Pediatric Charcot-Marie-Tooth disease: A case report and diagnostic challenges

Charcot-Marie-Tooth (CMT) disease is a hereditary motor sensory neuropathy affecting about one in 2500 individuals that is characterized by progressive weakness and loss of touch sensation affecting different parts of the body. Despite its significant genetic heterogeneity, CMT is rarely reported in the Indian literature. We report a 10-year-old boy with CMT presented with severe calf pain, bilateral pes cavus deformity, and areflexia. His mother also had similar symptoms, and the diagnosis was confirmed by neuroimaging and nerve conduction studies. This highlights the importance of considering CMT disease in patients with progressive muscle weakness and deformities, especially with a family history of similar symptoms.

Charcot’s osteoarthropathy – Lest we forget

Charcot’ osteoarthropathy (COA) is a rare, often misdiagnosed inflammatory debilitating complication of conditions most common being diabetes that needs to be discussed further to prevent associated morbidity. The natural history of the disease sees four stages and requires prompt diagnosis and treatment to ensure the desired outcome. We describe a case series of two cases of diabetes-associated osteoarthropathy and their management. A 72-year-old male with the early COA was managed with a total contact cast for both lower limbs and an 80-year-old male with the early COA with bone marrow edema in the tibia and talus, as well as, subtalar effusion, managed conservatively. The follow-up review documented clinical recovery in the form of a marked reduction in swelling of the lower limbs with the resolution of the functional status of lower limbs. It is the responsibility of every physician to ensure the goals of management which includes immediate offloading and good glycemic control.

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.

Diagnostic value of F wave changes in patients with Charcot-Marie-Tooth1A and chronic inflammatory demyelinating polyneuropathy / 北京大学学报(医学版)

OBJECTIVE@#To analyze and compare the characteristics and causes of F wave changes in patients with Charcot-Marie-Tooth1A (CMT1A) and chronic inflammatory demyelinating polyneuropathy (CIDP).@*METHODS@#Thirty patients with CMT1A and 30 patients with CIDP were enrolled in Peking University Third Hospital from January 2012 to December 2018. Their clinical data, electrophysiological data(nerve conduction velocity, F wave and H reflex) and neurological function scores were recorded. Some patients underwent magnetic resonance imaging of brachial plexus and lumbar plexus, and the results were analyzed and compared.@*RESULTS@#The average motor conduction velocity (MCV) of median nerve was (21.10±10.60) m/s in CMT1A and (31.52±12.46) m/s in CIDP. There was a significant difference between the two groups (t=-6.75, P < 0.001). About 43.3% (13/30) of the patients with CMT1A did not elicit F wave in ulnar nerve, which was significantly higher than that of the patients with CIDP (4/30, 13.3%), χ2=6.65, P=0.010. Among the patients who could elicit F wave, the latency of F wave in CMT1A group was (52.40±17.56) ms and that in CIDP group was (42.20±12.73) ms. There was a significant difference between the two groups (t=2.96, P=0.006). The occurrence rate of F wave in CMT1A group was 34.6%±39%, and that in CIDP group was 70.7%±15.2%. There was a significant difference between the two groups (t=-5.13, P < 0.001). The MCV of median nerve in a patient with anti neurofascin 155 (NF155) was 23.22 m/s, the latency of F wave was 62.9-70.7 ms, and the occurrence rate was 85%-95%. The proportion of brachial plexus and lumbar plexus thickening in CMT1A was 83.3% (5/6) and 85.7% (6/7), respectively. The proportion of brachial plexus and lumbar plexus thickening in the CIDP patients was only 25.0% (1/4, 2/8). The nerve roots of brachial plexus and lumbar plexus were significantly thickened in a patient with anti NF155 antibody.@*CONCLUSION@#The prolonged latency of F wave in patients with CMT1A reflects the homogenous changes in both proximal and distal peripheral nerves, which can be used as a method to differentiate the CIDP patients characterized by focal demyelinating pathology. Moreover, attention should be paid to differentiate it from the peripheral neuropathy caused by anti NF155 CIDP. Although F wave is often used as an indicator of proximal nerve injury, motor neuron excitability, anterior horn cells, and motor nerve myelin sheath lesions can affect its latency and occurrence rate. F wave abnormalities need to be comprehensively analyzed in combination with the etiology, other electrophysiological results, and MRI imaging.

Outcome of Surgical Fixation for Midfoot Charcot Neuroarthropathy - A Systematic Review

@#Introduction: Charcot arthropathy is a condition which is progressive, non-infectious, destructive and debilitating that commonly affect foot and ankle. This systematic review is to evaluate the occurrence of common outcomes associated with each intervention of Charcot neuroarthropathy in midfoot. Materials and methods: A systematic review on literatures that were published from Jan 2010 to Jan 2020 were collected, reviewed and selected regarding the surgical treatment procedures of Charcot neuroarthropathy in midfoot. Results: The initial search yielded 231 reports and after exclusion, nine out of the total studies were included in the outcome analysis for review. These were studies that included data concerning surgical reconstruction of Charcot arthropathy in the midfoot. Conclusion: It is suggested that soft tissue preparation and usage of combination of implants thus reduce the risk of infection as well as increase rigidity of construct, respectively. These factors will aid to improve outcome of midfoot Charcot arthropathy reconstruction.

A Case Report of Congenital Insensitivity to Pain with Anhidrosis / 罕见病研究

Congenital insensitivity to pain with anhidrosis (CIPA) is associated with Charcot arthropathy and is a rare clinical syndrome, with limited treatment options. Through a decade-long follow-up of a single case, we aim to provide new insights for clinicians regarding the choice of surgical strategies and postoperative complications. The diagnosed patient exhibited congenital insensitivity to pain and anhidrosis, accompanied by severe Charcot arthropathy affecting the spine. Multiple postoperative complications, including implant displacement, adjacent segment pathology, and pedicle screw loosening, occurred after surgical intervention, leading to five subsequent revision surgeries. Considering the limited experience in managing CIPA-related Charcot spinal arthropathy in the literature, surgical correction remains the preferred treatment. Among the 16 cases reviewed, common postoperative complications included implant displacement, adjacent segment pathology, and pedicle screw loosening. Based on current experience, we do not recommend extensive resection and reconstruction after removing the affected vertebral body, as this may increase the risk of implant displacement. Instead, a 360° long-segment fusion may help reduce the risk of adjacent segment degeneration. Additionally, we discuss potential reasons for revision surgery after Charcot spinal arthropathy surgery and perioperative management strategies for such cases. Meticulous care, appropriate rehabilitation exercises, and metabolic therapy for bone mineralization are crucial components of the treatment for this condition.

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.

Enfermedad de Charcot de pie y tobillo en pacientes con diabetes mellitus: análisis de las causas de re consultas en una unidad de pie diabético hospitalaria / Charcot´s disease of the foot and ankle in diabetic patients: analysis of the reasons for re admission at the hospital diabetic unity / Neuroartropatía de Charcot do pé e tornozelo em pacientes com diabetes mellitus: análise das causas das novas consultas em uma unidade de pés diabéticos do hospital

La neuroartropatia de Charcot es una complicación devastadora para los pacientes diabéticos, generando deformidades osteoarticulares con riesgo de ulceración, infección y amputación de miembros inferiores. El objetivo fue analizar en una población de pacientes diabéticos con secuela de neuroartropatía de Charcot, el motivo de re consulta y los tratamientos a los que fueron sometidos. El mismo se realizó en forma retrospectiva mediante observación de historias clínicas y estudios radiológicos de 22 pacientes tratados entre 2014 y 2018 en el Hospital Policial de Montevideo - Uruguay, con un tiempo de evolución mínimo de un año al momento de la revisión. Se contó con la aprobación del Comité de Ética de dicho hospital habiéndose completado un formulario con datos demográficos, tratamiento inicial, causas de las re consultas y tratamientos secundarios. Si bien al inicio de la enfermedad se siguieron los protocolos de tratamiento con alto nivel de recomendación, se observaron en las re consultas elevados porcentajes de re ulceración y necesidad de cirugías complementarias (59%). Se vinculan los resultados a la falta de categorización de paciente de riesgo para lograr seguimiento y captación precoz. El categorizar al paciente de riesgo permite establecer estrategias de educación y de tratamientos tendientes a disminuir porcentajes de nuevas lesiones que lleven a la necesidad de tratamientos secundarios o amputaciones.

One of the most devastating complications within diabetic patients is Diabetic Charcot neuroarthropathy. It can lead to osteoarticular deformities, with risk of ulceration, infection or even lower limb amputation. In this paper, a population of diabetic patients with Charcot neuroarthropathy sequelae was studied. Data was analyzed on the reasons for the patients re consultation, the treatments they were subjected to and the obtained results. The study was conducted retrospectively by the examination of medical records from 22 patients that were treated between 2014 and 2018, with a follow-up of at least a year, at the Hospital Policial in Montevideo, Uruguay. Furthermore, it had the hospital's Ethics Committee approval. The data analysis was conducted by the completion of a form including demographic data, initial treatment, reasons for re consultation and secondary treatments. According to the findings, even though highly recommended protocols were followed at the onset of the disease, high percentage of ulceration and complementary surgeries were observed (59%) within the patient's data. The results are linked to the lack of risk patient´s categorization in order to achieve early uptake. Categorizing the patient at risk makes it possible to establish health education and treatment strategies aimed at reducing percentages of new injuries that lead to the need for secondary treatments or amputations.

A neuroartropatia de Charcot é uma complicação devastadora para os pacientes com diabetes, gerando deformidades osteoarticulares residuais com risco de úlceras, infecção e amputação maior dos membros inferiores. O objetivo foi analisar em uma população de pacientes diabéticos com sequelas da neuroartropatia de Charcot, o motivo da nova consulta e os tratamentos a que foram submetidos, bem como os resultados obtidos. Foi realizado retrospectivamente por meio de observação de histórias clinicas e estudos radiológicos de 22 pacientes atendidos no periodo de 2014 a 2018 no Hospital da Polícia de Montevidéu - Uruguai, com tempo de evolução mínimo de um ano na época da revisão. Foi aprovado pelo Comité de Ética do referido hospital, tendo sido preenchido um formulário com dados demográficos, tratamento inicial, causas das novas consultas e tratamentos secundários. Embora protocolos de tratamento com alto nível de recomendação tenham sido seguidos no início da doença, elevados percentuais de re ulcerações e cirurgias complementares (59%) foram observados nas novas consultas. Os resultados estão ligados à falta de categorização dos pacientes de risco para obter captação precoces A categorização do paciente de risco permite estabelecer estratégias de educação e tratamento com o objetivo de reduzir os percentuais de novas lesões que levam à necessidade de tratamentos secundários ou amputações.

The charcot joint osteoarthropathy: a case report

The Charcot Joint Osteoarthropathy also referred as Charcot foot syndrome is a serious lower limb-threatening complication of diabetes. A patient was diagnosed with Charcot joint osteoarthropathy (COA) and found to have uncontrolled Diabetes Mellitus since more than 10 years. This case is crucial considering that Diabetes mellitus is a common case that we encounter, but the consequences of not being controlled can lead to serious complications. Accurate diagnosis is not always easy and can be a considerable clinical challenge. It needs to be differentiated from other conditions that has similar symptoms. Early diagnosis and initiation of treatment is crucial to avoid devastating and permanent complications.

Diagnóstico clínico y por imagen de rodilla de Charcot por neuroartropatía diabética

RESUMEN Introducción: La neuroartropatía es una afección secundaria a enfermedades metabólicas, infecciosas o genéticas. Su localización usual está reportada en el pie, pero puede afectar cualquier articulación, compromete su estado vascular y modifica la condición ósea, genera fracturas, contracturas y luxaciones. Objetivos: Reportar los hallazgos clínicos e imagenológicos de una paciente con neuroartropatía de Charcot por diabetes mellitus, en una localización articular, poco frecuente. Caso Clínico: Paciente femenina de 62 años, procedente del suroccidente colombiano, con antecedentes de diabetes mellitus y complicaciones micro y macrovasculares. Presentó un cuadro clínico de dolor articular en la rodilla derecha, que evolucionó a una imposibilidad para la marcha. En su atención se realizaron diferentes estudios de imagen; se encontró una fractura del cóndilo femoral izquierdo y de los platillos tibiales. Estas características radiológicas típicas, más los cambios clínicos de la articulación, llevaron al diagnóstico de rodilla de Charcot. Se realizaron intervenciones farmacológicas analgésicas, además de inmovilización articular, con adecuada evolución en el seguimiento clínico. Conclusiones: La neuroartropatía con rodilla de Charcot es una afección que debe ser evaluada en todos los pacientes con diabetes mellitus y otras enfermedades, ampliar el panorama de revisión articular a localizaciones menos frecuentes, como la rodilla. Una intervención temprana y multidisciplinaria puede favorecer los desenlaces clínicos positivos.

ABSTRACT Introduction: Neuroarthropathy is a condition secondary to metabolic, infectious, or genetic diseases. Its usual localization is reported in the foot, but it can affect any joint, compromising its vascular status and modifying the bone condition generating fractures, contractures, and dislocations. Objectives: To report the clinical and imaging findings of a patient with Charcot neuroarthropathy due to diabetes mellitus in a rare joint location. Clinical Case: A 62-year-old woman from Colombian southwestern, with a history of diabetes mellitus, in addition to micro and macrovascular complications. She presented a clinical picture of joint pain in the right knee that evolved to an inability to walk. During her care, different imaging tests were performed, finding a fracture of the left femoral condyle and tibial plateau, these typical radiological characteristics plus the clinical changes of the joint, led to the diagnosis of Charcot's knee. Pharmacological interventions were performed in pain in addition to joint immobilization, with adequate evolution in clinical follow-up. Conclusions: Neuroarthropathy is a condition that should be evaluated in all patients with diabetes mellitus and other conditions, expanding the joint revision panorama to less frequent locations such as the knee; early and multidisciplinary intervention can favor positive clinical outcomes.

The genetic distribution in Chinese patients with Charcot-Marie-Tooth diseases: a 14-year cohort study / 中华神经科杂志

Objective:To investigate the genetic distribution of pathogenic genes of Charcot-Marie-Tooth diseases (CMT) in Chinese Han population, and compare the similarity and difference with the data in Peking University Third Hospital in 2013.Methods:Five hundred and twenty families with CMT and related diseases in Peking University Third Hospital and China-Japan Friendship Hospital from January 2007 to March 2021 were collected. After peripheral myelin protein 22 (PMP22) gene duplication and deletion mutations were initially detected by multiple ligation probe amplification, the probands of these families were sequenced by next-generation sequencing (NGS) gene panel or whole exome sequencing, and validated by Sanger sequencing.Results:Among the 520 families, 336 CMT families were genetically confirmed, and the mutation detection rate increased from 48.6% (51/105) in 2013 to 64.6% (336/520) in 2021 (χ 2=9.54, P=0.003). Among them, 139 families had PMP22 gene duplication mutation (139/520, 26.7%), 46 families had gap junction beta-1 (GJB1) gene mutation (46/520, 8.8%), 26 families had mitofusin-2 (MFN2) gene mutation (26/520, 5.0%), 12 families had myelin protein zero (MPZ) gene mutation (12/520, 2.3%), 11 families had PMP22 gene point mutation (11/520, 2.1%), and 10 families had heat shock protein B1 gene mutation (10/520, 1.9%). There were 10 families with ganglioside induced differentiation associated protein 1 (GDAP1) gene mutation (10/520, 1.9%), 8 families with SH3 domain and tetratricopeptide repeats 2 (SH3TC2) gene mutation (8/520, 1.5%), 7 families with immunoglobulin mu DNA binding protein 2 (IGHMBP2) gene mutation (7/520, 1.3%), 6 families with MORC family CW-type zinc finger 2 (MORC2) gene mutation (6/520, 1.2%), 5 families with sorbitol dehydrogenase (SORD) gene mutation (5/520, 1.0%), 16 families with very rare gene mutation (16/520, 3.1%) and 184 families without genetic diagnosis (184/520, 35.4%). Conclusions:Compared with the results in 2013, the 3 most common genes affecting CMT were still PMP22, GJB1 and MFN2 genes, but the proportion difference of patients with MPZ gene mutation gradually decreased with other genes such as SH3TC2 and GDAP1 genes. The proportion of newly discovered CMT genes, such as MORC2 and SORD genes, was similar with IGHMBP2 gene, which should be paid more attention. NGS greatly improved the detection rate of CMT, especially for patients with autosomal recessive-CMT.

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.

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.

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.

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.

Jean Martin Charcot, padre de la neurología moderna / Jean Martin Charcot, father of modern neurology

RESUMEN Jean Martin Charcot (1825-1893) es considerado el mayor exponente del nacimiento de la neurología en el mundo. Fundó y dirigió el servicio de neurología más grande de Europa en el hospital de la Salpétriére en París y, en 1882, dirigió la primera cátedra universitaria en el mundo sobre enfermedades del sistema nervioso. Existen por los menos 14 epónimos en medicina que recuerdan sus aportes en diferentes disciplinas. Fue un gran pintor, un afamado profesor universitario y demostró grandes habilidades en gestión hospitalaria. Fue uno de los fundadores de la revista Archives de Neurologie, junto con su discípulo Pierre Marie en 1872, y director de la publicación Iconographie de la Salpétriére, inmensa obra que contiene material visual, dibujos y fotos de gran valor para la enseñanza de la neurología. Por este y otros múltiples aportes a esta disciplina, es considerado el padre de la neurología.

SUMMARY Jean Martin Charcot (1825-1893) is considered the greatest exponent of the origin of Neurology in the world. He founded and directed the largest neurology service in Europe at the Salpétriére hospital in Paris, and in 1882 he directed the first ever university chair on diseases of the nervous system. There are at least 14 eponyms in medicine that recall his contributions in different disciplines. He was a great painter, a famous university professor, and demonstrated great skills in hospital management. He was one of the founders of the magazine Archives de Neurologie together with his disciple Pierre Marie in 1872, and director of the publication Iconographie de la Salpétriére, immense work containing visual material, drawings, and photos of great value for the teaching of Neurology. For this and many other contributions to this discipline, he is considered the father of modern Neurology.

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.