Unveiling the clinical and electrophysiological profile of CMTX6: Insights from two Brazilian families.

BACKGROUND AND AIMS: X-linked Charcot-Marie-Tooth disease type 6 (CMTX6) is an extremely rare condition associated with mutations in the PDK3 gene. To date, only three families from different countries have been reported (Australia, South Korea, and Germany). In this study, we sought to provide a comprehensive clinical and electrophysiological characterization of two Brazilian families. METHODS: We conducted comprehensive clinical assessments, extensive electrophysiological evaluations, and performed whole-exome sequencing in the probands to investigate the genetic basis of the disease. RESULTS: Males in the family carrying the Arg162His mutation displayed early-onset motor and/or sensory axonal neuropathy, absence of tendon jerks, pes cavus, and frequently reported pain. Females in the same family exhibited a milder phenotype of the disease with later onset and some remained asymptomatic into their 50s. In the unrelated family with a single affected male, the clinical presentation was characterized by severe progressive sensorimotor polyneuropathy accompanied by neuropathic pain. INTERPRETATION: We report two Brazilian families with CMTX6 including one harboring a previously unpublished variant in the PDK3 gene, which co-segregates with the disease as expected in a X-linked disease. Notably, the clinical presentations across the five families with available descriptions, including our study, share striking similarities. Furthermore, the proximity of the three reported mutations suggests potential functional similarities and common underlying mechanisms. This study contributes to the growing knowledge of CMTX6 and underscores the importance of international collaborations in studying rare genetic disorders.

Effectiveness of exercise therapy for individuals diagnosed with Charcot-Marie-Tooth disease: A systematic review of randomized clinical trials.

BACKGROUND AND AIMS: Effective treatments for Charcot-Marie-Tooth (CMT) disease lack. Current treatments, such as ankle and foot surgery/orthoses, analgesics, and physiotherapy, focus on relieving the symptoms. Few randomized controlled trials (RCTs) investigated the effectiveness of exercise in patients with CMT, and a systematic review summarizing the effects of such treatments is outdated. This study aims to systematically review the effects of exercise on muscle strength, function, aerobic capacity, and quality of life in CMT. METHODS: We included RCTs that compared exercise programs against sham exercise, usual care, no exercise, and different exercise programs in individuals diagnosed with CMT. Searches were performed on 10 electronic databases from inception up to July 2021. Authors analyzed titles, abstracts, and full texts and extracted information from the eligible trials. We used the Physiotherapy Evidence Database (PEDro) scale and the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach to evaluate the risk of bias and the certainty of the evidence, respectively. Results were synthesized narratively. RESULTS: Eight citations (six studies; pooled n = 214) met the inclusion criteria. The mean age of participants was 38.49 (±13.02) years, and 83% were diagnosed with CMT1A. The mean PEDro score was 5.25 (range 2-9). Six trials were considered to have a high risk of bias. Moderate-quality evidence suggests that strengthening the ankle dorsiflexors minimizes the progression of weakness at 24 months in children with CMT1A. For other outcomes, quality of the evidence ranged from very low to low. INTERPRETATION: Based on the available, evidence we can only recommend exercise to improve muscle strength in children with CMT. More high quality and robust trials are needed.

High diagnostic yield with algorithmic molecular approach on hereditary neuropathies

SUMMARY OBJECTIVE: Charcot-Marie-Tooth disease covers a group of inherited peripheral neuropathies. The aim of this study was to investigate the effect of targeted next-generation sequencing panels on the molecular diagnosis of Charcot-Marie-Tooth disease and its subtypes in routine clinical practice, and also to show the limitations and importance of next-generation sequencing in the diagnosis of Charcot-Marie-Tooth diseases. METHODS: This is a retrospective study. Three different molecular methods (multiplex ligation probe amplification, next-generation sequencing, and whole-exome sequencing) were used to detect the mutations related to Charcot-Marie-Tooth disease. RESULTS: In total, 64 patients (33 males and 31 females) with suspected Charcot-Marie-Tooth disease were analyzed for molecular etiology. In all, 25 (39%) patients were diagnosed by multiplex ligation probe amplification. With an extra 11 patients with normal PMP22 multiplex ligation probe amplification results that were consulted to our laboratory for further genetic analysis, a total of 50 patients underwent next-generation sequencing for targeted gene panels associated with Charcot-Marie-Tooth disease. Notably, 18 (36%) patients had pathogenic/likely pathogenic variants. Whole-exome sequencing was performed on five patients with normal next-generation sequencing results; the diagnostic yield by whole-exome sequencing was 80% and it was higher in the childhood group. CONCLUSION: The molecular etiology in Charcot-Marie-Tooth disease patients can be determined according to pre-test evaluation, deciding the inheritance type with pedigree analysis, the clinical phenotype, and an algorithm for the genetic analysis. The presence of patients without a molecular diagnosis in all the literature suggests that there are new genes or mechanisms waiting to be discovered in the etiology of Charcot-Marie-Tooth disease.

Clinical and Genetic Aspects of Childhood-Onset Demyelinating Charcot-Marie-Tooth's Disease in Brazil.

Charcot-Marie-Tooth's disease (CMT) represents the most common inherited neuropathy. Most patients are diagnosed during late stages of disease course during adulthood. We performed a review of clinical, neurophysiological, and genetic diagnoses of 32 patients with genetically defined childhood-onset demyelinating CMT under clinical follow-up in a Brazilian Center for Neuromuscular Diseases from January 2015 to December 2019. The current mean age was 33.1 ± 18.3 years (ranging from 7 to 71 years) and mean age at defined genetic diagnosis was 36.1 ± 18.3 years. The mean age at onset was 6.1 ± 4.4 years. The most common initial complaint was bilateral pes cavus. The genetic basis included PMP22 duplication (CMT1A) ( n = 18), GJB1 (CMTX1) ( n = 5), MPZ (CMT1B) ( n = 3), FIG4 (CMT4J) ( n = 3), SH3TC2 (CMT4C) ( n = 1), PLEKHG5 (CMTRIC) ( n = 1), and PRX (CMT4F) ( n = 1). Almost all patients ( n = 31) presented with moderate or severe compromise in the CMT neuropathy score 2 with the highest values observed in CMT1B. Medical history disclosed obstructive sleep apnea ( n = 5), aseptic meningitis ( n = 1/ MPZ ), akinetic-rigid parkinsonism ( n = 1/ FIG4 ), and overlapping chronic inflammatory demyelinating polyneuropathy ( n = 1/ MPZ ). Motor conduction block was detected in three individuals ( PMP22 , FIG4 , MPZ ). Acute denervation occurred in seven patients. Nonuniform demyelinating patterns were seen in four individuals (two CMT1A, one CMT1B, and one CMTX1). Abnormal cerebral white matter findings were detected in CMT1A and CMTX1, while hypertrophic roots were seen in CMT1A, CMT1B, and CMTX1. Our study emphasizes a relative oligogenic basis in childhood-onset demyelinating CMT and atypical findings may be observed especially in MPZ , PMP22 , and GJB1 gene variants.

Charcot-Marie-Tooth disease: from historical landmarks in Brazil to current care perspectives / Doença de Charcot-Marie-Tooth: dos marcos históricos no Brasil até as perspectivas atuais de cuidado

Abstract Hereditary motor and sensory neuropathy, also known as Charcot-Marie-Tooth disease (CMT), traditionally refers to a group of genetic disorders in which neuropathy is the main or sole feature. Its prevalence varies according to different populations studied, with an estimate between 1:2,500 to 1:10,000. Since the identification of PMP22 gene duplication on chromosome 17 by Vance et al., in 1989, more than 100 genes have been related to this group of disorders, and we have seen advances in the care of patients, with identification of associated conditions and better supportive treatments, including clinical and surgical interventions. Also, with discoveries in the field of genetics, including RNA interference and gene editing techniques, new treatment perspectives begin to emerge. In the present work, we report the most import landmarks regarding CMT research in Brazil and provide a comprehensive review on topics such as frequency of different genes associated with CMT in our population, prevalence of pain, impact on pregnancy, respiratory features, and development of new therapies.

Resumo A neuropatia sensitivo-motora hereditária, também conhecida como doença de Charcot-Marie-Tooth (CMT), tradicionalmente se refere a um grupo de doenças genéticas em que a neuropatia é a principal ou única manifestação. Sua prevalência varia de acordo com as diferentes populações estudadas, com estimativa entre 1:2.500 a 1:10.000. Desde a identificação da duplicação do gene PMP22 no cromossomo 17, por Vance et al., em 1989, mais de 100 genes foram relacionados a esse grupo de doenças e temos visto avanços no atendimento aos pacientes, com identificação de condições associadas e melhores tratamentos de suporte, incluindo intervenções clínicas e cirúrgicas. Além disso, com as descobertas no campo da genética, incluindo técnicas de interferência de RNA e de edição genética, novas perspectivas de tratamento começaram a surgir. No presente trabalho, relatamos os marcos mais importantes sobre a pesquisa de CMT no Brasil e fornecemos uma revisão abrangente sobre tópicos como frequência de diferentes genes associados à CMT em nossa população, prevalência de dor, impacto na gravidez, alterações respiratórias e desenvolvimento de novas terapias.

Management of Stress Urinary Incontinence With Pelvic Floor Muscle Training for a Woman With Charcot-Marie-Tooth Disease: A Case Report.

Objective: The purpose of this report is to describe the effects of pelvic floor muscle training (PFMT) in stress urinary incontinence (SUI) of a woman with Charcot-Marie-Tooth (CMT) disease. Clinical Features: A 50-year-old female patient with a diagnosis of type II CMT disease was referred to treatment as a result of a complaint of urinary loss upon effort (ie, coughing and sneezing). She reported that the symptoms started about 36 months prior. The urodynamic study revealed SUI with a Valsalva leak point pressure of 84 cmH2O. Intervention and Outcome: The treatment of SUI was carried out through a PFMT program for 12 weeks (with supervision) and exercises at home for another 12 weeks. A specialized physiotherapist measured symptoms and severity of SUI (3-day urinary diary, 1-hour pad test), pelvic floor muscle function (digital palpation, manometry and dynamometry), effect of the SUI on quality of life (Incontinence Quality of Life Questionnaire), and adherence to the outpatient sessions and to home exercise sets, which also were assessed (exercise diary). Conclusion: In this patient with CMT disease, improvements in urinary symptoms and severity of SUI, pelvic floor muscle function, and effect of SUI on quality of life were noted after PFMT.

Recording cutaneous silent period parameters in hereditary and acquired neuropathies / Registro do período de silêncio cutâneo em neuropatias adquiridas e hereditárias

Abstract Background Cutaneous silent period (CSP) is the interruption in muscle activity after painful stimulation of a sensory nerve. Objective The aim of the present study is to assess CSP changes in patients with polyneuropathy (PNP). Methods The present study was carried out to assess CSP in individuals with diabetes (DM) and Charcot-Marie-Tooth (CMT) disease. The sample comprised 24 individuals with DM, 10 individuals with CMT1 disease, and 10 individuals with CMT2 disease. The control group (CG) consisted of 59 individuals. Results The mean latencies recorded for the upper limbs in the CG were 79.2 milliseconds (onset latency), 69.3 milliseconds (50% reduction latency), 112.2 milliseconds (end latency), and 33.1 milliseconds (CSP duration). On the other hand, the mean latencies recorded for the lower limbs were 99.0 milliseconds (onset latency), 85.0 milliseconds (50% reduction latency), 136.9 milliseconds (end latency), and 38.2 milliseconds (CSP duration). The mean latencies recorded for the CG were significantly lower than the ones recorded for other groups, both in the upper and lower limbs. Conclusions Cutaneous silent period values recorded for the CG in the present study were close to the ones reported in studies available in the literature. Abnormal CSP parameters were observed in the group of individuals with PNP. The end latency in the lower limbs helped differentiating the demyelinating subgroup from the axonal one.

Resumo Antecedentes Período de silêncio cutâneo (PSC) é uma interrupção da atividade muscular após a estimulação dolorosa de um nervo sensitivo. Objetivo O presente estudo tem como objetivo avaliar alterações do PSC em indivíduos com polineuropatia. Métodos O presente estudo avaliou PSC em indivíduos com diabetes mellitus (DM) e com doença de Charcot-Marie-Tooth (CMT). A amostra compreendia 24 indivíduos com DM, 10 indivíduos com CMT tipo 1 e 10 indivíduos com CMT tipo 2. Um grupo controle continha 59 indivíduos. Resultados A média das latências do PSC registradas nos membros superiores no grupo controle foi 79,2 milissegundos (latência de início), 69,3 milissegundos (latência com redução de 50%), 112,2 milissegundos (latência final) e 33,1 milissegundos (duração do PSC). Por outro lado, a média das latências do PSC registradas nos membros inferiores foi 99,0 milissegundos (latência de início), 85,0 milissegundos (latência com redução de 50%), 136,9 milissegundos (latência final) e 38,2 milissegundos (duração do PSC). A média das latências registradas no grupo controle foi significativamente menor do que as registradas nos outros grupos (DM e CMT), tanto nos membros inferiores quanto nos superiores. Conclusões Os valores do PSC registrados no grupo controle no presente estudo estiveram próximos aos reportados na literatura. Parâmetros anormais foram observados no grupo de indivíduos com polineuropatia. A latência final do PSC obtida nos membros inferiores ajudou a diferenciar os subgrupos desmielinizantes e axonais.

Charcot-Marie-Tooth disease type 4C associated with myasthenia gravis: coincidental or a foreseeable association?

We reported one patient with Charcot-Marie-Tooth type 4C (CMT4C) who developed seropositive myasthenia gravis. Neuromuscular junction alterations in CMT4C patients have not yet been reported. However, few patients have been reported to simultaneously have MG and CMT, but none with CMT4C. Our report suggests that additional research is required to confirm whether genetic neuropathies may predispose to MG.

Atypical presentation of Charcot-Marie-Tooth disease type 2Q by mutations on DHTKD1 and NTRK2 genes / Presentación atípica de enfermedad de Charcot-Marie-Tooth tipo 2Q por mutaciones en los genes DHTKD1 y NTRK2

Abstract Background: Charcot-Marie-Tooth disease type 2Q (CMT2Q) is a rare disorder (< 1/1,000,000 individuals worldwide) linked to chromosome 10p14 in the DHTKD1 gene. This phenotype is characterized by an adolescent or adulthood-onset, slowly progressive distal muscle weakness and symmetrical atrophy associated with reduced or absent deep tendon reflexes. Currently, only two familiar cases from China have been reported: one familiar case of eight individuals affected by isolated DHTKD1 gene mutation and one familiar case of two individuals affected by DHTKD1 gene mutation and GJB1 gene mutation. Case report: We present the case of a 10-year-old male patient with obesity, frequent falls, swollen legs and thighs, and pain in the lower and upper limbs. We performed the clinical evaluation and a clinical targeted exome test, which reported mutations on DHTKD1 y NTRK2 genes. Conclusions: Due to scientific and technological advances, genetic dysfunctions that can cause different diseases have been identified with greater sensitivity. Globally, this is the eleventh case reported of DHTKD1 gene mutation linked to CMT2Q. Moreover, this is the first case related to NTRK2 gene mutation (linked to obesity, hyperphagia, and delayed development). The patient showed an atypical CMT2Q phenotype additional to obesity. Therefore, we propose to study metabolic disorders linked to hereditary peripheral neuropathies.

Resumen Introducción: La enfermedad de Charcot-Marie-Tooth tipo 2Q (CMT2Q) es una alteración poco frecuente (< 1/1,000,000 habitantes en todo el mundo) condicionada por mutaciones en el gen DHTKD1, localizado en el cromosoma 10p14. El padecimiento inicia en la adolescencia o la edad adulta de manera lenta y progresiva, con debilidad muscular y atrofia distal simétrica, y afecta predominantemente las extremidades inferiores y los reflejos tendinosos profundos, que se encuentran reducidos o ausentes. Solo se ha reportado un caso familiar de ocho personas afectadas con la mutación aislada en el gen DHTKD1 y un caso familiar de dos personas afectadas con mutaciones en los genes DHTKD1 y GJB1, ambas familias de China. Caso clínico: Se presenta el caso de un paciente de sexo masculino de 10 años y 11 meses de edad con obesidad, caídas frecuentes, edema de miembros pélvicos y dolor en las extremidades inferiores y superiores. Se realizaron valoración clínica y estudio genético molecular de exoma dirigido, el cual reportó mutaciones en los genes DHTKD1 y NTRK2. Conclusiones: Gracias al avance científico y tecnológico se han podido identificar con mayor precisión las alteraciones genéticas causantes de diferentes enfermedades. Este es el undécimo caso reportado en el mundo de una mutación en el gen DHTKD1 asociada con la enfermedad de CMT2Q. También es el primer caso relacionado con una mutación del gen NTRK2 (asociada con obesidad, hiperfagia y retraso en el desarrollo). El paciente presentó un cuadro clínico atípico de enfermedad de CMT2Q agregado a obesidad. Por ello, se sugiere estudiar a fondo la conexión entre trastornos metabólicos y neuropatías periféricas hereditarias.

Atypical presentation of Charcot-Marie-Tooth disease type 2Q by mutations on DHTKD1 and NTRK2 genes.

Background: Charcot-Marie-Tooth disease type 2Q (CMT2Q) is a rare disorder (< 1/1,000,000 individuals worldwide) linked to chromosome 10p14 in the DHTKD1 gene. This phenotype is characterized by an adolescent or adulthood-onset, slowly progressive distal muscle weakness and symmetrical atrophy associated with reduced or absent deep tendon reflexes. Currently, only two familiar cases from China have been reported: one familiar case of eight individuals affected by isolated DHTKD1 gene mutation and one familiar case of two individuals affected by DHTKD1 gene mutation and GJB1 gene mutation. Case report: We present the case of a 10-year-old male patient with obesity, frequent falls, swollen legs and thighs, and pain in the lower and upper limbs. We performed the clinical evaluation and a clinical targeted exome test, which reported mutations on DHTKD1 y NTRK2 genes. Conclusions: Due to scientific and technological advances, genetic dysfunctions that can cause different diseases have been identified with greater sensitivity. Globally, this is the eleventh case reported of DHTKD1 gene mutation linked to CMT2Q. Moreover, this is the first case related to NTRK2 gene mutation (linked to obesity, hyperphagia, and delayed development). The patient showed an atypical CMT2Q phenotype additional to obesity. Therefore, we propose to study metabolic disorders linked to hereditary peripheral neuropathies.

Introducción: La enfermedad de Charcot-Marie-Tooth tipo 2Q (CMT2Q) es una alteración poco frecuente (< 1/1,000,000 habitantes en todo el mundo) condicionada por mutaciones en el gen DHTKD1, localizado en el cromosoma 10p14. El padecimiento inicia en la adolescencia o la edad adulta de manera lenta y progresiva, con debilidad muscular y atrofia distal simétrica, y afecta predominantemente las extremidades inferiores y los reflejos tendinosos profundos, que se encuentran reducidos o ausentes. Solo se ha reportado un caso familiar de ocho personas afectadas con la mutación aislada en el gen DHTKD1 y un caso familiar de dos personas afectadas con mutaciones en los genes DHTKD1 y GJB1, ambas familias de China. Caso clínico: Se presenta el caso de un paciente de sexo masculino de 10 años y 11 meses de edad con obesidad, caídas frecuentes, edema de miembros pélvicos y dolor en las extremidades inferiores y superiores. Se realizaron valoración clínica y estudio genético molecular de exoma dirigido, el cual reportó mutaciones en los genes DHTKD1 y NTRK2. Conclusiones: Gracias al avance científico y tecnológico se han podido identificar con mayor precisión las alteraciones genéticas causantes de diferentes enfermedades. Este es el undécimo caso reportado en el mundo de una mutación en el gen DHTKD1 asociada con la enfermedad de CMT2Q. También es el primer caso relacionado con una mutación del gen NTRK2 (asociada con obesidad, hiperfagia y retraso en el desarrollo). El paciente presentó un cuadro clínico atípico de enfermedad de CMT2Q agregado a obesidad. Por ello, se sugiere estudiar a fondo la conexión entre trastornos metabólicos y neuropatías periféricas hereditarias.

HINT1 founder mutation causing axonal neuropathy with neuromyotonia in South America: A case report.

BACKGROUND: Recessive loss-of-function mutations in HINT1 are associated with predominantly motor axonal peripheral neuropathy with neuromyotonia. Twenty-four distinct pathogenic variants are reported all over the world, including four confirmed founder variations in Europe and Asia. The majority of patients carry the ancient Slavic founder variant c.110G>C (p.Arg37Pro) that shows a distribution gradient from east to west throughout Europe. METHODS: We report a case of HINT1 neuropathy in South America, identified by massive parallel sequencing of a neuropathy gene panel. To investigate the origin of the variant, we performed haplotyping analysis. RESULTS: A Brazilian adolescent presented with recessive axonal motor neuropathy with asymmetric onset and fasciculations. Neuromyotonia was found on needle electromyography. His parents were not consanguineous and had no European ancestry. The patient carried biallelic pathogenic p.Arg37Pro alterations in the first exon of HINT1. Both alleles were identical by descent and originated from the same ancestral founder allele as reported in Europe. CONCLUSION: Our findings expand the geographic distribution of HINT1 neuropathy to South America, where we describe a recognized founder variant in a Brazilian adolescent with no apparent European ancestry. We confirm the association of the hallmark sign of neuromyotonia with the disease.

Charcot-Marie-Tooth disease: Genetic profile of patients from a large Brazilian neuromuscular reference center.

This study aimed to describe the clinical, genetic, and epidemiological features of Charcot-Marie-Tooth disease (CMT) in Brazilian patients from a tertiary center, and to compare our data with previously published findings. This retrospective observational study conducted between February 2015 and July 2020 evaluated 503 patients (94 families and 192 unrelated individuals), diagnosed with CMT. Clinical and neurophysiological data were obtained from electronic medical records and blood samples were used for genetic analyses. Multiplex ligation-dependent probe amplification was used to assess duplications/deletions in PMP22. Sanger sequencing of GJB1 was performed in cases of suspected demyelinating CMT. Targeted gene panel sequencing was used for the remaining negative demyelinating cases and all axonal CMT cases. The first decade of life was the most common period of disease onset. In all, 353 patients had demyelinating CMT, 39 had intermediate CMT, and 111 had axonal CMT. Pathogenic or likely pathogenic variants were identified in 197 index cases. The most common causative genes among probands were PMP22 (duplication) (n = 116, 58.88%), GJB1 (n = 23, 11.67%), MFN2 (n = 12, 6.09%), GDAP1 (n = 7, 3.55%), MPZ (n = 6, 3.05%), PMP22 (point mutation) (n = 6, 3.05%), NEFL (n = 3, 1.52%), SBF2 (n = 3, 1.52%), and SH3TC2 (n = 3, 1.52%). Other identified variants were ≤1% of index cases. This study provides further data on the frequency of CMT subtypes in a Brazilian clinical-based population and highlights the importance of rarer and previously undiagnosed variants in clinical practice.

Childhood onset homozygous recessive GDAP1 (p.Pro231Leu) mutation in a 9-year-old puerto rican pediatric female with axonal Charcot-Marie-Tooth disease: A case report.

Charcot-Marie-Tooth disease (CMT) is a progressive hereditary neuromuscular neuropathy with pathology in the myelin sheath or the axon. CMT caused by mutations in the Ganglioside-induced differentiation associated protein 1 (GDAP1) gene has been described by a spectrum of phenotypic presentations. GDAP1 is a mitochondrial protein responsible for protecting neuronal bodies from oxidative stress. It is associated with axonal and demyelinating pathophysiology with recessive and dominant modes of inheritance.We describe a case of a 9-year-old Puerto Rican female with clinical and electrodiagnostic results compatible with an axonal sensory-motor neuropathy where a genetic test describes a homozygous GDAP1 missense mutation at the c.692C>T (p.Pro231Leu), previously undetected in a pediatric Latino patient. Mutations in GDAP1 have been previously described in Tunisian, Old Order Amish, European and Japanese families with varying modes of inheritance. To our knowledge, this homozygous variant presentation of the GDAP1 gene is the first to be described in a pediatric Puerto Rican patient without a family history of hereditary sensory motor neuropathy.

Prevalence and characterization of pain in patients with Charcot-Marie-Tooth disease type 1A / Prevalência e caracterização da dor na doença de Charcot-Marie-Tooth tipo 1A

ABSTRACT Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common form of hereditary neuropathy. Objective: To investigate the prevalence and characteristics of pain in patients with CMT1A. Methods: Nineteen patients with a diagnosis of CMT1A were evaluated between September 2018 and October 2019, and other causes of neuropathy were ruled out. The following tools were used for the pain assessment: neurological assessment, LANSS, DN4, clinical evaluation, VAS, CMTNS2 and SF-36. Statistical analysis was performed using prevalence analysis, t test, chi-square test and Spearman's rho. Results: The prevalence of pain was 84.2% in the sample of this study, with moderate intensity and nociceptive characteristics according to the LANSS scale (75%) and clinical evaluation (50%), but differing from DN4, which found neuropathic pain in the majority of the patients (56.2%). Mixed pain was also observed in 43.7% of the patients, according to clinical criteria. There was a statistically significant correlation between pain intensity and SF-36, thus demonstrating that the lower the pain was, the lower the impairment was, in all domains. Conclusion: Pain is a prevalent and important symptom in CMT1A, with moderate intensity and nociceptive characteristics according to two tools, but neuropathic pain is also present, and there may even be a mixed pattern of pain. The correlation of the pain with SF-36 suggests that pain relief could provide improvements to the quality of life of these individuals.

RESUMO Introdução: A doença de Charcot-Marie-Tooth tipo 1 A (CMT1A) é a forma mais comum de neuropatia hereditária. Objetivo: Investigar a prevalência e as características de dor nos pacientes com a doença de CMT1A. Métodos: Dezenove pacientes com diagnóstico de CMT1A foram avaliados de setembro 2018 a outubro de 2019, e outras causas de neuropatia foram excluídas. As seguintes ferramentas foram utilizadas para avaliar a dor: avaliação neurológica, LANSS, DN4, avaliação clínica, EVA, CMTNS2 e SF-36. A análise estatística foi realizada pelo teste de análise de prevalência, bem como pelos testes T, do qui-quadrado e rô de Sperman. Resultados: A prevalência de dor foi de 84,2% na amostra do estudo, com intensidade moderada e características nociceptivas de acordo com a escala LANSS (75%) e a avaliação clínica (50%), diferentemente da escala DN4, que encontrou dor neuropática na maioria dos pacientes (56,2%). Dor mista também foi verificada em 43,7% dos pacientes, de acordo com os critérios clínicos. Houve significância estatística da correlação entre a intensidade da dor e o SF-36, demonstrando que quanto menor a dor, menor o comprometimento em todos os domínios. Conclusão: A dor é um sintoma prevalente e relevante na CMT1A, com intensidade moderada e características nociceptivas de acordo com duas ferramentas, mas dor neuropática também está presente, e ainda pode haver padrão misto de dor. A correlação da dor com SF-36 sugere que o alívio da dor pode proporcionar melhorias na qualidade de vida desses indivíduos.

GDAP1 mutations are frequent among Brazilian patients with autosomal recessive axonal Charcot-Marie-Tooth disease.

Mutations in ganglioside-induced differentiation-associated-protein 1 (GDAP1) are associated with several subtypes of Charcot-Marie-Tooth (CMT) disease, including autosomal recessive and demyelinating (CMT4A); autosomal recessive and axonal (AR-CMT2K); autosomal dominant and axonal (CMT2K); and an intermediate and recessive form (CMTRIA). To date, at least 103 mutations in this gene have been described, but the relative frequency of GDAP1 mutations in the Brazilian CMT population is unknown. In this study, we investigated the frequency of GDAP1 mutations in a cohort of 100 unrelated Brazilian CMT patients. We identified five variants in unrelated axonal CMT patients, among which two were novel and probably pathogenic (N64S, P119T) one was novel and was classified as VUS (K207L) and two were known pathogenic variants (R125* and Q163*). The prevalence rate of GDAP1 among the axonal CMT cases was 7,14% (5/70), all of them of recessive inheritance, thus suggesting that the prevalence was higher than what is observed in most countries. All patients exhibited severe early-onset CMT that was rapidly progressive. Additionally, this study widens the mutational spectrum of GDAP1-related CMT through identification of two novel likely pathogenic variants.

Disfagia na doença de Carcot-Marie-Tooth: relato de caso / Dysphagia in Charcot-Marie-Tooth disease: a case report

A doença de Charcot-Marie-Tooth (CMT) é uma polineuropatia motora, sensitiva, hereditária e de predomínio distal. Os membros inferiores são os mais afetados e, ocasionalmente, há comprometimento dos membros superiores. Este estudo descreve a presença de disfagia orofaríngea e a intervenção fonoaudiológica em uma paciente de 58 anos com diagnóstico de CMT, encaminhada à avaliação fonoaudiológica devido a queixas na deglutição. Na avaliação inicial identificaram-se alterações, tanto de caráter estrutural quanto funcional, que resultaram em uma disfagia orofaríngea leve. Também se utilizou o Questionário de Qualidade de Vida na Disfagia para identificar o impacto na qualidade de vida da paciente. Após um mês de acompanhamento observou-se melhora dos sintomas e aumento do conforto e segurança ao deglutir. (AU)

Charcot-Marie-Tooth (CMT) disease is a motor and sensory, hereditary, distally predominant polyneuropathy. The lower limbs are most affected and, occasionally, there is upper limb impairment; however, presence of oropharyngeal dysphagia has been identified. The present study describes the findings and speech therapy intervention in a 58-year-old patient, with CMT diagnosis, referred to speech therapy evaluation due to swallowing complaints. In an initial evaluation, presence of structural and functional alterations, resulting in mild oropharyngeal dysphagia, was identified. The Swallowing Quality of Life questionnaire was also used to identify the impact of dysphagia in the patient's quality of life. After a month of follow-up, an improvement was observed in the presenting symptoms, as well as an increase in comfort and safety during swallowing. (AU)

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.

Spinal anesthesia in a patient with Charcot-Marie-Tooth disease undergoing orthopedic surgery: case report / Anestesia raquídea en un paciente con enfermedad de Charcot-Marie-Tooth sometido a cirugía ortopédica: reporte de caso

Abstract Introduction: It is uncommon to come across patients with neuromuscular diseases in the daily practice of anesthesia, given the low prevalence of those conditions. Charcot-Marie-Tooth (CMT) disease is the most frequently, caused by an inherited abnormal myelin structure pattern. In view of the low prevalence of this condition (1:25,000), there is little information, derived mostly from case reports, about the use of neuroaxial anesthesia in these patients. Case presentation: Description of a patient with underlying CMT disease compromising lower limb mobility, who comes to the emergency service due to lower limb pain. After being diagnosed with an acetabular fracture, the patient underwent orthopedic surgery under spinal anesthesia, selected based on patient comorbidities, and the immediate postoperative follow-up. Results: The anesthetic and surgical procedures proceeded uneventfully and no neuropathic worsening was observed during the next 24 hours. Conclusion: Uneventful neuroaxial anesthesia is reported in a patient with neuromuscular disease. The case contributes to show the benefits and safety of this form of anesthesia when compared with other options.

Resumen Introducción: En la práctica anestésica diaria es raro enfrentarse a pacientes con patologías neuromusculares, dada la poca pre-valencia de dichas patologías. La más frecuente de ellas es la enfermedad de Charcot-Marie-Tooth, en la cual se hereda un patrón alterado en la estructura de la mielina. Debido a la baja prevalencia de esta patología (1:25000), el uso de anestesia neuroaxial en dichos pacientes no cuenta con mucha información, y mucha de ella proviene de reportes de casos. Presentación del caso: Se describe el caso de un paciente con enfermedad de Charcot-Marie-Tooth, de base, con compromiso de la movilidad en miembros inferiores, y quien asiste a urgencias por dolor en miembro inferior. Tras ser diagnosticado con fractura de acetábulo, fue sometido a cirugía ortopédica bajo anestesia raquídea, indicada a la luz de sus comorbilidades, y el posterior seguimiento inmediato. Resultados: Se realiza el procedimiento anestésico y quirúrgico sin complicaciones, y no se presenta empeoramiento de la neuropatía en las 24 horas posteriores. Conclusiones: Se reporta un caso de anestesia neuroaxial en paciente con enfermedad neuromuscular sin incidencias, que ayuda así a ir mostrando los beneficios de la mencionada anestesia y su seguridad frente a otras opciones.

Role of Connexin-Based Gap Junction Channels in Communication of Myelin Sheath in Schwann Cells.

Peripheral nerves have the capacity to conduct action potentials along great distances and quickly recover following damage which is mainly due to Schwann cells (SCs), the most abundant glial cells of the peripheral nervous system (PNS). SCs wrap around an axonal segment multiple times, forming a myelin sheath, allowing for a significant increase in action potential conduction by insulating the axons. Mature myelin consists of compact and non-compact (or cytoplasmic) myelin zones. Non-compact myelin is found in paranodal loops bordering the nodes of Ranvier, and in the inner and outermost cytoplasmic tongues and is the region in which Schmidt-Lanterman incisures (SLI; continuous spirals of overlapping cytoplasmic expansions within areas of compact myelin) are located. Using different technologies, it was shown that the layers of non-compact myelin could be connected to each other by gap junction channels (GJCs), formed by connexin 32 (Cx32), and their relative abundance allows for the transfer of ions and different small molecules. Likewise, Cx29 is expressed in the innermost layer of the myelin sheath. Here it does not form GJCs but colocalizes with Kv1, which implies that the SCs play an active role in the electrical condition in mammals. The critical role of GJCs in the functioning of myelinating SCs is evident in Charcot-Marie-Tooth disease (CMT), X-linked form 1 (CMTX1), which is caused by mutations in the gap junction protein beta 1 (GJB1) gene that codes for Cx32. Although the management of CMT symptoms is currently supportive, there is a recent method for targeted gene delivery to myelinating cells, which rescues the phenotype in KO-Cx32 mice, a model of CMTX1. In this mini-review article, we discuss the current knowledge on the role of Cxs in myelin-forming SCs and summarize recent discoveries that may become a real treatment possibility for patients with disorders such as CMT.

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.