Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Charcot-Marie-Tooth (CMT) disease is the most common genetically determined neurological condition in the world. It is characterized by a slow and progressive degeneration of the peripheral nerves, leading to weakness and atrophy of distal limb muscles. CMT is classified in two main subgroups: CMT type 1 (CMT1), demyelinating form, and CMT type 2 (CMT2), axonal form. The first objective of this study was to conduct a systematic review of the prevalence of CMT disease in the world and the second was to evaluate the epidemiological, socio-demographic and psychosocial profile of families with CMT disease in the State of Sergipe, Brazil. Methods: a systematic survey of the literature was carried out using the following databases: MEDLINE-PubMed, Web of Science, Scopus and CINAHL (January 1990 to May 2015). Apart from this, a descriptive, observational and cross-sectional epidemiological study was carried out by means of interview and clinical evaluation of patients with the disease (CMT Group or CMTG) and non-affected family members called the control group (CG) in the municipalities of Tobias Barreto, Pedrinhas and Itabaianinha - SE. The collection of data included evaluation of socio-demographic characteristics, anthropometric measurements, lifestyle, clinical conditions, co-morbidities, mental health (levels of anxiety and depression), standards of feminine sexual behavior and gynecological and obstetric profiles. Results: in article 1, 12 studies were included in the systematic review, where the prevalence of CMT varied from 9.7/ 100,000 inhabitants in Serbia to 82.3/ 100,000 in Norway. The frequency of the main subtypes in the countries varied from 37.6% to 84% for CMT1 and from 12% to 35.9% for CMT2. In article 2, 90 individuals from 6 families with CMT were interviewed; the prevalence of CMT in Sergipe was of 62/ 100,000 inhabitants; the prevalence of CMT1 was of 37/ 100,000 inhabitants and of CMT2 was of 25/ 100,000. The majority presented the onset of signs and symptoms in childhood. There was a greater incidence of illiteracy among those affected, with a significant difference between the groups CMTG (19.5%) and CG (6%). Elevated levels of anxiety and depression were observed. Changes in sexual activity were observed in 47% of the women. Of these, 88% related to rarely or never use condoms; the most used contraceptive methods were oral and injectable contraceptives; as to fertility, the CG had on average 1.93 children, while the CMTG had on average 2.47 children. Conclusion: the results reveal the gaps, which still exist in the epidemiological knowledge of CMT across the world. The high prevalence of CMT in Sergipe, the elevated index of illiteracy among the individuals presenting signs and symptoms of CMT and the shorter reproductive cycle of women with CMT indicate the impact of the disease in the state. Future research is needed with a focus on the epidemiological characteristics of CMT in different nations and ethnic groups. / A doença de Charcot-Marie-Tooth (CMT) é a afecção neurológica geneticamente determinada mais comum em todo o mundo. Caracteriza-se por provocar degeneração lenta e progressiva dos nervos periféricos, acarretando fraqueza e atrofia dos músculos distais dos membros. CMT é classificada em dois subgrupos principais: CMT tipo 1 (CMT1), forma desmielinizante e CMT tipo 2 (CMT2), forma axonal. O primeiro objetivo deste estudo foi realizar uma revisão sistemática sobre a prevalência da doença de CMT no mundo e o segundo foi avaliar o perfil epidemiológico, sociodemográfico e psicossocial de famílias com a doença de CMT no Estado de Sergipe, Brasil. Métodos: pesquisa sistemática na literatura foi realizada, utilizando como base de dados a MEDLINE-PubMed, Web of Science, Scopus e CINAHL (janeiro de 1990 a maio de 2015). Além disso, foi realizado estudo epidemiológico descritivo, observacional e transversal, por meio de entrevista e avaliação clínica de pacientes, grupo com a doença CMT (GCMT), e familiares não afetados, denominados de grupo controle (GC), nos municípios de Tobias Barreto, Pedrinhas e Itabaianinha- SE. A coleta de dados incluiu avaliação das características sociodemográficas, parâmetros antropométricos, hábitos de vida, condições clínicas, comorbidades, saúde mental (níveis de ansiedade e depressão), padrão de comportamento sexual feminino e perfis ginecológicos e obstétricos. Resultados: no artigo 1, doze estudos foram incluídos na revisão sistemática, cuja prevalência de CMT variou de 9,7/ 100.000 habitantes, na Sérvia, para 82,3/ 100.000, na Noruega. A frequência dos principais subtipos nos países variou de 37,6% a 84% CMT1 é de 12% para 35,9% CMT2. No artigo 2, foram entrevistados 90 indivíduos de seis famílias com CMT; a prevalência de CMT em Sergipe foi de 62/ 100.000 habitantes; a prevalência CMT1 foi de 37/ 100.000 habitantes e CMT2 foi de 25/ 100.000. A maioria apresentou início do surgimento dos sinais e sintomas na infância. Houve maior índice de analfabetismo entre os afetados, com diferença significativa entre os grupos GCMT (19,5%) e GC (6%). Foram observados elevados níveis de ansiedade e depressão. Verificou-se alteração na atividade sexual em 47% das mulheres, das quais 88% relataram o uso de preservativo raramente ou nunca; os métodos contraceptivos mais utilizados foram os anticoncepcionais orais e injetáveis; em relação à fecundidade, o GC apresentou média de 1,93 filho, enquanto o GCMT obteve média de 2,47 filhos. Conclusão: os resultados revelam as lacunas que ainda existem no conhecimento epidemiológico de CMT em todo o mundo. A alta prevalência de CMT em Sergipe, o elevado índice de analfabetismo entre os indivíduos que apresentam os sinais e sintomas de CMT e o ciclo reprodutivo das mulheres CMT mais curto indicam o impacto da doença no Estado. São necessárias pesquisas futuras com foco em características epidemiológicas de CMT em diferentes nações e grupos étnicos.

Charcot-Marie-Tooth 1B (CMT1B) is a progressive inherited demyelinating disease of human peripheral nervous system leading to sensory and/or motor function disability and is caused by mutations in the P0 gene. Mice heterozygously deficient for P0 (P0+/-) are an adequate model of this human disorder showing myelin degeneration, formation of onion bulbs, remyelination and a reduced motor conduction velocity of around 30m/s similar to patients. Previously, it had been shown that T-lymphocytes and macrophages play a crucial role during pathogenesis in peripheral nerves of P0+/- mice. Both, T-lymphocytes and macrophages increase in number in the endoneurium and deletion of T-lymphocytes or deletion of a macrophage-directed cytokine ameliorates the disease. In this study the monocyte chemoattractant protein-1 (MCP-1) was identified as an early regulated cytokine before onset of disease is visible at the age of six months. MCP-1 mRNA and protein expression could be detected in femoral quadriceps and sciatic nerves of P0+/- mice already at the age of one month but not in cutaneous saphenous nerves which are never affected by the disease. MCP-1 was shown to be expressed by Schwann cells and to mediate the immigration of immune cells into peripheral nerves. Deletion of MCP-1 in P0+/- mice accomplished by crossbreeding P0 and MCP-1 deficient mice revealed a substantial reduction of immune cells in peripheral nerves of P0+/-/MCP-1+/- and P0+/-/MCP-1-/- mice at the age of six months. In twelve months old mice reduction of immune cells in peripheral nerves is accompanied by amelioration of demyelinating disease in P0+/-/MCP-1+/- and aggravation of demyelinating disease in lumbar ventral roots of P0+/ /MCP-1-/- mice in comparison to P0+/ /MCP 1+/+ mice. Furthermore, activation of the MEK1/2-ERK1/2 signalling cascade could be demonstrated to take place in Schwann cells of affected peripheral nerves of P0+/- mice overlapping temporarily and spatially with MCP-1 expression. An animal experiment using a MEK1/2-inhibitor in vivo, CI-1040, revealed that upon reduction of ERK1/2 phosphorylation MCP-1 mRNA expression is diminished suggesting that the activation of the MEK1/2-ERK1/2 signalling cascade is necessary for MCP-1 expression. Additionally, peripheral nerves of P0+/- mice showing reduced ERK1/2 phosphorylation and MCP-1 mRNA expression also show reduced numbers of macrophages in the endoneurium. This study shows a molecular link between a Schwann cell based mutation and immune cell function. Inhibition of the identified signalling cascade might be a putative target for therapeutic approaches. / Die humane Erkrankung Charcot-Marie-Tooth 1B (CMT1B) ist eine erbliche, chronisch fortschreitende Erkrankung des peripheren Nervensystems die durch Mutation des P0-Gens verursacht wird und zu motorischen und/oder sensorischen Defiziten führt. Sehr ähnlich der humanen Erkrankung weist das Mausmodell, eine für das Myelinprotein P0 heterozygot-defiziente Maus (P0+/-), Degeneration peripheren Myelins, aufeinanderfolgende Zyklen von De- und Remyelinisierung als auch reduzierte Nervenleitgeschwindigkeiten auf. Wissenschaftliche Untersuchungen am Mausmodell ergaben eine Beteiligung von T-Lymphozyten und Makrophagen an der Pathogenese. In dieser Studie wurde das Chemokin „Monocyte Chemoattractant Protein-1“ (MCP-1) als pathogen-relevant in P0+/- Mäusen identifiziert. MCP-1 mRNA und Protein wurden sowohl im Alter von sechs und zwölf Monaten nachgewiesen, Stadien, in denen morphologische Veränderungen peripherer Nerven von P0+/- Mäusen zu erkennen sind, aber auch im Alter von einen und drei Monaten, ein Alter bei dem pathologischen Veränderungen nicht zu finden sind. Mit Hilfe von MCP-1 defizienten Mäusen (MCP-1-/-) und Verpaarung mit P0-defizienten Mäusen konnten weiterführende Untersuchungen zur Rolle von MCP-1 im peripheren Nerv der Maus durchgeführt werden. So zeigte es sich mittels Transplantation von GFP-positivem Knochenmark, dass MCP 1 die Infiltration von Makrophagen aus dem Blut in periphere Nerven vermittelt. Weiterhin konnte gezeigt werden, dass periphere Nerven von sechs Monate alten P0+/-/MCP-1+/- und P0+/-/MCP-1-/- Mäusen trotz signifikant niedrigerer Anzahl von Immunzellen keine Milderung der Demyelinisierung zeigen. Hingegen weisen periphere Nerven von zwölf Monate alten P0+/ /MCP-1+/- Mäusen sowohl weniger Makrophagen und T-Lymphozyten als auch wesentlich weniger pathologische Veränderungen auf. Periphere Nerven von P0+/-/MCP-1-/- Tieren dagegen zeigen nur eine nicht signifikante Reduktion von Immunzellen und sogar eine Verschlechterung des Phänotyps im Vergleich zu ventralen Spinalwurzeln von P0+/-/MCP-1+/+ Mäusen. Weiterführende Untersuchungen ergaben, dass eine Aktivierung der MEK1/2-ERK1/2 Signalkaskade sowohl in peripheren Nerven von drei und sechs Monate alten P0+/- Mäusen zu finden ist, allerdings, ähnlich der Expression von MCP-1, nur in peripheren Nerven, die von der Demyelinisierung betroffen sein können. Unter Verwendung eines Inhibitors der Kinasen MEK1 und 2 konnte in vivo gezeigt werden, dass Phosphorylierung von ERK1/2 für die erhöhte MCP-1 Expression in peripheren Nerven von P0+/- Mäusen notwendig ist. Darüber hinaus wurde durch Verminderung der ERK1/2-Phosphorylierung eine Reduktion von Makrophagen im Endoneurium von P0+/- Tieren erzielt.

Die Charcot-Marie-Tooth Typ 1 Erkrankungen sind eine genetisch heterogene Gruppe, aktuell nicht kurativ therapierbarer, erblicher Neuropathien des Peripheren Nervensystems. Klinische Manifestationen reichen von Sensibilitäts-störungen, verminderten Muskeleigenreflexen, sowie fortschreitenden Lähmungen, bis hin zu Muskelatrophie und bedeuten für die betroffenen Patienten eine starke Einschränkung der Lebensqualität. Anhand früherer Studien wurde Makrophagen, als Teil des angeborenen Immunsystems, eine entscheidende Rolle in der Pathogenese dreier CMT1-Unterformen zugeschrieben. Abgesehen von den morphologischen Manifestationen der demyelinisierenden CMT1-Erkrankungen, wie simultanes Auftreten von Dedifferenzierung, sowie Hypo-, und Demyelinisierung erkrankter Schwann-Zellen, sind pathologische Veränderungen der Domänengliederung der Ranvier’schen Schnürringe betroffener Nervenfasern ebenfalls von der Aktivierung pathogener Makrophagen abhängig. Auf der Basis verschiedener veröffentlichter Studien, welche sowohl demyelinisierende Erkrankungen des ZNS, aber auch primär durch axonale Schäden gekennzeichnete Erkrankungen des PNS beinhalten, besteht ein möglicher räumlicher Zusammenhang zwischen Architekturstörungen der RS und aktivierten pathogenen Mikrogliazellen bzw. Makrophagen. In dieser Studie konnte, anhand morphologischer Analysen von peripherem Nervengewebe, in Wt-Mäusen erstmals eine unerwartete präferentielle Lokalisation von Makrophagen im räumlichen Umfeld von RS beobachtet werden. Hierbei scheint, trotz des Fehlens einer direkten Zell-Zell-Interaktion zwischen Makrophagen und RS, vor allem im Hinblick auf die ebenfalls im räumlichen Umfeld von RS nachweisbare EZM und Fibroblasten, eine funktionelle Relevanz der assoziierten Makrophagen für die Aufrechterhaltung der Domänengliederung bzw. elektrophysiologischen Eigenschaften myelinisierter peripherer Nervenfasern denkbar. Im Gegensatz dazu wurde trotz der signifikanten Zunahme der Makrophagenanzahlen in den drei untersuchten CMT1-Mausmodellen keine erhöhte räumliche Assoziation mit den RS der mutierten Schwann-Zellen beobachtet. Vielmehr konnten anhand des Vergleiches mit wildtypischen Kontrollmäusen signifikant erniedrigte Assoziationsraten beider Strukturen in den CMT1-Modelltieren festgestellt werden. Folglich scheint die von der Einwanderung und Aktivierung pathogener Makrophagen abhängige Störung der Domänengliederung der RS der mutierten Schwann-Zellen, nicht durch eine direkte Interaktion bzw. räumliche Assoziation von Makrophagen mit RS ausgelöst zu werden. / The Charcot-Marie-Tooth neuropathies are a heterogenous group of inherited neuropathies oft he peripheral nervous system currenly incurable. Clinical symptoms vary from sensory loss, reduced tendon reflexes, muscular atrophy to progressive disability. According to different studies macrophages, as a part oft he innate immune system, play a crucial role in the pathogenesis of three different CMT-1 subtypes. Apart from morphological changes like dedifferentiation as well as hypo- and demyelination of diseased Schwann-cells, pathological alterations of nodes of Ranvier are also driven by activated marophages. As already described for demyelinating disoders oft he CNS, as well as neruodegenerative disorders oft he PNS, we investigated the spatial association of macrophages with diseased nodes of Ranvier. According to morphological analysis of peripheral nerve tissue this study is the first to describe an unexpected preferential spatial localization of macrophages near nodes of Ranvier in healthy nerves. Despite direct cell-cell interactions macrohages might play a functional role regarding the turnover of ECM and fibroblasts surrounding nodes of Ranvier, as well as the maintenance oft he architecture and electrophysiological features of peripheral nerve fibers.

No description available.

The aim of this 4 year long work was to study the Connexin32 (Cx32), a protein that forms hemichannels anchored in the plasma membrane. Two hemichannels of adjacent cells form a gap junction. Mutations in Cx32 have been associated to the X-linked form of Charcot-Marie-Tooth disease, a neurodegenerative illness affecting the peripheral nervous system. Cx32 is expressed in Schwann cells, in the paranodal zones. Using Xenopus laevis oocytes to express Cx32 hemichannels, we have monitored simultaneously the release of ATP and the ionic currents. ATP in the medium was detected with luciferin-luciferase reaction and the ionic currents were recorded under two electrode voltage clamp. Depolarization of oocytes expressing Cx32, from -40mV to +80mV induced an outward current and at the end of the pulse a transitory peak of ATP release. Using Cx32 transfected HeLa cells, we captured the luminescence due to ATP release, when cells were under a hypotonic solution containing luciferin-luciferase mixture. Isotonic solution was 280 mOsm and hypotonic solution was 150 mOsm. We also studied the release of ATP in Schwann cell cultures and again the hypotonic conditions induced a rapid increase of extracellular ATP. Finally, when we repeated the voltage clamp experiments expressing Cx32 and also syntaxin 1A, we saw a partial inhibition that of the currents and the release of ATP, which didn't happen when we repeated the hypotonic shock with HeLa cells expressing Cx32 and syntaxin. In order to keep on working in the ATP release through Cx32 hemichannels and its relation with CMT disease five different mutation already described in CMTX patients were generated in the lab, to study the ATP release through Cx32 mutated hemichannels in TEVC experiments with oocytes and transfecting mammal cells. This last part is not finished but it is conyinued by a predoctoral student of Dr. Solsona. / L'objectiu d'aquest treball desenvolupat Durant 4 anys ha estat estudiar la Connexina32 (Cx32), sis unitats d'aquest proteína formen un hemicanal anclat a la membrana plasmàtica, dos hemicanals de cèl·lules adjacents formen una unió tipus gap. Mutacions en la Cx32 s'han relacionat amb la forma lligada al cromosoma X de la malaltia de Charcot-Marie-Tooth, una malaltia neurodegenerativa perifèrica. La Cx32 s'expressa en molts teixits però les mutacions només afecten les cèl·lules de Schwann, on la Cx32 s'expressa als paranodes i a les cissures d'Schmidt-Lanterman. Utilitzant oòcits de Xenopus per expressar Cx32, hem mesurat l'alliberació d'ATP i la corrent generada després de sotmetre el oòcits a una despolarització. L'ATP es va detectar utilitzant els enzims luciferina i luciferasa i les corrents utilitzant el sistema de fixació de voltatge amb dos elèctrodes. Després vem estimula electricament nervi ciàtic sencer de rata i ratolí i vem poder captar alliberació d'ATP amb preferència per certes regions diferènciades. Per tal de diferenciar si aquest ATP alliberat provenia de les cèl·lules de Schwann i no dels axons de les neurones també vam estudiar l'alliberació d'ATP en cèl·lules de Schwann en cultiu i el xoc hipotònic també provoca alliberació d'ATP. Vem veure que les cèl·lules de Schwann alliberen ATP però no si ho fan a través de connexines. Primer vem realitzar inmunofuorescències per detectar la presència i posició de les connexines expressades a les cel·lules de Schwann (Cx32, Cx29 i Cx43) i vem trobar presència de Cx32 i Cx29 en les regions paranodals i a les cissures d'Schmidt-Lanterman, i Cx43 al llarg de la veina formada per la cel·lula de Schwann, amb certa preferència per les regions paranodals. Finalment, donada la periodicitat de la Cx32 era un bon candidat per l'alliberació d'ATP a través de les c'el·lules de Schwann que envolten els axons del nervi ciàtic, per veure i la Cx32 alliberava ATP vem Utilitzar cèl·lules HeLa transfectades amb Cx32 i vam capturar l'alliberació d'ATP després d'un xoc hipotònic, també utilitzant la luciferina i la luciferasa, però no vem trobar diferències entre les cèl·lules transfectades amb Cx32 i les que no ho estaven. Així, la Cx32 no allibera ATP en resposta a un estímul hipotònic, però podria en resposta a una depolarització, l'estíml fisiològic que activa l'obertura d'hemicanals de Cx32. Finalment, en experiments de fixació de voltatge expressant la Cx32 amb sintaxina 1A hi havia una inhibició parcial de les corrents d'entrada i de sortia, i de l'ATP alliberat, inhibició que no es va reproduir en els experiments de xoc hipotònic en cèl·lules HeLa transfectades amb Cx32 i sintaxina. Per seguir traballant en la línia de l'estudi de la Cx32 i l'alliberació d'ATP, i la relació que això pot tenir an el desenvolupament de la malaltia de CMT es van triar i generar cinc constructes de Cx32 humana amb mutacions diferents descrites en malalts de CMTX, per tal d'observar l'alliberació d'ATP a través d'hemicanals de Cx32 mutada tant en els experiments de TEVC amb oòctis, com en experiments amb cèl·lules de mamífer transfectades. Aquesta darrera part no va ser acabad però en l'actualitat està esssent realitzada per un altre becari predoctoral del Dr. Solsona.

Hereditary Motor and Sensory Neuropathy-Russe (HMSNR) is a rare recessive form of Charcot-Marie-Tooth disease (CMT) that has been identified in the European Gypsy (Roma) population. Clinically, HMSNR manifests with typical CMT symptoms, while no associated features have been detected. Distinct neuropathological features of HMSNR include the presence of numerous clusters of thinly myelinated fibres originating from regenerative activity. HMSNR has been previously mapped to chromosome 10q using a large Bulgarian Gypsy kindred. Subsequent identification of related chromosome 10q haplotypes in Spanish and Romanian Gypsy families suggested a founder mutation in the Gypsy population as the cause of HMSNR. This thesis describes the refined mapping of the HMSNR gene by generating a high-density physical-genetic map of the HMSNR region containing 20 microsatellite markers and 229 SNPs and insertion/deletions which allowed meticulous mapping of recombination breakpoints resulting in a reduction of the HMSNR gene region from 1 Mb to just 63.8 kb. Analysis of positional candidates by direct sequencing included 14 known genes, 7 predicted genes and 42 expressed sequence tags (ESTs) nonoverlapping with the genes. 78 putative HMSNR mutations were identified, two of which exhibit complete segregation with the HMSNR phenotype. Both are located in the so-called testis-specific part of unexpected candidate gene hexokinase 1 (HK1), in a rare alternative untranslated 5’ exon of HK1 and in the adjacent downstream intron. Expression analysis of transcripts containing the alternative exon suggests that the exon is not confined to testis but may be expressed in the nervous system. It remains to be speculated how a gene that functions in the fundamental process of energy generation might be involved in a neuropathy. Further investigations are likely to expand the knowledge about the importance of HK1 in the peripheral nervous system and may elucidate new roles of HK1

[Truncated abstract] Hereditary Motor and Sensory Neuropathy Lom (HMSNL) is a severe autosomal recessive peripheral neuropathy, the most common form of demyelinating Charcot-Marie-Tooth (CMT) disease in the Roma (Gypsy) population. The mutated gene, N-myc downstream-regulated gene 1 (NDRG1) on chromosome 8q24, is widely expressed and has been implicated in a wide range of processes and pathways. In this study we have aimed to assess the overall contribution of this gene to the pathogenesis of peripheral neuropathies, in cases where the most common causes of CMT disease havebeen excluded, as well as to gain clues about its function through the identification of its interactions with other proteins. Sequence analysis of NDRG1 in 104 patients with CMT disease and of diverse ethnicity identified one novel disease-causing mutation, IVS8-1G>A (g.2290787G>A), which affects the splice-acceptor site of IVS8 and results in the skipping of exon 9 . . . The results suggest a defect in Schwann cell lipid trafficking as a major pathogenetic mechanism in CMT4D. At the same time, database searches showed that the chromosomal location of NDRG1 coincides with a reported High-Density Lipoprotein-Cholesterol Quantitive Trait Locus (HDL-CQTL) in humans and in mice. A putative role of NDRG1 in the general mechanisms of HDL-mediated cholesterol transport was supported by biochemical studies of blood lipids, which revealed an association between the Gypsy founder mutation, R148X, and decreased HDL-C levels. These findings suggest that while peripheral neuropathy is the drastic result of NDRG1 deficiency, the primary role of the protein may be related to general mechanisms of lipid transport⁄metabolism.

Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 4 uppsatser.

Diss. (sammanfattning) Umeå : Univ., 2009.

p. 1-65 / Submitted by Antonio Geraldo Couto Barreto (ppgms@ufba.br) on 2013-10-04T11:20:17Z No. of bitstreams: 1 versao tese para capa dura.pdf: 1577001 bytes, checksum: 3bd3885581360f614dc66aa861b621fe (MD5) / Approved for entry into archive by Patricia Barroso(pbarroso@ufba.br) on 2013-10-08T17:11:25Z (GMT) No. of bitstreams: 1 versao tese para capa dura.pdf: 1577001 bytes, checksum: 3bd3885581360f614dc66aa861b621fe (MD5) / Made available in DSpace on 2013-10-08T17:11:25Z (GMT). No. of bitstreams: 1 versao tese para capa dura.pdf: 1577001 bytes, checksum: 3bd3885581360f614dc66aa861b621fe (MD5) Previous issue date: 2013 / Objetivo: O diabetes melito é a principal causa da neuroartropatia de Charcot e clinicamente se classifica em: Pé de Charcot, pé de Charcot agudo (PCA) quando existe processo inflamatório e pé de Charcot inativo quando os sinais inflamatórios estão ausentes. O objetivo deste estudo foi identificar os fatores de risco para o PCA nos pacientes com diabetes tipo 2. Métodos: Conduzimos um estudo caso-controle pareado, para avaliar os fatores de risco associados ao PCA, de fevereiro de 2000 até setembro de 2012. Selecionamos quatro controles para cada caso. 47 casos de PCA e 188 controles sem PCA foram arrolados. Casos e controles foram pareados para o ano de início do tratamento. Regressão logística condicional foi usada para estimar os odds ratios ajustados (ORs) e intervalos de confiança de 95% (95%ICs). Resultados: Na análise multivariada, pacientes com idade menor que 55 anos (ORs 4.10, 95% IC; 1.69 - 9.94), alfabetizados (ORs 3.73, 95% IC; 1.40 - 9.92), isolados socialmente (ORs 5.84, 95% IC; 1.49 - 22.86) e história prévia de úlcera (ORs 4.84, 95% IC; 1.62 - 14.51) tiveram maior risco do PCA. Porém, a doença arterial obstrutiva periférica (ORs 0.16, 95% IC; 0.05 - 0.52) OR 6.25 (1.92 – 20.0) foi um fator protetor. Discussão: Os resultados sugerem que o PCA no diabetes tipo 2, acomete principalmente os paciente com menos de 55 anos que vivem só, têm história prévia de úlcera, e que a doença arterial periférica seria um fator de proteção. / Salvador