Co-Occurrence of Myotonic Dystrophy Type 1 and Limb-Girdle Muscular Dystrophy Type 2B: A Case Report.

Introduction: Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disease whose pattern of weakness is predominantly distal. Limb-girdle muscular dystrophy type 2B/R2-dysferlin-related (LGMD2B/R2) is another neuromuscular disease, which presents an autosomal recessive inheritance and is marked by proximal muscle weakness. Even if uncommon, comorbid inherited pathologies must be considered in cases of atypical presentations, especially in those with family history of consanguinity. Case Presentation: Herein, we report the unique case of a patient diagnosed with both DM1 and LGMD2B/R2: a 38-year-old woman in follow-up of DM1 in a neuromuscular disease service presenting prominent proximal weakness. The patient's parents were consanguineous, and creatine kinase levels were elevated. A multi-gene panel test was performed and revealed the diagnosis of LGMD2B/R2. Conclusion: Genetic diseases with atypical presentations should raise the possibility of a second disorder, prompting an appropriate investigation. Overlooking a second diagnosis can implicate in not offering adequate genetic counseling, support, or specific treatment.

Diagnostic yield of multi-gene panel for muscular dystrophies and other hereditary myopathies.

Genetic testing is being considered the first-step in the investigation of hereditary myopathies. However, the performance of the different testing approaches is little known. The aims of the present study were to evaluate the diagnostic yield of a next-generation sequencing panel comprising 39 genes as the first-tier test for genetic myopathies diagnosis and to characterize clinical and molecular findings of families from southern Brazil. Fifty-one consecutive index cases with clinical suspicion of genetic myopathies were recruited from October 2014 to March 2018 in a cross-sectional study. The overall diagnostic yield of the next-generation sequencing panel was 52.9%, increasing to 60.8% when including cases with candidate variants. Multi-gene panel solved the diagnosis of 12/25 (48%) probands with limb-girdle muscular dystrophies, of 7/14 (50%) with congenital muscular diseases, and of 7/10 (70%) with muscular dystrophy with prominent joint contractures. The most frequent diagnosis for limb-girdle muscular dystrophies were LGMD2A/LGMD-R1-calpain3-related and LGMD2B/LGMD-R2-dysferlin-related; for congenital muscular diseases, RYR1-related-disorders; and for muscular dystrophy with prominent joint contractures, Emery-Dreifuss-muscular-dystrophy-type-1 and COL6A1-related-disorders. In summary, the customized next-generation sequencing panel when applied in the initial investigation of genetic myopathies results in high diagnostic yield, likely reducing patient's diagnostic odyssey and providing important information for genetic counseling and participation in disease-specific clinical trials.

Speech characteristics in individuals with myasthenia gravis: a case control study.

INTRODUCTION: Myasthenia Gravis (MG) is an autoimmune disease. The characteristic symptoms of the disease are muscle weakness and fatigue. These symptoms affect de oral muscles causing dysarthria, affecting about 60% of patients with disease progression. PURPOSE: Describe the speech pattern of patients with MG and comparing with healthy controls (HC). MATERIAL AND METHODS: Case-control study. Participants were divided in MG group (MGG) with 38 patients MG diagnosed and HC with 18 individuals matched for age and sex. MGG was evaluated with clinical and motor scales and answered self-perceived questionnaires. Speech assessment of both groups included: recording of speech tasks, acoustic and auditory-perceptual analysis. RESULTS: In the MGG, 68.24% of the patients were female, with average age of 50.21 years old (±16.47), 14.18 years (±9.52) of disease duration and a motor scale of 11.19 points (±8.79). The auditory-perceptual analysis verified that 47.36% (n = 18) participants in MGG presented mild dysarthria, 10.52% (n = 4) moderate dysarthria, with a high percentage of alterations in phonation (95.2%) and breathing (52.63%). The acoustic analysis verified a change in phonation, with significantly higher shimmer values in the MGG compared to the HC and articulation with a significant difference between the groups for the first formant of the /iu/ (p = <.001). No correlation was found between the diagnosis of speech disorder and the dysarthria self-perception questionnaire. CONCLUSION: We found dysarthria mild in MG patients with changes in the motor bases phonation and breathing, with no correlation with severity and disease duration.

Evoked potentials as biomarkers of hereditary spastic paraplegias: A case-control study.

INTRODUCTION: The Hereditary Spastic Paraplegias (HSP) are a group of genetic diseases that lead to slow deterioration of locomotion. Clinical scales seem to have low sensitivity in detecting disease progression, making the search for additional biomarkers a paramount task. This study aims to evaluate the role of evoked potentials (EPs) as disease biomarkers of HSPs. METHODS: A single center cross-sectional case-control study was performed, in which 18 individuals with genetic diagnosis of HSP and 21 healthy controls were evaluated. Motor evoked potentials (MEP) obtained with transcranial magnetic stimulation and somatosensory evoked potentials (SSEP) were performed in lower (LL) and upper limbs (UL). RESULTS: Central motor conduction time in lower limbs (CMCT-LL) was prolonged in HSP subjects, with marked reductions in MEP-LL amplitudes when compared to the control group (p<0.001 for both comparisons). CMCT-UL was 3.59ms (95% CI: 0.73 to 6.46; p = 0.015) prolonged and MEP-UL amplitudes were reduced (p = 0.008) in the HSP group. SSEP-LL latencies were prolonged in HSP subjects when compared to controls (p<0.001), with no statistically significant differences for upper limbs (p = 0.147). SSEP-UL and SSEP-LL latencies presented moderate to strong correlations with age at onset (Rho = 0.613, p = 0.012) and disease duration (Rho = 0.835, p<0.001), respectively. Similar results were obtained for the SPG4 subgroups of patients. CONCLUSION: Motor and somatosensory evoked potentials can adequately differentiate HSP individuals from controls. MEP were severely affected in HSP subjects and SSEP-LL latencies were prolonged, with longer latencies being related to more severe disease. Future longitudinal studies should address if SSEP is a sensitive disease progression biomarker for HSP.

Cognitive performance in patients with Myasthenia Gravis: an association with glucocorticosteroid use and depression.

We investigated the cognitive performance of patients with Myasthenia Gravis (MG) through a cross-sectional study. A battery of cognitive assessments and self-report questionnaires regarding quality of life (QoL), sleep, and depression were applied. The sample consisted of 39 patients diagnosed with MG. The scores showed a predominance of cognitive impairment in the Montreal Cognitive Assessment screening test (MoCA) (66.7%) and in the immediate (59.0%) and recent memory (56.4%) tests. However, after the Poisson regression analysis with robust variance, it was found that patients diagnosed with depression had a prevalence ratio (PR) of 1,887 (CI 1,166‒3,054) for lower MoCA scores, PR=9,533 (CI 1,600‒56,788) for poorer phonemic verbal fluency scores, and PR=12,426 (CI 2,177‒70,931) for the Semantic Verbal Fluency test. Moreover, concerning a decline in short-term memory retention, patients using glucocorticosteroids (GC) and with Beck Depression Inventory scores indicating depression showed PR=11,227 (CI 1,736‒72,604) and PR=0.35 (CI 0.13‒0.904), respectively. No correlation was found between the QoL questionnaire and performance in cognitive tests. We found worse performance in tasks of memory and executive functions in MG patients. These are not associated with the length and severity of the disease. However, a significant prevalence ratio was found for poorer memory performance in patients diagnosed with depression and in those using GC.

Investigamos o desempenho cognitivo de pacientes com miastenia gravis (MG) por meio de um estudo transversal. Aplicou-se uma bateria de avaliações cognitivas e questionários de autopercepção sobre qualidade de vida (QV), sono e depressão. A amostra foi composta por 39 pacientes com diagnóstico de MG. Os escores mostraram predominância de comprometimento cognitivo no teste de rastreio Montreal Cognitive Assessment (MoCA) (66,7%) e nas tarefas de memória imediata (59,0%) e recente (56,4%). Entretanto, após a análise de regressão de Poisson com variância robusta, verificou-se que os pacientes diagnosticados com depressão apresentaram uma razão de prevalência (RP)=1.887 (IC 1.166‒3.054) para escores mais baixos no MoCA, RP=9.533 (IC 1.600‒56.788) nos testes de fluência verbal fonêmica e RP=12.426 (IC 2.177‒70.931) no teste de fluência verbal semântica. Além disso, uma associação entre pior desempenho nas tarefas de memória de retenção de curto prazo nos pacientes em uso de glucocorticoides (GC) e com os escores do Beck Depression Inventory indicando depressão, com RP=11.227 (IC 1.736‒72.604) e RP=0.35 (IC 0.13‒0.904), respectivamente. Não foi encontrada correlação entre o questionário de QV e o desempenho em testes cognitivos. Sendo assim, conclui-se que foi observado pior desempenho em tarefas de memória e funções executivas em pacientes com MG. Estes não estão associados ao tempo e à gravidade da doença. No entanto, uma taxa de prevalência significativa foi encontrada para pior desempenho da memória em pacientes diagnosticados com depressão e naqueles em uso de glucocorticoides.

Cognitive performance in patients with Myasthenia Gravis: an association with glucocorticosteroid use and depression / Desempenho cognitivo em pacientes com Miastenia Gravis: uma associação com o uso de glucocorticoides e depressão

ABSTRACT. We investigated the cognitive performance of patients with Myasthenia Gravis (MG) through a cross-sectional study. A battery of cognitive assessments and self-report questionnaires regarding quality of life (QoL), sleep, and depression were applied. The sample consisted of 39 patients diagnosed with MG. The scores showed a predominance of cognitive impairment in the Montreal Cognitive Assessment screening test (MoCA) (66.7%) and in the immediate (59.0%) and recent memory (56.4%) tests. However, after the Poisson regression analysis with robust variance, it was found that patients diagnosed with depression had a prevalence ratio (PR) of 1,887 (CI 1,166‒3,054) for lower MoCA scores, PR=9,533 (CI 1,600‒56,788) for poorer phonemic verbal fluency scores, and PR=12,426 (CI 2,177‒70,931) for the Semantic Verbal Fluency test. Moreover, concerning a decline in short-term memory retention, patients using glucocorticosteroids (GC) and with Beck Depression Inventory scores indicating depression showed PR=11,227 (CI 1,736‒72,604) and PR=0.35 (CI 0.13‒0.904), respectively. No correlation was found between the QoL questionnaire and performance in cognitive tests. We found worse performance in tasks of memory and executive functions in MG patients. These are not associated with the length and severity of the disease. However, a significant prevalence ratio was found for poorer memory performance in patients diagnosed with depression and in those using GC.

RESUMO. Investigamos o desempenho cognitivo de pacientes com miastenia gravis (MG) por meio de um estudo transversal. Aplicou-se uma bateria de avaliações cognitivas e questionários de autopercepção sobre qualidade de vida (QV), sono e depressão. A amostra foi composta por 39 pacientes com diagnóstico de MG. Os escores mostraram predominância de comprometimento cognitivo no teste de rastreio Montreal Cognitive Assessment (MoCA) (66,7%) e nas tarefas de memória imediata (59,0%) e recente (56,4%). Entretanto, após a análise de regressão de Poisson com variância robusta, verificou-se que os pacientes diagnosticados com depressão apresentaram uma razão de prevalência (RP)=1.887 (IC 1.166‒3.054) para escores mais baixos no MoCA, RP=9.533 (IC 1.600‒56.788) nos testes de fluência verbal fonêmica e RP=12.426 (IC 2.177‒70.931) no teste de fluência verbal semântica. Além disso, uma associação entre pior desempenho nas tarefas de memória de retenção de curto prazo nos pacientes em uso de glucocorticoides (GC) e com os escores do Beck Depression Inventory indicando depressão, com RP=11.227 (IC 1.736‒72.604) e RP=0.35 (IC 0.13‒0.904), respectivamente. Não foi encontrada correlação entre o questionário de QV e o desempenho em testes cognitivos. Sendo assim, conclui-se que foi observado pior desempenho em tarefas de memória e funções executivas em pacientes com MG. Estes não estão associados ao tempo e à gravidade da doença. No entanto, uma taxa de prevalência significativa foi encontrada para pior desempenho da memória em pacientes diagnosticados com depressão e naqueles em uso de glucocorticoides.

Diagnostic yield of targeted sequential and massive panel approaches for inherited neuropathies.

Diagnostic yield of genetic studies for Charcot-Marie-Tooth disease (CMT) is little known, with a lack of epidemiological data to build better diagnostic strategies outside the United States and Europe. We aimed to evaluate the performance of two molecular diagnostic strategies for patients with CMT, and to characterize epidemiological findings of these conditions in southern Brazil. We performed a single-center cross-sectional study, in which 94 patients (55 families) with CMT suspicion were evaluated. Overall, the diagnostic yield of the combined strategy of Multiplex-ligation-dependent-probe-amplification (MLPA) of PMP22/GJB1/MPZ and GJB1/MPZ/PMP22 Sanger sequencing was 63.6% (28/44) for index cases with demyelinating/intermediate CMT suspicion (21 CMT1A-PMP22, 5 CMTX1-GJB1 and 2 with probably CMT1B-MPZ diagnosis). Five of the 11 index cases (45.4%) with axonal CMT had at least a possible diagnosis with next generation sequencing (NGS) panel of 104 inherited neuropathies-related genes (one each with CMT1A-PMP22, CMT2A-MFN2, CMT2K-GDAP1, CMT2U-MARS, CMT2W-HARS1). Detailed clinical, neurophysiological and molecular data of families are provided. Sequential molecular diagnosis strategies with MLPA plus target Sanger sequencing for demyelinating/intermediate CMT had high diagnostic yield, and almost half of axonal CMT families had at least a possible diagnosis with the comprehensive NGS panel. Most frequent subtypes of CMT in our region are CMT1A-PMP22 and CMTX1-GJB1.

Dropped head syndrome as a manifestation of Charcot-Marie-Tooth disease type 4C.

Charcot Marie Tooth disease type 4C (CMT4C) is considered the most frequent autosomal recessive form of CMT worldwide, being described as an early-onset disorder with marked clinical heterogeneity. We report a CMT4C case associated with dropped head syndrome and predominant involvement of proximal muscles. An 11-year-old boy born to consanguineous parents presented with predominantly proximal muscle weakness with facial involvement, associated with dropped head and severe scoliosis. Symptoms started at the age of 3 years-old with frequent falls. Nerve conduction studies showed a sensorimotor demyelinating polyneuropathy. A comprehensive multigene next-generation sequencing panel for CMT revealed the homozygous pathogenic missense variant c.1969G > A (p.E657K) in SH3TC2 gene, confirming CMT4C diagnosis. The present report broadens the phenotype associated with CMT4C and raises the importance of considering early-onset inherited polyneuropathies in the differential diagnosis of patients with proximal muscle wasting associated with dropped head syndrome.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay: a family report from South Brazil.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset, neurodegenerative disorder caused by mutations in SACS, firstly reported in Quebec, Canada. The disorder is typically characterized by childhood onset ataxia, spasticity, neuropathy and retinal hypermyelination. The clinical picture of patients born outside Quebec, however, is often atypical. In the present article, the authors describe clinical and neuroradiological findings that raised the suspicion of an ARSACS diagnosis in two female cousins with Germanic background from Rio Grande do Sul, Brazil. We present a review on the neuroimaging, ophthalmologic and neurophysiologic clues for ARSACS diagnosis. The early-onset, slowly progressive, spastic-ataxia phenotype of reported patients was similar to ARSACS patients from Quebec. The SACS sequencing revealed the novel homozygous c.5150_5151insA frameshift mutation confirming the ARSACS diagnosis. ARSACS is a frequent cause of early onset ataxia/spastic-ataxia worldwide, with unknown frequency in Brazil.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay: a family report from South Brazil / Ataxia espástica autossômica recessiva de Charlevoix-Saguenay: relato de uma família do sul do Brasil

ABSTRACT Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset, neurodegenerative disorder caused by mutations in SACS, firstly reported in Quebec, Canada. The disorder is typically characterized by childhood onset ataxia, spasticity, neuropathy and retinal hypermyelination. The clinical picture of patients born outside Quebec, however, is often atypical. In the present article, the authors describe clinical and neuroradiological findings that raised the suspicion of an ARSACS diagnosis in two female cousins with Germanic background from Rio Grande do Sul, Brazil. We present a review on the neuroimaging, ophthalmologic and neurophysiologic clues for ARSACS diagnosis. The early-onset, slowly progressive, spastic-ataxia phenotype of reported patients was similar to ARSACS patients from Quebec. The SACS sequencing revealed the novel homozygous c.5150_5151insA frameshift mutation confirming the ARSACS diagnosis. ARSACS is a frequent cause of early onset ataxia/spastic-ataxia worldwide, with unknown frequency in Brazil.

RESUMO A ataxia espástica autossômica recessiva de Charlevoix-Saguenay (ARSACS) é uma doença neurodegenerativa de início precoce causada por mutações no gene SACS que foi inicialmente descrita na região de Quebec, Canadá. A apresentação típica de ARSACS é caracterizada por ataxia, espasticidade, polineuropatia e hipermielinização das fibras nervosas da retina de início infantil. No presente artigo, descrevemos os achados clínicos e neurorradiológicos que levaram à suspeita de ARSACS em duas primas descendentes de alemães naturais do Rio Grande do Sul, Brasil e revisamos os achados de neuroimagem, oftalmológicos e neurofisiológicos de ARSACS. O fenótipo de ataxia-espástica de início infantil precoce apresentado pelas pacientes era similar ao classicamente descrito em Quebec. O sequenciamento do SACS revelou a mutação nova c.5150_5151insA (mudança na matriz de leitura), em homozigose, confirmando o diagnóstico de ARSACS. A ARSACS é uma causa frequente de ataxia/ataxia-espástica de início precoce mundialmente, entretanto sua frequência é desconhecida no Brasil.

Promising treatments for neuropathic pain.

In the last few years the understanding of mechanisms and, consequently, the diagnosis of neuropathic pain (NP) has becoming progressively clearer in clinical practice. However, the treatment of such condition remains challenging so far. One of the reasons for such difficulty is the diversity of mechanisms involved in NP generation and its persistency. In the present review we discuss several treatment modalities for NP that are scantily applied in daily clinical practice. For that, we collected positive clinical evidence of unusual and SECS (Safe, Easy, Cheap, and Sensible) approaches for NP. The aim of this review is not to establish the "state of the art" or rigid guidelines for NP treatment. In a different way, we only want bring new possibilities of treatment to the readers and also to motivate investigators to confirm those positive preliminary but promising results for NP reliev.

Promising treatments for neuropathic pain / Tratamentos promissores para dor neuropática

In the last few years the understanding of mechanisms and, consequently, the diagnosis of neuropathic pain (NP) has becoming progressively clearer in clinical practice. However, the treatment of such condition remains challenging so far. One of the reasons for such difficulty is the diversity of mechanisms involved in NP generation and its persistency. In the present review we discuss several treatment modalities for NP that are scantily applied in daily clinical practice. For that, we collected positive clinical evidence of unusual and SECS (Safe, Easy, Cheap, and Sensible) approaches for NP. The aim of this review is not to establish the “state of the art” or rigid guidelines for NP treatment. In a different way, we only want bring new possibilities of treatment to the readers and also to motivate investigators to confirm those positive preliminary but promising results for NP reliev.

Nos últimos anos, a compreensão dos mecanismos e consequentemente do diagnóstico da dor neuropática (DN) têm se tornado cada vez mais claros na prática clínica. Entretanto, o tratamento desta condição continua sendo um desafio. Uma das razões para tal dificuldade é diversidade de mecanismos envolvidos na geração e perpetuação da DN. Na presente revisão, os autores discutem várias modalidades de tratamento para DN pouco utilizadas na prática clínica diária. Para isso, selecionamos evidências clínicas positivas de abordagens para DN consideradas não-convencionais e do tipo “SFBR” (Seguro, Fácil, Barato e Racional). O objetivo desta revisão não é estabelecer o “estado da arte” ou diretrizes rígidas para o tratamento da DN. Diferente disso, pretendemos apenas trazer aos leitores novas possibilidades de tratamento assim como motivar pesquisadores a confirmar estes resultados preliminares, mas promissores para o alívio da DN.

Oppositionality and sympathetic skin response in adolescents: specific associations with the headstrong/hurtful dimension.

Oppositionality encompasses distinct dimensions, and few studies have investigated the validity of such distinctions from a pathophysiological perspective. Our aim was to investigate the association between sympathetic skin responses (SSR) and distinct oppositional dimensions in a community sample of adolescents. Forty adolescents aged 13.84±1.46 years participated in this study. Oppositionality was measured by externalizing behavior and bullying scores (dependent variables), while SSR was recorded by electrical changes at the skin level (independent variables). Results showed that increased SSRs were associated with oppositionality; however, these associations were specific to the headstrong/hurtful dimension. Further exploratory analyses demonstrated that increased SSRs were associated with several types of headstrong/hurtful behaviors and underscore the importance of the first aversive stimuli to differentiate groups with low and high headstrong/hurtful behaviors. There were no differences between groups regarding time until habituation. This study provides insights about how dysfunctions in autonomic balance may contribute to the emergence of oppositional behavior among adolescents.