Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

A doença de Charcot-Marie-Tooth tipo 1A (CMT1A), associada à duplicação do gene da proteína da mielina periférica 22(PMP22), é a neuropatia hereditária mais comum. Administração diária de progesterona a modelos animais desta doença resultou em progressão mais rápida da neuropatia. Algumas mulheres por ela afetadas desenvolveram piora neurológica durante suas gravidezes. O objetivo deste estudo foi avaliar a influência de gestações sobre a neuropatia de pacientes com CMT1A. Mulheres afetadas responderam questões sobre sinais e sintomas apresentados durante suas gravidezes presentes e passadas. Pontuações nas escalas CMTNS (Charcot-Marie-Tooth Neuropathy Score) e SF-36 (Short Form Health Survey - 36) e dados coletados de avaliações clínicas e eletrofisiológicas dessas pacientes, de mulheres que nunca tiveram filhos e de homens foram comparados. Seis pacientes foram prospectivamente avaliadas durante suas gestações. Cinquenta e uma mulheres responderam questões sobre 130 gravidezes. Vinte e nove delas relataram piora de seus sintomas neurológicos em 61 gravidezes: vinte e cinco, tiveram cãibras dolorosas, três, fraqueza progressiva, duas, ataxia sensitiva, oito referiram sintomas sensitivos positivos. Algumas dessas pacientes apresentaram mais de um tipo de sintomas. As comparações entre mulheres e homens mostraram diferenças significativas nos seguintes aspectos, com pior desempenho pelas mulheres: pontuação no item do CMTNS relacionado a sintomas de membros superiores, força de abdução dos primeiros e segundos quirodáctilos, força da flexão do quadril bilateralmente, pelo MRC (Medical Research Council), amplitude do CMAP (potencial de ação muscular composto) do nervo ulnar direito em millivolts. O SF-36 teve diferença significativa nos seguintes itens, também com piores pontuações pelas mulheres: limitações devido a problemas emocionais, estado geral de saúde, saúde mental, funcionamento social, dor e vitalidade. Quando realizado cotejo entre homens, mulheres com filhos e mulheres sem filhos, dados relativos a força dos abdutores curtos dos polegares direito e esquerdo, força da flexão do quadril bilateralmente, amplitude do CMAP do nervo ulnar direito e os mesmo itens do SF-36, exceto dor e estado geral de saúde, continuaram a ter diferença significativa entre homens e mulheres, mas não entre mulheres com filhos e mulheres sem filhos. Também não houve diferença entre os dados relativos a mulheres que tiveram piora na gravidez e mulheres que não referiram piora. Das seis pacientes avaliadas prospectivamente, cinco, com a duplicação do PMP22, apresentaram piora de algum aspecto de sua neuropatia, porem retornaram à sua condição clínica prévia à gravidez em períodos variáveis de tempo. Uma, que apresentava duas muatçoes, a duplicação 17p11.2-p12 e a mutação de ponto Ser72Leu, não teve qualquer alteração. Nesta casuística, embora tenham sido encontradas diferenças significativas entre os dois gêneros, e até entre homens e mulheres com filhos, não foi observada nenhuma diferença significativa entre mulheres que referiram piora na gravidez e as que não apresentaram. A gestação teve diferentes consequências sobre a neuropatia de pacientes avaliadas, prospectivamente, porem houve retorno às condições clínica anteriores à gravidez. / The Charcot-Marie-Tooth type 1A (CMT1A) associated with PMP22 duplication is the most common hereditary neuropathy. Daily administration of progesterone resulted in more progressive clinical neuropathy of transgenic rats over-expressing PMP22. There are reports of women with CMT1A who had worsening of their neurological status during pregnancy. The aim of this study was to investigate the influence of pregnancy on CMT1A neuropathy and its natural history. Women with CMT1A answered questions about neurological signs and symptoms during their past and present pregnancies. CMT NS (Charcot-Marie-Tooth Neuropathy Score) and SF 36 (Short Form Survey - 36) scores and data collected from clinical and electrophysiological evaluations of these patients, of women who didn\'t have child and of men were compared. Six patients were prospectively evaluated during pregnancies. Fifty-one patients answered questions about 130 pregnancies. Twenty-nine patients (56%) reported worsening of their neurological symptoms during 61 pregnancies: twenty-five women had painful cramps, three, reported progressive weakness, two patients had sensitive ataxia, six patients had positive sensory symptoms. Some of these patients had more than one kind of symptoms. Comparison between men and women showed some significant differences: CMT NS item about upper limbs symptoms; strength of right and left first dorsal interosseos muscle(ID), strength of right and left abductor pollicis brevis(APB), strength of right and left flexors of the hip, CMAP of right ulnar nerve in millivolts; SF-36 had significant difference in the following items: limitations due to emotional problems, general health, mental health, social functioning, pain and vitality, in which female had worst scores. When comparison between men, women who had child and women who didn\'t have child was made, data regarding strength of right and left APB, strength of right and left flexors of the hip, amplitude of right CMAP and the same items of SF-36, except pain and general health, continued to have significant differences between men and women, but not between women who had child and women who didn\'t had child. There was no difference between data of women who got worst during their pregnancy and women who didn\'t. CMT worsening during pregnancy has previously been described. Some of these patients recovered their previous status after delivery, while others did not. Several explanations have been proposed for this deterioration. In our series, five patients had deterioration during pregnancy. It seems that pregnancy may affect CMT patients in different ways. There were also some differences between men and women, but no significant worsening was found in the neurological status of women that had been pregnant. A larger prospective study should be conducted to better understand the effects of pregnancy on CMT.

A doença de Charcot-Marie-Tooth tipo 1A (CMT1A), associada à duplicação do gene da proteína da mielina periférica 22(PMP22), é a neuropatia hereditária mais comum. Administração diária de progesterona a modelos animais desta doença resultou em progressão mais rápida da neuropatia. Algumas mulheres por ela afetadas desenvolveram piora neurológica durante suas gravidezes. O objetivo deste estudo foi avaliar a influência de gestações sobre a neuropatia de pacientes com CMT1A. Mulheres afetadas responderam questões sobre sinais e sintomas apresentados durante suas gravidezes presentes e passadas. Pontuações nas escalas CMTNS (Charcot-Marie-Tooth Neuropathy Score) e SF-36 (Short Form Health Survey - 36) e dados coletados de avaliações clínicas e eletrofisiológicas dessas pacientes, de mulheres que nunca tiveram filhos e de homens foram comparados. Seis pacientes foram prospectivamente avaliadas durante suas gestações. Cinquenta e uma mulheres responderam questões sobre 130 gravidezes. Vinte e nove delas relataram piora de seus sintomas neurológicos em 61 gravidezes: vinte e cinco, tiveram cãibras dolorosas, três, fraqueza progressiva, duas, ataxia sensitiva, oito referiram sintomas sensitivos positivos. Algumas dessas pacientes apresentaram mais de um tipo de sintomas. As comparações entre mulheres e homens mostraram diferenças significativas nos seguintes aspectos, com pior desempenho pelas mulheres: pontuação no item do CMTNS relacionado a sintomas de membros superiores, força de abdução dos primeiros e segundos quirodáctilos, força da flexão do quadril bilateralmente, pelo MRC (Medical Research Council), amplitude do CMAP (potencial de ação muscular composto) do nervo ulnar direito em millivolts. O SF-36 teve diferença significativa nos seguintes itens, também com piores pontuações pelas mulheres: limitações devido a problemas emocionais, estado geral de saúde, saúde mental, funcionamento social, dor e vitalidade. Quando realizado cotejo entre homens, mulheres com filhos e mulheres sem filhos, dados relativos a força dos abdutores curtos dos polegares direito e esquerdo, força da flexão do quadril bilateralmente, amplitude do CMAP do nervo ulnar direito e os mesmo itens do SF-36, exceto dor e estado geral de saúde, continuaram a ter diferença significativa entre homens e mulheres, mas não entre mulheres com filhos e mulheres sem filhos. Também não houve diferença entre os dados relativos a mulheres que tiveram piora na gravidez e mulheres que não referiram piora. Das seis pacientes avaliadas prospectivamente, cinco, com a duplicação do PMP22, apresentaram piora de algum aspecto de sua neuropatia, porem retornaram à sua condição clínica prévia à gravidez em períodos variáveis de tempo. Uma, que apresentava duas muatçoes, a duplicação 17p11.2-p12 e a mutação de ponto Ser72Leu, não teve qualquer alteração. Nesta casuística, embora tenham sido encontradas diferenças significativas entre os dois gêneros, e até entre homens e mulheres com filhos, não foi observada nenhuma diferença significativa entre mulheres que referiram piora na gravidez e as que não apresentaram. A gestação teve diferentes consequências sobre a neuropatia de pacientes avaliadas, prospectivamente, porem houve retorno às condições clínica anteriores à gravidez. / The Charcot-Marie-Tooth type 1A (CMT1A) associated with PMP22 duplication is the most common hereditary neuropathy. Daily administration of progesterone resulted in more progressive clinical neuropathy of transgenic rats over-expressing PMP22. There are reports of women with CMT1A who had worsening of their neurological status during pregnancy. The aim of this study was to investigate the influence of pregnancy on CMT1A neuropathy and its natural history. Women with CMT1A answered questions about neurological signs and symptoms during their past and present pregnancies. CMT NS (Charcot-Marie-Tooth Neuropathy Score) and SF 36 (Short Form Survey - 36) scores and data collected from clinical and electrophysiological evaluations of these patients, of women who didn\'t have child and of men were compared. Six patients were prospectively evaluated during pregnancies. Fifty-one patients answered questions about 130 pregnancies. Twenty-nine patients (56%) reported worsening of their neurological symptoms during 61 pregnancies: twenty-five women had painful cramps, three, reported progressive weakness, two patients had sensitive ataxia, six patients had positive sensory symptoms. Some of these patients had more than one kind of symptoms. Comparison between men and women showed some significant differences: CMT NS item about upper limbs symptoms; strength of right and left first dorsal interosseos muscle(ID), strength of right and left abductor pollicis brevis(APB), strength of right and left flexors of the hip, CMAP of right ulnar nerve in millivolts; SF-36 had significant difference in the following items: limitations due to emotional problems, general health, mental health, social functioning, pain and vitality, in which female had worst scores. When comparison between men, women who had child and women who didn\'t have child was made, data regarding strength of right and left APB, strength of right and left flexors of the hip, amplitude of right CMAP and the same items of SF-36, except pain and general health, continued to have significant differences between men and women, but not between women who had child and women who didn\'t had child. There was no difference between data of women who got worst during their pregnancy and women who didn\'t. CMT worsening during pregnancy has previously been described. Some of these patients recovered their previous status after delivery, while others did not. Several explanations have been proposed for this deterioration. In our series, five patients had deterioration during pregnancy. It seems that pregnancy may affect CMT patients in different ways. There were also some differences between men and women, but no significant worsening was found in the neurological status of women that had been pregnant. A larger prospective study should be conducted to better understand the effects of pregnancy on CMT.

No description available.

X-linked Charcot-Marie-Tooth disease (CMTX1), a peripheral neuropathy, is clinically characterised by slow progressive weakness and wasting of the distal muscles with associated sensory loss. The CMTX1 locus had previously been localised to the pericentromeric region of the X chromosome. Our initial linkage analysis utilising Restriction Fragment Length Polymorphisms (RFLPs) confirmed that CMTX1 mapped proximally to the DXYS1X locus (Xq21.31). Subsequent linkage analysis, carried out as part of an international consortium, utilising microsatellite polymorphisms further delineated the CMTX1 locus to a 2cM region around DXS453 (Xq31.1). To help with this analysis new microsatellites are generated at the loci DXS106 and DXS227. In parallel with the linkage analysis a physical map of the region was under construction simultaneously with candidate gene evaluation. The physical map was constructed by Pulsed Field Gel Electrophoresis (PFGE) used in conjunction with partial digestion of Yeast Artificial Chromosomes (YACs). The physical map of nine YACs had been obtained in which seven potential CpG islands were identified. Candidate genes were investigated by sequencing Polymerase Chain Reaction (PCR) amplified gene fragments from DNA isolated from patients with CMTX1. This led to the identification of missense, nonsense and base pair deletion mutations within the previously described GJβ1 gene. This gene encodes, connexin 32, a gap junction subunit. Gap junctions are channels which allow direct transfer of cellular components, which are below 900D in diameter, between coupled cells. It is proposed that mutations affecting the GJβ1 gene are the underlying biological defect which results in the CMTX1 phenotype.

Abstract Development of Assessment and Screening Tool to Assist with Prevention and Identification of Charcot Foot in Type 2 Diabetics by Louise Wade MSN, RN MS, West Texas A&M University, 2010 BS, West Texas A&M University, 2010 Project Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Nursing Practice Walden University August 2016 Abstract According to the World Health Organization, up to 50% of type 2 diabetic patients develop neuropathy, which may cause major infections, amputation, and Charcot foot due to impaired sensation. Early recognition and care is essential for treatment of Charcot foot and prevention of further injury. Due to the complexity of this potentially life threatening complication, assessment is challenging, especially when practitioners who treat adult diabetic patients may not be familiar with Charcot foot. The purpose of this scholarly project was to develop an assessment, screening tool, and algorithm for detecting Charcot foot; an additional goal was to develop practice guidelines for practitioners to assist in the early recognition, treatment, and referral of adult diabetic patients at risk for Charcot foot. Lippitt's theory of change was used to guide the project. An interdisciplinary team of stakeholders was assembled to guide development of the tool, algorithm, and practice guidelines. Products were developed in accordance with evidence in current peer-reviewed literature and American Diabetes Association recommendations for Charcot foot diagnosis, treatment, and referral. Content was validated using a scale content validation instrument process to obtain input from experts in the care of Charcot foot. An implementation plan was developed to guide introduction of the products into practice, and an evaluation plan created to determine the extent to which intermediate term outcomes are met using these products. The project may contribute to social change by identifying patients at risk for Charcot foot prior to the onset of the complication, therefore preventing further injury, deformity, or amputation in populations that are often unable to afford quality healthcare.

Die Charcot-Marie-Tooth-Neuropathie umfasst eine heterogene Gruppe von erblichen unter anderem demyelinisierenden Erkrankungen des peripheren Nervensystems. Trotz ihrer hohen Prävalenz von 1:2.500 gibt es bis dato keine kausalen Therapiemöglichkeiten. Durch den progressiven Krankheitsverlauf wird die Lebensqualität der Patienten stetig gemindert; der fortschreitende Verlust der Muskelkraft und Störungen des Gangbildes sind besonders belastend. Ursächlich für die CMT1-Neuropathie sind unter anderem Mutationen in Genen, die für Moleküle des Myelins von Schwannzellen codieren. Diese Mutationen führen zu einer verminderten Stabilität und Funktion des Myelins und so letzten Endes zu einer Demyelinisierung und axonalen Schädigung der peripheren Nerven. Weitere Studien in CMT1-Mausmodellen zeigten jedoch, dass nicht nur die verringerte Myelinstabilität sondern auch eine durch das Immunsystem vermittelte geringgradige Entzündungsreaktion für die Symptome ursächlich sein könnte. Hier spielen vor allem Makrophagen eine zentrale Rolle. Das Zytokin CSF-1 aktiviert die Makrophagen und verursacht so eine Demyelinisierung der peripheren Nerven. In P0het und Cx32def Mausmodellen konnte nachgewiesen werden, dass eine medikamentöse Inhibition des CSF-1-Rezeptors an Makrophagen zu einem verbesserten Nervphänotypen und einer deutlichen Abmilderung des Krankheitsbildes führte. In dieser Arbeit wurden in P0het und Cx32def Mausmodellen weiterführende Behandlungsstudien mit einem CSF-1-RI durchgeführt, die untersuchen, zu welchem Zeitpunkt innerhalb des Krankheitsverlaufs (therapeutisch oder präventiv) eine erfolgreiche Therapie noch möglich ist und ob bei einem früheren Beginn eine noch bessere Wirkung erzielt werden kann. Abhängig von den verschiedenen Start- und Endpunkten waren unterschiedliche Ergebnisse zu beobachten: Hinsichtlich der klinischen Parameter wie der Greifkraft und der Anzahl an abnormal innervierten Synapsen zeigten die Tiere im präventiven Behandlungszweig in beiden Mausmodellen das beste Ergebnis im Vergleich zu den Kontrolltieren. Diese substantielle Verbesserung ließ sich unabhängig von einem Makrophagen-Reflux sogar noch 6 Monate nach Behandlungsabbruch nachweisen. Bezüglich der endoneuralen Makrophagendepletion war sowohl in den P0het als auch den Cx32def Tieren im präventiven sowie im therapeutischen Behandlungszweig eine signifikante Verbesserung zu beobachten. Diese Ergebnisse heben ein weiteres Mal die Bedeutung der Makrophagen als Teil einer Entzündungsreaktion in der Pathogenese der CMT1-Neuropathie hervor. Des Weiteren konnte die These gefestigt werden, dass eine Inhibition des CSF-1-Rezeptors zu verbesserten histopathologischen sowie funktionellen Parametern führt. Um ein gutes Ansprechen auf die Therapie zu erzielen, müssen ein möglichst früher Therapiebeginn sowie eine nachhaltige Behandlungsdauer gewährleistet sein. / "Macrophage-mediated inflamma3on is a potent driver of disease progression in mouse models of Charcot-Marie-Tooth (CMT) 1 diseases. This leads to the possibility to consider these cells as therapeu3c targets to dampen disease outcome in the so far non-treatable neuropathies. As a pharmacological proof-of-principle study, long-term targe3ng of nerve macrophages with the orally applied CSF-1 receptor specific kinase (c-FMS) inhibitor PLX5622 showed a substan3al allevia3on of the neuropathy in dis3nct CMT1 mouse models. However, regarding transla3onal op3ons, clinically relevant ques3ons emerged regarding treatment onset, dura3on and termina3on. Corrobora3ng previous data, we here show that in a model for CMT1B, peripheral neuropathy was substan3ally alleviated aQer early con3nuous PLX5622 treatment in CMT1B mice, leading to preserved motor func3on. However, late-onset treatment failed to mi3gate histopathological and clinical features, despite a similar reduc3on in the number of macrophages. Surprisingly, in CMT1B mice, termina3ng early PLX5622 treatment at six months was s3ll sufficient to preserve motor func3on at 12 months of age, sugges3ng a long-las3ng, therapeu3c effect of early macrophage deple3on. This novel and unexpected finding may have important transla3onal implica3ons, since we here show that con3nuous macrophage targe3ng appears not to be necessary for disease allevia3on, provided that the treatment starts within an early, cri3cal 3me window.” (Ostertag et al., Experimental Neurology, 2022)

The present study is focused on understanding the aetiology of the human clubfoot deformity. Although this pathology has been studied since Classical Antiquity, the mechanisms that lead to this abnormality in new-born patients remain elusive. Clubfoot is a deformity of one or both feet present at birth, in which the foot is abnormally positioned in a hand-like position, that is, the foot is turned and rotated inwards while pointing down; and is resistant to any further movements. Very little is known about the aetiology and genetics of clubfoot in the human population. Only recently, mutations in the PITX1 gene have been associated with a small number of patients. Because the genetic basis is not understood and the phenotypic observations are complex and variable in human patients, many mechanisms have been proposed to explain clubfoot. In this study, these pressing questions were addressed using the peroneal muscular atrophy (pma) mouse, a spontaneous mutant that has been shown to be a surprisingly good model for clubfoot, recapitulating the key features of the human phenotype. In order to confirm that the pma mouse is in fact an idiopathic model of clubfoot, it was important to understand if the pma clubfoot-like phenotype occurs in isolation or within a syndromic pathology. In addition to clubfoot, it was found that these animals show a retinal degeneration phenotype. However, this phenotype was associated with the Pde6brd1 mutation, suggesting that clubfoot occurs independently of the retinal phenotype and thus the pma is a good model for human idiopathic clubfoot. Clubfoot in the pma mouse has been associated with the observed failure of the foot rotation during embryonic development. This defect is thought to result from the extensive regional muscular atrophy that occurs at earlier stages. The peroneal nerve is also absent in the adult pma mouse, a defect that has remained unexplored. As such, this neuronal defect was studied to understand the reason for the peroneal nerve absence in the adult animals. The results indicate that the nerve fails to branch from the developing sciatic nerve during embryogenesis and is unable to innervate its target muscles. This abnormal branching process is associated with a neural growth delay. In respect to the genetics of the pma, it was not possible to identify the exact mutation that is responsible for the inheritance of the clubfoot phenotype. However, strong evidence was found in favour of a regulatory mutation resulting in over-expression of the gene Limk1, which encodes for a kinase involved in neuronal guidance and growth. Further work was performed on chicken embryos to understand the foot rotation process. By removing defined regions of muscle tissue from the developing limb zeugopod, it was possible to conclude that lack of function of the anterior and lateral hindlimb tissue is associated with abnormal foot rotation, resulting in a similar phenotype to clubfoot. By examining the affected muscles, it was possible to identify the tibialis cranialis and the peroneus longus muscles as relevant candidates involved in clubfoot aetiology. In summary, the evidence presented here suggests that the pma clubfoot results from a regulatory mutation that induces Limk1 over-expression and nerve growth delay. This in turn prevents the proper development of the peroneal nerve, resulting in the degeneration of its target muscle tibialis anterior and peroneus longus muscles. This degeneration will interfere with foot rotation and result in clubfoot. Thus, the results described by this work are of utmost importance for the understanding of the clubfoot pathology, as it supports a neuro-muscular aetiology dependent on a physical dynamic equilibrium of muscular forces. This is of scientific interest as it expands the current understanding of the foot rotation and the integrative interactions during the limb organogenesis; poorly described developmental processes, and of clinical relevance as it establishes important ideas and concepts for study in human patients.

Thesis (Ph.D.)--University of Western Australia, 2005.

Würzburg, Univ., Diss., 2009. / Zsfassung in dt. Sprache.