RESUMO
OBJECTIVE: Protein misfolding plays a central role not only in amyotrophic lateral sclerosis (ALS), but also in other conditions, such as frontotemporal dementia (FTD), inclusion body myopathy (hIBM) or Paget's disease of bone. The concept of multisystem proteinopathies (MSP) was created to account for those rare families that segregate at least 2 out of these 4 conditions in the same pedigree. The calcium-dependent phospholipid-binding protein annexin A11 was recently associated to ALS in European pedigrees. Herein, we describe in detail 3 Brazilian families presenting hIBM (isolated or in combination with ALS/FTD) caused by the novel p.D40Y change in the gene encoding annexin A11 (ANXA11). METHODS: We collected clinical, genetic, pathological and skeletal muscle imaging from 11 affected subjects. Neuroimaging was also obtained from 8 patients and 8 matched controls. RESULTS: Clinico-radiological phenotype of this novel hIBM reveals a slowly progressive predominant limb-girdle syndrome, but with frequent axial (ptosis/dropped head) and distal (medial gastrocnemius) involvement as well. Muscle pathology identified numerous rimmed vacuoles with positive annexin A11, TDP-43 and p62 inclusions, but no inflammation. Central nervous system was also involved: two patients had FTD, but diffusion tensor imaging uncovered multiple areas of cerebral white matter damage in the whole group (including the corticospinal tracts and frontal subcortical regions). INTERPRETATION: These findings expand the phenotypic spectrum related to ANXA11. This gene should be considered the cause of a novel multisystem proteinopathy (MSP type 6), rather than just ALS. ANN NEUROL 2021;90:239-252.
Assuntos
Anexinas/genética , Variação Genética/genética , Mutação de Sentido Incorreto/genética , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/genética , Idoso , Sequência de Aminoácidos , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Linhagem , Sequenciamento do Exoma/métodosRESUMO
BACKGROUND: Hereditary spastic paraplegia presents spasticity as the main clinical manifestation, reducing gait quality and producing incapacity. Management with botulinum toxin type A (BoNT-A) is not well elucidated. The objective of the current study was to evaluate the efficacy and safety of BoNT-A in patients with hereditary spastic paraplegias. METHODS: This was a double-blind, randomized, placebo-controlled crossover trial. Each participant was randomly assigned to receive 1 injection session of either BoNT-A (100 IU/2 mL of Prosigne in each adductor magnus and each triceps surae) or saline 0.9% (2 mL). The primary outcome measure was change from baseline in maximal gait velocity, and secondary outcome measures included changes in gait at self-selected velocity, spasticity, muscle strength, Spastic Paraplegia Rating Scale, pain, fatigue, and subjective perception of improvement. We also looked at adverse events reported by the patients. RESULTS: We enrolled 55 patients, 36 of whom were men and 41 with the pure phenotype. Mean age was 43 ± 13.4 years (range, 19-72 years), mean age of onset waws 27 ± 13.1 years (range, <1 to 55 yars), and mean disease duration was 17 ± 12.7 years (range, 1-62 years). Compared with baseline, we did not find significant differences between groups in primary and secondary outcomes, except for reduction in adductor tone (P = 0.01). The adverse events were transient and tolerable, and their incidence did not significantly differ between treatments (P = 0.17). CONCLUSIONS: BoNT-A was safe in patients with hereditary spastic paraplegias and reduced the adductor tone, but it was not able to produce functional improvement considering the doses, injection protocol, measures, and instruments used. © 2021 International Parkinson and Movement Disorder Society.
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Toxinas Botulínicas Tipo A , Fármacos Neuromusculares , Paraplegia Espástica Hereditária , Adolescente , Adulto , Criança , Pré-Escolar , Método Duplo-Cego , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Espasticidade Muscular/tratamento farmacológico , Fármacos Neuromusculares/uso terapêutico , Paraplegia Espástica Hereditária/tratamento farmacológico , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Bulbar involvement is a hallmark of amyotrophic lateral sclerosis (ALS), but surprisingly very few studies have addressed the frequency, pattern and clinical relevance of laryngeal involvement in the disease. METHODS: Twenty-six patients with spinal-onset ALS underwent nasofibroscopy (NF), followed by laryngeal electromyography (LEMG). We also studied resting activity and motor unit potentials of the genioglossus and masseter muscles. RESULTS: Twenty-four patients presented neurogenic changes in at least one laryngeal muscle. There were fibrillation and/or fasciculation potentials associated with chronic neurogenic changes in the same muscle in 16 patients; of these, 9 had no alteration in the genioglossus. We found no patient with tongue neurogenic changes and normal LEMG. NF was abnormal in 14 patients; in the remaining 12, LEMG identified neurogenic changes in 11 of them. CONCLUSION: LEMG is able to identify laryngeal denervation in patients with ALS, sometimes before clinical manifestations are noticed. This technique may be a useful diagnostic tool for selected patients with suspicion of ALS.
Assuntos
Esclerose Lateral Amiotrófica/fisiopatologia , Músculos Laríngeos/fisiopatologia , Adulto , Idoso , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios Motores/fisiologiaRESUMO
Sensory neuronopathies (SN) result from dorsal root ganglia damage and manifest with a combination of sensory deficits and proprioceptive ataxia. Characterization of the natural history and development of therapeutic trials are hampered by the lack of clinical scales that capture the whole spectrum of SN-related manifestations. We propose and validate a rating instrument for SN. Three experienced neuromuscular specialists developed items to rate SN. The resultant instrument was later validated by the assessment of the intra-class correlation coefficient, for inter-rater validity in 48 SN patients, and later in a smaller subset of 16 patients to assess its intra-rater validity. Standardized Crombach's alpha and Oblimin rotation analysis were performed to verify internal consistency and items' relationship, respectively. Evaluation of Sensory Ataxia Rating Scale (SEARS)'s external validity was performed by comparison to: scale for the assessment and rating of ataxia (SARA), Beck balance scale (BBS), and INCAT sensory sum score (ISS). A 10-item scale with an intra-class correlation coefficient >0.95 for intra- and inter-rating measurements with a good internal consistency (standardized Cronbach's alpha of 0.83) were observed. There was a normal distribution of the scores without a floor or ceiling effect. A moderate to good correlation between SEARS and SARA, BBS, and ISS was observed. SEARS is a reliable, easy-to-perform and consistent instrument to rate SN. Larger cohorts and multicenter studies are needed to validate its usefulness towards possible treatment trials.
Assuntos
Ataxia/diagnóstico , Adulto , Idoso , Ataxia/fisiopatologia , Avaliação da Deficiência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Avaliação de SintomasRESUMO
Neurological phenotypes of human T cell lymphotropic virus type I (HTLV-1) are numerous and rarely may not manifest the classic HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We report a case of HTLV-1-related sensory neuronopathy heralding the classic HAM/TSP.
Assuntos
Infecções por HTLV-I/diagnóstico , Paraparesia Espástica Tropical/diagnóstico , Doenças do Sistema Nervoso Periférico/diagnóstico , Idoso , Brasil , Diagnóstico Diferencial , Feminino , Infecções por HTLV-I/imunologia , Infecções por HTLV-I/patologia , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/crescimento & desenvolvimento , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Humanos , Paraparesia Espástica Tropical/imunologia , Paraparesia Espástica Tropical/patologia , Paraparesia Espástica Tropical/virologia , Doenças do Sistema Nervoso Periférico/imunologia , Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/virologia , Células Receptoras Sensoriais/patologia , Células Receptoras Sensoriais/virologia , Linfócitos T/patologia , Linfócitos T/virologiaRESUMO
INTRODUCTION: Chediak-Higashi syndrome (CHS) is a very rare autosomal recessive disorder (gene CHS1/LYST) characterized by partial albinism, recurrent infections, and easy bruising. Survivors develop a constellation of slowly progressive neurological manifestations. METHODS: We describe clinical, laboratory, electrophysiological, and genetic findings of a patient who developed an immune-mediated demyelinating neuropathy as the main clinical feature of CHS. RESULTS: The patient presented with subacute flaccid paraparesis, absent reflexes, and reduced vibration sense. Protein and immunoglobulins (Igs) were elevated in the cerebrospinal fluid. Electrodiagnostic tests indicated an acquired chronic demyelinating polyneuropathy. Intravenous Ig and immunosuppressant treatment resulted in neurological improvement. The patient later developed organomegaly and pancytopenia. Bone-marrow smear revealed giant azurophilic granules pathognomonic for CHS. Two novel mutations in the LYST gene were identified through whole exome sequencing [c.7786C>T and c.9106 + 1G>T]. CONCLUSIONS: This case expands the clinical phenotype of CHS and highlights inflammatory demyelinating neuropathy as a manifestation of the disease. Muscle Nerve 55: 756-760, 2017.
Assuntos
Síndrome de Chediak-Higashi/complicações , Síndrome de Guillain-Barré/etiologia , Adolescente , Síndrome de Chediak-Higashi/genética , Síndrome de Chediak-Higashi/fisiopatologia , Progressão da Doença , Eletrodiagnóstico , Feminino , Síndrome de Guillain-Barré/genética , Síndrome de Guillain-Barré/fisiopatologia , Humanos , Mutação , Proteínas de Transporte Vesicular/genéticaRESUMO
BACKGROUND: Celiac disease is described in association with several autoimmune diseases, but rarely with myasthenia gravis. CASE REPORT: We describe the case of a 31-year-old white woman with celiac disease who presented manifestations related to a hyperactive immune system, including macroamylasemia, false-positive anti-HCV, positive antinuclear antibody, and Raynaud's phenomenon. The introduction of a gluten-free diet (GFD) resolved these features, but myasthenia gravis (MG) symptoms unexpectedly occurred on that occasion. DISCUSSION: The role of a GFD in the course of autoimmune diseases has been studied and improvement has been reported in many diseases. However, there is no consensus in the literature regarding the course of neurological disorders associated with celiac disease. In the present case, a GFD did not prevent the appearance of symptoms related to myasthenia gravis. There are few reports on the association of celiac disease with myasthenia gravis and therefore little is known about the course and time of onset of myasthenia in celiac patients. The present case increases the knowledge about this unusual autoimmune neurological disease associated with celiac disease.
Assuntos
Doença Celíaca/complicações , Doenças do Sistema Imunitário/complicações , Miastenia Gravis/complicações , Adulto , Doença Celíaca/sangue , Doença Celíaca/dietoterapia , Dieta Livre de Glúten , Feminino , Humanos , Miastenia Gravis/dietoterapia , Miastenia Gravis/tratamento farmacológicoRESUMO
Infections of the central nervous systems (CNS) present a diagnostic problem for which an accurate laboratory diagnosis is essential. Invasive practices, such as cerebral biopsy, have been replaced by obtaining a polymerase chain reaction (PCR) diagnosis using cerebral spinal fluid (CSF) as a reference method. Tests on DNA extracted from plasma are noninvasive, thus avoiding all of the collateral effects and patient risks associated with CSF collection. This study aimed to determine whether plasma can replace CSF in nested PCR analysis for the detection of CNS human herpesvirus (HHV) diseases by analysing the proportion of patients whose CSF nested PCR results were positive for CNS HHV who also had the same organism identified by plasma nested PCR. In this study, CSF DNA was used as the "gold standard," and nested PCR was performed on both types of samples. Fifty-two patients with symptoms of nervous system infection were submitted to CSF and blood collection. For the eight HHV, one positive DNA result-in plasma and/or CSF nested PCR-was considered an active HHV infection, whereas the occurrence of two or more HHVs in the same sample was considered a coinfection. HHV infections were positively detected in 27/52 (51.9%) of the CSF and in 32/52 (61.5%) of the plasma, difference not significant, thus nested PCR can be performed on plasma instead of CSF. In conclusion, this findings suggest that plasma as a useful material for the diagnosis of cases where there is any difficulty to perform a CSF puncture.
Assuntos
Viroses do Sistema Nervoso Central/diagnóstico , Líquido Cefalorraquidiano/virologia , Técnicas de Laboratório Clínico/métodos , Infecções por Herpesviridae/diagnóstico , Herpesviridae/isolamento & purificação , Plasma/virologia , Reação em Cadeia da Polimerase/métodos , Adolescente , Adulto , Idoso , Viroses do Sistema Nervoso Central/virologia , Criança , Pré-Escolar , DNA Viral/genética , DNA Viral/isolamento & purificação , Feminino , Herpesviridae/genética , Infecções por Herpesviridae/virologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemAssuntos
Ataxia Cerebelar/fisiopatologia , Polineuropatias/fisiopatologia , Síndrome de Sjogren/fisiopatologia , Distúrbios Somatossensoriais/fisiopatologia , Adulto , Idoso , Ataxia/diagnóstico por imagem , Ataxia/etiologia , Ataxia/fisiopatologia , Atrofia , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/etiologia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Eletrodiagnóstico , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Condução Nervosa , Polineuropatias/etiologia , Síndrome de Sjogren/complicações , Distúrbios Somatossensoriais/etiologiaRESUMO
Autonomic dysfunction has been already described in patients with SCA3/MJD, but several important questions remain unanswered. The objectives of this study are to determine the frequency and the intensity of autonomic manifestations in SCA3/MJD, as well as to identify possible correlations between autonomic manifestations and genetic and clinical parameters. We have performed clinical and electrophysiological evaluations of 40 patients with SCA3/MJD and 38 healthy controls. We used the Scale for the Assessment and Rating of Ataxia (SARA) and the scales for Outcomes in Parkinson's Disease: Autonomic Questionnaire to quantify the severity of ataxia and autonomic complaints, respectively. We also studied heart rate variability at rest, during orthostatic challenge (30:15 ratio), Valsalva maneuver (Valsalva index), and deep breathing (E/I ratio). We evaluated spectral analyses of RR intervals at rest and the sympathetic skin response. Mean RR intervals at rest and the 30:15 ratio were different between patients and controls (811.8 versus 933.4 ms; p = 0.001 and 1.10 versus 1.15; p = 0.038, respectively). The Valsalva index and the E/I ratio were similar between the groups (p = 0.373 and p = 0.08). Spectral analysis presented distinct results in patients and controls, related to low- and high-frequency power (p < 0.001 and <0.001, respectively). We found cardiovascular and sympathetic sweat disautonomia in 30 % and 45 % of the patients with SCA3/MJD. Autonomic manifestations were related neither to genetic (CAG repeat length) nor clinical parameters (age, disease duration, SARA scores). Autonomic dysfunction is frequent and sometimes disabling in SCA3/MJD. We found evidence of both cardiovascular and sudomotor dysfunction in the disease.
Assuntos
Resposta Galvânica da Pele/fisiologia , Frequência Cardíaca/fisiologia , Doença de Machado-Joseph/diagnóstico , Doença de Machado-Joseph/fisiopatologia , Disautonomias Primárias/diagnóstico , Disautonomias Primárias/fisiopatologia , Adulto , Técnicas de Diagnóstico Neurológico , Feminino , Humanos , Doença de Machado-Joseph/epidemiologia , Masculino , Pessoa de Meia-Idade , Disautonomias Primárias/epidemiologiaAssuntos
Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/patologia , Transtornos de Sensação/etiologia , Transtornos de Sensação/patologia , Infecção por Zika virus/complicações , Infecção por Zika virus/patologia , Adulto , Progressão da Doença , Fenômenos Eletrofisiológicos , Feminino , Marcha Atáxica/etiologia , Marcha Atáxica/reabilitação , Humanos , Exame Neurológico , Doenças do Sistema Nervoso Periférico/reabilitação , Fenótipo , Recuperação de Função Fisiológica , Transtornos de Sensação/reabilitaçãoRESUMO
BACKGROUND: The distinction between sensory neuronopathies (SN), which is by definition purely sensory, and sensory polyneuropathies (SP) and sensory multineuropathies (SM) is important for etiologic investigation and prognosis estimation. However, this task is often challenging in clinical practice. We hypothesize that F-wave assessment might be helpful, since it is able to detect subtle signs of motor involvement, which are found in SP and SM, but not in SN. OBJECTIVE: The aim of the present study was to determine whether F-waves are useful to distinguish SN from SP and SM. METHODS: We selected 21 patients with SP (12 diabetes mellitus, 4 transthyretin familial amyloid polyneuropathy, 4 others), 22 with SM (22 leprosy), and 26 with SN (13 immune-mediated, 10 idiopathic, 3 others) according to clinical-electrophysiological-etiological criteria. For every subject, we collected data on height and performed 20 supramaximal distal stimuli in median, ulnar, peroneal, and tibial nerves, bilaterally, to record F-waves. Latencies (minimum and mean) and persistences were compared across groups using the Kruskal-Wallis and Bonferroni tests. P-values < 0.05 were considered significant. RESULTS: All groups were age, gender, and height-matched. Overall, there were no significant between-group differences regarding F-wave latencies. In contrast, F-wave persistence was able to stratify the groups. Peroneal F-wave persistence was higher, bilaterally, in the SN group compared to SM and SP (p < 0.05). In addition, F-waves persistence of the ulnar and tibial nerves was also helpful to separate SN from SP (p < 0.05). CONCLUSION: F-wave persistence of the peroneal nerves might be an additional and useful diagnostic tool to differentiate peripheral sensory syndromes.
ANTECEDENTES: A distinção entre neuronopatias sensitivas (SN) e polineuropatias sensitivas (SP) e multineuropatias sensitivas (SM) é importante para a investigação etiológica e para o prognóstico. Contudo, esta tarefa é desafiadora na prática clínica. Hipotetizou-se que a avaliação das ondas-F pode ser útil, por ser capaz de detectar envolvimento motor nas SP e SM, mas não nas SN. OBJETIVO: Determinar se as ondas-F podem ajudar a distinguir entre SN, SP e SM. MéTODOS: Selecionou-se 21 pacientes com SP (12 diabetes mellitus, 4 ATTR-FAP e 4 com outras neuropatias), 22 com SM (22 hanseníases) e 26 com SN (13 imunomediadas, 10 idiopáticas e 3 com outras neuronopatias), de acordo com critérios clínicos, etiológicos e eletrofisiológicos. Para cada indivíduo, foi aferida a altura e foram aplicados 20 estímulos distais supramáximos nos nervos mediano, ulnar, fibular e tibial, bilateralmente, para registrar as ondas-F. Uma comparação foi feita, por grupo, das latências (mínimas e médias) e persistências pelos testes Kruskal-Wallis e Bonferroni. Valores de p < 0.05 foram considerados estatisticamente significativos. RESULTADOS: Todos os grupos foram pareados por idade, sexo e altura. Não houve diferença estatística significativa entre os grupos quanto às latências das ondas-F. A persistência da onda-F foi capaz de estratificar os grupos, sendo as dos nervos fibulares bilateralmente maiores no grupo SN que nos grupos SM e SP (p < 0.05). Adicionalmente, a persistência das ondas-F dos nervos ulnares e tibiais também foi útil para distinguir SN de SP (p < 0.05). CONCLUSãO: A persistência das ondas-F dos nervos fibulares pode ser uma ferramenta adicional e útil para diferenciar síndromes sensitivas periféricas.
Assuntos
Condução Nervosa , Polineuropatias , Humanos , Condução Nervosa/fisiologia , Nervo Mediano , Nervo Ulnar/fisiologia , Nervo Tibial , Nervo Fibular , Síndrome , Nervos Periféricos/fisiologiaRESUMO
OBJECTIVE: To characterize and compare autonomic function in patients with sporadic (sALS) and familial ALS type 8 (fALS8). METHODS: We selected 11 patients with sALS (7 men), 14 with fALS8 (8 men) and 26 controls (15 men). All groups were gender and age-matched. For each subject, Scale for Outcomes in Parkinson's Disease for Autonomic Symptoms (SCOPA-AUT) was applied and data from heart rate variability, Quantitative Sudomotor Axon Reflex Test (QSART) and skin sympathetic response (SSR) were collected. These data were compared across groups using nonparametric tests. P-values < 0.05 were considered significant. RESULTS: SCOPA-AUT revealed predominant clinical complaints in thermoregulatory, pupillomotor and sexual domains in fALS8 relative to sALS as well as controls. Neurophysiological tests demonstrated significant differences in Valsalva ratio, Expiratory:Inspiratory index and RR minimum values in both ALS groups relative to controls. Sudomotor dysfunction was also observed in sALS and fALS8 groups, as shown by reduced medial forearm and foot QSART volumes and absence of SSR in lower limbs. CONCLUSIONS: Dysautonomia - cardiac and sudomotor - is part of the phenotype in sALS and fALS8. The profile of autonomic symptoms, however, is different in each group. SIGNIFICANCE: Patients with fALS8 and sALS have autonomic dysfunction involving both sympathetic and parasympathetic divisions.
RESUMO
In the last few decades, there have been considerable improvements in the diagnosis and care of Duchenne muscular dystrophy (DMD), the most common childhood muscular dystrophy. International guidelines have been published and recently reviewed. A group of Brazilian experts has developed a standard of care based on a literature review with evidence-based graded recommendations in a two-part publication. Implementing best practice management has helped change the natural history of this chronic progressive disorder, in which the life expectancy for children of the male sex in the past used to be very limited. Since the previous publication, diagnosis, steroid treatment, rehabilitation, and systemic care have gained more significant insights with new original work in certain fields. Furthermore, the development of new drugs is ongoing, and some interventions have been approved for use in certain countries. Therefore, we have identified the need to review the previous care recommendations for Brazilian patients with DMD. Our objective was to create an evidence-based document that is an update on our previous consensus on those topics.
Nas últimas décadas, houve progressos significativos no diagnóstico e no tratamento da distrofia muscular de Duchenne (DMD), considerada a distrofia muscular mais comum na infância. Diretrizes internacionais foram publicadas e revisadas recentemente. Um grupo de especialistas brasileiros desenvolveu um padrão de atendimento baseado em revisão de literatura, com recomendações graduadas pautadas em evidências compiladas em uma publicação dividida em duas partes. A implementação de melhores práticas de manejo ajudou a modificar a história natural desta doença crônica, progressiva, que, no passado, oferecia uma expectativa de vida muito limitada para crianças do sexo masculino. Desde a publicação desse consenso anterior, o diagnóstico, o tratamento com esteroides, a reabilitação e os cuidados sistêmicos ganharam novas possibilidades a partir da divulgação dos resultados de trabalhos originais em algumas dessas áreas. Além disso, as pesquisas e o desenvolvimento de novos fármacos estão em andamento, e algumas intervenções já foram aprovadas para uso em determinados países. Nesse contexto, identificamos a necessidade de rever as recomendações anteriores sobre o manejo dos pacientes brasileiros com DMD. Nosso objetivo principal foi elaborar uma atualização baseada em evidências sobre esses tópicos do consenso.
Assuntos
Distrofia Muscular de Duchenne , Criança , Humanos , Masculino , Distrofia Muscular de Duchenne/diagnóstico , Brasil , ConsensoRESUMO
OBJECTIVE: To characterize and quantify autonomic involvement in patients with RFC1-related disorder of adult-onset cerebellar ataxia and idiopathic sensory neuropathy. METHODS: We enrolled 16 subjects with biallelic RFC1 (AAGGG)n expansions and 16 age and sex-matched healthy controls that underwent comprehensive clinical and neurophysiological evaluation. Scales for Outcomes in Parkinson's Disease Autonomic Dysfunction (SCOPA-AUT) score was used to assess autonomic symptoms. Electrophysiological testing included assessment of heart rate variability and quantitative sudomotor axon reflex test (QSART). Between-group comparisons were assessed using non-parametric tests. RESULTS: In the patient group, there were 9 men/7 women and the median age was 60.5 years. SCOPA-AUT scores were significantly higher in the RFC1 group compared to controls (22 vs 10, p < 0.001). Half of patients had cardiac autonomic neuropathy. In neurophysiology, there was resting tachycardia combined with abnormal responses during Valsalva maneuver and deep breathing among patients. QSART responses were also significantly reduced in the RFC1 group, especially in the lower limbs. CONCLUSIONS: Autonomic dysfunction is frequent, clinically relevant and involves multiple domains in RFC1-related disorder. Patients have both sympathetic and parasympathetic involvement. From a topographical perspective, this condition is characterized by a small fiber autonomic axonopathy. SIGNIFICANCE: Dysautonomia is frequent, severe and related to peripheral damage in RFC1-related disorder.
Assuntos
Doenças do Sistema Nervoso Autônomo , Doenças do Sistema Nervoso Periférico , Disautonomias Primárias , Adulto , Sistema Nervoso Autônomo , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neurofisiologia , Disautonomias Primárias/diagnóstico , Manobra de ValsalvaRESUMO
Dystrophinopathies are a group of X-linked neuromuscular disorders that result from pathogenic variants in the DMD gene. Their pathophysiological substrate is the defective expression of dystrophin in many tissues. While patients from the same pedigree usually present similar dystrophin expression and clinical course, the extent of cardiac and skeletal muscle involvement may not correlate in the same individual. We identified a new splice site variant c.2803+5G>C (NM_004006) ClinVar VCV000803902, located in intron 22 of DMD in a Brazilian family that present a broad phenotypic and histological heterogeneity. One of the subjects had a typical Duchenne muscular dystrophy (DMD) phenotype, whereas the others had Becker muscular dystrophy (BMD). Cardiac involvement was remarkable in some of the BMD patients, but not in the DMD patient. Western blot analysis of skeletal muscle revealed much lower levels of calsequestrin in the most severely affected patient compared to his brother, whose phenotype is BMD, highlighting the potential role of proteins involved in skeletal muscle calcium homeostasis in differential degrees of dystrophinopathies.
Assuntos
Distrofina/genética , Distrofia Muscular de Duchenne/genética , Adolescente , Adulto , Brasil , Humanos , Íntrons , Masculino , Músculo Esquelético/patologia , Mutação , Linhagem , Fenótipo , Sítios de Splice de RNARESUMO
Many genes associated with familial forms of the amyotrophic lateral sclerosis (fALS) have been identified in European and North American cohorts. However, little is known about the genetic bases of fALS in Latin America and Brazil, in particular. To address this question, we recruited 107 patients with fALS from 93 unrelated families from Southeastern, Southern, and Northeastern regions of the country. A 3-step diagnostic approach was used: 1) Triplet repeat primed polymerase chain reaction to search for C9orf72 expansions, then 2) fragment digestion to search for the c.166 C>T VAPB variant, and finally, 3) whole exome sequencing for those who tested negative. We identified the genetic cause for fALS in 70% of the families. VAPB and C9orf72 were the most frequent genes (30% and 22%, respectively), followed by SOD1, TARDBP, ANXA11, and FUS. Five novel variants in known ALS genes were found, including the SOD1 Val120Leu and ANXA11 Asp40Tyr, which were seen in 2 unrelated families each. In conclusion, VAPB and then C9orf72 are the genes most commonly related to fALS in Brazil.
Assuntos
Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/genética , Proteína C9orf72/genética , Estudos de Associação Genética/métodos , Variação Genética/genética , Proteínas de Transporte Vesicular/genética , Brasil/epidemiologia , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Reação em Cadeia da Polimerase , Proteína FUS de Ligação a RNA/genética , Superóxido Dismutase-1/genética , Sequenciamento do ExomaRESUMO
Little is known about the genetic basis of amyotrophic lateral sclerosis (ALS) outside Europe and US. In this study, we investigated whether intermediate CAG expansions at ATXN1 were associated to ALS in the Brazilian population. To accomplish that, representative samples from 411 unrelated patients and 436 neurologically normal controls from 6 centers spread over the territory were genotyped to quantify ATXN1 expansions. We found that ATXN1 intermediate-length expansion (≥34 CAG repeats) are associated with the disease (odds ratioâ¯=â¯2.19, 95% CIâ¯=â¯1.081-4.441, pâ¯=â¯.026). Most ATXN1-positive patients had classical phenotype, but some of them presented predominant lower motor neuron involvement. None of them had associated ataxia. Frontotemporal dementia was concomitantly found in 12.5% of patients carrying the intermediate ATXN1 expansion. Further studies are needed to validate these findings and to understand the pathophysiological mechanisms that connect ataxin-1 and ALS.