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.

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)

Analysis of a Chinese pedigree with autosomal dominant Charcot-Marie-Tooth disease type 2A2A / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis of a pedigree affected with peroneal muscular atrophy.@*METHODS@#Neuroelectrophysiological examination and whole exome sequencing were carried out for the proband, a six-year-and-ten-month-old boy. Suspected variant was verified in his family members through Sanger sequencing. Bioinformatic analysis was carried to predict the conservation of amino acid sequence and impact of the variant on the protein structure and function.@*RESULTS@#Electrophysiological examination showed demyelination and axonal changes of motor and sensory nerve fibers. A heterozygous missense c.1066A>G (p. Thr356Ala) variant was found in exon 11 of the MFN2 gene in the proband and his mother, but not in his sister and father. Bioinformatic analysis using PolyPhen-2 and Mutation Taster software predicted the variant to be pathogenic, and that the sequence of variation site was highly conserved among various species. Based no the American College of Medical Genetics and Genomics standards and guidelines, the c.1066A>G (p. Thr356Ala) variant of MFN2 gene was predicted to be likely pathogenic (PS1+ PM2+ PP3+ PP4).@*CONCLUSION@#The heterozygous missense c.1066A>G (p.Thr356Ala) variant of the MFN2 gene probably underlay the disease in the proband, and the results have enabled genetic counseling and prenatal diagnosis for this family.

Research advance of underlying pathogenesis and target therapies in Charcot-Marie-Tooth disease type 1A / 中华医学遗传学杂志

Charcot-Marie-Tooth disease (CMT) is the commonest form of inherited neuropathy and has an incidence of 1/2500. CMT1A is the commonest subtype of CMT, which is caused by duplication of peripheral myelin protein 22 (PMP22) gene and accounts for approximately 50% of CMT diagnosed by genetic testing. Duplication of PMP22 may influence the production of PMP22 mRNA and protein, and interfere with the proliferation, differentiation and apoptosis of Schwann cells. In addition, deregulation of NRG1/ErbB pathway and lipid metabolism can also lead to dysfunction of Schwann cells. Such factors may disturb the myelination process, leading to axon degeneration, muscle weakness, and atrophy subsequently. Accordingly, drug therapies for CMT1A are developed by targeting such factors. PXT3003, antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) are supposed to down-regulate the level of PMP22 mRNA, while recombinant human NRG-1 (rhNRG1) and neurotrophin-3 (NT-3) may enhance Schwann cells survival and differentiation. In addition, lipid-supplemented diet may remedy the defect of lipid metabolism and maintain the proper structure of myelin. Other targeting drugs include ascorbic acid, progesterone antagonists, IFB-088, ADX71441, and ACE-083. This review is to sum up the pathogenesis of CMT1A and promising targeting drug therapies for further research.

Identification of a novel c.1A>G variant of GDAP1 gene in a pedigree affected with autosomal recessive fibula atrophy / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a pedigree affected with Charcot-Marie-Tooth (CMT) disease through high-throughput sequencing.@*METHODS@#Potential variants of the genes associated with CMT were screened by next-generation sequencing (NGS) of the members of the pedigree.@*RESULTS@#NGS has revealed that the two affected sisters both harbored homozygous c.1A>G variant of the GDAP1 gene, which caused replacement of the first amino acid Methionine by Valine (p.Met1Val). Their parents were both carriers of the heterozygous c.1A>G variant. The variant was unreported previously and has an extremely low frequency in the population. Meanwhile, one of the sisters and the mother also carried heterozygous c.710A>T variant of the BAG3 gene.@*CONCLUSION@#The homozygous c.1A>G variant of the GDAP1 gene probably underlay the CMT in both children. Above result has enabled clinical diagnosis and genetic counseling for this pedigree.

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.

Neuropatía sensitiva y motora hereditaria: Enfermedad de Charcot Marie Tooth / Hereditary Motor and Sensory Neuropathy: Charcot Marie Tooth disease

La enfermedad de Charcot Marie Tooth (ECMT) o neuropatía sensitiva y motora hereditaria es el grupo de trastornos degenerativos más común del sistema nervioso periférico, asociado a un conjunto de alteraciones genéticas que cambia la estructura, formación y mantenimiento de la mielina. Afecta a 1 de cada 2500 personas sin guardar relación con la edad, género o etnia; su etiología es únicamente genética. Según la velocidad de conducción nerviosa se clasifca en desmielinizante o CMT1, axonal o CMT2 e intermedia la misma que posee características de los dos anteriores. La ECMT en la mayoría de los casos es una enfermedad lentamente progresiva, se presenta con signos característicos de pie cavo, pierna de cigüeña, atrofa y disminución de la fuerza muscular, alteración en la percepción de estímulos vibratorios, de comienzo distal con progresión a proximal; arreflexia y alteración de la marcha. El diagnóstico se realiza en base a los antecedentes familiares, clínica y examen físico, complementando con estudios electromiográfcos para determinar su clasifcación. Las pruebas genéticas se deben realizar dependiendo al tipo de ECMT en sospecha, las mismas que servirán para realizar consejería familiar. En la actualidad no existe tratamiento específco ni curativo, por lo que se debe brindar apoyo con terapia física y de rehabilitación, psicológica, ocupacional, así como un manejo óptimo del dolor.

Charcot Mariet Tooth's disease (ECMT) or hereditary sensory and motor neuropathy is the one of the most common group of degenerative disorders of the peripheral nervous system, related with a set of genetic alterations that changes the structure, formation and maintenance of myelin. It affects 1 out of 2500 people without considering the age, gender or ethnicity; its etiology is entirely genetic. According to the nerve conduction velocity it is classifed in demyelinating or CMT1, axonal or CMT2 and intermediate the same that has the features of the two previous ones. ECMT in majority of cases it is a slowly progressive disease, presenting with characteristic signs of high instep, stork leg, atrophy and decreased muscle strength, altered perception of vibratory stimuli, distal beginning with proximal progression; arreflexia and alteration of march. The diagnosis is based on family history, clinical and physical examination, complemented by electromyography studies, to determine their classifcation. Genetic tests are taken, based on the type of suspected ECMT, and these will be used for family counseling. Nowadays there is no specifc and curative treatment, that's why support should be provided with physical and rehabilitation therapies, psychological, occupational, as well as an optimal pain control.

A genotyping study of 13 cases of early-onset Charcot-Marie-Tooth disease / 中国当代儿科杂志

OBJECTIVE@#To study the clinical characteristics and genetic variation of early-onset Charcot-Marie-Tooth disease (CMT).@*METHODS@#Children with a clinical diagnosis of early-onset CMT were selected for the study. Relevant clinical data were collected, and electromyogram and CMT-related gene detection were performed and analyzed.@*RESULTS@#A total of 13 cases of early-onset CMT were enrolled, including 9 males (69%) and 4 females (31%). The mean age at consultation was 4.0±2.1 years. Among them, 12 children (92%) had an age of onset less than 2 years, 9 children (69%) were diagnosed with CMT type 1 (including 6 cases of Dejerine-Sottas syndrome), 1 child (8%) with intermediate form of CMT, and 3 children (23%) with CMT type 2. The genetic test results of these 13 children showed 6 cases (46%) of PMP22 duplication mutation, 3 cases (23%) of MPZ gene insertion mutation and point mutation, 3 cases (23%) of MFN2 gene point mutation, and 1 case (8%) of NEFL gene point mutation. Eleven cases (85%) carried known pathogenic mutations and 2 cases (15%) had novel mutations. The new variant c.394C>G (p.P132A) of the MPZ gene was rated as "possibly pathogenic" and the new variant c.326A>G (p.K109R) of the MFN2 gene was rated as "pathogenic".@*CONCLUSIONS@#Early-onset CMT is mainly caused by PMP22 gene duplication mutation and MPZ gene mutations. The clinical phenotype is mainly CMT type 1, among which Dejerine-Sottas syndrome accounts for a considerable proportion.

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.

Analysis of a pedigree with autosomal dominant intermediate Charcot-Marie-Tooth disease type E and nephropathy / 中华医学遗传学杂志

OBJECTIVE@#To explore phenotypic and mutational characteristics of a pedigree affected with autosomal dominant Charcot-Marie-Tooth disease (CMT) and nephropathy.@*METHODS@#Clinical data of the proband and his family members was collected. Electrophysiology, renal biopsy and next-generation sequencing were carried out for the proband.@*RESULTS@#The proband presented with distal lower limb weakness and proteinuria in childhood. His mother and brother had similar symptoms. Electrophysiological test of the proband revealed demyelination and axonal changes in both motor and sensory nerves. Renal biopsy suggested focal segmental glomerulosclerosis. Genetic testing revealed a heterozygous c.341G>A (p.G114D) mutation in exon 2 of the INF2 gene.@*CONCLUSION@#The phenotypic feature of the pedigree is autosomal dominant intermediate CMT and focal segmental glomerulosclerosis, which may be attributed to the c.341G>A mutation of the INF2 gene.

Pain in Charcot-Marie-Tooth disease: an update / Dor na doença de Charcot-Marie-Tooth: atualização

ABSTRACT Charcot-Marie-Tooth (CMT) disease, the most common inherited peripheral neuropathy, has pain as one of its clinical features, yet it remains underdiagnosed and undertreated. This literature review assessed data related to pain from CMT to determine its prevalence, type and importance as a symptom, which, unlike other symptoms, is likely to be treated. The research encompassed 2007 to 2017 and included five articles that addressed pain from CMT. All of the papers concurred that pain is frequently present in CMT patients, yet its classification remains undefined as there has been no consensus in the literature about the mechanisms that cause it.

RESUMO A doença de Charcot-Marie-Tooth (CMT), a neuropatia periférica hereditária mais comum, tem a dor como uma de suas características clínicas, a qual permanece subdiagnosticada e subtratada. Essa revisão de literatura avaliou os dados relacionados à dor em CMT com objetivo de observar sua prevalência, tipo e importância como sintoma que, em detrimento de outros, é possível ser tratado. O intervalo da pesquisa foi entre 2007 e 2017, através de cinco artigos abordando a dor em CMT. Todos os artigos concordam que a dor é frequente nos pacientes com a doença de CMT e a sua classificação permanece indefinida por não haver consenso na literatura sobre os mecanismos da dor.

X-linked Charcot-Marie-Tooth disease case with a novel missense mutation in GJB1 gene

X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is caused by the mutation in GJB1 gene, characterized by the transient central nervous system involvement and long standing peripheral polyneuropathy which does not fulfill the criteria of demyelination or axonopathy. We describe a 37-year-old man with progressive bilateral leg weakness since his early teen. He suffered transient right hemiparesis, followed by quadriparesis at 14 years of age. When we examined him at 37 years of age, he presented a distal muscle weakness on lower extremities with a sensory symptom. The nerve conduction study demonstrated a motor conduction velocity between 26 and 49 m/s. The whole exome sequencing revealed a novel variant c.136 G>A in GJB1. This report will raise awareness in this rare disease, which is frequently misdiagnosed early in its course.

Coexistence of Amyotrophic Lateral Sclerosis in the Proband of an X-Linked Charcot-Marie-Tooth Disease Type 1 Pedigree in China

No abstract available.

Clinical and Genetic Features of Chinese X-linked Charcot-Marie-Tooth Type 1 Disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>X-linked Charcot-Marie-Tooth type 1 (CMT1X) disease is one of the most common forms of inherited neuropathy caused by mutations in the gap junction beta-1 protein (GJB1) gene (also known as connexin 32). This study presented the clinical and genetic features of a series of Chinese patients with GJB1 gene mutations.</p><p><b>METHODS</b>A total of 22 patients from unrelated families, who were referred to Department of Neurology, Peking University First Hospital from January 2005 to January 2016, were identified with GJB1 mutations. Their clinical records and laboratory findings were retrospectively collected and reviewed. Mutations in the GJB1 gene were analyzed by targeted next-generation sequencing (NGS). Nucleotide alternations were confirmed with Sanger sequencing.</p><p><b>RESULTS</b>The CMT1X patients predominantly showed distal muscle weakness of lower limbs with mild sensory disturbance. The mean age of onset was 15.6 ± 8.7 years (ranging from 1 year to 42 years). The sudden onset of cerebral symptoms appeared in four patients (18.2%); two were initial symptoms. One case had constant central nervous system (CNS) signs. There were 19 different heterozygous mutations, including 15 known mutations and four novel mutations (c.115G>T, c.380T>A, c.263C>A, and c.818_819insGGGCT). Among the 22 Chinese patients with CMT1X, the frequency of the GJB1 mutation was 4.5% in transmembrane domain 1 (TM1), 4.5% in TM2, 22.7% in TM3, 9.1% in TM4, 4.5% in extracellular 1 (EC1), 27.3% in EC2, 9.1% in intracellular loop, 13.6% in the N-terminal domain, and 4.5% in the C-terminal domain. CMT1X with CNS impairment appeared in five (22.7%) of these patients.</p><p><b>CONCLUSIONS</b>This study indicated that CNS impairment was not rare in Chinese CMT1X patients. Mutations in the EC2 domain of the GJB1 gene were hotspot in Chinese CMT1X patients.</p>

Pé cavo: revisão da literatura / Cavus foot: review

OBJETIVO: Realizar uma revisão sobre o pé cavo, sua fisiopatologia, avaliação clínica, diagnósticos diferenciais com ênfase na doença de Charcot-Marie-Tooth e tratamento. MÉTODO: Revisão não sistemática de artigos abordando a fisiopatologia do pé cavo, avaliação clínica, diagnósticos diferenciais e tratamento. RESULTADOS E DISCUSSÃO: Foram utilizados 33 artigos de língua inglesa e 02 artigos em português para a confecção desta revisão. CONCLUSÃO: O pé cavo é geralmente secundário a doenças neurológicas, em especial a doença de Charcot-Marie-Tooth e raramente é originado por doenças não neurológicas. O diagnóstico etiológico do pé cavo permite um melhor tratamento, cirúrgico ou não, com adequada orientação ao paciente quanto ao prognóstico e eficácia da terapia.

OBJECTIVE: We realize a review about cavus foot, discussing pathophysiology, clinical evaluation, differential diagnosis with emphasis on Charcot-Marie-Tooth Disease and treatment. METHOD: We perform a non-systematic review of articles about cavus foot pathophysiology, physical examination, etiology and treatment. RESULTS AND DISCUSSION: We used 33 articles in english and 02 articles in portuguese for this review. CONCLUSION: The cavus foot is mostly a consequence of neurological etiologies, in particular Charcot-Marie-Tooth disease and rarely is caused by non-neurological diseases. The correct diagnosis allows better treatment, conservative or surgical, with appropriate guidance to patients in terms of prognosis and therapy effectiveness.

Enfermedad de Charcot-Marie-Tooth en numerosos miembros de una familia / Charcot-Marie-Tooth disease in several members of a family

La enfermedad de Charcot-Marie-Tooth es una afección degenerativa del sistema nervioso periférico, que presenta gran heterogeneidad genética y clínica. La presentación con patrón autosómico dominante, conocida en algunas clasificaciones como de tipo 1, es la más frecuente; asimismo, la confección del árbol genealógico resulta ser el instrumento de mayor importancia para conocer el tipo de herencia. A tales efectos, se describen 2 casos clínicos pertenecientes a una familia con 35 miembros afectados por este trastorno neurológico, atendidos en el Centro Provincial de Genética Médica de Santiago de Cuba.

Charcot-Marie-Tooth disease is a degenerative affection of the peripheral nervous system that presents great genetic and clinic heterogeneity. The presentation with autosomal dominant pattern, well-known in some classifications as type I, is the most frequent; also, the making of the genealogical tree turns out to be the most important instrument to know the inheritance type. To such effects, 2 case reports belonging to a family with 35 members affected by this neurological dysfunction are described, assisted in the Provincial Center of Medical Genetics in Santiago de Cuba.

Síndrome de Davidenkow: Una neuropatía periférica rara / Davidenkow syndrome. A rare peripheral neuropathy

En 1939 Davidenkow describió un tipo de atrofia diferente y rara con un patrón predominante en distribución escápulo-peroneal. Algunos investigadores caracterizaron el síndrome como una variante de la enfermedad de Charcot-Marie-Tooth; sin embargo, Davidenkow percibió que las manifestaciones clínicas y de laboratorio no corroboraban exactamente esta hipótesis. Describimos el caso de una mujer de 39 años, con cuadro clínico semejante al síndrome descrito por Davidenkow, presentando atrofia escápulo-peroneal. Sus primeros síntomas comenzaron cuando tenía 24 años, inicialmente con debilidad motora proximal en los miembros superiores. No tenía historia familiar de miopatía o neuropatía y se excluyeron otros síndromes que se podrían incluir entre los diagnósticos diferenciales mediante la realización de pruebas de mutación genética, además del examen físico y electromiografía. El amplio espectro de enfermedades neuromusculares a veces dificulta su diagnóstico y debe ser siempre considerado en el diagnóstico diferencial.

A different and rare type of atrophy with a predominant pattern in scapulo-peroneal distribution was described by Davidenkow in 1939. The syndrome was characterized by some researchers as a variant of Charcot-Marie-Tooth disease, however Davidenkow noticed that clinical and laboratorial manifestations did not corroborate exactly with this hypothesis. We describe a case of a female patient, 39 years-old, clinical picture similar to the syndrome described by Davidenkow, presenting scapulo-peroneal atrophy. Her first symptoms had appeared when she was 24, initially with proximal motor weakness in the upper limbs. This patient did not have family history of myopathy or neuropathy. Several tests were performed to exclude other syndromes that could be included in the differential diagnosis, by testing gene mutation, in addition to the physical examination and electromyography. The large spectrum of neuromuscular diseases makes difficult the diagnosis of Davidenkow’s syndrome which always should be considered in the differential diagnosis.

Mutation analysis for a family affected with Charcot-Marie-Tooth disease type 4C / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To identify potential mutation in a Chinese family affected with Charcot-Marie-Tooth disease(CMT).</p><p><b>METHODS</b>Clinical data of the family was collected, and genomic DNA was extracted from peripheral blood samples of the family members. Seventy-two candidate genes of the proband were captured and sequenced by targeted next-generation sequencing, and the results were confirmed by Sanger sequencing. The protein structure was predicted with PyMOL-1 software.</p><p><b>RESULTS</b>A homozygous missense mutation c.1894G>A(p.E632K) was identified in the exon 11 of the SH3TC2 gene in the proband. Heterozygous c.1894G>A mutation was also detected in the proband's father, mother and daughter, but not in the healthy family members and 300 normal controls. Retrieval of the NCBI, HGMD and 1000 genome databases has verified the c.1894G>A to be as a novel mutation. Computer simulation has suggested that the mutation has altered the 3D structure of the SH3TC2 protein.</p><p><b>CONCLUSION</b>The proband was diagnosed as CMT4C, for which the underlying gene was SH3TC2. This finding has expanded the spectrum of SH3TC2 mutation in association with CMT4C.</p>

Establishment of L-periaxin gene knock-out RSC96 cell line / 生物工程学报

Periaxin, a protein of noncompact myelin, is specifically expressed in the peripheral nervous system (PNS). There are two protein isoform L-periaxin and S-Periaxin by alternative splicing of periaxin gene, playing an important role in the initiation of myelin formation. So far, 18 different mutation sites in L-periaxin gene have been found to induce the peripheral demyelinating neurological charcot-marie-tooth diseases subtype 4F (CMT4F). The technique of activation of transcription activator-like effector nucleases (TALENS) was used to knock out the L-periaxin gene in RSC 96 cell line of Rattus. According to the design principle, the knock-out site of L-periaxin was assured to NLS domain of L-periaxin, which is target sequence of left and right arms of TALEN. The knock-out vectors of TALEN-L and TALEN-R were established and transfected into RSC96 cell. After puromycin screening, L-periaxin was knocked out successfully in RSC96 cell, which is confirmed by DNA sequence. The mutation efficiency is 21.6%. S-periaxin, not L-periaxin can be detected by Western blotting in L-periaxin gene knock-out RSC96 cell. The cell growth rate was decreased and the number of cells in G1 increased and decreased in S phase in L-periaxin gene knock-out RSC96 cell by flow cytometry and MTT assay.