Clinical and genetic analysis of 2 families with Charcot-Marie-Tooth disease / 临床神经病学杂志

Objective To investigate the clinical characteristics of Charcot-Marie-Tooth disease(CMT),and conduct genetic analysis.Methods The clinical data of 2 families were retrospectively analyzed.Results The proband of family 1 had atrophy of bilateral thigh and calf muscles,serum creatine kinase(CK)was 292 U/L,and EMG examination showed peripheral nerve damage of upper and lower limbs(mainly axonal).Genetic testing revealed that the proband carried a heterozygous mutation of NEFH:NM＿02107:c.3057dupG:p.K1020Efs*43.According to American College of Medical Genetics and Genomics(ACMG),the variant of NEFH gene was interpreted as likely pathogenic(PS3＿moderate+PM2+PM4+PP1).The proband of family 2 had scoliosis,calf muscle atrophy,flat foot,blood creatine kinase 80 U/L,and EMG examination showed peripheral nerve damage in the upper and lower limbs(mainly axonal).Genetic testing revealed that the proband carried a heterozygous mutation of the MFN2:NM＿014874:c.746C＞G:p.S249C.This mutation had not been reported and included in the relevant literature,and was likely to be pathogenic according to the ACMG regulation rating(Likely Pathogenic:PM1+PM2+PM5+PP3).Conclusions The clinical manifestations of the two families are muscle weakness with muscle atrophy,normal or mild elevation of creatine kinase,disappearance of tendon reflex,arched foot,and electromyography indicating neurogenic damage.Gene testing reveals that the probands carried heterozygous mutations in the NEFH and MFN2 genes,respectively.

Autosomal recessive axonal neuropathy with neuromyotonia in a Tibetan family caused by HINT1 gene variation and literature review / 中华实用儿科临床杂志

Objective:To summarize the characteristics of autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM) caused by HINT1 gene mutation. Methods:Retrospective case summary.Clinical data of 2 Tibetan siblings diagnosed with ARAN-NM in the Department of Pediatrics of Peking University First Hospital in August 2023 were retrospectively analyzed.A review of literature reporting relevant Chinese patients was conducted.Results:The proband and her elder brother were aged 13 and 19, respectively.Both developed abnormal gait at the age of 11, followed by varus, claudication, and weak thumb strength.The proband also had neuromyotonia.Physical examinations showed that the proband and her elder brother had decreased muscle strength of the extremities, mainly in the thumbs and distal ends of lower limbs.The distal muscles of the proband′s lower extremities and the muscles of both hands of the proband′s elder brother were atrophied.Both feet showed talipes equinovarus in the proband and her elder brother.The proband′s electromyography (EMG) showed peripheral nerve injuries (motor and sensory axonal involvement, especially in distal ends) and myotonic potentials.The trio-whole exon sequencing detected homozygous pathogenic variation in HINT1 gene in both the proband and her elder brother, who were diagnosed as ARAN-NM based on c. 169A>G (p.K57E). After the Carbamazepine treatment, the proband′s neuromyotonia, numbness and weakness were relieved.Both the proband and her elder brother underwent orthopaedic surgery and rehabilitation.Their foot deformities and gait were significantly improved.Two Chinese literatures (2 patients) and four English literatures (8 patients) were retrieved.Including the proband and her elder brother in this study, there were 12 ARAN-NM patients, 10 of whom had clinical data.The ages of onset and diagnosis were 2-16 (1 case unknown) and 13-33 years old, respectively.Myasthenia was present in 9 patients, especially in distal ends.Eight patients were complicated with neuromyotonia, nine patients with muscle atrophy, seven patients with foot deformity, and two patients with sensory disturbance.Creatine kinase(CK) was elevated in all 9 patients tested or CK.EMG showed neurogenic injuries in all patients and neuromyotonia discharge in six patients.Three patients were treated with Carbamazepine, and some symptoms were relieved.Missense/nonsense mutations were found in the 12 patients, and the high-frequency variation was c. 112T>C (p.C38R). Conclusions:ARAN-NM is a rare autosomal recessive neuromuscular disease caused by HINT1 gene mutation.There is no ethnic difference in clinical manifestations, mainly distal limb weakness with neuromyotonia.Carbamazepine can alleviate some symptoms, and orthopaedic surgery can improve foot deformity and gait.

The c.91C>T mutation in DNAJB2 gene associated distal hereditary motor neuropathy and early-onset Parkinson′s disease: a family report / 中华神经科杂志

A family carrying a homozygous variant of DNAJB2 gene C.91C>T (p.His31Tyr) with distal hereditary motor neuropathy (dHMN) associated with early-onset Parkinson′s disease was reported. The patient presented with distal limb weakness and atrophy at the early stage of the disease, and developed Parkinson′s symptoms more than 10 years later. Neuroelectrophysiological examination suggested motor and sensory axonal involvement. This mutation site had not been reported and was considered to be a neogenic mutagenicity of dHMN, excluding other mutations that can cause early-onset Parkinson′s disease.

The genetic and clinical features of MORC2 gene-related neuropathy in Chinese patients / 中华神经科杂志

Objective:To summarize the genetic and phenotypic features of MORC family CW-type zinc finger 2 (MORC2) gene-related neuropathy in Chinese patients. Methods:The clinical and whole exome sequencing data of MORC2 gene-related neuropathy families with a definitive genetic diagnosis were collected from the Third Xiangya Hospital of Central South University between 2010 and 2023. Literature involving Chinese families with MORC2 gene-related neuropathy was extensively reviewed to provide a comprehensive summary of the genetic and phenotypic spectrum of the disease. Results:A total of 10 families with MORC2 gene-related neuropathy were identified and analyzed. Six different heterozygous pathogenic variants in the MORC2 gene were observed among these families, including the novel variant c.1330G>C (p.G444R) that had not been previously reported. Six families presented as axonal Charcot-Marie-Tooth disease caused by variants in the MORC2 gene (CMT2Z) phenotype with childhood or adult onset, and carried variants c.754C>T (p.R252W), c.1199A>G (p.Q400R), c.1330G>C (p.G444R), or c.1396G>A (p. D466N); 3 families manifested as severe spinal muscular atrophy (SMA)-like phenotype with infantile onset, all carried c.260C>T (p.S87L); 1 family carried c.1181A>G (p.Y394C), presented as DIGFAN syndrome phenotype with infantile onset combined with mental and motor retardation. Systematic review showed 8 Chinese families carried pathogenic variants of the MORC2 gene, among which 5 families were associated with the CMT2Z phenotype, carrying c.754C>T (p.R252W), c.1079A>G (p.E360G), c.1220G>A (p.C407Y), or c.1397A>G (p.D466G); 1 family was associated with SMA-like phenotype, carrying c.260C>T (p.S87L); and 2 families were associated with DIGFAN syndrome, carrying c.79G>A (p.E27K) and c.292G>A (p.G98R). Conclusions:A novel pathogenic variant c.1330G>C (p.G444R) of the MORC2 gene associated with the CMT2 phenotype is reported. Eleven pathogenic variants of the MORC2 gene have been reported in the Chinese patients to date, and c.754C>T(p.R252W) may be the most common. Patients with MORC2 gene-related neuropathy carrying different variants present with significant clinical heterogeneity, manifesting as CMT2Z, early-onset severe SMA-like myasthenia, or DIGFAN syndrome.

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.

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.

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.

Clinical features of a pedigree of charcot-marie-tooth disease type 2cc caused by the point mutation of NEFH gene / 中华实用儿科临床杂志

The clinical data of 4 patients in a pedigree of charcot-marie-tooth disease type 2cc (CMT2cc) caused by the NEFH gene mutation from the Department of Rehabilitation, Tianjin Children′s Hospital in March 2020 were reviewed and analyzed retrospectively.The purpose of this study was to improve clinicians′ awareness of the di-sease.The pedigree had signs and symptoms of varying degrees of pyramidal fasciculus involvement, high arched feet, and achilles tendon contracture.The electrophysiological testing of both lower extremities suggested sensory and motor nerve axonal damage, and an abnormal visual evoked potential was observed.Second-generation sequencing revealed that the pathogenic factor was the NEFH gene variation: c.1319G>A (p.Ser440Asn), which is a new mutation site that has never been reported before. NEFH mutations can cause a complex clinical phenotype of CMT2cc, which is therefore easily misdiagnosed.Central and peripheral nerves are simultaneously involved in CMT2cc patients.Electrophysiological testing and genetic analysis are required to clarify the diagnosis of CMT2cc.

Clinical features of a pedigree of charcot-marie-tooth disease type 2cc caused by the point mutation of NEFH gene / 中华实用儿科临床杂志

The clinical data of 4 patients in a pedigree of charcot-marie-tooth disease type 2cc (CMT2cc) caused by the NEFH gene mutation from the Department of Rehabilitation, Tianjin Children′s Hospital in March 2020 were reviewed and analyzed retrospectively.The purpose of this study was to improve clinicians′ awareness of the di-sease.The pedigree had signs and symptoms of varying degrees of pyramidal fasciculus involvement, high arched feet, and achilles tendon contracture.The electrophysiological testing of both lower extremities suggested sensory and motor nerve axonal damage, and an abnormal visual evoked potential was observed.Second-generation sequencing revealed that the pathogenic factor was the NEFH gene variation: c.1319G>A (p.Ser440Asn), which is a new mutation site that has never been reported before. NEFH mutations can cause a complex clinical phenotype of CMT2cc, which is therefore easily misdiagnosed.Central and peripheral nerves are simultaneously involved in CMT2cc patients.Electrophysiological testing and genetic analysis are required to clarify the diagnosis of CMT2cc.

Novel MFN2, BSCL2 and LRSAM1 variants in a cohort of Chinese patients with Charcot-Marie-Tooth disease / 中华内科杂志

Objective:Charcot-Marie-Tooth disease (CMT) comprises a group of clinically and genetically heterogeneous inherited neuropathies with an estimated prevalence of 1 in 2500. This study aimed to analyze the clinical and mutational characteristics of Chinese CMT patients with MFN2, BSCL2 and LRSAM1 variants.Methods:In this study, genetic analysis was performed in 206 Chinese patients at Chinese PLA General Hospital from December 2012 to March 2020 with clinical diagnosis of CMT, and reported variants of MFN2, BSCL2 and LRSAM1 related to CMT2.Results:We reported ten MFN2 mutations in ten unrelated patients (7 male, 3 female), two of whom had positive family history. Three novel mutations were detected including c.475-2A>G (splicing); c.687dupA (p.E230Rfs*16) and c.558dupT (p.S186fs). We reported three BSCL2 mutations of four unrelated patients, including c.461C>G (p.S154W), c.461C>T(p.S154L), and novel variants of c.1309G>C (p.A437P) and c.845C>T (p.A282V). Furthermore, two novel variants of LRSAM1, including c.1930G>T (p.G644C) and c.1178T>A (p.L393Q) were detected in two unrelated patients.Conclusion:Mutational spectrum of MFN2-, BSCL2-and LRSAM1-related CMT disease is expanded with the identification of novel variants in Chinese patients.

SPTLC2 gene mutation leads to intermediate Charcot-Marries-Tooth disease: a family report / 中华神经科杂志

Objective:To report a SPTLC2 gene mutation in a family with a phenotype of Charcot-Marie-Tooth disease.Methods:To screen the family of patients with pathogenic mutations of SPTLC2 gene from the database of hereditary peripheral neuropathy in the Department of Neurology, Peking University First Hospital, and to collect their clinical data, peripheral nerve conduction examination, nerve ultrasound examination, pathological examination of the peroneal nerve and whole exome sequencing results of prohand.Results:One family was screened, the proband was a 16-year-old female with 4 years of sensory loss and anhidrosis of both lower limbs and 16 months of walking difficulty who admitted to Peking University First Hospital in January 2022. Physical examination showed sensory loss, dry skin and weakness in distal limbs. Her father had numbness and dry skin in the distal lower limbs from childhood,weakness and atrophy of his lower limbs in adulthood. He died at age of 52 years old. The nerve conduction study revealed no action potentials of the sensory and motor nerves of the lower limbs in the proband. The amplitude of the compound muscle action potential of the motor conduction of the bilateral ulnar nerve and median nerve decreased, and the nerve conduction velocity of the bilateral median nerve were 32 m/s and 24 m/s. Neurosonography showed thickening of peripheral nerves. Sural biopsy revealed severe loss of myelinated and unmyelinated nerve fibers with onion bulbs formation. SPTLC2 gene showed a known heterozygous p.G435V mutation. The lower limb weakness was improved after oral L-serine.Conclusions:SPTLC2 gene mutation can lead to an intermediate Charcot-Marie-Tooth disease phenotype. L-serine can improve the limb weakness.

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.

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.

Non-invasive prenatal test for autosomal dominant Charcot-Marie-Tooth disease in a fetus using droplet digital polymerase chain reaction / 中华围产医学杂志

We report the use of droplet digital polymerase chain reaction (ddPCR) in non-invasive prenatal test fetal Charcot-Marie-Tooth disease (CMT) caused by MFN2 gene mutation. The proband, namely the husband, was found with heterozygous mutation of c.919A>G(p.K307E) in the MFN2 gene, which was diagnosed as CMT type 2A2A at a local hospital. The proband's wife underwent genetic counseling after conception at the First Affiliated Hospital of Zhengzhou University. Peripheral blood obtained from the pregnant woman was analyzed by ddPCR at eight gestational weeks, which found the fetus to carry a paternal pathogenic gene mutation. Sanger sequencing for the chorionic sample at 11 gestational weeks further verified that the fetus was a c.919G>A(p.K307E) heterozygous mutation carrier, the same as the proband. ddPCR could be applied to cell-free fetal DNA to detect the paternal pathogenic gene mutation in the non-invasive prenatal test.

Longitudinal Evaluation of Calf MRI in a Patient with Charcot-Marie-Tooth Disease 2E：A Case Study / The Japanese Journal of Rehabilitation Medicine

We present a case report that a longitudinal calf MR evaluation was performed for a patient with Charcot-Marie-Tooth disease who underwent bilateral reconstructive foot surgeries. A 39 years-old female was referred to our department because of severe bilateral cavus foot deformities and difficulty to walk. On radiological findings, severe bilateral cavus foot deformities were confirmed. On MR findings, fatty infiltrations were detected in the wide range of bilateral lower leg compartments. Difficulty to walk aggravated despite of the conservative treatment, so bilateral reconstructive foot surgeries were performed. She acquired plantigrade and better walking function postoperatively. Two years after surgery, no recurrence of cavus foot deformity was observed, but claw toe deformities and fatty infiltrations were mildly progressing. Since CMT is slowly progressive, we need to conduct a careful follow-up.

Longitudinal Evaluation of Calf MRI in a Patient with Charcot-Marie-Tooth Disease 2E：A Case Study / The Japanese Journal of Rehabilitation Medicine

We present a case report that a longitudinal calf MR evaluation was performed for a patient with Charcot-Marie-Tooth disease who underwent bilateral reconstructive foot surgeries. A 39 years-old female was referred to our department because of severe bilateral cavus foot deformities and difficulty to walk. On radiological findings, severe bilateral cavus foot deformities were confirmed. On MR findings, fatty infiltrations were detected in the wide range of bilateral lower leg compartments. Difficulty to walk aggravated despite of the conservative treatment, so bilateral reconstructive foot surgeries were performed. She acquired plantigrade and better walking function postoperatively. Two years after surgery, no recurrence of cavus foot deformity was observed, but claw toe deformities and fatty infiltrations were mildly progressing. Since CMT is slowly progressive, we need to conduct a careful follow-up.

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)

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.

Analysis of gene mutation in a pedigree with autosomal dominant Charcot-Marie-Tooth disease / 南方医科大学学报

OBJECTIVE@#To investigate the molecular genetic mechanism of Charcot- Marie-Tooth (CMT) disease in a pedigree.@*METHODS@#Genomic DNA was extracted from the peripheral blood of the family members of a pedigree with autosomal dominant CMT disease, and 65 candidate genes of the proband were screened using target exon capture and the next generation sequencing, and the suspicious genes were verified using Sanger sequencing. PolyPhen-2, PROVEAN and SIFT software were used to predict the function of the mutant genes, and PyMOL-1 software was used to simulate the mutant protein structure.@*RESULTS@#A heterozygous missense mutation [c.371A>G (p.Y124C)] was detected in exon 3 of gene of the proband. This heterozygous mutation was also detected in both the proband's mother and her brother, but not in her father. Multiple sequence alignment analysis showed that tyrosine at codon 124 of GDAP1 protein was highly conserved. All the 3 prediction software predicted that the mutation was harmful. Molecular structure simulation showed a weakened interaction force between the amino acid residues at codon 124 and the surrounding amino acid residues to affect the overall stability of the protein.@*CONCLUSIONS@#The mutation of gene may be related to the pathogenesis of autosomal dominant AD-CMT in this pedigree. The newly discovered c.371A>G mutation (p.Y124C) expands the mutation spectrum of gene, but further study is needed to clarify the underlying pathogenesis.

Clinical application of assessment scales related to Charcot-Marie-Tooth disease / 中华神经科杂志

Charcot-Marie-Tooth (CMT) disease is the most common monogenic peripheral neuropathy with high clinical and genetic heterogeneity.With the development of orphan drugs for different genotypes of CMT,the use of standardized scales is essential for assessing the therapeutic effect of drugs and the natural course of the disease.At present,there are different types of outcome measures for assessing the severity of dysfunction,therapeutic effect,quality of life and prognosis of CMT patients.In this article the CMT-related assessment scales which are commonly used in clinical practice are reviewed.