Les chimiothérapies à base de sels de platine exercent leurs effets anti-tumoraux en compromettant l'intégrité de l'ADN. Cette cytotoxicité conduit à une augmentation du stress oxydant qui, à son tour, favorise les processus de mort cellulaire. L'oxaliplatine indiquée dans les cancers métastatiques secondaires du colon et dans les cancers colorectaux, induit une augmentation des espèces réactives de l’oxygène en diminuant le glutathion réduit dans les cellules cancéreuses. Similairement aux autres chimiothérapies à base de sels de platine, elle doit être utilisée avec précaution. En effet, la majorité des patients recevant de l'oxaliplatine développent des neuropathies périphériques. Cette neurodégénérescence est un facteur limitant de cette chimiothérapie puisqu'elle peut nécessiter une réduction du dosage ou même une interruption du traitement si cet effet secondaire atteint une sévérité de grade 3. Les toxicités neurologiques peuvent se manifester dans les heures suivant l'injection sous forme aiguë. La forme chronique résulte d'injections cumulées de doses élevées. La forme aiguë, caractérisée par une paresthésie transitoire et une myotonie, est réversible et se résout généralement en quelques jours tandis que la forme chronique présente une paresthésie et une thermoalgie persistantes résultant de la dégradation axonale distale et de la démyélinisation des fibres nerveuses de gros diamètre. Les voies inflammatoires ont été incriminées dans l'étiologie de cette neurodégénérescence. Le niclosamide, un ténicide modulant les voies Stat3, Wnt, Notch et Beta-caténine, a été étudié in vitro et in vivo. Ayant déjà démontré les propriétés anti-inflammatoires de ce composé dans la sclérodermie systémique, nous avons cherché à déterminer si le niclosamide pourrait également prévenir la neurotoxicité de l'oxaliplatine. Le niclosamide a démontré une neuroprotection à la fois in vitro sur les neurones traités par l'oxaliplatine et in vivo dans les modèles de neuropathies périphériques induites par l'oxaliplatine. Le niclosamide est déjà utilisé en clinique avec des effets secondaires limités. L'association de cette molécule avec l'oxaliplatine pourrait augmenter l'indice thérapeutique de cette chimiothérapie. La benztropine est un inhibiteur des récepteurs muscariniques M1 et M3 possédant un potentiel de remyélinisation démontré dans le système nerveux central en favorisant la différenciation et la prolifération des cellules précurseurs des oligodendrocytes. La répartition différentielle entre les sous-types de récepteurs peut permettre le ciblage spécifique des cellules tumorales, notamment par l'inhibition de la signalisation autocrine de l'acétylcholine. La benztropine est un composé bien toléré qui ne provoque aucune réaction immunologique lors de son administration. Cette molécule présente un effet neuroprotecteur in vitro sur les neurones traités par l'oxaliplatine au cours d’études de viabilité cellulaire ainsi qu’in vivo dans les modèles murins de neuropathies périphériques induites par l'oxaliplatine et le diabète. L'association de cette molécule avec l'oxaliplatine pourrait augmenter l'indice thérapeutique de cette chimiothérapie, en potentialisant ses effets antitumoraux tout en diminuant la neurotoxicité. L’ubiquité des propriétés neuroprotectrices de la benztropine a été démontrée sur des neuropathies périphériques résultants d’autres étiologies. Nous avons ici décrit deux molécules permettant de conserver l’efficacité antitumorale du traitement par oxaliplatine tout en limitant ses effets neurotoxiques. Nous avons décrit les mécanismes par lesquels ces molécules exercent leur neuroprotection. Les résultats prometteurs obtenus au cours de ces travaux permettent d’envisager l’utilisation en clinique de ces molécules afin de prévenir non seulement les neuropathies périphériques induites par l'oxaliplatine, mais aussi les neuropathies périphériques résultant d'autres étiologies. / Platinum-based chemotherapies have been shown to elicit their anti-tumoral effects by compromising DNA integrity. These impairments ultimately lead to a burst in oxidative stress which in turn promotes cell death processes. Oxaliplatin, a platinum-based antineoplastic drug is usually indicated in secondary metastatic colon cancers and colorectal cancers and mediates a rise in reactive oxygen species through the depletion of reduced glutathione in cancerous cells. This chemotherapy is indicated as a frontline and an adjuvant treatment and similarly to other platinum-based chemotherapies, it warrants for particular caution. Most patients receiving oxaliplatin develop peripheral neuropathies. This neurodegeneration is a limiting factor of this chemotherapy since it may require the lowering of dosage or even the interruption of the treatment if this side-effect is assessed as a grade 3 peripheral neuropathy. Neurological toxicities may manifest within hours of injection as an acute form or as a chronic form resulting from cumulated high-dosage injections. The acute form, characterized by transient paresthesia and myotonia, is reversible and usually resolves within days while the chronic form presents persistent paresthesia and thermoalgia resulting from distal axonal degradation and demyelination of large fibers. Inflammatory pathways have also been incriminated in the etiology of this neurodegeneration. Niclosamide, a teniacide known to downregulate Stat3, Wnt, Notch and Beta-catenin pathways was investigated in vitro and in vivo. Having previously demonstrated this compound’s anti-inflammatory properties in systemic sclerosis, we sought to investigate whether niclosamide could also prevent oxaliplatin’s neurotoxicity. Niclosamide demonstrated neuroprotection both in vitro on oxaliplatin-treated neurons and in vivo in models of oxaliplatin-induced peripheral neuropathies. Niclosamide is used in humans with limited side-effects. The association of this molecule with oxaliplatin could increase the therapeutic index of this chemotherapy. Benztropine is an inhibitor of muscarinic M1 and M3 receptors with known remyelinating potential in the central nervous system by promoting oligodendrocytes precursor cells differentiation and proliferation. The differential distribution between subtypes of receptors can allow the specific targeting of tumor cells, namely through the inhibition of autocrine acetylcholine signaling. This compound is well tolerated and does not elicit any immunological reaction upon its administration. These observations of potential for both, preventing neurotoxicity as well as increasing the efficacy profile of neurotoxic chemotherapies, prompted us to investigate this M1 and M3 receptors inhibitor. Benztropine demonstrated neuroprotection in vitro on oxaliplatin-treated neurons as demonstrated by viability assays studies as well as in vivo in models of oxaliplatin-induced as well as diabetic peripheral neuropathies. The association of this molecule with oxaliplatin could increase the therapeutic index of this chemotherapy, potentiate this chemotherapy’s antitumoral effects against certain cancers as well as decrease the occurrence of diabetic neuropathies, a prevalent complication of diabetes. We have herein described two molecules which allow oxaliplatin treatment to exert its cytotoxic effects without eliciting its neurotoxicity. Furthermore, we have described the mechanisms by which these molecules exert their neuroprotection. The neuroprotective abilities of one of these molecules have also been broadened by the study of other types of peripheral neuropathies, namely diabetic neuropathies. The promising results obtained over the course of these works allow for optimism in the prospect of finding therapies to counteract not only oxaliplatin-induced peripheral neuropathies but peripheral neuropathies resulting from other etiologies.

As neuropatias periféricas hereditárias são um grupo heterogêneo de doenças relacionadas que afetam o sistema nervoso periférico. Elas podem ser classificadas de acordo com a velocidade de condução motora nos membros superiores (tipo 1 - CMT1, tipo 2 - CMT2 ou intermediário - iCMT), de acordo com o padrão de herança (autossômicas dominantes, autossômicas recessivas ou ligadas ao X) e quanto ao fenótipo de apresentação (neuropatias hereditária sensitivo e motora - CMT, neuropatia hereditária sensitiva - HSN ou neuropatia motora hereditária distal - dHMN). O uso das tecnologias de sequenciamento de nova geração (NGS) para diagnóstico de pacientes com neuropatia hereditária é particularmente eficiente uma vez que representa uma doença Mendeliana com mais de 90 genes diferentes relacionados. Foram avaliados 30 pacientes com diferentes subtipos de neuropatia hereditária (3 CMT1, 12 CMT2, 8 iCMT, 4 dHMN e 3 HSN). Foram identificadas 6 mutações (SH3TC2, GDAP1, MME, IGHMBP2, 2 AARS) e 7 variantes provavelmente patogênicas (KIF1A, DRP2, MME, MPZ, VRK1, SIGMAR1, FLVCR1). Com uma taxa de positividade de 43.3%. As variantes provavelmente patogênicas foram consideradas como a causa da apresentação fenotípica apresentada pelos pacientes baseado na frequência de variantes nos bancos de população normal, no efeito bioquímico das variantes sobre a estrutura proteica e pela análise in silico. No entanto, essas variantes necessitam de evidências adicionais que confirmem sua patogenicidade. Foram identificadas variantes novas nos genes MPZ, KIF1A, DRP2, IGHMBP2, VRK1, SIGMAR1 e FLVCR1 ampliando a variabilidade genotípica desses genes. A associação das mutações identificadas nos genes VRK1, KIF1A, IGHMBP2 e FLVRC1 permitiu a expansão dos fenótipos relacionados a esses genes. Mutações no gene VRK1 podem causar uma dHMN com sinais de liberação piramidal e envolviemento preferencial do compartimento posterior da perna. Transtorno do espectro autista pode ser observado em associação a mutações no gene KIF1A e mutações no gene FLVRC1 podem causar um fenótipo grave caracterizado por insensibilidade congénita a dor e acromutilações. Mutações no gene IGHMBP2 podem causar uma sobreposição entre os fenótipos SMARD1/CMT2S com disautonomia restrita ao trato gastro intestinal. Esse estudo demonstra que o uso de WES para o diagnóstico molecular de doenças geneticamente heterogêneas como as neuropatias hereditárias é uma ferramenta útil. / The hereditary peripheral neuropathies are a heterogeneous group of genetic disorders in which peripheral nervous system degeneration leads to weakness, atrophy and loss of sensation. It can be classified according motor conduction velocities in the upper limbs (type 1 - CMT1, type 2 - CMT2 or intermediate - iCMT), according to inheritance pattern (autosomal dominant, autosomal recessive or X linked) and according to the mainly group of fibres clinically involved (hereditary sensory and motor neuropathy - CMT, hereditary sensory neuropathy - HSN or distal hereditary motor neuropathy - dHMN). The use of next generation sequencing technologies (NGS) for the diagnosis of patients with genetic diseases is well established, as CMT is a Mendelian disease with more than 90 different related genes already reported. We evaluated 30 patients with all subtypes of hereditary neuropathy (3 CMT1, 12 CMT2, 8 iCMT, 4 dHMN and 3 HSN). Six mutations (SH3TC2, GDAP1, MME, IGHMBP2, 2 AARS) and 7 likely pathogenic variants (KIF1A, DRP2, MME, MPZ, VRK1, SIGMAR1, FLVCR1) were detected, leading to a positive rate of 43.3%. Likely pathogenic variants were considered based on their frequency in normal population, in silico analysis and segregation with phenotype. Despite they have strong evidences to support their causative status further evidence of their pathogenicity is required. New variants were identified in the genes MPZ, KIF1A, DRP2, IGHMBP2, VRK1, SIGMAR1 and FLVCR1 amplifying their genotypic variability. The mutations identified in VRK1, KIF1A, IGHMBP2 and FLVRC1 expanded their phenotype spectrum. Mutations in the VRK1 gene may cause dHMN with upper motor neuron signs. Autistic spectrum disorder may be observed in association with mutations in the KIF1A gene and mutations in the FLVRC1 gene may cause a severe phenotype characterized by congenital insensitivity to pain and acromutilations. Mutations in the IGHMBP2 gene may cause an overlap between SMARD1 and CMT2S phenotypes with organ specific dysautonomia. This study demonstrates that WES is a powerful tool for molecular diagnosis of hereditary neuropathies. Additionally, this study provides new information on the mutations in the VRK1, KIF1A and FLVRC1 genes by adding new mutations and increasing the phenotypic variability of the neuropathies associated with these genes.This study demonstrates WES is a powerful tool for molecular diagnosis of hereditary neuropathies.

[ES] Las neuropatías periféricas son patologías que deterioran los nervios situados fuera del sistema nervioso central y que afectan significativamente las funciones sensoriomotoras. Existen varias alternativas terapéuticas, entre ellas las órtesis. Estos dispositivos se encargan de proteger la musculatura, corregir alteraciones y asistir la función de la extremidad afectada. Su efectividad está demostrada; sin embargo, depende directamente del adecuado cumplimiento del protocolo de uso. El objetivo principal de esta tesis fue identificar los criterios ergonómicos aplicables al desarrollo de órtesis que incrementen la adherencia al tratamiento en pacientes con neuropatías radial, cubital y mediana. Con este fin, se evaluó la posibilidad de optimizar las propiedades terapéuticas a partir de la inclusión de agentes electrofísicos en el dispositivo. Para ello, se llevó a cabo una revisión sistemática y metaanálisis de la evidencia disponible en los en los últimos cuarenta años en torno a la efectividad de las principales modalidades aplicadas. Se determinó que algunas modalidades cuando se aplican conjuntamente a una órtesis se ven favorecidas. No obstante, ninguno de los resultados de la revisión puede considerarse clínicamente significativos. Posteriormente, se planteó un protocolo de co-creación que incluyó las principales fases de un proceso de diseño con la participación de usuarios de órtesis. La primera fase, Perspectiva de Usuarios, contó con 100 sujetos con neuropatías periféricas. Se obtuvo información tanto para la identificación de necesidades y preferencias como para la clasificación de los aspectos que intervienen en la adherencia. Se emplearon modelos lineales y no lineales, como el modelo de Kano. Se encontró que este modelo permite una identificación más precisa acerca de qué atributos tienen más importancia y del grado de influencia de éstos en la adherencia. Asimismo, se comprobó que la satisfacción es una medida indirecta de la importancia y constituye un adecuado predictor de la adherencia a órtesis. Por el contrario, la importancia explícita no cuenta con la misma fiabilidad. La segunda fase, Diseño Participativo, incluyó a 9 personas voluntarias que evaluaron las propuestas de órtesis y brindaron recomendaciones de diseño. En la tercera fase, Modelado y Prototipado, se produjeron una serie de iteraciones de diseño, dando lugar a un nuevo desarrollo de órtesis. En la cuarta fase, Validación, se comprobó la funcionalidad y usabilidad de la órtesis con 11 sujetos sanos a través de un estudio con electromiografía de superficie. Con ello se demostró que la inclusión de un mecanismo deformable en el diseño del muelle articular permite una óptima asistencia motora en condiciones normales. Por último, en la fase de Desarrollo Final, se fabricó un prototipo funcional de órtesis radial teniendo en cuenta las oportunidades de mejora identificadas. / [CA] Les neuropaties perifèriques són patologies que deterioren els nervis situats fora del sistema nerviós central i que afecten significativament les funcions sensorimotrius. Hi ha diverses alternatives terapèutiques, entre elles les òrtesis. Aquests dispositius s'encarreguen de protegir la musculatura, corregir alteracions i assistir la funció de l'extremitat afectada. La seva efectivitat està demostrada; no obstant això, depèn directament del correcte compliment del protocol d'ús. L'objectiu principal d'aquesta tesi va ser identificar els criteris ergonòmics aplicables al desenvolupament d'ortesis que incrementen l'adherència al tractament en pacients amb neuropaties radial, cubital i mitjana. Amb aquest fi, es va avaluar la possibilitat d'optimitzar les propietats terapèutiques a partir de la inclusió d'agents electrofísics en el dispositiu. Per a això, es va dur a terme una revisió sistemàtica i metaanàlisi de l'evidència disponible en els últims 40 anys entorn de l'efectivitat de les principals modalitats aplicades. Es va determinar que algunes modalitats, quan s'apliquen conjuntament a una òrtesi, es veuen beneficiades. No obstant això, cap dels resultats de la revisió va ser clínicament significatiu. Posteriorment, es va plantejar un protocol de co-creació que va incloure les principals fases d'un procés de disseny amb la participació d'usuaris d'ortesis. La primera fase, Perspectiva d'Usuaris, va comptar amb 100 subjectes amb neuropaties perifèriques. Es va obtenir informació tant per a la identificació de necessitats i preferències com per a la classificació dels aspectes que intervenen en l'adherència. Es van emprar models lineals i no lineals, com el model de Kano. Es va trobar que aquest model permet una identificació més precisa sobre quins atributs tenen més importància i el grau d'influència d'aquests en l'adherència. Així mateix, es va comprovar que la satisfacció és una mesura indirecta de la importància i constitueix un predictor adequat de l'adherència a ortesis. Per contra, la importància explícita no compta amb la mateixa fiabilitat. La segona fase, Disseny Participatiu, va incloure 9 persones voluntàries que van avaluar les propostes d'ortesis i van donar recomanacions de disseny. En la tercera fase, Modelatge i Prototipatge, es van produir una sèrie d'iteracions de disseny, donant lloc a un nou desenvolupament d'òrtesis. En la quarta fase, Validació, es va comprovar la funcionalitat i usabilitat de l'òrtesi amb 11 subjectes sans mitjançant un estudi amb electromiografia de superfície. Amb això es va demostrar que la inclusió d'un mecanisme deformable en el disseny del moll articular permet una òptima assistència motora en condicions normals. Finalment, en la fase de Desenvolupament Final, es va fabricar un prototip funcional d'òrtesi radial tenint en compte les oportunitats de millora identificades. / [EN] Peripheral neuropathies are pathologies that deteriorate the nerves located outside the central nervous system and significantly affect sensorimotor functions. There are several therapeutic alternatives, including orthoses. These devices are responsible for protecting the musculature, correcting alterations, and assisting the function of the affected limb. Their effectiveness has been demonstrated. However, it depends directly on proper compliance with the usage protocol. The main objective of this thesis was to identify ergonomic criteria applicable to the development of orthoses that increase treatment adherence in patients with radial, ulnar, and median neuropathies. To this end, the possibility of optimizing therapeutic properties by including electrophysical agents in the device was evaluated. To achieve this, a systematic review and meta-analysis of the available evidence in the last 40 years regarding the effectiveness of the primary applied modalities. It was determined that some modalities are favored when used in conjunction with an orthosis. Nevertheless, none of the review results were clinically significant. Subsequently, a co-creation protocol was proposed, involving the main phases of a design process with the participation of orthosis users. The first phase, User Perspective, involved 100 subjects with peripheral neuropathies. Information was obtained for the identification of needs and preferences, as well as for the classification of aspects involved in adherence. Linear and non-linear models, such as the Kano model, were employed. It was found that this model allows a more precise identification of which attributes are more important and their influence on adherence. Additionally, it was verified that satisfaction is an indirect measure of importance and constitutes an adequate predictor of orthosis adherence. In contrast, explicit importance is not a reliable indicator. The second phase, Participatory Design, included nine voluntary individuals who evaluated orthosis proposals and provided design recommendations. In the third phase, Modeling and Prototyping, a series of design iterations were carried out, resulting in a new orthosis development. The fourth phase, Validation, tested the functionality and usability of the orthosis with 11 healthy subjects through a study with surface electromyography. It was demonstrated that including a deformable mechanism in the joint spring design allows optimal motor assistance under normal conditions. Finally, in the Final Development phase, a functional prototype of the radial orthosis was manufactured, considering the identified opportunities for improvement. / Bula Oyola, EL. (2023). Factores ergonómicos en el diseño de órtesis de mano para rehabilitación sensoriomotora de neuropatías radial, cubital y mediana [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/199996

L'objectif de notre travail était dans un premier temps d'étudier les liens entre l'altération des fibres nerveuses de petit diamètre et la présence de douleurs chez des patients ayant une neuropathie périphérique. Notre deuxième objectif était d'évaluer la pertinence de certaines techniques neurophysiologiques pour mettre en évidence l'atteinte de ces petites fibres nerveuses. Notre première étude réalisée sur une large cohorte de patients présentant divers types de neuropathie a montré, grâce à une étude quantifiée de la sensibilité, qu'il n'y avait pas de corrélation entre la perte ou perte de fonction des fibres nerveuses de petit diamètre et la présence de douleurs. Ceci a été confirmé par notre deuxième étude portant sur une population plus homogène de patients ayant une neuropathie amyloïde familiale et étudiés avec une batterie neurophysiologique plus large. Ainsi, les douleurs neuropathiques des patients présentant une neuropathie périphérique sont probablement dues à la combinaison de facteurs d'hyperexcitabilité périphérique et de sensibilisation centrale et non directement liée à la perte en petites fibres. Il reste cependant pertinent de développer des techniques objectives d'exploration de ces petites fibres notamment dans un but de diagnostic clinique. Notre troisième étude a montré que certaines méthodes neurophysiologiques étaient particulièrement sensibles dans ce cadre en prenant pour exemple la détection d'anomalies précoces d'atteinte des petites fibres au cours de la neuropathie amyloïde familiale. Une batterie de tests comprenant l'enregistrement des potentiels évoqués laser, la mesure du seuil de détection du chaud et de la conductance cutanée, s'est avérée être la combinaison la plus pertinente, comme l'a montré notre quatrième étude sur une grande cohorte de patients susceptibles de présenter une neuropathie des petites fibres. / The aim of our work was initially to study the relationship between alterations in small diameter nerve fibers and the presence of pain in patients with peripheral neuropathy. Our second objective was to assess the relevance of some neurophysiological tests to characterize these alterations in small nerve fibers. Our first study of a large cohort of patients with various types of neuropathy showed, using quantitative sensory testing, that there was no correlation between the loss or loss of function of small nerve fibers and the presence of pain. This was confirmed by our second study focused on a more homogeneous population of patients with familial amyloid neuropathy and studied with a larger neurophysiological battery. Thus, neuropathic pain in patients with peripheral neuropathy is probably due to a combination of factors of peripheral hyperexcitability and central sensitization and not directly related to the loss of small nerve fibers. However, it remains relevant to develop techniques of objective investigation of these small nerve fibers for a purpose of clinical diagnosis. Our third study showed that some neurophysiological methods were particularly sensitive in this context, taking the example of the detection of early alteration of small nerve fibers in familial amyloid neuropathy. A battery of tests, including laser evoked potential recording, warm detection threshold and electrochemical skin conductance measurement, proved to be the most appropriate combination for this diagnostic purpose, as shown by our fourth study on a large cohort of patients likely to have a small fiber neuropathy.

Entre as neuropatias periféricas hereditárias, a Doença de Charcot Marie Tooth (CMT) é a mais prevalente, sendo o Charcot Marie Tooth Lidado ao X tipo 1 (CMTX1) o segundo subtipo mais comum, causado por mutações no gene GJB1 e de herança ligada ao X. A sintomatologia de fraqueza, atrofia e alteração de sensibilidade progressiva, de padrão simétrico e distal é característica da CMT e, no CMTX1, o acometimento do sistema nervoso central pode estar associado ao quadro típico. Com relação à eletroneurofisiologia, há redução dos parâmetros de velocidade de condução nervosa, com prolongamento da latência de onda F. Não há terapias modificadoras do curso da doença, sendo importante acompanhamento multidiciplinar a fim de assistir as possíveis deformidades, dando mais conforto e otimização das atividades de vida diária dos pacientes. O objetivo do presente estudo é relatar casos diagnosticados como CMTX1 atendidos pelo ambulatório de Neurogenética do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP-USP) e comparar aos dados da literatura pertinente. Os critérios de inclusão foram idade no atendimento abaixo de 17 anos e 11 meses e confirmação do CMTX1 por exame genético molecular, com mutação em GJB1. Assim, foram encontradas quatro crianças, três do sexo feminino e uma do masculino, com idade variando de 3 a 17 anos, sendo que em dois deles foi observado atraso na marcha independente. Os sinais clínicos e eletroneuromiográficos observados foram concordantes com a literatura, exceto por não apresentarem sinais de acometimento do sistema norvoso central (SNC) associados. A presença de atraso na marcha e surgimento de casos precoces suscita a necessidade de protocolo adequado para crianças no primeiro e segundo anos de vida; 1. Anotar época de aparecimento e duração do movimento de levantar-se e postura ereta ou não do tronco ao se manter sentado. 2. Tipo do engatinhar. 3. Idade em meses no início de sentar e andar com e sem apoio. 4. Análise da funcionalidade manual, motricidade fina com auxílio de testes da especialidade em terapia ocupacional, desde os primeiros meses. 5. Tipo de marcha e época de início da marcha. 6. Reflexos fásicos - evolução - com atenção especial aos aquilianos, que são os mais precocemente acometidos. 7. Verificação de clônus de tornozelo, no sentido de detecção de sinais de espasticidade. Para crianças maiores de 3 anos de idade: 1. Início do uso de chinelo (capacidade de reter o chinelo nos pés - desenvolvimento da propriocepção). 2. Verificação do equilíbrio estático e dinâmico de acordo com Lefèvre (1972), nas faixas etárias de 3 a 7 anos. / Among the hereditary peripheral neuropathies, Charcot-Marie-Tooth disease (CMT) is the most prevalent, being the second most common the subtype CMTX1, caused by mutations in the GJB1 gene and producing a X-linked inheritance. The symptoms of symmetrical and distal weakness, atrophy and progressive sensory changes, are characteristics of the CMT and in the CMTX1 central nervous system involvement is often associated with the typical picture. With respect to eletroneurophysiology, there is reduction of nerve conduction velocity parameters, with extension of F wave latency. There is no modifier therapies of the course of the disease, being important, multidisciplinary monitoring to assist the possible deformities, giving more comfort and optimization of daily life activities of patients. The main objective of this study is to report cases diagnosed as CMTX1 by Neurogenetics Clinic of the Hospital of Clinics of the School of Medicine at Ribeirão Preto, São Paulo University (HCFMRPUSP) and to compare the data from the relevant literature. Inclusion criteria were age in attendance below 17 years and 11 months and CMTX1 confirmation by genetic testing, mutation GJB1. Four children were included, three female and a male, with age ranging from 3 to 17 years. Two of them presented late onset of independent walking. Clinical and eletroneuromiographics finds resulted similar to that observed in the literature, except for the absence of clinical signs of CNS involvement. The presence of delay for independent walking raises the need for proper protocol for children in the first and second years of life: 1. Time of onset (age) and duration of motion to lift from a horizontal position and upright posture of trunk to keep sitting. 2. Type of crawl. 3. Age in months earlier to sit and walk with and without support. 4. Analysis of manual functionality, fine motricity with specialty tests in occupational therapy, since the first few months age. 5. Type of gear when he or she begins to walk with support, and then, without support, the use of the heels. 6. Stretch Reflex - evolution - with special attention to the aquileus, that are the most affected early. 7. Ankle clonus checking, aimed to detecting signs of spasticity. For children after 3 years of age: 1. Initiation of the use of slippers (ability to retain the slippers on the feet - proprioception development). 2. Verification of static and dynamic balance according to Lefèvre (1972), in the age groups from 3 to 7 years.

Entre as neuropatias periféricas hereditárias, a Doença de Charcot Marie Tooth (CMT) é a mais prevalente, sendo o Charcot Marie Tooth Lidado ao X tipo 1 (CMTX1) o segundo subtipo mais comum, causado por mutações no gene GJB1 e de herança ligada ao X. A sintomatologia de fraqueza, atrofia e alteração de sensibilidade progressiva, de padrão simétrico e distal é característica da CMT e, no CMTX1, o acometimento do sistema nervoso central pode estar associado ao quadro típico. Com relação à eletroneurofisiologia, há redução dos parâmetros de velocidade de condução nervosa, com prolongamento da latência de onda F. Não há terapias modificadoras do curso da doença, sendo importante acompanhamento multidiciplinar a fim de assistir as possíveis deformidades, dando mais conforto e otimização das atividades de vida diária dos pacientes. O objetivo do presente estudo é relatar casos diagnosticados como CMTX1 atendidos pelo ambulatório de Neurogenética do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP-USP) e comparar aos dados da literatura pertinente. Os critérios de inclusão foram idade no atendimento abaixo de 17 anos e 11 meses e confirmação do CMTX1 por exame genético molecular, com mutação em GJB1. Assim, foram encontradas quatro crianças, três do sexo feminino e uma do masculino, com idade variando de 3 a 17 anos, sendo que em dois deles foi observado atraso na marcha independente. Os sinais clínicos e eletroneuromiográficos observados foram concordantes com a literatura, exceto por não apresentarem sinais de acometimento do sistema norvoso central (SNC) associados. A presença de atraso na marcha e surgimento de casos precoces suscita a necessidade de protocolo adequado para crianças no primeiro e segundo anos de vida; 1. Anotar época de aparecimento e duração do movimento de levantar-se e postura ereta ou não do tronco ao se manter sentado. 2. Tipo do engatinhar. 3. Idade em meses no início de sentar e andar com e sem apoio. 4. Análise da funcionalidade manual, motricidade fina com auxílio de testes da especialidade em terapia ocupacional, desde os primeiros meses. 5. Tipo de marcha e época de início da marcha. 6. Reflexos fásicos - evolução - com atenção especial aos aquilianos, que são os mais precocemente acometidos. 7. Verificação de clônus de tornozelo, no sentido de detecção de sinais de espasticidade. Para crianças maiores de 3 anos de idade: 1. Início do uso de chinelo (capacidade de reter o chinelo nos pés - desenvolvimento da propriocepção). 2. Verificação do equilíbrio estático e dinâmico de acordo com Lefèvre (1972), nas faixas etárias de 3 a 7 anos. / Among the hereditary peripheral neuropathies, Charcot-Marie-Tooth disease (CMT) is the most prevalent, being the second most common the subtype CMTX1, caused by mutations in the GJB1 gene and producing a X-linked inheritance. The symptoms of symmetrical and distal weakness, atrophy and progressive sensory changes, are characteristics of the CMT and in the CMTX1 central nervous system involvement is often associated with the typical picture. With respect to eletroneurophysiology, there is reduction of nerve conduction velocity parameters, with extension of F wave latency. There is no modifier therapies of the course of the disease, being important, multidisciplinary monitoring to assist the possible deformities, giving more comfort and optimization of daily life activities of patients. The main objective of this study is to report cases diagnosed as CMTX1 by Neurogenetics Clinic of the Hospital of Clinics of the School of Medicine at Ribeirão Preto, São Paulo University (HCFMRPUSP) and to compare the data from the relevant literature. Inclusion criteria were age in attendance below 17 years and 11 months and CMTX1 confirmation by genetic testing, mutation GJB1. Four children were included, three female and a male, with age ranging from 3 to 17 years. Two of them presented late onset of independent walking. Clinical and eletroneuromiographics finds resulted similar to that observed in the literature, except for the absence of clinical signs of CNS involvement. The presence of delay for independent walking raises the need for proper protocol for children in the first and second years of life: 1. Time of onset (age) and duration of motion to lift from a horizontal position and upright posture of trunk to keep sitting. 2. Type of crawl. 3. Age in months earlier to sit and walk with and without support. 4. Analysis of manual functionality, fine motricity with specialty tests in occupational therapy, since the first few months age. 5. Type of gear when he or she begins to walk with support, and then, without support, the use of the heels. 6. Stretch Reflex - evolution - with special attention to the aquileus, that are the most affected early. 7. Ankle clonus checking, aimed to detecting signs of spasticity. For children after 3 years of age: 1. Initiation of the use of slippers (ability to retain the slippers on the feet - proprioception development). 2. Verification of static and dynamic balance according to Lefèvre (1972), in the age groups from 3 to 7 years.