sangueRESUMO
Menkes disease is a rare neurodegenerative disorder due to an intracellular defect of a copper transport protein. We describe a 7 months male patient who presented with seizures, hypoactivity and absence of visual contact. The investigation disclosed pilli torti and thrycorrexis nodosa in the hair, low serum levels of both copper and ceruloplasmin, brain magnetic resonance study showed atrophy and white matter hypointensities on T1-weighted images, electroencephalogram reveals moderate background activity disorganization and epileptiform activity, and muscle biopsy with type 2 fiber atrophy. The clinical, laboratorial, genetic, muscle biopsy and neurophysiological findings in Menkes disease are discussed.
Assuntos
Ceruloplasmina/análise , Cobre/sangue , Síndrome dos Cabelos Torcidos/diagnóstico , Eletroencefalografia , Eletromiografia , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Síndrome dos Cabelos Torcidos/sangueRESUMO
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.
Assuntos
Miastenia Gravis/diagnóstico , Complicações na Gravidez/diagnóstico , Adulto , Feminino , Ruptura Prematura de Membranas Fetais/diagnóstico , Ruptura Prematura de Membranas Fetais/epidemiologia , Seguimentos , Humanos , Miastenia Gravis/epidemiologia , Gravidez , Complicações na Gravidez/epidemiologia , Adulto JovemRESUMO
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.
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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.
Assuntos
Medicina Baseada em Evidências , Glucocorticoides/uso terapêutico , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/tratamento farmacológico , Brasil , Ensaios Clínicos como Assunto , Técnica Delphi , Seguimentos , Testes Genéticos , Humanos , Distrofia Muscular de Duchenne/genética , Equipe de Assistência ao Paciente , Literatura de Revisão como Assunto , Resultado do TratamentoRESUMO
Dropped head is a syndrome caused by weakness of the neck extensor muscles found in different kinds of neuromuscular disorders and also in amyotrophic lateral sclerosis. This is a cases report of three women with motor neuron disease with beginning of dysphagia and cervical weakness that it evolved with dropped head. The investigation showed normal magnetic resonance imaging of brain and cervical column. Needle electromyography showed active and chronic denervation in bulbar muscles and cervical, thoracic and lumbosacral segments. We discuss the characteristic of disease, specially the clinical manifestations and electromyography features, with emphasis at the clinical evaluation of dropped head in the suspicion of motor neuron disease.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Debilidade Muscular/diagnóstico , Músculos do Pescoço , Idoso , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/fisiopatologia , Eletromiografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Debilidade Muscular/fisiopatologia , Músculos do Pescoço/fisiopatologia , Postura , SíndromeRESUMO
We described a patient with clinical findings from Kennedy's disease and positive genetic study for Kugelberg-Welander's disease. A 24 years old man with negative family history presented with progressive spinal and bulbar muscular atrophy and gynecomastia at the age of 14. He was clinically diagnosed as having Kennedy's disease. However, a genetic study performed later was found to be negative for this disease and was positive for Kugelberg-Welander's disease, with deletion of the exons 7 and 8 in the "survival of motor neuron" gene.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteínas do Tecido Nervoso/genética , Fenótipo , Proteínas de Ligação a RNA/genética , Atrofias Musculares Espinais da Infância/diagnóstico , Adulto , Diagnóstico Diferencial , Éxons/genética , Deleção de Genes , Humanos , Masculino , Atrofia Muscular Espinal/diagnóstico , Proteínas do Complexo SMN , Atrofias Musculares Espinais da Infância/genéticaRESUMO
The association between the use of statins and neuromuscular disease is currently being intensely discussed. We relate a 63 years old man with possible case of statin-induced neuropathy in a patient with dislipidemia in use of simvastatina at high doses. The electrophysiologic studies disclosed findings compatible with mononeuropathy multiplex, suggested by clinical prescutation of asymmetrical numbness and weakness. More common causes of mononeuropathy multiplex were excluded and the patient improved after the discontinuation of the drug.
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Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Mononeuropatias/induzido quimicamente , Sinvastatina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Mononeuropatias/diagnósticoRESUMO
We describe a female patient with hemimasticatory spasm, a rare movement disorder due to dysfunction of the motor trigeminal nerve of unknown origin. This patient had an excellent response to botulinum toxin therapy.
Assuntos
Antidiscinéticos/uso terapêutico , Toxinas Botulínicas/uso terapêutico , Espasmo Hemifacial/tratamento farmacológico , Doenças do Nervo Trigêmeo/complicações , Adulto , Feminino , HumanosRESUMO
Cerebrotendinous xanthomatosis is a treatable rare autossomal recessive disease characterized by lipid storage secondary to a sterol 27-hydroxylase deficiency in the formation of cholic and chenodeoxycholic acids. We describe two Brazilian brothers with cognitive impairement and chronic diarrhea. One of them also presents bilateral cataracts. Neurological findings were progressive walking deficit, limb ataxia and pyramidal signs. Both patients had bilateral Achilles tendon xanthomata. Magnetic resonance image showed signal alterations in cerebellar hemispheres. We describe these cases with molecular genetic analysis confirming diagnosis and comparing with previous literature. The CYP27A1 gene study showed a C1187T mutation on exon 6.