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Sample records for den diabetiske charcots

  1. Charcot Foot

    MedlinePlus

    ... help prevent recurrence of Charcot foot, development of ulcers, and possibly amputation. In cases with significant deformity, ... instructions for long-term treatment to prevent recurrences, ulcers, and amputation. and or or and or or, ...

  2. Before Charcot.

    PubMed

    Pearce, J M S

    2014-01-01

    From the time of Greco-Roman Medicine, the uncertain nature of hysterical illness was a fertile source of controversy. Because there were no testable objective signs of disease, the diverse ideas relating hysteria to the uterus and to psychological and physiological causes generated persisting polemics. Theories fluctuated chaotically, influenced by social changes of prosperity or deprivation, current attitudes, and issues of gender. Faced with a large number of patients with such illnesses as well as many with epilepsy, mental illnesses, and organic nervous disorders, Charcot set about investigating hysterics to determine what neurological abnormalities might explain them. His many predecessors, from Sydenham and Willis in the 17th century to Briquet and Bourneville in the 19th century, whose views are outlined in this chapter, both conditioned and influenced his efforts. Charcot succeeded in promoting his work at Salpêtrière, which for a time was respected throughout the world. PMID:25273484

  3. [The intimate Charcot].

    PubMed

    Bonduelle, M

    1994-01-01

    Charcot's first inner circle of relationships was at work at the Salpêtrière, face to face with his intern who Charcot then invited to his home. At the Clinic, Charcot gave his official lectures that attracted crowds, but the small circle of "his" students--interns, residents and other rare and privileges students saw some of the "best" moments, as long as they aquiesced totally and did not question the "maître". They all got together for dinner on Tuesday night at his sumptuous "hôtel" on Boulevard Saint-Germain, followed by a reception where they could meet writers, artists and politicians. When the outsiders had left, Charcot tightened together his inner circle, those he would invite to his summer home in Neuilly. Léon Daudet was one of these. He saw the art-lover, the enlightened connaisseur of classical literature. He saw Charcot let down his severe mask of a professor and become a pleasant joking man, yet his fascination with Charcot did not stop him from criticizing Charcot's materialism and anticlericalism. He also repudiated Charcot's autoritarism and depotism over his family (whom he adored) and recognized in Charcot a certain timidity and "proud malaise". These evenings, rare occasions in a life filled with work, went on long into the night in the solitary silence of his library. Only his long trips which he used as a "cure" broke the intimacy of his inner circle. His letters to his wife, who never accompanied him, offer a glimpse into the personality of this secret man. They let us perceive the effect of overwhelming scientific success and flattering applause, but also the shadow of susceptibility as seen by his daughter Jeanne who accompanied him on his last trips. He never gave up, never confided in others, yet he was a charmer, one whose silence was often a prelude to an explosion of rage. PMID:7754287

  4. [Charcot's epistemological concept].

    PubMed

    Lellouch, A

    1994-01-01

    Through a brilliant medical way, Charcot was, at the same time, rheumatologist, geriatric, clinician, pathologist - and mainly neuro-pathologist - ending as a psychiatrist (according to todays medical terminology). Here, we will point out how much scientific theory and philosophy may support an original concept very unusual during the second half of XIXth century medicine. Describing connection between biology and medicine according to Auguste Comte thoughte, the author is thoroughly going into the course introduced by Charcot: scientific medicine instead of empirical one; structural medical-anatomy against rudimentary approach and rising of experimental medicine; impact of human sciences on medical knowledge; appearance of specialists near general practitioners; idea of organic disturbances denying any 'faith healing". In fact, Charcot asserts that bedside instruction prevails against accurate sciences. PMID:11640482

  5. [Jean-martin charcot].

    PubMed

    Sakuta, Manabu

    2014-11-01

    Charcot created a system for the classification and diagnosis of neurological patients in the 1850s. His methodology consisted of listening to a patient's family history and present history, observing the patient scrupulously, and confirming lesions by autopsy once the patient was dead. He compared two different diseases in order to make their differences clear. Once he understood the fundamental form of a disease, he proceeded to study less perfect forms that had a single symptom. By this process, Charcot developed many new symptomatologies in Neurology. PMID:25407058

  6. Charcot foot syndrome.

    PubMed

    Jeffcoate, W J

    2015-06-01

    Charcot foot syndrome is an uncommon complication of diabetes but is potentially devastating in its consequences. Outcome is made worse by widespread professional ignorance leading to delayed diagnosis, but it is also hampered by lack of understanding of its causes and lack of treatments with proven effectiveness, other than offloading. There remains a desperate need for studies into its causes as well as comparative audit and trials designed to determine the best treatment for this difficult condition. Such work can probably only be effectively carried out through the establishment of multicentre networks. Nevertheless, improved understanding in recent years of the likely role of inflammatory pathways has raised awareness of the multiple ways in which the effects of neuropathy may be manifest in the development of the Charcot foot. This awareness is also leading to the realization that similar processes may conceivably contribute to the refractoriness of other foot diseases in diabetes, including both chronic unhealing ulcers and osteomyelitis. PMID:25818542

  7. Charcot-Marie-Tooth disease

    MedlinePlus

    Charcot-Marie-Tooth disease is a group of disorders passed down through families that affect the nerves outside the brain and ... Charcot-Marie-Tooth is one of the most common nerve-related disorders passed down through families (inherited). Changes to at least ...

  8. [How Charcot got his chair].

    PubMed

    Gelfand, T

    1994-01-01

    Charcot's career, as is well-known, reached a summit with his acquisition of the Faculty clinical chair of diseases of the nervous system inaugurated in 1882. Based upon previously untapped archival materials at the Charcot Library and the National Archives, this paper explores four questions: I. Was "Charcot's chair" really the first specialized chair for neurology?; 2. Was it founded specifically for Charcot?; 3. What role did the Faculty of Medicine play and did it offer any opposition?; 4. How important was the creation of the chair for the flourishing of the Salpêtrière school. Evidence is presented to show that Charcot considered a specialized chair in nervous diseases a high priority for his career and his school. Sometime around 1880, convinced of the importance of this project, he began to assemble arguments in its behalf from French and foreign sources, particularly from his German colleagues, Westphal and Erb. He learned that there were no precedents, not even in Berlin. Charcot's carefully prepared manuscript memoir presented a strong case for the "necessity" of the chair based on the recent progress and theoretical as well as practical importance of his subject. He described psychiatry, which already had a Faculty clinical chair, as but a "small part" of neuropathology and rejected the idea of combining the two disciplines. Although the project encountered opposition from several Faculty colleagues, who claimed that it was a personal favor for Charcot, powerful support from political allies such as Gambetta and Ferry ensured government funding. In fact, government action in behalf of the creation of the chair for Charcot preceded and surprised the medical Faculty. This paper shows the extent to which Charcot's own initiatives and arguments set the agenda and defined the role he envisaged for the new foundation at the center of the clinical research and teaching centre emerging under his direction at the Salpêtrière. PMID:11640483

  9. Charcot foot and ankle with osteomyelitis

    PubMed Central

    Donegan, Ryan; Sumpio, Bauer; Blume, Peter A.

    2013-01-01

    This paper presents a review of the current literature discussing topics of Charcot osteoarthropathy, osteomyelitis, diagnosing osteomyelitis, antibiotic management of osteomyelitis, and treatment strategies for management of Charcot osteoarthropathy with concurrent osteomyelitis. PMID:24098835

  10. Charcot-Marie-Tooth Disease

    MedlinePlus

    Charcot-Marie-Tooth disease (CMT) is a group of genetic nerve disorders. It is named after the three doctors who first identified it. ... a nerve biopsy. There is no cure. The disease can be so mild you don't realize ...

  11. Theater in professor Charcot's galaxy.

    PubMed

    Poirier, Jacques; Philippon, Jacques

    2013-01-01

    Jean-Martin Charcot, famous professor of the Chair of Clinic for Diseases of the Nervous System at Salpêtrière Hospital in Paris, was himself an artist, surrounded by artists, and adored the theater. His close colleague Charles Brown-Séquard was ridiculed by Georges Feydeau in a brief freakish monologue recited by Coquelin Cadet, from the Comédie-Française, concerning his claims to rejuvenate himself and others with animal testicle extracts. His friend and patient Alphonse Daudet had written many novels, short stories, and plays. Léon Daudet, Alphonse Daudet's son (and friend of Jean-Baptiste Charcot, the son of the professor), after having abandoned his medical studies, became a writer whose novel Les morticoles was a cruel satire of the medical profession. Among Charcot's pupils, Alfred Binet, Gilbert Ballet, Édouard Brissaud, and Joseph Babinski were particularly involved in the theater. Gilbert Ballet wrote the foreword to La folie au théâtre (Madness in Theatre) by André de Latour. Édouard Brissaud wrote a satiric play Le chèque (The Check), and Joseph Babinski, under the pseudonym of Olaf, was the coauthor with Palau of the drama Les détraquées (The Deranged Women). However, when all is said and done, perhaps the greatest actor in his entourage was Charcot himself. PMID:23485903

  12. Charcot's son, commander Jean-Baptiste Charcot: from neurology to "Pourquoi Pas?".

    PubMed

    Teive, Hélio A G; Munhoz, Renato P; Simões, Jefferson C

    2012-04-01

    Charcot name became very famous around the world, firstly because of the work of Professor Jean-Martin Charcot, the founder of Clinical Neurology, and, secondly, because of his son, Jean-Baptiste, the world famous maritime explorer. PMID:22510742

  13. Charcot spinal arthropathy in a diabetic patient.

    PubMed

    van Eeckhoudt, S; Minet, M; Lecouvet, F; Galant, C; Banse, X; Lambert, M; Lefèbvre, C

    2014-08-01

    We report a case of Charcot spinal arthropathy in a diabetic patient and emphasize the clinical reasoning leading to the diagnosis, discuss the differential diagnosis, and insist on the crucial role of the radiologist and pathologist which allows the distinction between Charcot spinal arthropathy and infectious or tumoural disorders of the spine. PMID:25012751

  14. Charcot-Marie-Tooth disease

    PubMed Central

    Sivera, Rafael; Vílchez, Juan Jesús; Martínez-Rubio, Dolores; Chumillas, María José; Vázquez, Juan Francisco; Muelas, Nuria; Bataller, Luis; Millán, José María; Palau, Fancesc; Espinós, Carmen

    2013-01-01

    Objectives: To determine the genetic distribution and the phenotypic correlation of an extensive series of patients with Charcot-Marie-Tooth disease in a geographically well-defined Mediterranean area. Methods: A thorough genetic screening, including most of the known genes involved in this disease, was performed and analyzed in this longitudinal descriptive study. Clinical data were analyzed and compared among the genetic subgroups. Results: Molecular diagnosis was accomplished in 365 of 438 patients (83.3%), with a higher success rate in demyelinating forms of the disease. The CMT1A duplication (PMP22 gene) was the most frequent genetic diagnosis (50.4%), followed by mutations in the GJB1 gene (15.3%), and in the GDAP1 gene (11.5%). Mutations in 13 other genes were identified, but were much less frequent. Sixteen novel mutations were detected and characterized phenotypically. Conclusions: The relatively high frequency of GDAP1 mutations, coupled with the scarceness of MFN2 mutations (1.1%) and the high proportion of recessive inheritance (11.6%) in this series exemplify the particularity of the genetic distribution of Charcot-Marie-Tooth disease in this region. PMID:24078732

  15. [Demonology and demonopathy under Charcot].

    PubMed

    Céard, J

    1994-01-01

    What an advantage, he, who is studying devil and witchcraft stories, would get with "Retrospective medicine" carried through the "Ecole de la Salpêtrière"? Those are collected in the Sister Jeanne des Anges autobiography plentiful annotations, printed by the "Bibliothèque Diabolique" from Bourneville (1886) and "Les démoniaques dans l'art", written by Charcot and Richer (1887). The first one is proposing to evoque the nun's symptoms as hysterical facts and to find every typical expression regarding that disease. It does not go thoroughly into the hallucinations content, that is to say the imaginative part of them, as well as contemporary people minding that hysteria remains unchanging year after year and that its cultural alterations are really uninteresting. Charcot and Richer's book asserts that the devilish is a devilish without fiend, that is why it is approving the Saint-Médard's convulsive people but, on the contrary, nothing is said about the bright witchcraft pictures. Then, despite its history, devilish contain is going hand to hand. Those historical studies are not trying to give a run down on a medical view of devilish approach but to make clear real hysterical knowledge; it means that before the medical deepening every one knows that dense disease. PMID:11640487

  16. An overview of the Charcot foot pathophysiology

    PubMed Central

    Kaynak, Gökhan; Birsel, Olgar; Güven, Mehmet Fatih; Öğüt, Tahir

    2013-01-01

    Charcot arthropathy of the foot is a rare but devastating complication of diabetes that remains to be a challenging issue for the foot and ankle surgeons. Charcot foot fails to be an obvious diagnostic option that comes to mind, even in a pathognomonic clinical appearance. The rarity of the disorder, more common pathologies that mimic the condition, and the self-limiting prognosis deviate the clinician from the right diagnosis. The clinical challenges in the diagnosis of Charcot foot require in-depth investigations of its enigmatic nature to establish useful guidelines. Yet, this goal seems to be beyond reach, without a holistic view of the immense literature concerning the pathophysiology of the disorder. The primary objective of this article is to put together and review the recent advancements about the etiology and intrinsic mechanisms of diabetic Charcot foot. PMID:23919113

  17. Hysteria after Charcot: back to the future.

    PubMed

    Bogousslavsky, Julien

    2011-01-01

    The studies on hysteria and hypnotism probably constitute the most important long-term work of Jean-Martin Charcot and his school, starting around 1870 until Charcot's death in 1893. Désiré Bourneville, Charcot's sixth interne at La Salpêtrière, was probably instrumental in stimulating his mentor's interest in hysteria, while Charles Richet's 1875 article on somnambulism was the trigger for Charcot to introduce hypnotism into the management of hysterics. Albert Pitres, Paul Richer, Georges Gilles de la Tourette, Paul Sollier, Joseph Babinski, Sigmund Freud and Pierre Janet became the most famous of Charcot's collaborators on hysteria, either as 'guardians of the temple' (Richer, Gilles de la Tourette, who defended their mentor's concepts against Hippolyte Bernheim and the Nancy school in the dispute during the 1880-1890s), or in renewing the field in psychology (Janet and Freud, in the 1890s) or clinical neurology (Babinski in the 1900s). In 1908, a 'quarrel of hysteria' led several of Charcot's pupils into opposition with each other, from which Babinski was considered victorious against Charcot's successor Fulgence Raymond, despite the weaknesses of his theory on 'pithiatism'. During World War I, there was a new surge of interest in hysteria associated with war psycho-neuroses, and several students of Charcot became actively involved in medical military care (Sollier, Babinski, Gilbert Ballet, Achille Souques). Babinski's pupil Clovis Vincent developed a treatment called torpillage (torpedoing) against war hysteria, associating painful galvanic current discharges with 'persuasion', but this was dismissed after the soldiers, considering it as torture, rebelled. After World War I, the neurological and psychiatric interest in hysteria again faded away, and this condition largely went back to the no-man's land, where it had been before Charcot initiated his studies. A comprehensive look at the evolution of ideas on hysteria in the followers of Charcot shows that

  18. Jean-Martin Charcot and his legacy.

    PubMed

    Bogousslavsky, Julien

    2014-01-01

    Jean-Martin Charcot (1825-1893) rightly is considered the father of both modern neurology and psychiatry in France and much beyond. While he never was interested in mental disease and what was called 'alienism' at the time, his career at La Salpêtrière Hospital over 30 years was mainly marked by the development of a huge group of students which focused on the study and management of hysteria. When Charcot took office at the beginning of 1862, hysteria was a 'no-man's land', medically speaking, since neither the alienists nor the internists had much interest in this condition. At La Salpêtrière, these chronic patients were largely left to themselves before Désiré Bourneville, one of Charcot's first students, convinced his chief to care for them. Subsequently, the studies of Charcot with Paul Richer, Joseph Babinski, Georges Gilles de la Tourette, Paul Sollier, Pierre Janet, and many others allowed the condition to be addressed in detail. During his stay with Charcot in 1885-1866, Sigmund Freud, a young neuropathologist at the time, became fascinated by hysteria, an interest which probably was the main start of his interest in psychology. Charcot emphasized the concept of mental factors in hysteria, along with that of a 'dynamic' lesion, which accounted for the lack of neuropathological findings in the patients. While his ideas on hysteria and hypnotism were criticized after his death even by former pupils, such as Babinski, recent findings from functional studies using magnetic resonance imaging show how accurate and often visionary Charcot's thinking was in this field. PMID:25273488

  19. Jean-martin charcot pathologist, neurologist, psychiatrist and physician.

    PubMed

    Pandey, Sanjay

    2012-10-01

    Jean-Martin Charcot is known as father of modern neurology. Before him, neurology was only limited to select disorders like chorea. His contributions were not limited to neurology only, as he was instrumental in many new developments in the field of pathology, psychiatry, and internal medicine. Even after 100 years, Charcot`s clinical methods remain the pillar of modern neurology. PMID:23349597

  20. [Edouard Brissaud (1852-1909), Charcot's favorite pupil].

    PubMed

    Poirier, Jacques; Ricou, Philippe

    2010-01-01

    Edouard Brissaud's career and scientific work are deeply marked by the influence of professor Jean-Martin Charcot, Head of the Chair of clinics of nervous system diseases at the Salpêtrière. Brissaud was his "externe" in 1875 and his "interne" in 1879. In 1880, his medical thesis was presided over by Charcot, who also served as a jury member for his "agrégation" in 1886. Brissaud was the king pin and the cornerstone of the famous medical handbook (Traité de médecine), which was kindly supported by Charcot and Bouchard. In 1893, a few months before Charcot's death, Brissaud, encouraged by Charcot, founded the Revue neurologique with Pierre Marie. When, after Charcot's death, Brissaud, in charge of the interim of the Salpêtrière's Chair, paid a glowing tribute to him, in his first lecture. Charcot thought highly of Brissaud and was fond of him. Two unpublished letters from Charcot to Brissaud gave evidence of his attachment to him. In one of these letters, Charcot friendly discussed the medical handbook with Brissaud and left his son Jean-Baptiste Charcot, as an "interne", in the care of Brissaud. In the other letter, Charcot gave Brissaud an original observation of alcoholic paralysis and asked him what he thought of it. On the whole, as pertinently written by late professor Jean-Louis Signoret, "Edouard Brissaud was undoubtedly Charcot's favourite disciple". PMID:21560379

  1. Jean-Martin Charcot Pathologist, Neurologist, Psychiatrist and Physician

    PubMed Central

    Pandey, Sanjay

    2012-01-01

    Jean-Martin Charcot is known as father of modern neurology. Before him, neurology was only limited to select disorders like chorea. His contributions were not limited to neurology only, as he was instrumental in many new developments in the field of pathology, psychiatry, and internal medicine. Even after 100 years, Charcot`s clinical methods remain the pillar of modern neurology. PMID:23349597

  2. Charcot-Marie-Tooth disease

    PubMed Central

    Manganelli, Fiore; Nolano, Maria; Pisciotta, Chiara; Provitera, Vincenzo; Fabrizi, Gian M.; Cavallaro, Tiziana; Stancanelli, Annamaria; Caporaso, Giuseppe; Shy, Michael E.

    2015-01-01

    Objective: To evaluate, by skin biopsy, dermal nerve fibers in 31 patients with 3 common Charcot-Marie-Tooth (CMT) genotypes (CMT1A, late-onset CMT1B, and CMTX1), and rarer forms of CMT caused by mutations in RAB7 (CMT2B), TRPV4 (CMT2C), and GDAP1 (AR-CMT2K) genes. Methods: We investigated axonal loss by quantifying Meissner corpuscles and intrapapillary myelinated endings and evaluated morphometric changes in myelinated dermal nerve fibers by measuring fiber caliber, internodal, and nodal gap length. Results: The density of both Meissner corpuscles and intrapapillary myelinated endings was reduced in skin samples from patients with CMT1A and all the other CMT genotypes. Nodal gaps were larger in all the CMT genotypes though widening was greater in CMT1A. Perhaps an altered communication between axons and glia may be a common feature for multiple forms of CMT. Internodal lengths were shorter in all the CMT genotypes, and patients with CMT1A had the shortest internodes of all our patients. The uniformly shortened internodes in all the CMT genotypes suggest that mutations in both myelin and axon genes may developmentally impede internode formation. The extent of internodal shortening and nodal gap widening are likely both important in determining nerve conduction velocities in CMT. Conclusions: This study extends the information gained from skin biopsies on morphologic abnormalities in various forms of CMT and provides insights into potential pathomechanisms of axonal and demyelinating CMT. PMID:26362287

  3. Migrating bone shards in dissecting Charcot joints.

    PubMed

    Forrester, D M; Magre, G

    1978-06-01

    Extensive periarticular calcification is characteristic of Charcot joints. Fragmentation of the articular margins of bone contributes to the bony detritus, but the majority forms de novo in the joint capsule. Occasionally the calcific debris is seen far removed from the joint. Dissection of a chronically distended joint along muscle planes is most commonly associated with the inflammatory joint disease of rheumatoid arthritis. Its occurrence in Charcot joints is documented by arthrography, which demonstrates continuity of the joint space and the distant calcifications. PMID:418652

  4. Charcot foot associated with chronic alcohol abuse

    PubMed Central

    Arapostathi, Christina; Tentolouris, Nicholas; Jude, Edward B

    2013-01-01

    Two patients without a history of diabetes mellitus but with a history of chronic alcohol abuse were referred to our foot clinic due to pain and deformity of the midfoot. On examination both of the feet of the first patient and the left foot of the second patient were swollen and warm but all the inflammatory markers were negative. Subsequent imaging revealed Charcot deformity and the patients were treated with casting and special shoes. The temperature and the swelling of the feet after the offloading improved. x-Rays which were performed 1 and 2 years after the diagnosis did not show any progression of the Charcot deformity. PMID:23563675

  5. Surgical treatment of the Charcot foot.

    PubMed

    Pinzur, Michael S

    2016-01-01

    With the increased number of diabetics worldwide and the increased incidence of morbid obesity in more prosperous cultures, there has become an increased awareness of Charcot arthropathy of the foot and ankle. Outcome studies would suggest that patients with deformity associated with Charcot Foot arthropathy have impaired health related quality of life. This awareness has led reconstructive-minded foot and ankle surgeons to develop surgical strategies to treat these acquired deformities. This article outlines the current clinical approach to this disabling medical condition. PMID:26813619

  6. Neurology outside Paris following Charcot.

    PubMed

    Moulin, Thierry; Clarac, François; Petit, Henri; Broussolle, Emmanuel

    2011-01-01

    The Middle Ages saw the development of numerous universities in the different provinces that later became the kingdom of France. In 1794, Napoleon I established 3 medical schools in Paris, Montpellier and Strasbourg, which were transformed into medical faculties in 1808. France had always been a highly centralized country, but during the 19th century, this trend started to change with the creation of medical faculties in Nancy (1872), Lille (1877), Lyon (1878), Bordeaux (1879), Toulouse (1891), Algiers (1910) and Marseille (1930). Following the creation of the 12 foundation courses, specialized chairs were progressively established in Paris, but for a long time this remained restricted to the French capital. However, with the emergence of medicine as an academic discipline in several towns outside Paris, came the development of neurology. This was greatly influenced by former students of Jean-Martin Charcot, local personalities, and the interactions between the two. Leading figures included Albert Pitres in Bordeaux, Léon Ingelrans in Lille, Eugène Devic and Jules Froment in Lyon, Lucien Cornil in Marseille, Joseph Grasset in Montpellier, and Marcel Riser in Toulouse. The interaction between French and Germanic medical communities also developed at this turbulent time under the influence of several great physicians such as Wilhelm Waldeyer, Adolf Kussmaul, and later Jean Alexandre Barré in Strasbourg, and Hippolyte Bernheim in Nancy. There are a number of other university towns outside Paris in which the development of neurology was probably influenced by the same interactions with psychiatry. It would be worth carrying out a thorough analysis of these towns in order to present an exhaustive overview of the development of neurology in France. PMID:20938155

  7. Charcot neuroarthropathy of the foot and ankle.

    PubMed

    Schon, L C; Easley, M E; Weinfeld, S B

    1998-04-01

    The goal of this study was to characterize Charcot neuroarthropathy of the foot and ankle by specific sites of involvement (ankle, hindfoot, midfoot, and forefoot), modes of presentation, methods of management, and outcome. A summary of treatment and results for 50 ankles, 22 hindfeet, 131 midfeet, and 18 forefeet is presented. Nondisplaced neuropathic ankle fractures typically healed uneventfully with casting and bracing. For displaced ankle fractures, closed reduction and casting generally resulted in loss of reduction and progressive deterioration; better results were obtained with open reduction and internal fixation, using supplemental Kirschner wires and screws. Ankles with Charcot neuroarthropathy and preexisting arthritis typically required arthrodesis. Of the ankles with neuropathic avascular talar necrosis, approximately 1/3 did well with nonoperative intervention and 2/3 required surgery. Chronic, unstable, malaligned Charcot ankles often required arthrodesis. Neuropathic calcaneal fractures were managed successfully nonoperatively. For feet with transverse tarsal joint involvement (Schon Type IV), management was more complex. Nonoperative treatment was successful for less than 1/2. Two thirds of the feet with midtarsus involvement (Schon Types I, II, and III) were managed successfully nonoperatively; 1/3 required surgery for recurrent ulceration, instability, or osteomyelitis. Half of the feet with forefoot neuroarthropathy required surgery for malalignment, ulceration, and/or difficulty with shoewear or braces. This review has established patterns of Charcot involvement of the foot and ankle with corresponding methods of treatment and subsequent responses. From this extensive clinical experience with 221 neuropathic fractures or Charcot joints, recommendations were derived to assist in selecting appropriate management options. PMID:9584374

  8. [Charcot and his legacy to medicine].

    PubMed

    Camacho Aguilera, José Francisco

    2012-01-01

    Jean-Martin Charcot (1825-1893) was a French physician whose professional life is divided into two phases: the first dedicated to neurology, and the second dedicated to the psychiatry area. Charcot is considered the father of modern neurology. In the Hospice de la Salpêtrière he began his research on neurological diseases, founded a laboratory of pathology (including microscopy and photography), and gave hospital classes based on pathological anatomy related to clinical manifestations based in the field of neurology. His research led to the description and study of different neurological diseases, such as multiple sclerosis, lateral amyotrophic sclerosis, hereditary motor and sensory neuropathy, motor ataxia, Parkinson`s disease, Gilles de la Tourette syndrome, epilepsy, visual aphasia and agnosia, to name a few. Some signs and diseases took their name as an eponym, and some are still mentioned in the current medicine, while others are left in oblivion. PMID:22820369

  9. The prefaces by Charcot: leitmotifs of an international career.

    PubMed

    Goetz, Christopher G

    2003-04-22

    The objective of this article was to examine the prefaces that Jean-Martin Charcot wrote for other colleagues' books and to evaluate these short essays from three perspectives: scientific material discussed, medicopolitical strategies revealed, and larger thematic issues developed. Charcot (1825-1893) was the most celebrated clinical neurologist of his epoch. In his mid and late career, he wrote very few manuscripts, delegating such work to junior colleagues or to Bourneville, who compiled Charcot's Complete Works. One particular source of direct writing from Charcot's mature career is the group of prefaces he composed for selected monographs authored by other colleagues. The prefaces from the Gasser tabulation (Bibliothèque Charcot, Paris) of Charcot's works were examined and analyzed in the context of Charcot's career. Of the 21 prefaces, 10 concerned books by other colleagues with whom he had not worked, and 11 introduced books of his students or direct colleagues. The prefaces concerned primarily two topics of direct medical interest to Charcot: localization studies of cortical and spinal cord diseases, and the combined subject of hysteria and hypnotism. In placing the works in scientific context, Charcot systematically emphasized the contributions of French neurologists, largely focusing on the Salpêtrière school and its (his) discoveries. Charcot used these prefaces to summarize the major thematic elements of his career, drafting the essays in the context of such topics as medical specialization, the concept of experimental medicine, and the prioritization of human studies over experimental laboratory medicine. Although an exhaustive reading of Charcot's entire opus is needed to provide a comprehensive view of his ideas, the short and pithy prefaces, comprising fewer than 60 pages, coalesce and distill the primary themes of his international career. PMID:12707438

  10. The Charcot foot: pathophysiology, diagnosis and classification.

    PubMed

    Trieb, K

    2016-09-01

    Neuropathic changes in the foot are common with a prevalence of approximately 1%. The diagnosis of neuropathic arthropathy is often delayed in diabetic patients with harmful consequences including amputation. The appropriate diagnosis and treatment can avoid an extensive programme of treatment with significant morbidity for the patient, high costs and delayed surgery. The pathogenesis of a Charcot foot involves repetitive micro-trauma in a foot with impaired sensation and neurovascular changes caused by pathological innervation of the blood vessels. In most cases, changes are due to a combination of both pathophysiological factors. The Charcot foot is triggered by a combination of mechanical, vascular and biological factors which can lead to late diagnosis and incorrect treatment and eventually to destruction of the foot. This review aims to raise awareness of the diagnosis of the Charcot foot (diabetic neuropathic osteoarthropathy and the differential diagnosis, erysipelas, peripheral arterial occlusive disease) and describe the ways in which the diagnosis may be made. The clinical diagnostic pathways based on different classifications are presented. Cite this article: Bone Joint J 2016;98-B:1155-9. PMID:27587513

  11. Recognizing Charcot disease in a man with diabetes.

    PubMed

    Womack, Jamie M

    2016-05-01

    Charcot disease is a neurogenic osteoarthropathy that occurs in the foot and ankle following the loss of normal muscle tone, vascularization, and protective reflexes. Diabetes is its most common cause in the Western world. Fragmentation, destruction, and dislocation of the bones can occur spontaneously or after trauma. This article describes the care of a patient with Charcot disease. PMID:27124227

  12. Did Jean-Martin Charcot contribute to stroke?

    PubMed

    Bogousslavsky, Julien; Paciaroni, Maurizio

    2010-01-01

    Stroke was never identified as a significant, autonomous field of activity of the emerging school of neurology at La Salpêtrière, which developed after the appointment of Jean-Martin Charcot (1825-1893) during the last days of 1861. However, stroke was already present in Charcot's first paper (1851), which dealt with a case of multiple organ cardiac embolism, including middle cerebral artery infarction, at a time when the studies of Rudolf Virchow on thromboembolism were unknown in France. A few years later, Charcot made a still up-to-date description of vascular intermittent claudication, which had only been reported in the horse. In the 1860s, Charcot and his pupils presented several major works dealing with cerebrovascular disease, including famous studies on miliary aneurysms in cerebral hemorrhage. This work was done with Charles Bouchard, at the time Charcot's 'interne', but who would become one of his 'political' opponents 2 decades later, when in 1892, as president of the 'agrégation' jury, he rejected the professorship application of 4 protégés of Charcot, including Joseph Babinski and Georges Gilles de la Tourette. Further work on cerebrovascular disease by Charcot included histological studies of brain 'softening', paraneoplastic cerebral arterial occlusion and consequences of stroke (e.g. arthropathies, vegetative changes, contractures and abnormal movements). Brain localization, one of Charcot's major neurological topics, was also largely based on stroke case studies. Charcot's work on stroke remains poorly recognized, but it demonstrates his unique skills in stimulating scientific work in younger colleagues, many of whom subsequently became major figures of neurology and psychiatry. PMID:20588046

  13. Jean-Baptiste Charcot, the French Antarctic expedition and scurvy.

    PubMed

    Teive, Hélio Afonso Ghizoni; Germiniani, Francisco Manoel Branco; Munhoz, Renato Puppi

    2014-07-01

    During the second expedition to the South Pole, Commander Jean-Baptiste Charcot and some members of the crew of "Pourquoi Pas?" developed symptoms suggestive of scurvy. The clinical picture was totally reversed after dietary changes. PMID:25054991

  14. Jean-Martin Charcot: neurologist by avocation, nephrologist by yearning.

    PubMed

    Eknoyan, Garabed

    2011-01-01

    In an age of medical advances and specialization, Jean-Martin Charcot (1825-1893) helped found the discipline of neurology and in 1882 was appointed the first Professor of Diseases of the Nervous System in France. As an investigator with broad interests and vast knowledge, Charcot contributed to several other disciplines. An early mentor and dominant figure in Charcot's formative years was Pierre Rayer (1793-1867), famous for his seminal contributions to the study of the kidney, who gifted to Charcot his passion for clinical pathological correlations and likely a yearning for the study of kidney diseases. Famous for the clarity and incisiveness of his formal teaching presentations, Charcot lectured on the kidney at the Faculty of Medicine in Paris in 1877. Translated into English and published as a book titled Lectures on Bright's Disease, those lectures became widely accessible and quoted in the literature through the 1940s. In addition, at a time when he was already concentrating on the study of neurological disorders, Charcot maintained his life-long interest in the kidney and published original studies on the pathological changes of the kidney in gout and experimental lead poisoning, as well as supporting a study of hysterical ischuria by his students. PMID:21614774

  15. The Charcot foot: medical and surgical therapy.

    PubMed

    Ulbrecht, Jan S; Wukich, Dane K

    2008-12-01

    Charcot neuro-osteoarthropathy (CN) is among the most devastating complications of neuropathy and now most commonly occurs in the feet of diabetic patients. Because it is relatively rare and because most patients and practitioners do not expect major bone pathology in the absence of significant pain, CN is often misdiagnosed as cellulitis, deep venous thrombosis, or gout. Also, radiographs early in the process are often relatively unremarkable. Although MRI findings are characteristic, treatment should not wait for the MRI result. The hot swollen erythematous neuropathic foot suspected to be CN should be emergently mechanically protected, usually in an irremovable total contact cast. Mechanical protection is the mainstay of conservative therapy, but surgical reconstruction of a deformed foot can usually also be successful. Unless diagnosed very early, significant decrements in quality of life result. Controlled studies are urgently needed to identify best practices. PMID:18990300

  16. Update on Charcot-Marie-Tooth Disease

    PubMed Central

    Patzkó, Ágnes; Shy, Michael E.

    2011-01-01

    Charcot-Marie-Tooth disease (CMT) disease encompasses a genetically heterogeneous group of inherited neuropathies, also known as hereditary motor and sensory neuropathies. CMT results from mutations in more than 40 genes expressed in Schwann cells and neurons causing overlapping phenotypes. The classic CMT phenotype reflects length-dependent axonal degeneration characterized by distal sensory loss and weakness, deep tendon reflex abnormalities, and skeletal deformities. Recent articles have provided insight into the molecular pathogenesis of CMT, which, for the first time, suggest potential therapeutic targets. Although there are currently no effective medications for CMT, multiple clinical trials are ongoing or being planned. This review will focus on the underlying pathomechanisms and diagnostic approaches of CMT and discuss the emerging therapeutic strategies. PMID:21080241

  17. Jules Bernard Luys in Charcot's penumbra.

    PubMed

    Parent, Martin; Parent, André

    2011-01-01

    Jules Bernard Luys (1828-1897) is a relatively unknown figure in 19th century French neuropsychiatry. Although greatly influenced by Jean-Martin Charcot (1825-1893), Luys worked in the shadow of the 'master of La Salpêtrière' for about a quarter of a century. When he arrived at this institution in 1862, he used microscopy and photomicrography to identify pathological lesions underlying locomotor ataxia and progressive muscular atrophy. He later made substantial contributions to our knowledge of normal human brain anatomy, including the elucidation of thalamic organization and the discovery of the subthalamic nucleus. Luys's name has long been attached to the latter structure (corps de Luys), which is at the center of our current thinking about the functional organization of basal ganglia and the physiopathology of Parkinson's disease. As head of the Maison de santé d'Ivry, Luys developed a highly original view of the functional organization of the normal human brain, while improving our understanding of the neuropathological and clinical aspects of mental illnesses. In 1886, Luys left La Salpêtrière and became chief physician at La Charité hospital. Following Charcot, whom he considered as the father of scientific hypnotism, Luys devoted the last part of his career to hysteria and hypnosis. However, Luys ventured too deeply into the minefield of hysteria. He initiated experiments as unconventional as the distant action of medication, and became one of the most highly caricatured examples of the fascination that hysteria exerted upon neurologists as well as laypersons at the end of the 19th century. PMID:20938152

  18. Jean-Martin Charcot's Role in the 19th Century Study of Music Aphasia

    ERIC Educational Resources Information Center

    Johnson, Julene K.; Lorch, Marjorie; Nicolas, Serge; Graziano, Amy

    2013-01-01

    Jean-Martin Charcot (1825-93) was a well-known French neurologist. Although he is widely recognized for his discovery of several neurological disorders and his research into aphasia, Charcot's ideas about how the brain processes music are less well known. Charcot discussed the music abilities of several patients in the context of his "Friday…

  19. Freud with Charcot: Freud's discovery and the question of diagnosis.

    PubMed

    Lepoutre, Thomas; Villa, François

    2015-04-01

    Although Charcot's seminal role in influencing Freud is widely stated, although Freud's trip to Paris to study with Charcot is well recognized as pivotal in his shift from neurological to psychopathological work, a key fact of the Freudian heuristic remains largely underestimated: namely, that Freud's psychopathological breakthrough, which gave birth to psychoanalysis, cannot be separated from his 'diagnostic preoccupation', which is a crucial and at times the first organizing principle of his earliest writings. The purpose of this article is therefore to reopen the question of diagnosis by following its development along the path leading from Charcot to Freud. The authors demonstrate that Freud's careful attention to diagnostic distinctions follows strictly in the direction of Charcot's 'nosological method'. More importantly, the article intends to identify the precise way in which his ideas operate in Freud's own work, in order to understand how Freud reinvests them to forge his own nosological system. If the authors trace the destiny of Charcot's lessons as they reach Freud's hands, it is the importance granted to mixed neuroses in Freud's psychopathology that allows them to pinpoint the role played by the diagnostic process in the rationality of psychoanalysis. PMID:25363538

  20. Etiology, pathophysiology and classifications of the diabetic Charcot foot

    PubMed Central

    Papanas, Nikolaos; Maltezos, Efstratios

    2013-01-01

    In people with diabetes mellitus, the Charcot foot is a specific manifestation of peripheral neuropathy that may involve autonomic neuropathy with high blood flow to the foot, leading to increased bone resorption. It may also involve peripheral somatic polyneuropathy with loss of protective sensation and high risk of unrecognized acute or chronic minor trauma. In both cases, there is excess local inflammatory response to foot injury, resulting in local osteoporosis. In the Charcot foot, the acute and chronic phases have been described. The former is characterized by local erythema, edema, and marked temperature elevation, while pain is not a prominent symptom. In the latter, signs of inflammation gradually recede and deformities may develop, increasing the risk of foot ulceration. The most common anatomical classification describes five patterns, according to the localization of bone and joint pathology. This review article aims to provide a brief overview of the diabetic Charcot foot in terms of etiology, pathophysiology, and classification. PMID:23705058

  1. [Pathology of Charcot-Marie-Tooth Disease].

    PubMed

    Oka, Nobuyuki

    2016-01-01

    Although genetic testing is available, nerve biopsy is useful in selected patients for the diagnosis of Charcot-Marie-Tooth disease (CMT). These are sporadic cases of hereditary neuropathy, or familial cases in which genetic testing is negative. CMT is caused by mutations of various genes. The pathological features of CMT have mostly been investigated using nerve biopsy, which may shed light on the presumed functions of mutated gene products. PMP22 duplication in CMT1A induces numerous large onion bulb lesions (OB). Compared to chronic inflammatory demyelinating polyradiculoneuropathy, the differential features of CMT1A are patchy distribution of OB and non-inflammatory lesions. CMT1B also manifests as OB, but presents abnormal compaction of myelin sheaths caused by uncompacted myelin or excessive myelin folding. CMT2 includes axonal neuropathies and many causative genes have been found. CMT2A (MFN2 mutation) shows abnormal mitochondria with a spherical morphology instead of tubular in the longitudinal direction. CMT4 consists of autosomal recessive forms with demyelinating pathology. Most subtypes have mutations of genes relating to myelin maintenance, and pathologically, they show abnormal folding of the myelin structure. PMID:26764296

  2. [Rehabilitation of Charcot-Marie-Tooth Disease].

    PubMed

    Tajima, Fumihiro; Nakamura, Takeshi; Nishimura, Yukihide; Arakawa, Hideki; Kawasaki, Takashi; Ogawa, Takahiro; Nishiyama, Kazunari

    2016-01-01

    Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited neuromuscular diseases causing progressive muscle weakness; contracture; deformity in the feet, legs, and hands; and impairments of ambulation and handgrip. Reduced physical ability can be attributed not only to the disease but also to physical deconditioning. Previously, most physicians in the field of rehabilitation were anxious about the hypothesis of overwork weakness in CMT, and did not conduct intensive exercise programs for patients with CMT. However, recent studies have reported that progressive resistance strengthening programs for lower extremities are feasible, safe, beneficial, and improve exercise intolerance and undue fatigue in patients with CMT. Although the improvement in exercise tolerance may be partly due to the reversal of deconditioning effect of related sedentary lifestyle, progressive resistance training and physical fitness can improve walking function, activities of daily living, and subjective perception of pain and fatigue in patients with CMT. To increase the daily physical function, some studies described the potential benefits of ankle-foot orthoses (AFOs); however, no control study supported it. So far, the training programs on CMT have been dependent on the exercise programs for able-bodied individuals. To increase the effects of rehabilitation, optimal programs that combine the training protocol and AFO strategies will have to be designed for patients with CMT. PMID:26764300

  3. An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients

    ClinicalTrials.gov

    2015-04-28

    Charcot Marie Tooth Disease (CMT); Hereditary Sensory and Motor Neuropathy; Nerve Compression Syndromes; Tooth Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System

  4. Charcot Marie Tooth disease (CMT): historical perspectives and evolution.

    PubMed

    Kazamel, Mohamed; Boes, Christopher J

    2015-01-01

    Prior to Charcot and Marie's and Tooth's reports, patients with peroneal muscular atrophy had been described by Virchow, Eulenburg, Friedreich, Osler, and others. In February 1886, Charcot and Marie published their original description of five patients who had what they called Progressive Muscular Atrophy. They surmised that the lesion could be in the spinal cord. Three months later, Tooth presented his M.D. degree thesis entitled "Peroneal Type of Progressive Muscular Atrophy", to the University of Cambridge, UK. Tooth localized the pathology to the peripheral nerves. Dyck and Lambert (Arch Neurol 18:619-625, 1968) classified several CMT kinships based on differences in modes of inheritance, natural history, biochemical features, nerve conduction velocity, and pathologic characteristics. This article will focus on historical landmarks and major discoveries pertinent to the disease since its original description through the second half of the twentieth century. PMID:25201224

  5. Jean-Martin Charcot at the birth of Russian neurology.

    PubMed

    Vein, Alla A

    2011-01-01

    Russian neurology was virtually nonexistent in the middle of the 19th century which made a traineeship abroad an absolute necessity. Charcot and his school did not just offer professional training, but created the best minds, which would determine the direction of neurology and psychiatry in Russia for many decades. After returning home, young Russian doctors not only implemented everything they had learned in Western Europe, but proceeded to make their own original contributions. The most talented pupils of Charcot, including such prominent names as Kozhevnikov, Korsakov, Minor, Bekhterev and Darkshevich, became the founders of neurological schools in Russia. They laid the basis for the further development of neurology and psychiatry. Remarkably, though trained by the same teachers, each of these future 'founding fathers' of these neurological and psychiatric schools followed his own individual path which resulted in an undeniable diversity in Russian neurology and psychiatry during the period of their formation. PMID:21252555

  6. Charcot neuroarthropathy: An often overlooked complication of diabetes.

    PubMed

    Botek, Georgeanne; Anderson, Martha A; Taylor, Ryan

    2010-09-01

    In patients with long-standing, poorly controlled diabetes and peripheral neuropathy, a red, hot, swollen foot without open ulceration should raise the suspicion of Charcot neuroarthropathy, an often-overlooked diabetic foot complication. The authors discuss key diagnostic features and how to differentiate this condition from cellulitis, osteomyelitis, and other conditions. They review key elements of the workup and emphasize the importance of early diagnosis and prompt treatment to preserve a functioning foot. PMID:20810870

  7. Charcot arthropathy in ultrasound examination – a case report

    PubMed Central

    Nowakowska-Płaza, Anna; Walentowska-Janowicz, Marta; Chojnowski, Marek; Sudoł-Szopińska, Iwona

    2016-01-01

    This article presents a patient with a long history of type 1 diabetes mellitus complicated with neuropathy and Charcot disease. The most common cause of neuropathic osteoarthropathy, called Charcot osteoarthropathy, is poorly controlled diabetes. The clinical picture is characterized by considerable edema, redness and increased skin temperature with relatively slight pain due to injury to nerve fibers responsible for pain sensation. The differential diagnosis should include bacterial or autoimmune arthritis, arthritis associated with gout as well as venous thrombosis and injury. The contribution of a local inflammatory reaction and abnormal bone turnover with excessive osteoclast activity might play a role in the etiopathogenesis of this disease. As a result, osseous and articular destruction progresses rapidly leading to irreversible deformity of the foot. Avoiding weight-bearing and resting the foot in a specially selected plaster cast is the most important part of treatment. Patients with the aforementioned complaints are referred to radiologists for imaging examinations. An ultrasonographer should pay attention to changes typical of Charcot arthropathy, such as: inflammatory and destructive changes in joints of the foot, uneven contour of bones with thickening and periosteal hyperemia as well as soft tissue swelling. PMID:27446605

  8. Charcot arthropathy in ultrasound examination - a case report.

    PubMed

    Płaza, Mateusz; Nowakowska-Płaza, Anna; Walentowska-Janowicz, Marta; Chojnowski, Marek; Sudoł-Szopińska, Iwona

    2016-06-01

    This article presents a patient with a long history of type 1 diabetes mellitus complicated with neuropathy and Charcot disease. The most common cause of neuropathic osteoarthropathy, called Charcot osteoarthropathy, is poorly controlled diabetes. The clinical picture is characterized by considerable edema, redness and increased skin temperature with relatively slight pain due to injury to nerve fibers responsible for pain sensation. The differential diagnosis should include bacterial or autoimmune arthritis, arthritis associated with gout as well as venous thrombosis and injury. The contribution of a local inflammatory reaction and abnormal bone turnover with excessive osteoclast activity might play a role in the etiopathogenesis of this disease. As a result, osseous and articular destruction progresses rapidly leading to irreversible deformity of the foot. Avoiding weight-bearing and resting the foot in a specially selected plaster cast is the most important part of treatment. Patients with the aforementioned complaints are referred to radiologists for imaging examinations. An ultrasonographer should pay attention to changes typical of Charcot arthropathy, such as: inflammatory and destructive changes in joints of the foot, uneven contour of bones with thickening and periosteal hyperemia as well as soft tissue swelling. PMID:27446605

  9. Quality-of-life in Charcot-Marie-Tooth disease: the patient's perspective.

    PubMed

    Johnson, Nicholas E; Heatwole, Chad R; Dilek, Nuran; Sowden, Janet; Kirk, Callyn A; Shereff, Denise; Shy, Michael E; Herrmann, David N

    2014-11-01

    This study determines the impact of symptoms associated with Charcot-Marie-Tooth disease on quality-of-life. Charcot-Marie-Tooth patients in the Inherited Neuropathies Consortium Rare Diseases Clinical Research Network Contact Registry were surveyed. The survey inquired about 214 symptoms and 20 themes previously identified as important to Charcot-Marie-Tooth patients through patient interviews. Symptom population impact was calculated as the prevalence multiplied by the relative importance of each symptom identified. Prevalence and symptom impact were analyzed by age, symptom duration, gender, Charcot-Marie-Tooth type, and employment status. 407 participants returned the survey, identifying foot and ankle weakness (99.7%) and impaired balance (98.6%) as the most prevalent themes. Foot and ankle weakness and limitations with mobility were the themes with the highest impact. Both symptom prevalence and impact gradually increased with age and symptom duration. Several themes were more prevalent in women with Charcot-Marie-Tooth, including activity limitations, pain, fatigue, hip-thigh weakness, and gastrointestinal issues. All of the themes, except emotional or body image issues, were more prevalent among unemployed individuals. There were minimal differences in symptom prevalence between Charcot-Marie-Tooth types. There are multiple symptoms that impact Charcot-Marie-Tooth quality-of-life in adults. These symptoms have different levels of importance, are readily recognized by patients, and represent critical areas of Charcot-Marie-Tooth health. PMID:25092060

  10. Charcot Arthropathy of the Lumbosacral Spine Mimicking a Vertebral Tumor after Spinal Cord Injury

    PubMed Central

    Son, Soo-Bum; Kim, Eun-Sang; Eoh, Whan

    2013-01-01

    Charcot spinal arthropathy is a rare, progressive type of vertebral joint degeneration that occurs in the setting of any preexisting condition characterized by decreased afferent innervation to the extent that normal protective joint sensation in the vertebral column is impaired. The authors report on a case of Charcot arthropathy of the lower lumbar spine mimicking a spinal tumor following cervical cord injury. PMID:24527202

  11. [Jean-Martin Charcot (1825-1893): a physician with multiple facets].

    PubMed

    Lellouch, Alain

    2013-12-01

    This work is registered in the year (2013) commemorating the 120 years since Jean-Martin Charcot's (1825-1893) death. Presently, the event takes place during 2013, in France, in Paris, at Hôpital de la Salpêtrière where Charcot practiced as medical chief of l'Hospice de la Vieillesse-Femmes, from 1862 until he died in 1893. The aim of the research is to show, from various examples and sources (printed and handwritten: fonds d'archives Charcot de la Salpêtrière) how talented Charcot was as a clinician, pathologist and microscopist, researcher and experimenter, teacher, artist, designer, cartoonist, polyglot and traveller), how varied his medical career was and how innovative his scientific method was. All this permitted Charcot to make an impressive number of medical discoveries in various fields which are today known as geriatrics and rheumatology, internal medicine, cardiology, neurology, psychiatry and paranormal processes. PMID:26035927

  12. Diabetic Lisfranc fracture-dislocations and Charcot neuroarthropathy.

    PubMed

    Levitt, Bradley A; Stapleton, John J; Zgonis, Thomas

    2013-04-01

    The goal with Lisfranc fracture-dislocations is to regain joint congruity and reestablish midfoot stability to avoid debilitating posttraumatic arthrosis and chronic pain in the sensate patient. In the diabetic population, dense peripheral neuropathy and/or vascular disease are equally important and may alter the surgical approach to traumatic tarsometatarsal injuries. The initial diagnosis in the diabetic population may be delayed due to subtle radiographic findings and/or patient unawareness of trauma in the insensate foot. Failure to initiate treatment in the early stages of acute diabetic neuropathic Lisfranc injuries can predispose the patient to midfoot instability, potential ulceration, infection, and Charcot neuroarthropathy. PMID:23465814

  13. Diabetic charcot neuroarthropathy of the foot and ankle with osteomyelitis.

    PubMed

    Ramanujam, Crystal L; Stapleton, John J; Zgonis, Thomas

    2014-10-01

    One of the most devastating foot and/or ankle complications in the diabetic population with peripheral neuropathy is the presence of Charcot neuroarthropathy (CN). In recent years, diabetic limb salvage has been attempted more frequently as opposed to major lower extremity amputation for CN of the foot and ankle with ulceration and/or deep infection. Treatment strategies for osteomyelitis in the diabetic population have evolved. This article reviews some of the most common surgical strategies recommended for the diabetic patient with CN of the foot and/or ankle and concomitant osteomyelitis. PMID:25281510

  14. Charcot and Les névroses traumatiques: scientific and historical reflections.

    PubMed

    Micale, M S

    1995-06-01

    Between 1878 and 1893, Jean-Martin Charcot published over twenty detailed case histories dealing with what he termed 'traumatic hysteria' and what today would be labelled the psychoneurology of trauma. Charcot's cases record a highly diverse clinique tableau of symptoms. Etiologically, Charcot posited a dual model of a hereditary diathèse, or constitutional predilection to nervous degeneration, and an environmental agent provocateur. Increasingly during the 1880s, he emphasized the role of 'psychical shock'. These writings of Charcot also exhibit many of the same, superb clinical qualities that distinguish his work on other medical topics. Charcot isolated several hystero-traumatic formations and provided outstanding clinical depictions of subgenres of the disorder, most notably brachial monoplegias. His clinical demonstrations of the differential diagnosis of organic and functional post-traumatic pathologies represent Charcot the virtuoso neurologist at his finest. Taken together, these writings offer a penetrating exploration of the complex and elaborate functional sequelae of minor bodily injury and the phenomenon of traumatic psychogenic somatic symptom-formation. The revival today of medical interest in psycho-traumatic pathology, including the traumatic origins of certain dissociative states, provides an important context for the renewed appreciation of Charcot's work in this area. PMID:11619017

  15. Chapter 15: Jean-Martin Charcot and the anatomo-clinical method of neurology.

    PubMed

    Goetz, Christopher G

    2010-01-01

    Jean-Martin Charcot (1825-1893) was the premier clinical neurologist of the 19th century. Charcot's research was anchored in the anatomo-clinical method, a two-part methodology that linked clinical signs with anatomical lesions. The first step of this method involved the careful documentation of clinical signs with longitudinal observation. At the time of death, the second step involved autopsy examination of the brain and spinal cord. With combined clinical and anatomical data, Charcot was able to suggest concrete clinical-anatomical correlations. This method helped to define the tracts and nuclei responsible for normal and abnormal neurological signs and was pivotal to a new classification of neurological diseases based on anatomy. The best-developed example of this method was Charcot's work with motor system degenerative disorders, specifically amyotrophic lateral sclerosis. These studies led to the international designation of amyotrophic lateral sclerosis as Charcot's disease. Other examples of the fruits of the anatomo-clinical method included several stroke syndromes and the linkage of specific signs to specific lesions in multiple sclerosis. The discipline fostered cortical localization theory, which moved neurologists away from the concept of the brain as a homogenous organ in preference to the concept that brain regions controlled specific motor, sensory and language functions. Charcot's attempts to apply his anatomo-clinical method to the knotty neurological diagnosis of hysteria led him to experiments and conclusions that drew criticism and even scorn from colleagues. These events tarnished Charcot's reputation at the close of his career. In the context of Charcot's extensive discoveries and lasting contributions, the anatomo-clinical method remains the anchor of modern neurological diagnosis and is Charcot's most important contribution to clinical neurology. PMID:19892118

  16. De novo PMP2 mutations in families with type 1 Charcot-Marie-Tooth disease.

    PubMed

    Motley, William W; Palaima, Paulius; Yum, Sabrina W; Gonzalez, Michael A; Tao, Feifei; Wanschitz, Julia V; Strickland, Alleene V; Löscher, Wolfgang N; De Vriendt, Els; Koppi, Stefan; Medne, Livija; Janecke, Andreas R; Jordanova, Albena; Zuchner, Stephan; Scherer, Steven S

    2016-06-01

    We performed whole exome sequencing on a patient with Charcot-Marie-Tooth disease type 1 and identified a de novo mutation in PMP2, the gene that encodes the myelin P2 protein. This mutation (p.Ile52Thr) was passed from the proband to his one affected son, and segregates with clinical and electrophysiological evidence of demyelinating neuropathy. We then screened a cohort of 136 European probands with uncharacterized genetic cause of Charcot-Marie-Tooth disease and identified another family with Charcot-Marie-Tooth disease type 1 that has a mutation affecting an adjacent amino acid (p.Thr51Pro), which segregates with disease. Our genetic and clinical findings in these kindred demonstrate that dominant PMP2 mutations cause Charcot-Marie-Tooth disease type 1. PMID:27009151

  17. Patient Identification of the Symptomatic Impact of Charcot Marie Tooth Disease Type 1A

    PubMed Central

    Johnson, Nicholas E; Heatwole, Chad R.; Ferguson, Michele; Sowden, Janet E.; Jeanat, Shanie; Herrmann, David N.

    2013-01-01

    Objective The burden of Charcot Marie Tooth type 1A, the most common inherited peripheral neuropathy, including impact on patient quality of life is not well understood. This study aims to qualitatively describe the range of symptoms associated with Charcot Marie Tooth type 1A and impact on quality of life. Methods We performed qualitative interviews with 16 adult Charcot Marie Tooth type 1A patients. Each interview was analyzed using a qualitative framework technique to identify and index symptoms by theme. Results Sixteen patients provided 656 quotes. One hundred and forty-five symptoms of importance were identified representing 20 symptomatic themes. Symptoms associated with difficulty with mobility and ambulation, specific activity impairment, and emotional distress were the most frequently mentioned. Conclusions Multiple symptoms contribute to Charcot Marie Tooth type 1A disease burden, some previously under-recognized. Improved recognition of under-recognized symptoms will optimize patient care and quality of life. PMID:23965405

  18. Dens invaginatus (Type III B)

    PubMed Central

    Kallianpur, Shreenivas; Sudheendra, US; Kasetty, Sowmya; Joshi, Prathamesh

    2012-01-01

    Dens invaginatus or ‘dens in dente’ is a developmental malformation of the tooth resulting from infolding of the dental papilla before calcification. This article presents a case of dens invaginatus occurring in maxillary right lateral incisor of a 45-year-old male patient. The patient presented with pain and clinically missing maxillary right canine. The tooth was found to be non-vital. Radiographic examination revealed the tooth-in-tooth appearance of lateral incisor with a dilated pulp chamber. The crown of impacted canine was found within the pulp chamber of lateral incisor. Owing to this unique clinical presentation, both the lateral incisor and the impacted canine were extracted. Histopathologic examination confirmed the diagnosis of Dens invaginatus Type III B. A brief review on etiopathogenesis, radiographic features and treatment of dens invaginatus has also been included. PMID:22923901

  19. Jean-Martin Charcot's role in the 19th century study of music aphasia.

    PubMed

    Johnson, Julene K; Lorch, Marjorie; Nicolas, Serge; Graziano, Amy

    2013-05-01

    Jean-Martin Charcot (1825-93) was a well-known French neurologist. Although he is widely recognized for his discovery of several neurological disorders and his research into aphasia, Charcot's ideas about how the brain processes music are less well known. Charcot discussed the music abilities of several patients in the context of his 'Friday Lessons' on aphasia, which took place at the Salpêtrière Hospital in Paris in 1883-84. In his most comprehensive discussion about music, Charcot described a professional trombone player who developed difficulty copying music notation and playing his instrument, thereby identifying a new isolated syndrome of music agraphia without aphasia. Because the description of this case was published only in Italian by one of his students, Domenico Miliotti, there has been considerable confusion and under-acknowledgement of Charcot's ideas about music and the brain. In this paper, we describe Charcot's ideas regarding music and place them within the historical context of the growing interest in the neurological underpinnings of music abilities that took place in the 1880s. PMID:23576129

  20. Charcot foot in diabetes and an update on imaging.

    PubMed

    Ergen, Fatma Bilge; Sanverdi, Saziye Eser; Oznur, Ali

    2013-01-01

    Charcot neuroarthropathy (CN) is a serious complication of diabetes mellitus that can cause major morbidity including limb amputation. Since it was first described in 1883, and attributed to diabetes mellitus in 1936, the diagnosis of CN has been very challenging even for the experienced practitioners. Imaging plays a central role in the early and accurate diagnosis of CN, and in distinction of CN from osteomyelitis. Conventional radiography, computed tomography, nuclear medicine scintigraphy, magnetic resonance imaging, and positron emission tomography are the imaging techniques currently in use for the evaluation of CN but modalities other than magnetic resonance imaging appeared to be complementary. This study focuses on imaging findings of acute and chronic neuropathic osteoarthropathy in diabetes and discrimination of infected vs. non-infected neuropathic osteoarthropathy. PMID:24273635

  1. Charcot foot in diabetes and an update on imaging

    PubMed Central

    Ergen, Fatma Bilge; Sanverdi, Saziye Eser; Oznur, Ali

    2013-01-01

    Charcot neuroarthropathy (CN) is a serious complication of diabetes mellitus that can cause major morbidity including limb amputation. Since it was first described in 1883, and attributed to diabetes mellitus in 1936, the diagnosis of CN has been very challenging even for the experienced practitioners. Imaging plays a central role in the early and accurate diagnosis of CN, and in distinction of CN from osteomyelitis. Conventional radiography, computed tomography, nuclear medicine scintigraphy, magnetic resonance imaging, and positron emission tomography are the imaging techniques currently in use for the evaluation of CN but modalities other than magnetic resonance imaging appeared to be complementary. This study focuses on imaging findings of acute and chronic neuropathic osteoarthropathy in diabetes and discrimination of infected vs. non-infected neuropathic osteoarthropathy. PMID:24273635

  2. Two New Letters by Denning

    NASA Astrophysics Data System (ADS)

    Beech, Martin

    2010-06-01

    Two letters written by W. F. Denning to R. P. Greg in March and April of 1879 that had been tucked into the folds of an 1876 edition of the British Association for the Advancement of Science Reports were recently found at the Carnegie Institution in Washington D.C. The letters are wonderfully preserved, and offer us a snap-shot of the work being performed by a young Denning at the time when his influence in the field of meteor studies was in its ascendency. The contents of these two letters is analyzed and placed within context to Denning's other publications and private life.

  3. Charcot, la salpêtrière, and hysteria as represented in European literature.

    PubMed

    Koehler, Peter J

    2013-01-01

    In this chapter, I describe the influence of Jean-Martin Charcot (1825-1893), his neurological school at the Salpêtrière (Paris), and his teaching of hysteria on European literature. Many references to Charcot and descriptions of hysterical attacks are found not only in French naturalistic literature but also subsequently in naturalistic novels from other European countries (the Netherlands, Russia, Scandinavian countries, Spain, Italy, and Germany) and furthermore in novels written in new literary movements that followed naturalism. At first, objective descriptions were presented, but in the periods that followed, in particular during the past decades, criticism, rather than objective descriptions, became the motivation for continuing to use Charcot and his teaching of hysteria as inspiration for novels and plays, although Charcot as an admired founder of neurology did not quite disappear, even in recent novels. It is quite impressive to observe how Charcot and his demonstrations of hysterical attacks still resound throughout European literature, even after more than a century. PMID:24290478

  4. Jean-Martin Charcot and his vibratory chair for Parkinson disease.

    PubMed

    Goetz, Christopher G

    2009-08-11

    Vibration therapy is currently used in diverse medical specialties ranging from orthopedics to urology to sports medicine. The celebrated 19th-century neurologist, J.-M. Charcot, used vibratory therapy to treat Parkinson disease (PD). This study analyzed printed writings by Charcot and other writers on vibratory therapy and accessed unpublished notes from the Salpêtrière Hospital, Paris. Charcot lectured on several occasions on vibratory therapy and its neurologic applications. He developed a vibration chair for patients with PD after he observed that patients were more comfortable and slept better after a train or carriage ride. He replicated this experience by having patients undergo daily 30-minute sessions in the automated vibratory chair (fauteuil trépidant). His junior colleague, Gilles de la Tourette, extended these observations and developed a helmet that vibrated the head on the premise that the brain responded directly to the pulsations. Although after Charcot's death vibratory therapy was not widely pursued, vibratory appliances are reemerging in 21st century medicine and can be retested using adaptations of Charcot's neurologic protocols. PMID:19667323

  5. Édouard Brissaud, Fulgence Raymond and the succession of Charcot.

    PubMed

    Tatu, Laurent

    2011-01-01

    At the time of his death in 1893, Jean-Martin Charcot (1825-1893) had reigned supreme over neurology in Paris for some 10 years. The problem of finding a successor was not easy to solve, and it was initially agreed that a temporary replacement should be found. Édouard Brissaud (1852-1909), one of Charcot's students and close associates, was charged with this mission. With the support of some of Charcot's other former students, he held the position of chair for diseases of the nervous system for 1 year. In theory, there were a number of potential successors, but only three were officially declared: Édouard Brissaud, Jules Déjerine (1849-1917) and Fulgence Raymond (1844- 1910). Other students of Charcot such as Pierre Marie (1853-1940), Alix Joffroy (1844-1908), Joseph Babinski (1857-1932) and Georges Gilles de la Tourette (1857-1904) had to withdraw their candidature for various reasons. The election culminated in the appointment of Fulgence Raymond as Charcot's successor. Although such an impossible succession was beyond Raymond, his work in neurology, which is often unrecognised, made him one of the most important neurologists of the early 20th century. PMID:20938146

  6. ACQUIRED PES CAVUS IN CHARCOT-MARIE-TOOTH DISEASE

    PubMed Central

    Carvalho Maranho, Daniel Augusto; Volpon, José Batista

    2015-01-01

    Hereditary motor and sensory neuropathies, especially Charcot-Marie-Tooth disease, are frequently expressed with an acquired cavusvarus foot which is characterized by a fixed increase of the plantar arch and hindfoot inversion. Diagnosis of the underlying condition achieved through careful patient assessment and local evaluations is the keystone for decision-making about the adequate treatment. The cavus may present as an isolated deformity of the forefoot, hindfoot or it may be a combination of both locations. Related deformities, mainly the varus and toe clawing require appropriate evaluation; clinical characteristics such as severity of the deformity, impairment of the muscular power, flexibility and patient's age are important characteristics in the treatment decision. Conservative treatment of the cavusvarus foot with physiotherapy, insoles and shoe modifications are reserved to young patients and mild deformities. However, there is a tendency of the deformity to become more severe over time because of the progressive feature of the underlying neurological condition. So, the surgical treatment by using classical techniques is performed in early stages. Most importantly is the identification of the primary and main components of each deformity to properly correct them, if possible. Muscular transfers are used to treat the dynamic unbalance, retracted structures should be either divided or lengthened and localized osteotomies should be preferred over arthrodeses, which are reserved for stiff and severely deformed feet in adults. PMID:27077056

  7. Modeling protein misfolding in charcot-marie-tooth disease.

    PubMed

    Theocharopoulou, Georgia; Vlamos, Panayiotis

    2015-01-01

    Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder. Recent advancements in molecular biology have elucidated the molecular bases of this genetically heterogeneous neuropathy. Still, the major challenge lies in determining the individual contributions by malfunctions of proteins to the disease's pathology. This paper reviews the identified molecular mechanisms underlying major forms of CMT disease. A growing body of evidence has highlighted the role of protein misfolding in demyelinating peripheral neuropathies and neurodegenerative diseases. Several hypotheses have been proposed to explain how misfolded aggregates induce neuronal damage. Current research focuses on developing novel therapeutic targets which aim to prevent, or even reverse the formation of protein aggregation. Interestingly, the role of the cellular defence mechanisms against accumulation of misfolded proteins may play a key role leading to novel strategies for treatment accelerating the clearance of their toxic early aggregates. Based on these findings we propose a model for describing in terms of a formal computer language, the biomolecular processes involving proteins associated with CMT disease. PMID:25417019

  8. Systematic review of exercise for Charcot-Marie-Tooth disease.

    PubMed

    Sman, Amy D; Hackett, Daniel; Fiatarone Singh, Maria; Fornusek, Ché; Menezes, Manoj P; Burns, Joshua

    2015-12-01

    Charcot-Marie-Tooth disease (CMT) is a slowly progressive hereditary degenerative disease and one of the most common neuromuscular disorders. Exercise may be beneficial to maintain strength and function for people with CMT, however, no comprehensive evaluation of the benefits and risks of exercise have been conducted. A systematic review was completed searching numerous electronic databases from earliest records to February 2015. Studies of any design including participants of any age with confirmed diagnosis of CMT that investigated the effects of exercise were eligible for inclusion. Of 13,301 articles identified following removal of duplicates, 11 articles including 9 unique studies met the criteria. Methodological quality of studies was moderate, sample sizes were small, and interventions and outcome measures used varied widely. Although the majority of the studies identified changes in one or more outcome measurements across exercise modalities, the majority were non-significant, possibly due to Type II errors. Significant effects described included improvements in strength, functional activities, and physiological adaptations following exercise. Despite many studies showing changes in strength and function following exercise, findings of this review should be met with caution due to the few studies available and moderate quality of evidence. Well-powered studies, harmonisation of outcome measures, and clearly described interventions across studies would improve the quality and comparability of the evidence base. The optimal exercise modality and intensity for people with CMT as well as the long-term safety of exercise remain unclear. PMID:26010435

  9. Dominant Charcot-Marie-Tooth syndrome and cognate disorders.

    PubMed

    Pareyson, Davide; Marchesi, Chiara; Salsano, Ettore

    2013-01-01

    Charcot-Marie-Tooth neuropathy (CMT) is a group of genetically heterogeneous disorders sharing a similar phenotype, characterized by wasting and weakness mainly involving the distal muscles of lower and upper limbs, variably associated with distal sensory loss and skeletal deformities. This chapter deals with dominantly transmitted CMT and related disorders, namely hereditary neuropathy with liability to pressure palsies (HNPP) and hereditary neuralgic amyotrophy (HNA). During the last 20 years, several genes have been uncovered associated with CMT and our understanding of the underlying molecular mechanisms has greatly improved. Consequently, a precise genetic diagnosis is now possible in the majority of cases, thus allowing proper genetic counseling. Although, unfortunately, treatment is still unavailable for all types of CMT, several cellular and animal models have been developed and some compounds have proved effective in these models. The first trials with ascorbic acid in CMT type 1A have been completed and, although negative, are providing relevant information on disease course and on how to prepare for future trials. PMID:23931817

  10. The impossible succession of Charcot - the quest for a suitable heir.

    PubMed

    Tatu, Laurent; Bogousslavsky, Julien

    2011-01-01

    With the death of Jean-Martin Charcot (1825-1893) in 1893 came the impossible task of finding a suitable successor. The clinical chair for nervous system diseases was temporarily entrusted to Édouard Brissaud (1852-1909). There were a number of potential successors, but only three were officially declared: Brissaud, Jules Déjerine (1849-1917) and Fulgence Raymond (1844-1910). In the final vote, Raymond was appointed as Charcot's successor. Although this succession would prove too great a challenge for him, Raymond's work in neurology, which is often unrecognised, made him one of the most important French neurologists of the early 20th century. PMID:21412005

  11. Jean-Martin Charcot and art: relationship of the "founder of neurology" with various aspects of art.

    PubMed

    Bogousslavsky, Julien; Boller, François

    2013-01-01

    Jean-Martin Charcot (1825-1893), the "father of neurology" in France and much beyond, was also the man who established academic psychiatry in Paris, differentiating it from clinical alienism. In his teaching, he used artistic representations from previous centuries to illustrate the historical developments of hysteria, mainly with the help of his pupil Paul Richer. Charcot liked to draw portraits (in particular, sketches of colleagues during boring faculty meetings and students' examinations), caricatures of himself and others, church sculptures, landscapes, soldiers, etc. He also used this skill in his clinical and scientific work; he drew histological or anatomic specimens, as well as patients' features and demeanor. His most daring artistic experiments were drawing under the influence of hashish. Charcot's tastes in art were conservative; he displayed no affinity for the avant-gardes of his time, including impressionism, or for contemporary musicians, such as César Franck or Hector Berlioz. Léon Daudet, son of Charcot's former friend and famous writer Alphonse Daudet, described Charcot's home as a pseudo-gothic kitsch accumulation of heteroclite pieces of furniture and materials. However, as Henry Meige wrote a few years after his mentor's death, Charcot the artist remains "inseparable from Charcot the physician." PMID:24041281

  12. Charcot-Marie-Tooth disease and related inherited neuropathies.

    PubMed

    Murakami, T; Garcia, C A; Reiter, L T; Lupski, J R

    1996-09-01

    Charcot-Marie-Tooth disease (CMT) was initially described more than 100 years ago by Charcot, Marie, and Tooth. It was only recently, however, that molecular genetic studies of CMT have uncovered the underlying causes of most forms of the diseases. Most cases of CMT1 are associated with a 1.5-Mb tandem duplication in 17p11.2-p12 that encompasses the PMP22 gene. Although many genes may exist in this large duplicated region, PMP22 appears to be the major dosage-sensitive gene. CMT1A is the first autosomal dominant disease associated with a gene dosage effect due to an inherited DNA rearrangement. There is no mutant gene, but instead the disease phenotype results from having 3 copies of a normal gene. Furthermore, these findings suggest that therapeutic intervention in CMT1A duplication patients may be possible by normalizing the amount of PMP22 mRNA levels. Alternatively, CMT1A can be caused by mutations in the PMP22 gene. Other forms of CMT are associated with mutations in the MPZ (CMT1B) and Cx32 (CMTX) genes. Thus, mutations in different genes can cause similar CMT phenotypes. The related but more severe neuropathy, Dejerine-Sottas syndrome (DSS), can also be caused by mutations in the PMP22 and MPZ genes. All 3 genes thus far identified by CMT researchers appear to play an important role in the myelin formation or maintenance of peripheral nerves. CMT1A, CMT1B, CMTX, hereditary neuropathy with liability to pressure palsies (HNPP), and DSS have been called myelin disorders or "myelino-pathies." Other demyelinating forms, CMT1C and CMT-AR, may be caused by mutations of not yet identified myelin genes expressed in Schwann cells. The clinically distinct disease HNPP is caused by a 1.5-Mb deletion in 17p11.2-p12, which spans the same region duplicated in most CMT1A patients. Underexpression of the PMP22 gene causes HNPP just as overexpression of PMP22 causes CMT1A. Thus, 2 different phenotypes can be caused by dosage variations of the same gene. It is apparent that

  13. Biomarkers research in neuromuscular disease Charcot-Marie-Tooth.

    PubMed

    Seco-Cervera, Marta; Ibañez-Cabellos, Jose Santiago; Garcia-Gimenez, Jose Luis; Espinos, Carmen; Palau, Francesc; Pallardo, Federico V

    2014-10-01

    Charcot-Marie-Tooth disease (CMT) (ORPHA166) is the most frequent hereditary neuropathy. CMT is a heterogeneous group of disorders which, despite some variability in their clinical features, share the same general phenotype, usually characterized by wasting and weakness of distal limb muscles, decreased to absent deep tendon reflexes, distal sensory loss, and frequent skeletal deformities. Despite the clinical and molecular description of this disease in the last 20 years, there is no effective drug or advanced therapy available. Here we have pretend the identification of metabolic and oxidative stress biomarkers in plasmas from patients with duplication at PMP22 gene, the most frequent mutation causing CMT, and clinically characterized as CMT1A. The samples were collected in the neuropathy units from "La Fe" Hospital of Valencia, "Bellvitge" Hospital of Barcelona, "La Paz" Hospital of Madrid, and "Virgen del Rocío" Hospital of Sevilla. The metabolic biomarkers research was performed using 2D-DIGE analysis (Typhoon TRIO, GE) and DeCyder software (GE). Protein identification was made by mass spectrometry by MALDI-TOF-TOF (ABSciex) and liquid Chromatography analysis (ABSciex). The oxidative stress biomarkers research consisted in carbonylated proteins analysis by reaction with DNPH and Dot-blot. Total antioxidant capacity and GSSG/GSH ratio were analyzed with Antioxidant Assay kit (Cayman) and Glutathione Fluorescent detection Kit (Arbor Assays), respectively. Finally now we are performing the MDA levels by HPLC-UV. We found 8, 13 and 36 proteins with differential expression in mild, moderate and severely affected patients, respectively compared with their own matched controls. Also we found differences on oxidative stress parameters between de different groups analyzed. Our results suggest differences in the oxidative stress profile between the studied phenotypes in CMT1A patients. PMID:26461392

  14. Charcot-Marie-Tooth disease and related peripheral neuropathies.

    PubMed

    De Jonghe, P; Timmerman, V; Nelis, E; Martin, J J; Van Broeckhoven, C

    1997-01-01

    Soon after the description of Charcot-Marie-Tooth disease (CMT) in 1886, it became apparent that this syndrome is clinically and genetically heterogeneous. Neuropathological and electrophysiological studies have further dissected this syndrome into distinct categories that are now classified in a complex nosology of the inherited peripheral neuropathies. The recent advent of molecular genetics has dramatically increased our understanding of the underlying disease mechanisms. Genetic linkage studies have identified at least 17 genetic loci for different types of inherited neuropathies although most genes involved still remain to be found. The application of molecular genetics has already had an important impact on clinical practice and genetic counselling. Three genes responsible for hereditary motor and sensory neuropathy type I (HMSNI) or CMT1 have been identified: peripheral myelin protein 22 (PMP22) and myelin protein zero (MPZ) for the autosomal dominant form and connexin 32 (Cx32) for the X-linked dominant variant. The PMP22 gene is also involved in the majority of families with hereditary neuropathy with liability to pressure palsies (HNPP). The observation of a 1.5 Mb tandem duplication in chromosome 17p11.2, containing the PMP22 gene, in CMT1 and the reciprocal deletion in the same region in HNPP has provided a novel disease paradigm for autosomal dominant disorders, i.e. the gene dosage mechanism. The study of phenotype-genotype correlations in transgenic animal models for PMP22, MPZ and Cx32 mutations will help elucidate the underlying disease mechanisms and will provide a basis for gene therapy and/or other therapeutic approaches such as treatment with neurotrophic growth factors. PMID:10975746

  15. SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

    PubMed Central

    Ghezzi, Daniele; Chassagne, Maïté; Mayençon, Martine; Padet, Sylvie; Melchionda, Laura; Rouvet, Isabelle; Lannes, Béatrice; Bozon, Dominique; Latour, Philippe; Zeviani, Massimo; Mousson de Camaret, Bénédicte

    2013-01-01

    Objective: To investigate whether mutations in the SURF1 gene are a cause of Charcot-Marie-Tooth (CMT) disease. Methods: We describe 2 patients from a consanguineous family with demyelinating autosomal recessive CMT disease (CMT4) associated with the homozygous splice site mutation c.107-2A>G in the SURF1 gene, encoding an assembly factor of the mitochondrial respiratory chain complex IV. This observation led us to hypothesize that mutations in SURF1 might be an unrecognized cause of CMT4, and we investigated SURF1 in a total of 40 unrelated patients with CMT4 after exclusion of mutations in known CMT4 genes. The functional impact of c.107-2A>G on splicing, amount of SURF1 protein, and on complex IV activity and assembly was analyzed. Results: Another patient with CMT4 was found to harbor 2 additional SURF1 mutations. All 3 patients with SURF1-associated CMT4 presented with severe childhood-onset neuropathy, motor nerve conduction velocities <25 m/s, and lactic acidosis. Two patients had brain MRI abnormalities, including putaminal and periaqueductal lesions, and developed cerebellar ataxia years after polyneuropathy. The c.107-2A>G mutation produced no normally spliced transcript, leading to SURF1 absence. However, complex IV remained partially functional in muscle and fibroblasts. Conclusions: We found SURF1 mutations in 5% of families (2/41) presenting with CMT4. SURF1 should be systematically screened in patients with childhood-onset severe demyelinating neuropathy and additional features such as lactic acidosis, brain MRI abnormalities, and cerebellar ataxia developing years after polyneuropathy. PMID:24027061

  16. [PREGNANCY AND DELIVERY IN A PATIENT WITH CHARCOT-MARIE-TOOTH DISEASE].

    PubMed

    Pehlivanov, B; Matev, M

    2016-01-01

    We report a case of a 34 years old primigravida with Charcot-Marie-Tooth disease (CMTD). The course of pregnancy was uneventful with no deterioration of symptoms due to the disease. Performed amniocentesis showed healthy fetus. Planned cesarean section with spinal anesthesia was performed because of the restricted pelvis. The possible issues of combination pregnancy and CMTD are discussed. PMID:27514143

  17. Neuromuscular Hip Dysplasia in Charcot-Marie-Tooth Disease Type 1A

    ERIC Educational Resources Information Center

    Bamford, Nigel S.; White, Klane K.; Robinett, Stephanie A.; Otto, Randolph K.; Gospe, Sidney M., Jr.

    2009-01-01

    Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders, affecting 36 in 100,000 people. CMT type 1A (hereditary motor and sensory neuropathy) is the most frequent form of this disease, affecting 60 to 80% of the CMT population, but its diagnosis may be delayed because of inconsistent clinical signs and…

  18. Nerve Excitability Properties in Charcot-Marie-Tooth Disease Type 1A

    ERIC Educational Resources Information Center

    Nodera, Hiroyuki; Bostock, Hugh; Kuwabara, Satoshi; Sakamoto, Takashi; Asanuma, Kotaro; Jia-Ying, Sung; Ogawara, Kazue; Hattori, Naoki; Hirayama, Masaaki; Kaji, Ryuji

    2004-01-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is commonly considered a prototype of a hereditary demyelinating polyneuropathy. Apart from the myelin involvement, there has been little information on axonal membrane properties in this condition. Taking advantage of the uniform nature of the disease process, we undertook the "in vivo" assessment of…

  19. Broca and Charcot's research on Jacques Inaudi: the psychological and anthropological study of a mental calculator.

    PubMed

    Nicolas, Serge; Guida, Alessandro; Levine, Zachary

    2014-01-01

    In the nineteenth century, French scientific institutions became interested in young "mental calculators," arithmetical prodigies able to quickly and accurately perform complex mental calculations. The first scientists to study mental calculators were phrenologists who sought to prove the existence of a calculating organ in the frontal lobe. Paul Broca introduced one such mental calculator, Jacques Inaudi, to the Anthropological Society of Paris in 1880. Broca attributed extraordinary faculty for mental calculation to memory functioning (the psychological hypothesis) rather than physiological difference (the phrenological hypothesis). In 1892, prominent French Academy of Sciences member Jean-Martin Charcot produced a noteworthy study of Inaudi on the organization's behalf. Charcot observed that Inaudi called upon auditory memory rather than visual memory in his mental calculations, unlike most mental calculators who preceded him. Like Broca, Charcot was skeptical of the phrenological hypothesis, though he noted that Inaudi's skull was markedly plagiocephalic. Interestingly, anthropological examination of Inaudi is consistent with the themes of modern cognitive neuroscience. Thus, Charcot seems to have anticipated present research on the localization of mental calculation and memory for numbers. 1. (1)The Academy of Sciences, founded in 1666 by Louis XIV (1638-1715) with the goal of contributing to the advancement and application of the sciences in France, was one of the earliest European scientific institutions. As a prestigious society, it played an active role in defining scientific and technological research policy as well as drafting and publishing official reports. PMID:24697632

  20. Data Mining for Identifying Novel Associations and Temporal Relationships with Charcot Foot

    PubMed Central

    Munson, Michael E.; Wrobel, James S.; Holmes, Crystal M.; Hanauer, David A.

    2014-01-01

    Introduction. Charcot foot is a rare and devastating complication of diabetes. While some risk factors are known, debate continues regarding etiology. Elucidating other associated disorders and their temporal occurrence could lead to a better understanding of its pathogenesis. We applied a large data mining approach to Charcot foot for elucidating novel associations. Methods. We conducted an association analysis using ICD-9 diagnosis codes for every patient in our health system (n = 1.6 million with 41.2 million time-stamped ICD-9 codes). For the current analysis, we focused on the 388 patients with Charcot foot (ICD-9 713.5). Results. We found 710 associations, 676 (95.2%) of which had a P value for the association less than 1.0 × 10−5 and 603 (84.9%) of which had an odds ratio > 5.0. There were 111 (15.6%) associations with a significant temporal relationship (P < 1.0 × 10−3). The three novel associations with the strongest temporal component were cardiac dysrhythmia, pulmonary eosinophilia, and volume depletion disorder. Conclusion. We identified novel associations with Charcot foot in the context of pathogenesis models that include neurotrophic, neurovascular, and microtraumatic factors mediated through inflammatory cytokines. Future work should focus on confirmatory analyses. These novel areas of investigation could lead to prevention or earlier diagnosis. PMID:24868558

  1. MIDFOOT CHARCOT ARTHROPATHY IN DIABETIC PATIENTS: COMPLICATION OF AN EPIDEMIC DISEASE

    PubMed Central

    Ferreira, Ricardo Cardenuto; Gonçalez, Daniel Hidalgo; Filho, João Manoel Fonseca; Costa, Marco Túlio; Santin, Roberto Attilio Lima

    2015-01-01

    Objectives: To outline the epidemiological profile of diabetic patients with Charcot arthropathy affecting the midfoot alone or extending from the midfoot to the hindfoot; To assess the results from the treatment that these patients undergo, according to a preestablished protocol, over the medium term. Methods: We retrospectively evaluated 88 patients (110 extremities) with Charcot arthropathy of the midfoot. The minimum follow-up period was 12 months. We included 45 patients with Charcot arthropathy affecting the tarsal-metatarsal joints (51%); 20 patients in whom the talonavicular, calcaneocuboid and subtalar joints were affected (23%); and 23 patients in whom both the midfoot and hindfoot were affected (26%), as described by Brodsky and Trepman. We defined the treatment as successful when a functional foot was preserved; and unsuccessful when the foot was amputated. Results: From treating Charcot arthropathy primarily involving the midfoot were satisfactory in the cases of 75 patients (85%) treated according to our protocol. For the patients with severe lesions affecting both the midfoot and the hindfoot, a greater number of complex operations (i.e. arthrodesis) were needed in order to obtain the same overall rate of satisfactory results. The osteoarticular lesions originating in the midfoot probably extended progressively to the hindfoot because of delayed diagnosis with inadequate early treatment. Conclusion: It was possible to preserve a functional extremity in 85% of the patients. Severe lesions involving the midfoot and extending to the hindfoot required a greater number of surgical procedures to treat them. PMID:27047875

  2. A case report of Charcot arthropathy caused by syringomyelia and Chiari malformation complicated with scoliosis

    PubMed Central

    2014-01-01

    Background Although Charcot arthropathy, also known as neuropathic arthropathy, of which early diagnosis and treatment is extremely difficult, associated with other cause factor has been widely described, Charcot arthropathy caused by syringomyelia and Chiari malformation complicated with scoliosis has never been described in the literature. Case presentation A 44-year-old male was hospitalized for diagnosis and treatment due to complaining the progressively swelling and limitation of motion in his left shoulder joint for 1 year. The patient has no significant past medical history except for scoliosis 8 years prior to his presentation to our clinic; He denied any constitutional symptoms, trauma, or pain in the upper extremities at this time of presentation. Based on history, physical and auxiliary examination, following diagnoses were made: Charcot arthropathy of the left shoulder, syringomyelia, Chiari malformation and scoliosis. Conclusion Once Charcot arthritis was found, it was mostly in advanced stage and very difficult to treat. So we recommended that if patient suffering from scoliosis visited in clinic, further examination such as magnetic resonance imaging (MRI) and regular follow-up should be carried out, and early-stage of this devastating disease caused by syringomyelia and Chiari malformation may be diagnosed easily. PMID:24886292

  3. Double Dens Invaginatus: Report of Three Cases

    PubMed Central

    Zengin, A. Zeynep; Sumer, A. Pinar; Celenk, Peruze

    2009-01-01

    Dens invaginatus results from an infolding of the outer surface of a tooth. The clinical importance of dens invaginatus results from the risk of pulpal disease. So, all clinicians should be aware of this anomaly. The presence of double dens invaginatus is extremely rare. This article presents three cases of double dens invaginatus in permanent maxillary lateral incisors, one with preventive restoration on its palatal surface. They were classified as double dens invaginatus because of two enamel lined invaginations presented in the crowns of these teeth. PMID:19262734

  4. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.

    PubMed

    Montecchiani, Celeste; Pedace, Lucia; Lo Giudice, Temistocle; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, José L; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; St George-Hyslop, Peter H; Barsottini, Orlando G P; Kawarai, Toshitaka; Orlacchio, Antonio

    2016-01-01

    Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼ 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot

  5. Risk factors of diabetic foot Charcot arthropathy: a case-control study at a Malaysian tertiary care centre

    PubMed Central

    Fauzi, Aishah Ahmad; Chung, Tze Yang; Latif, Lydia Abdul

    2016-01-01

    INTRODUCTION This study aimed to determine the risk factors of diabetic Charcot arthropathy of the foot among diabetic patients with and without foot problems. METHODS This was a case-control study involving diabetic patients attending the Diabetic Foot Care and Wound Management Clinic at University Malaya Medical Centre, Kuala Lumpur, Malaysia, from June 2010 to June 2011. Data on sociodemographic profiles, foot factors and diabetes characteristics was collected and analysed. RESULTS A total of 48 diabetic patients with Charcot arthropathy of the foot were identified. Data from these 48 patients was compared with those of 52 diabetic patients without foot problems. Up to 83.3% of patients with diabetic Charcot arthropathy presented with unilateral Charcot foot, most commonly located at the midfoot (45.8%). Patients with a history of foot problems, including foot ulcer, amputation, surgery or a combination of problems, had the highest (26-time) likelihood of developing Charcot arthropathy (odds ratio 26.4; 95% confidence interval 6.4–109.6). Other significant risk factors included age below 60 years, more than ten years’ duration of diabetes mellitus and the presence of nephropathy. CONCLUSION A history of prior diabetic foot problems is the greatest risk factor for developing diabetic Charcot arthropathy, compared with other risk factors such as diabetes characteristics and sociodemographic profiles. Preventive management of diabetic foot problems in the primary care setting and multidisciplinary care are of paramount importance, especially among chronic diabetic patients. PMID:27075668

  6. Lisfranc fracture-dislocation precipitating acute Charcot arthopathy in a neuropathic diabetic foot: a case report

    PubMed Central

    Yeoh, Joey; Muir, Kenneth Ross; Dissanayake, Ajith Munasinghe; Tzu-Chieh, Wendy Yu

    2008-01-01

    The Lisfranc injury is relatively uncommon yet remains popular in the literature due to its variable causative mechanisms and subtleties in radiographic features despite its potential for disabling long term outcomes if treatment is inadequate, inappropriate or delayed. These injuries are especially pertinent in diabetic patients, especially those with neuropathy, since they are more common, can lead to Charcot neuropathic joint, ulcers and have different causative mechanisms compared to the general population. We describe the case of a neuropathic diabetic patient who presented with a Lisfranc injury which precipitated the development of acute Charcot arthropathy in the right foot. The case serves to illustrate several salient points about the Lisfranc joint and related injuries in diabetic patients. PMID:18973700

  7. Charcot neuroarthropathy in simultaneous kidney–pancreas transplantation: report of two cases

    PubMed Central

    del Vecchio, Jorge Javier; Raimondi, Nicolás; Rivarola, Horacio; Autorino, Carlos

    2013-01-01

    Charcot neuroarthropathy (CN) is considered a major complication in diabetes mellitus (DM), and it is estimated that 1% of diabetic patients may develop this complication. Simultaneous kidney–pancreas transplantation (SKPT) is one of the most effective therapies for patients with type 1 DM and end-stage diabetic nephropathy. Some cases with a Charcot-modified clinical presentation during the postoperative convalescence period after SKPT have been described. The clinical presentation may condition severe destructive lesions, and good practices include systematic follow-up. Based on the cases described, SKPT is one more entity that might lead to CN ‘foot-at-risk’. The aim of this article is to describe two cases of neuropathic arthropathy with rapid progression in the short term after SKPT. PMID:24003361

  8. De Novo duplication in Charcot-Marie-Tooth Type 1A

    SciTech Connect

    Mandich, P.; Bellone, E.; Ajmar, F.

    1996-09-01

    We read with interest the paper on {open_quotes}Prevalence and Origin of De Novo Duplications in Charcot-Marie-Tooth Disease Type 1A: First Report of a De Novo Duplication with a Maternal Origin,{close_quotes}. They reported their experience with 10 sporadic cases of Charcot-Marie-Tooth type 1A (CMT1A) in which it was demonstrated that the disease had arisen as the result of a de novo duplication. They analyzed the de novo-duplication families by using microsatellite markers and identified the parental origin of the duplication in eight cases. In one family the duplication was of maternal origin, whereas in the remaining seven cases it was of paternal origin. The authors concluded that their report was the first evidence of a de novo duplication of maternal origin, suggesting that this is not a phenomenon associated solely with male meiosis. 7 refs.

  9. Intra-Articular Giant Heterotopic Ossification following Total Knee Arthroplasty for Charcot Arthropathy

    PubMed Central

    Tsuge, Shintaro; Aoki, Yasuchika; Sonobe, Masato; Shibata, Yoshifumi; Sasaki, Yu; Nakagawa, Koichi

    2013-01-01

    Although the Charcot arthropathy may be associated with serious complications, total knee arthroplasty (TKA) is the preferred choice of treatment by patients. This case report presents an 80-year-old man with intra-articular giant heterotopic ossification following loosening of femoral and tibial implants and femoral condylar fracture. He had undergone TKA because of Charcot neuropathy seven years ago and had been doing well since. Immediately after a left knee sprain, he became unable to walk. Because he had developed a skin ulcer on his left calf where methicillin-resistant Staphylococcus aureus was detected, we postponed revision surgery until the ulcer was completely healed. While waiting, intra-articular bony fragments grew larger and formed giant heterotopic ossified masses. Eventually, the patient underwent revision surgery, and two major ossified masses were carefully and successfully extirpated. It should be noted that intra-articular heterotopic giant ossification is a significant complication after TKA for neuropathic arthropathy. PMID:24151574

  10. Laparoscopic appendectomy in a pediatric patient with type 1 Charcot-Marie-Tooth disease.

    PubMed

    Heller, Joshua A; Marn, Richard Y

    2015-12-01

    A pediatric patient with type 1 Charcot-Marie-Tooth disease-a disorder associated with a demyelinating polyneuropathy-presented for laparoscopic appendectomy in the setting of acute appendicitis. Induction and maintenance of anesthesia were successfully managed without the use of any depolarizing or nondepolarizing neuromuscular blocking agents. The patient was successfully extubated at the completion of the procedure without any respiratory or neuromuscular sequelae, with excellent pain control and no postoperative nausea or vomiting. PMID:26403061

  11. Overlapping molecular pathological themes link Charcot-Marie-Tooth neuropathies and hereditary spastic paraplegias.

    PubMed

    Timmerman, Vincent; Clowes, Virginia E; Reid, Evan

    2013-08-01

    In this review we focus on Charcot-Marie-Tooth (CMT) neuropathies and hereditary spastic paraplegias (HSPs). Although these diseases differ in whether they primarily affect the peripheral or central nervous system, both are genetically determined, progressive, long axonopathies that affect motor and sensory pathways. This commonality suggests that there might be similarities in the molecular pathology underlying these conditions, and here we compare the molecular genetics and cellular pathology of the two groups. PMID:22285450

  12. Refined genetic mapping of X-linked Charcot-Marie-Tooth neuropathy

    SciTech Connect

    Fain, P.R.; Barker, D.F.; Chance, P.F. )

    1994-02-01

    Genetic linkage studies were conducted in four multigenerational families with X-linked Charcot-Marie-Tooth disease (CMTX), using 12 highly polymorphic short-tandem-repeat markers for the pericentromeric region of the X Chromosome. Pairwise linkage analysis with individual markers confirmed tight linkage of CMTX to the pericentromeric region in each family. Multipoint analyses strongly support the order DXS337-CMTX-DXS441-(DXS56, PGK1). 38 refs., 2 figs., 1 tab.

  13. Conservative and surgical treatment of the chronic Charcot foot and ankle

    PubMed Central

    Güven, Mehmet Fatih; Karabiber, Atakan; Kaynak, Gökhan; Öğüt, Tahir

    2013-01-01

    Charcot neuroarthropathy (CN) is a severe joint disease in the foot and ankle that can result in fracture, permanent deformity, and limb loss. It is a serious and potentially limb-threatening lower-extremity late complication of diabetes mellitus. The aim of this manuscript was to evaluate modern concepts of chronic CN through a review of the available literature and to integrate a perspective of management from the authors’ extensive experience. PMID:23919114

  14. Birth of modern psychiatry and the death of alienism: the legacy of Jean-Martin Charcot.

    PubMed

    Bogousslavsky, Julien; Moulin, Thierry

    2011-01-01

    At the time of Jean-Martin Charcot, Paris--the main center for studies on the nervous system and its disorders--was home to critical exchanges between the developing discipline of neurology and psychiatry. Contrary to the commonly held view, and in spite of an established tradition concerning mental diseases, emerging neurology had a much stronger influence on psychiatry ('alienism') than the reverse. This was largely due to the school built up by Jean-Martin Charcot himself, which was organized around the study and management of hysteria. Although Charcot always claimed to be uninterested in mental medicine, he stimulated the development of an original scientific approach to nervous system conditions, based on Claude Bernard's method, along with structured academic teaching. Conversely, alienism paradoxically remained stuck in organicism, after Antoine Bayle's report in 1822 of 'arachnitis' as the substratum of general paresis of the insane. Contrary to alienism, the young neurological school was capable of self-criticism, and progressively highlighted mental factors in hysteria. This led to the paradox that neurologists were active in a disease with no organic cerebral lesion, while alienists were postulating brain lesions in all mental disorders. Pushed by Charcot, the academic evolution led to the launch of a faculty chair of mental and brain diseases in 1875, which was taken over for nearly half a century by his direct pupils Benjamin Ball, Alix Joffroy and Gilbert Ballet, who held the position until 1916, supporting the development of modern psychiatry in general hospitals, while alienism progressively disappeared at the turn of the century. PMID:20938143

  15. The posteriorly tilted dens. A normal variation mimicking a fractured dens.

    PubMed

    Swischuk, L E; Hayden, C K; Sarwar, M

    1979-02-26

    The normal dens occasionally can be posteriorly tilted and in such cases, can mimic a fractured, posteriorly tilted, dens. Differentiation of the two conditions depends on: [1] knowledge that this normal variation of the dens occurs, and [2] demonstrating that no fracture exists. In many cases, this latter determination can be accomplished on plain films, but in other cases, laminography is required. PMID:431988

  16. Syringomyelia with Chiari I malformation presenting as hip charcot arthropathy: a case report and literature review.

    PubMed

    Memarpour, Roya; Tashtoush, Basheer; Issac, Lydia; Gonzalez-Ibarra, Fernando

    2015-01-01

    Neuroarthropathy (neuropathic osteoarthropathy), also known as Charcot joint, is a condition characterized by a progressive articular surface destruction in the setting of impaired nociceptive and proprioceptive innervation of the involved joint. It is seen most commonly in the foot and ankle secondary to peripheral neuropathy associated with diabetes mellitus. Cases of hip (Charcot) neuroarthropathy are rare and almost exclusively reported in patients with neurosyphilis (tabes dorsalis). We report a case of a 36-year-old man who presented to the emergency department complaining of right hip pain. On physical examination, pain and thermal sensory deficits were noted in the upper torso with a cape-like distribution, as well as signs of an upper motor neuron lesion in the left upper and lower extremities. A magnetic resonance imaging study (MRI) of the right hip showed evidence of early articular surface destruction and periarticular edema consistent with hip Charcot arthropathy. An MRI of the spine revealed an Arnold-Chiari type I malformation with extensive syringohydromyelia of the cervical and thoracic spine. PMID:25692057

  17. Syringomyelia with Chiari I Malformation Presenting as Hip Charcot Arthropathy: A Case Report and Literature Review

    PubMed Central

    Memarpour, Roya; Gonzalez-Ibarra, Fernando

    2015-01-01

    Neuroarthropathy (neuropathic osteoarthropathy), also known as Charcot joint, is a condition characterized by a progressive articular surface destruction in the setting of impaired nociceptive and proprioceptive innervation of the involved joint. It is seen most commonly in the foot and ankle secondary to peripheral neuropathy associated with diabetes mellitus. Cases of hip (Charcot) neuroarthropathy are rare and almost exclusively reported in patients with neurosyphilis (tabes dorsalis). We report a case of a 36-year-old man who presented to the emergency department complaining of right hip pain. On physical examination, pain and thermal sensory deficits were noted in the upper torso with a cape-like distribution, as well as signs of an upper motor neuron lesion in the left upper and lower extremities. A magnetic resonance imaging study (MRI) of the right hip showed evidence of early articular surface destruction and periarticular edema consistent with hip Charcot arthropathy. An MRI of the spine revealed an Arnold-Chiari type I malformation with extensive syringohydromyelia of the cervical and thoracic spine. PMID:25692057

  18. Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.

    PubMed

    Sevilla, Teresa; Lupo, Vincenzo; Martínez-Rubio, Dolores; Sancho, Paula; Sivera, Rafael; Chumillas, María J; García-Romero, Mar; Pascual-Pascual, Samuel I; Muelas, Nuria; Dopazo, Joaquín; Vílchez, Juan J; Palau, Francesc; Espinós, Carmen

    2016-01-01

    Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a

  19. Role of Wnt/β-catenin and RANKL/OPG in bone healing of diabetic Charcot arthropathy patients

    PubMed Central

    Folestad, Agnetha; Ålund, Martin; Asteberg, Susanne; Fowelin, Jesper; Aurell, Ylva; Göthlin, Jan

    2015-01-01

    Background and purpose Charcot neuropathy is characterized by bone destruction in a foot leading to deformity, instability, and risk of amputation. Little is known about the pathogenic mechanisms. We hypothesized that the bone-regulating Wnt/β-catenin and RANKL/OPG pathways have a role in Charcot arthropathy. Patients and methods 24 consecutive Charcot patients were treated by off-loading, and monitored for 2 years by repeated foot radiography, MRI, and circulating levels of sclerostin, dickkopf-1, Wnt inhibitory factor-1, Wnt ligand-1, OPG, and RANKL. 20 neuropathic diabetic controls and 20 healthy controls served as the reference. Results Levels of sclerostin, Dkk-1 and Wnt-1, but not of Wif-1, were significantly lower in Charcot patients than in the diabetic controls at inclusion. Dkk-1 and Wnt-1 levels responded to off-loading by increasing. Sclerostin levels were significantly higher in the diabetic controls than in the other groups whereas Wif-1 levels were significantly higher in the healthy controls than in the other groups. OPG and RANKL levels were significantly higher in the Charcot patients than in the other groups at inclusion, but decreased to the levels in healthy controls at 2 years. OPG/RANKL ratio was balanced in all groups at inclusion, and it remained balanced in Charcot patients on repeated measurement throughout the study. Interpretation High plasma RANKL and OPG levels at diagnosis of Charcot suggest that there is high bone remodeling activity before gradually normalizing after off-loading treatment. The consistently balanced OPG/RANKL ratio in Charcot patients suggests that there is low-key net bone building activity by this pathway following diagnosis and treatment. Inter-group differences at diagnosis and changes in Wnt signaling following off-loading treatment were sufficiently large to be reflected by systemic levels, indicating that this pathway has a role in bone remodeling and bone repair activity in Charcot patients. This is of

  20. About medicine and the arts. Charcot and French literature at the fin-de-siècle.

    PubMed

    Koehler, P

    2001-03-01

    The relationship between medicine and the arts, literature in particular, has many aspects. One of the most obvious relations is the use of literature as a source for historical studies. Jean-Martin Charcot and his school often appear in French literature at the end of the 19th century. Several aspects will be highlighted in this study, including (1) the ideas about degenerative diseases in the work of Emile Zola, the main author of the naturalistic movement; (2) decadence and spiritism in two "transitional" novels by Joris Karl Huysmans, who, once supporter of the naturalistic movement, changed his ideas following observations of disease and cure that could not be explained in a scientific way. Charcot's work on hysteria and hypnosis, as well as Brown-Séquard's rejuvenation experiments with testicular extracts played an important role with this respect; (3) Charcot's relationship with the Daudets, in particular his treatment of Alphonse's tabes dorsalis and the ambivalent attitude of his son Léon Daudet towards Charcot; (4) the influence of the lectures at the Salpêtrière on the work of Guy de Maupassant, who attended the lessons in the mid-1880s. The reading of novels and biographies of these authors provides a part of the social context and the cultural atmosphere in Paris at the "fin-de-siècle" when Charcot and his school played an important role in medicine. Moreover, it shows the influence of medicine and science on society as recorded by writers. PMID:11446262

  1. Inhibition of TNF-α Reverses the Pathological Resorption Pit Profile of Osteoclasts from Patients with Acute Charcot Osteoarthropathy

    PubMed Central

    2015-01-01

    We hypothesised that tumour necrosis factor-α (TNF-α) may enhance receptor activator of nuclear factor-κβ ligand- (RANKL-) mediated osteoclastogenesis in acute Charcot osteoarthropathy. Peripheral blood monocytes were isolated from 10 acute Charcot patients, 8 diabetic patients, and 9 healthy control subjects and cultured in vitro on plastic and bone discs. Osteoclast formation and resorption were assessed after treatment with (1) macrophage-colony stimulating factor (M-CSF) and RANKL and (2) M-CSF, RANKL, and neutralising antibody to TNF-α (anti-TNF-α). Resorption was measured on the surface of bone discs by image analysis and under the surface using surface profilometry. Although osteoclast formation was similar in M-CSF + RANKL-treated cultures between the groups (p > 0.05), there was a significant increase in the area of resorption on the surface (p < 0.01) and under the surface (p < 0.01) in Charcot patients compared with diabetic patients and control subjects. The addition of anti-TNF-α resulted in a significant reduction in the area of resorption on the surface (p < 0.05) and under the surface (p < 0.05) only in Charcot patients as well as a normalisation of the aberrant erosion profile. We conclude that TNF-α modulates RANKL-mediated osteoclastic resorption in vitro in patients with acute Charcot osteoarthropathy. PMID:26137498

  2. Inhibition of TNF-α Reverses the Pathological Resorption Pit Profile of Osteoclasts from Patients with Acute Charcot Osteoarthropathy.

    PubMed

    Petrova, Nina L; Petrov, Peter K; Edmonds, Michael E; Shanahan, Catherine M

    2015-01-01

    We hypothesised that tumour necrosis factor-α (TNF-α) may enhance receptor activator of nuclear factor-κβ ligand- (RANKL-) mediated osteoclastogenesis in acute Charcot osteoarthropathy. Peripheral blood monocytes were isolated from 10 acute Charcot patients, 8 diabetic patients, and 9 healthy control subjects and cultured in vitro on plastic and bone discs. Osteoclast formation and resorption were assessed after treatment with (1) macrophage-colony stimulating factor (M-CSF) and RANKL and (2) M-CSF, RANKL, and neutralising antibody to TNF-α (anti-TNF-α). Resorption was measured on the surface of bone discs by image analysis and under the surface using surface profilometry. Although osteoclast formation was similar in M-CSF + RANKL-treated cultures between the groups (p > 0.05), there was a significant increase in the area of resorption on the surface (p < 0.01) and under the surface (p < 0.01) in Charcot patients compared with diabetic patients and control subjects. The addition of anti-TNF-α resulted in a significant reduction in the area of resorption on the surface (p < 0.05) and under the surface (p < 0.05) only in Charcot patients as well as a normalisation of the aberrant erosion profile. We conclude that TNF-α modulates RANKL-mediated osteoclastic resorption in vitro in patients with acute Charcot osteoarthropathy. PMID:26137498

  3. Denning of grizzly bears in the Yellowstone National Park area

    USGS Publications Warehouse

    Judd, Steven L.; Knight, Richard R.; Blanchard, Bonnie M.

    1986-01-01

    Radiotelemetry was used to locate 101 grizzly bear (Ursus arctos) dens from 1975 to 1980; 35 dens were examined on the ground. Pregnant females denned in late October, and most other bears denned by mid-November. Duration of denning average 113, 132, and 170 days for males, females, and females with new cubs, respectively. Males emerged from mid-February to late March, followed by single females and females with yearlings and 2-year-olds. Females with new cubs emerged from early mid-April. Den sites were associated with moderate tree cover (26%-75% canopy cover) on 30°-60° slopes. Dens occurred on all aspects, although northerly exposures were most common. Grizzly bears usually dug new dens but occasionally used natural cavities or a den from a previous year. Males usually dug larger dens than females with young. Eight excavated and 2 natural dens of the 35 examined dens were used for more than 1 year.

  4. The DenA/DEN1 Interacting Phosphatase DipA Controls Septa Positioning and Phosphorylation-Dependent Stability of Cytoplasmatic DenA/DEN1 during Fungal Development

    PubMed Central

    Schinke, Josua; Kolog Gulko, Miriam; Christmann, Martin; Valerius, Oliver; Stumpf, Sina Kristin; Stirz, Margarita; Braus, Gerhard H.

    2016-01-01

    DenA/DEN1 and the COP9 signalosome (CSN) represent two deneddylases which remove the ubiquitin-like Nedd8 from modified target proteins and are required for distinct fungal developmental programmes. The cellular DenA/DEN1 population is divided into a nuclear and a cytoplasmatic subpopulation which is especially enriched at septa. DenA/DEN1 stability control mechanisms are different for the two cellular subpopulations and depend on different physical interacting proteins and the C-terminal DenA/DEN1 phosphorylation pattern. Nuclear DenA/DEN1 is destabilized during fungal development by five of the eight CSN subunits which target nuclear DenA/DEN1 for degradation. DenA/DEN1 becomes stabilized as a phosphoprotein at S243/S245 during vegetative growth, which is necessary to support further asexual development. After the initial phase of development, the newly identified cytoplasmatic DenA/DEN1 interacting phosphatase DipA and an additional developmental specific C-terminal phosphorylation site at serine S253 destabilize DenA/DEN1. Outside of the nucleus, DipA is co-transported with DenA/DEN1 in the cytoplasm between septa and nuclei. Deletion of dipA resulted in increased DenA/DEN1 stability in a strain which is unresponsive to illumination. The mutant strain is dysregulated in cytokinesis and impaired in asexual development. Our results suggest a dual phosphorylation-dependent DenA/DEN1 stability control with stabilizing and destabilizing modifications and physical interaction partner proteins which function as control points in the nucleus and the cytoplasm. PMID:27010942

  5. Ostectomy and Medial Plantar Artery Flap Reconstruction for Charcot Foot Ulceration Involving the Midfoot.

    PubMed

    Sato, Tomoya; Ichioka, Shigeru

    2016-01-01

    Charcot foot is a serious complication of diabetes, characterized by deformity and overlying ulceration. The condition most commonly affects the midfoot. However, little information is available on the use of a medial plantar artery flap to treat diabetic midfoot ulceration. The purpose of the present study was to evaluate the versatility of ostectomy and medial plantar flap reconstruction for midfoot plantar ulceration associated with rocker-bottom deformity secondary to Charcot foot. Four patients underwent ostectomy and medial plantar flap reconstruction. Before flap reconstruction, the devitalized soft tissues and bone were radically resected. After the infection had been controlled, the ulcerated portion was minimally excised, and the bony prominence underlying the ulcer was removed. A medial plantar artery flap was applied to the ulcer. The donor site was covered with a split-thickness skin graft or artificial dermis. In all patients, the ulcers healed and independent ambulation was achieved. However, 1 patient experienced ulcer recurrence, and subsequent infection necessitated a major amputation. Limb salvage is challenging in the setting of deformity and intractable plantar ulceration. The advantages of medial plantar artery flap reconstruction are that tissues with a rich blood supply are used to cover the exposed bone, and the flap can withstand the pressure and shear stress of the patient's body weight. However, a dominant artery in the foot is sacrificed. Therefore, the patency of the dorsalis pedis artery must be confirmed in every patient. The results of the present study have demonstrated that a medial plantar artery can be an effective alternative for diabetic patients with a plantar ulcer secondary to Charcot foot. PMID:26190780

  6. A novel transgenic mouse model of Chinese Charcot-Marie-Tooth disease type 2L

    PubMed Central

    Zhang, Ruxu; Zhang, Fufeng; Li, Xiaobo; Huang, Shunxiang; Zi, Xiaohong; Liu, Ting; Liu, Sanmei; Li, Xuning; Xia, Kun; Pan, Qian; Tang, Beisha

    2014-01-01

    We previously found that the K141N mutation in heat shock protein B8 (HSPB8) was responsible for Charcot-Marie-Tooth disease type 2L in a large Chinese family. The objective of the present study was to generate a transgenic mouse model bearing the K141N mutation in the human HSPB8 gene, and to determine whether this K141NHSPB8 transgenic mouse model would manifest the clinical phenotype of Charcot-Marie-Tooth disease type 2L, and consequently be suitable for use in studies of disease pathogenesis. Transgenic mice overexpressing K141NHSPB8 were generated using K141N mutant HSPB8 cDNA cloned into a pCAGGS plasmid driven by a human cytomegalovirus expression system. PCR and western blot analysis confirmed integration of the K141NHSPB8 gene and widespread expression in tissues of the transgenic mice. The K141NHSPB8 transgenic mice exhibited decreased muscle strength in the hind limbs and impaired motor coordination, but no obvious sensory disturbance at 6 months of age by behavioral assessment. Electrophysiological analysis showed that the compound motor action potential amplitude in the sciatic nerve was significantly decreased, but motor nerve conduction velocity remained normal at 6 months of age. Pathological analysis of the sciatic nerve showed reduced myelinated fiber density, notable axonal edema and vacuolar degeneration in K141NHSPB8 transgenic mice, suggesting axonal involvement in the peripheral nerve damage in these animals. These findings indicate that the K141NHSPB8 transgenic mouse successfully models Charcot-Marie-Tooth disease type 2L and can be used to study the pathogenesis of the disease. PMID:25206829

  7. An Unusual Presentation of Charcot Arthropathy Caused by Syringomyelia Mimicking a Soft Tissue Tumor

    PubMed Central

    Atalar, Ebru; Ataoglu, Baybars

    2014-01-01

    Charcot arthropathy is a chronic, degenerative condition and is associated with decreased sensorial innervation. Numerous causes of this arthropathy have been described. Here we report a case of neuropathic arthropathy secondary to syringomyelia which was misdiagnosed as a soft tissue tumor and treated surgically and additionally with radiotherapy at another institution. The patient had clinical and radiological signs of syringomyelia, associated with a limited range of motion, swelling, and pain in the affected joint. Neuropathic arthropathy, although less common, should be considered in cases of unexplained joint swelling, pain, and limited range of motion of the affected joint. PMID:25126434

  8. Sport activity in Charcot-Marie-Tooth disease: A case study of a Paralympic swimmer.

    PubMed

    Vita, Giuseppe; La Foresta, Stefania; Russo, Massimo; Vita, Gian Luca; Messina, Sonia; Lunetta, Christian; Mazzeo, Anna

    2016-09-01

    This study reports the positive physical, emotional and psychosocial changes induced by sport activity in a Paralympic swimmer with Charcot-Marie-Tooth (CMT) type 4A. When we compared evaluations before initiating sport activity with those after five years of competitive activity, we found: i) increased proximal muscles strength of upper limbs; ii) augmented ability to propel wheelchair independently; iii) improved quality of life; iv) reduced trait anxiety and striking improvement of depression; v) enhanced self-esteem. Longitudinal studies in large cohorts to evaluate the positive effects of sport activity are needed to support provision of evidence-based advice to patients and families. PMID:27460291

  9. Osteomyelitis or Charcot neuro-osteoarthropathy? Differentiating these disorders in diabetic patients with a foot problem

    PubMed Central

    Ertugrul, Bulent M.; Lipsky, Benjamin A.; Savk, Oner

    2013-01-01

    Both osteomyelitis and Charcot neuro-osteoarthropathy (CN) are potentially limb-threatening complications of diabetic neuropathy, but they require quite different treatments. Almost all bone infections in the diabetic foot originate from an infected foot ulcer while diabetic osteoarthropathy is a non-infectious process in which peripheral neuropathy plays the critical role. Differentiating between diabetic foot osteomyelitis and CN requires careful evaluation of the patient, including the medical history, physical examination, selected laboratory findings, and imaging studies. Based on available studies, we review the approaches to the diagnostic differentiation of osteomyelitis from CN of the foot in diabetic patients. PMID:24205433

  10. Osteomyelitis or Charcot neuro-osteoarthropathy? Differentiating these disorders in diabetic patients with a foot problem.

    PubMed

    Ertugrul, Bulent M; Lipsky, Benjamin A; Savk, Oner

    2013-01-01

    Both osteomyelitis and Charcot neuro-osteoarthropathy (CN) are potentially limb-threatening complications of diabetic neuropathy, but they require quite different treatments. Almost all bone infections in the diabetic foot originate from an infected foot ulcer while diabetic osteoarthropathy is a non-infectious process in which peripheral neuropathy plays the critical role. Differentiating between diabetic foot osteomyelitis and CN requires careful evaluation of the patient, including the medical history, physical examination, selected laboratory findings, and imaging studies. Based on available studies, we review the approaches to the diagnostic differentiation of osteomyelitis from CN of the foot in diabetic patients. PMID:24205433

  11. [Charcot, working and 'Male Hysteria': A new approach to the Leçons du mardi (Tuesday Lessons) from the standpoint of psychodynamics of work].

    PubMed

    Molinier, Pascale

    2015-01-01

    This paper examines the role of work in Charcot's clinical teaching focusing on cases of male hysteria in The Tuesday's Lessons from 1887 to 1889. Today, we read the work of Charcot in a retrospective way as having ended in a failure: He would have missed the discovery of the sexual unconscious. From the perspective of psychodynamics of work, it appears an alternative way which was present in Charcot, though unfinished, opening on a possible development of a relationship between psychic and body. The role of work in traumatic hysteria has been forgotten by Freud's posterity and this obliteration continues today. PMID:27089167

  12. Reconstruction of Lisfranc joint dislocations secondary to Charcot neuroarthropathy using a plantar plate.

    PubMed

    Garchar, Dave; DiDomenico, Lawrence A; Klaue, Kaj

    2013-01-01

    Lisfranc joint dislocation secondary to Charcot arthropathy is a debilitating condition that often leads to ulceration and infection. After conservative treatment, such as bracing and appropriate shoe wear fail, the only option might be amputation. However, we have seen good clinical outcomes from applying a plate to the plantar (tension) side of the medial midfoot. In our retrospective study, 24 consecutive patients (25 feet) from April 1999 through July 2004 underwent Charcot reconstruction for Lisfranc dislocation. Clinical and radiographic follow-up examinations were performed every 3 weeks during the postoperative course. Union was achieved in 24 (96%) of the 25 feet. The average time to ambulation was 11.68 (range 7 to 20) weeks for the 24 patients. The average follow-up period was 38.0 (range 17 to 64) months. The union and interval to ambulation rates showed that a plate applied to the plantar aspect of the medial midfoot provides a strong, sturdy construct for arthrodesis and ambulation. PMID:23621976

  13. Copy Number Variations in a Population-Based Study of Charcot-Marie-Tooth Disease

    PubMed Central

    Høyer, Helle; Braathen, Geir J.; Eek, Anette K.; Nordang, Gry B. N.; Skjelbred, Camilla F.; Russell, Michael B.

    2015-01-01

    Copy number variations (CNVs) are important in relation to diversity and evolution but can sometimes cause disease. The most common genetic cause of the inherited peripheral neuropathy Charcot-Marie-Tooth disease is the PMP22 duplication; otherwise, CNVs have been considered rare. We investigated CNVs in a population-based sample of Charcot-Marie-Tooth (CMT) families. The 81 CMT families had previously been screened for the PMP22 duplication and point mutations in 51 peripheral neuropathy genes, and a genetic cause was identified in 37 CMT families (46%). Index patients from the 44 CMT families with an unknown genetic diagnosis were analysed by whole-genome array comparative genomic hybridization to investigate the entire genome for larger CNVs and multiplex ligation-dependent probe amplification to detect smaller intragenomic CNVs in MFN2 and MPZ. One patient had the pathogenic PMP22 duplication not detected by previous methods. Three patients had potentially pathogenic CNVs in the CNTNAP2, LAMA2, or SEMA5A, that is, genes related to neuromuscular or neurodevelopmental disease. Genotype and phenotype correlation indicated likely pathogenicity for the LAMA2 CNV, whereas the CNTNAP2 and SEMA5A CNVs remained potentially pathogenic. Except the PMP22 duplication, disease causing CNVs are rare but may cause CMT in about 1% (95% CI 0–7%) of the Norwegian CMT families. PMID:25648254

  14. Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q

    SciTech Connect

    Kwon, J.M.; Elliott, J.L.; Yee, W.C.

    1995-10-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited motor and sensory neuropathy. The neuronal form of this disorder is referred to as Charcot-Marie-Tooth type II disease (CMT2). CMT2 is usually inherited as an autosomal dominant trait with a variable age at onset of symptoms associated with progressive axonal neuropathy. In some families, the locus that predisposes to CMT2 has been demonstrated to map to the distal portion of the short arm of chromosome 1. Other families with CMT2 do not show linkage with 1p markers, suggesting genetic heterogeneity in CMT2. We investigated linkage in a single large kindred with autosomal dominant CMT2. The gene responsible for CMT2 in this kindred (CMT2B) was mapped to the interval between the microsatellite markers D3S1769 and D3S1744 in the 3q13-22 region. Study of additional CMT2 kindreds should serve to further refine the disease gene region and may ultimately lead to the identification of a gene defect that underlies the CMT2 phenotype. 21 refs., 3 figs., 1 tab.

  15. The memory of two great mental calculators: Charcot and Binet's neglected 1893 experiments.

    PubMed

    Nicolas, Serge; Gounden, Yannick; Levine, Zachary

    2011-01-01

    French neurologist Jean Martin Charcot (1825-1893) and French psychologist Alfred Binet (1857-1911) are almost unknown as investigators who conducted original and fascinating studies in the area of memory. In a series of 1893 experiments, they compared the performance of two expert mental calculators, Jacques Inaudi and Périclès Diamandi, in tasks that consisted of recalling digits. Inspired by Ribot's psychological work (1881), they believed in the existence of not one type of memory but several partial, special, and local memories, each devoted to a particular domain. In all arithmetical prodigies, memory for digits is abnormally developed compared with other memories. Inaudi was considered to be an auditory memory-based mental calculator; when memorizing digits, he did not rely onthe appearance of the items or create visual imagery of any kind. Rather, he remembered digits principally by their sounds. Inaudi's methods of calculation and memorization were original and different from those used by Diamandi, who was a typical visual memory-based mental calculator. The experiments presented in the 1893 article were among the first scientific demonstrations of the importance to psychology of studying different types of memory. The present work gives a translation of this pioneering experimental article on expert calculators by Charcot and Binet, instructive for the comprehension of normal memory. PMID:21834408

  16. Jean-Martin Charcot's house officers at La Salpêtrière Hospital.

    PubMed

    Walusinski, Olivier

    2011-01-01

    From the time he became chef de service at La Salpêtrière Hospital in 1866 until his death in 1893, Jean-Martin Charcot oversaw 32 house officers. Some of them became famous, such as D.M. Bourneville, E. Brissaud, P. Marie and G. Gilles de la Tourette. Others are less well known. The fact remains that Charcot knew how to surround himself with fine students and leverage their talents in order to make the neurological discoveries by which he would become famous throughout the world. Here, we present the biographies of H. Soulier (1862), J. Cotard (1865), R. Lépine (1867), A. Gombault (1872), A. Pierret (1874), A. Pitres (1876), P. Oulmont (1877), G. Guinon (1885), P. Blocq(1887), E. Huet (1888), E. Parmentier (1890) and A. Souques(1893). Each of these men with their unique paths and interests helped lay the foundations for the birth of neurology at the end of the 19th century in Paris. As Emile Littré said: 'La science de la Médecine, si elle ne veut pas être rabaissée au rang de métier, doit s'occuper de son histoire et soigner les vieux monuments que les temps passés lui ont légués', which could be translated as 'to avoid being reduced to a trade, the science of medicine must attend to its history and take care of the old monuments handed down by time'. PMID:20938144

  17. Novel use of a Dektak 150 surface profiler unmasks differences in resorption pit profiles between control and Charcot patient osteoclasts.

    PubMed

    Petrova, Nina L; Petrov, Peter K; Edmonds, Michael E; Shanahan, Catherine M

    2014-04-01

    We hypothesized that newly formed osteoclasts from patients with acute Charcot osteoarthropathy can resorb surfaces of bone more extensively compared with controls. Peripheral blood monocytes, isolated from eight Charcot patients and nine controls, were cultured in vitro on 24-well plates and bovine bone discs in duplicate with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κβ ligand (RANKL). Osteoclast formation was assessed by tartrate-resistant acid phosphatase staining (TRAcP) at day 17. Resorption was measured at day 21 after toluidine blue staining by two methods: (1) area of resorption at the surface by image analysis (%) and (2) area of resorption under the surface (μm(2)) measured by a Dektak 150 Surface Profiler. Ten 1,000 μm-long scans were performed per disc. Pits were classified as unidented, bidented, and multidented according to their shape. Although the number of newly formed TRAcP positive multinucleated cells (>3 nuclei) was similar in M-CSF + RANKL-treated cultures between controls and Charcot patients, the latter exhibited increased resorbing activity. The area of resorption on the surface by image analysis was significantly greater in Charcot patients compared with controls (21.1 % [14.5-26.2] vs. 40.8 % [35.4-46.0], median [25-75th percentile], p < 0.01), as was the area of resorption under the surface (2.7 x 10(3) μm(2) [1.6 x 10(3)- 3.9 x 10(3)] vs. 8.3 x 10(3) μm (2) [5.6 x 10(3)- 10.6 x 10(3), [corrected] p < 0.01) after profilometry. In Charcot patients pits were deeper and wider and more frequently presented as multidented pits. This application of the Dektak 150 Surface Profiler revealed novel differences in resorption pit profile from osteoclasts derived from Charcot patients compared with controls. Resorption in Charcot patients was mediated by highly aggressive newly formed osteoclasts from monocytes eroding large and deep areas of bone. PMID:24322885

  18. Polar bear maternity denning in the Beaufort Sea

    USGS Publications Warehouse

    Amstrup, S.; Gardner, C.

    1994-01-01

    The distribution of polar bears (Ursus maritimus) is circumpolar in the NOrthern Hemisphere, but known locations of maternal dens are concentrated in relatively few, widely scattered locations. Denning is either uncommon or unknown within gaps. To understand effects of industrial development and propose increases in hunting, the temporal and spatial distribution of denning in the Beaufort Sea must be known. We caputred and radiocollared polar bears between 1981 and 1991 and determined tht denning in the Beaufort Sea region was sufficient to account for the estimated population there. Of 90 dend, 48 were on drifting pack ice, 38 on land, and 4 on land-fast ice. The portions of dens on land was higher (P= 0.029) in later compared with earlier years of the study. Bears denning on pack ice drifting as far as 997 km (x=385km) while in dens. there was no difference in cun production by bears denning on land and pack ice (P =0.66). Mean entry and exit dates were 11 November and 5 April for land dens and 22 November and 26 March for pack-ice dens. Female polar bears captured in the Beaufort Sea appeared to be isolated from those caught eat of Cape Bathurst in Canada. Of 35 polar bears that denned along the mainland coast of Alaska and Canada 80% denned between 137 00'W snf 146 59'W. Bears followed to >1 den did not reuse sites and consecutive dens were 20-1,304 km apart. However radio-collared bears are largely faithful to substrate (pack-ice, land, and land-fast ice) and the general geographic area of previous dens. Bears denning on land may be vunerable to human activities such as hunting and industrial development. However, predictable denning chronology and alck of site fidelity indicate that many potential impacts on denning polar bears could be mitigated.

  19. Dragons' Den: promoting healthcare research and innovation.

    PubMed

    Mazhindu, Deborah; Gregory, Siobhan

    2015-07-01

    The changing health and social care landscape, and, in particular, the financial challenges affecting the NHS, can present difficulties for staff looking for funding to support innovation and new ways of working. One method of competitive tendering that is becoming more accepted as a way of allocating funds, encouraging staff engagement and developing innovation for research is a format based the BBC television series, Dragons' Den. This article describes how Hounslow and Richmond Community Healthcare NHS Trust, London, has developed a 'Dragons' Den initiative' of annual competitive research funding allocation to ensure that some of the most dynamic practice in the trust is captured. PMID:26135194

  20. Critical Limb Ischemia in Association with Charcot Neuroarthropathy: Complex Endovascular Therapy for Limb Salvage

    SciTech Connect

    Palena, Luis Mariano; Brocco, Enrico; Manzi, Marco

    2013-05-09

    Charcot neuroarthropathy is a low-incidence complication of diabetic foot and is associated with ankle and hind foot deformity. Patients who have not developed deep ulcers are managed with offloading and supportive bracing or orthopedic arthrodesis. In patients who have developed ulcers and severe ankle instability and deformity, below-the-knee amputation is often indicated, especially when deformity and cutaneous involvement result in osteomyelitis. Ischemic association has not been described but can be present as a part of peripheral arterial disease in the diabetic population. In this extreme and advanced stage of combined neuroischemic diabetic foot disease, revascularization strategies can support surgical and orthopedic therapy, thus preventing osteomyelitis and leading to limb and foot salvage.

  1. Piet Mondrian's trees and the evolution in understanding multiple sclerosis, Charcot Prize Lecture 2011.

    PubMed

    Steinman, Lawrence; Axtell, Robert C; Barbieri, Donald; Bhat, Roopa; Brownell, Sara E; de Jong, Brigit A; Dunn, Shannon E; Grant, Jacqueline L; Han, May H; Ho, Peggy P; Kuipers, Hedwich F; Kurnellas, Michael P; Ousman, Shalina S; Rothbard, Jonathan B

    2013-01-01

    Four questions were posed about multiple sclerosis (MS) at the 2011 Charcot Lecture, Oct. 22, 2011. 1. The Male/Female Disparity: Why are women developing MS so much more frequently than men? 2. Neuronal and Glial Protection: Are there guardian molecules that protect the nervous system in MS? 3. Predictive Medicine: With all the approved drugs, how can we rationally decide which one to use? 4. The Precise Scalpel vs. the Big Hammer for Therapy: Is antigen-specific therapy for demyelinating disease possible? To emphasize how our views on the pathogenesis and treatment of MS are evolving, and given the location of the talk in Amsterdam, Piet Mondrian's progressive interpretations of trees serve as a heuristic. PMID:23303879

  2. [Acute vincristine neurotoxicity in a non-Hodgkin's lymphoma patient with Charcot-Marie-Tooth disease].

    PubMed

    Uno, S; Katayama, K; Dobashi, N; Hirano, A; Ogihara, A; Yamazaki, H; Usui, N; Kobayashi, T; Inoue, K; Kuraishi, Y

    1999-05-01

    A 44-year-old, previously healthy man with a diagnosis of non-Hodgkin's lymphoma (NHL, diffuse large B-cell type, stage IIA) was treated with combination chemotherapy including vincristine (VCR). After receiving a cumulative dose of VCR, he experienced rapid and marked weakening which progressed to quadriplegia and bulbar palsy. Prior to this therapy, the patient had no neurological problems, and his siblings were asymptomatic. Physical examination identified pes cavus (hollow foot), and electrodiagnostic studies showed markedly slower nerve conduction velocity of myelinated fibers, with abundant "onion bulb" formations. Chromosomal analysis detected 17p11.2-12 duplication, thus yielding a diagnosis of Charcot-Marie-Tooth (CMT) 1A. CMT disease is a familial neuromuscular disorder, and the incidence is approximately 1 in 2,500. We concluded that if CMT disease is diagnosed, vincristine should be avoided due to the potential severity of neurotoxicity to small doses. PMID:10390891

  3. Anesthetic Management of a Patient With Charcot-Marie-Tooth Disease.

    PubMed

    Ohshita, Naohiro; Oka, Saeko; Tsuji, Kaname; Yoshida, Hiroaki; Morita, Shosuke; Momota, Yoshihiro; Tsutsumi, Yasuo M

    2016-01-01

    Charcot-Marie-Tooth disease (CMTD) is a hereditary peripheral neuropathy and is characterized by progressive muscle atrophy and motor-sensory disorders in all 4 limbs. Most reports have indicated that major challenges with general anesthetic administration in CMTD patients are the appropriate use of nondepolarizing muscle relaxants and preparation for malignant hyperthermia in neuromuscular disease. Moderate sedation may be associated with the same complications as those of general anesthesia, as well as dysfunction of the autonomic nervous system, reduced perioperative respiratory function, difficulty in positioning, and sensitivity to intravenous anesthetic agents. We decided to use intravenous sedation in a CMTD patient and administered midazolam initially and propofol continuously, with total doses of 1.5 mg and 300 mg, respectively. Anesthesia was completed in 3 hours and 30 minutes without adverse events. We suggest that dental anesthetic treatment with propofol and midazolam may be effective for patients with CMTD. PMID:27269665

  4. [Therapy for Charcot-Marie-Tooth Disease: From the Standpoint of Neurologists].

    PubMed

    Nakagawa, Masanori

    2016-01-01

    To date, there is no approved pharmacologic treatment for any form of Charcot-Marie-Tooth disease (CMT). However, some clinical or preclinical trials for CMT1A have been undertaken, for example Neurotrophin-3, PXT3003, and neuregulin-1. Gene therapy for CMT1X, CMT2F and Giant axonal neuropathy using animal model or culture cells have been reported with some interesting results. Stem cell research for example iPS cells derived from patients with CMT2A or CMT2E, is being conducted to clarify the mechanism of CMT and find therapeutic clues. The development of new surrogate markers for clinical trials is also needed. Additionally, steps should be taken to improve the quality of life of patients with CMT, including pain control and life style enhancement. PMID:26764298

  5. Charcot-Marie-Tooth 1A concurrent with schwannomas of the spinal cord and median nerve.

    PubMed

    Kwon, Joo Young; Chung, Ki Wha; Park, Eun Kyung; Park, Sun Wha; Choi, Byung-Ok

    2009-08-01

    We identified Charcot-Marie-Tooth disease type 1A (CMT1A) in a family with schwannomas in the spinal cord and median nerve. The CMT1A in this family showed an autosomal dominant pattern, like other CMT patients with PMP22 duplication, and the family also indicated a possible genetic predisposition to schwannomas by 'mother-to-son' transmission. CMT1A is mainly caused by duplication of chromosome 17p11.2-p12 (PMP22 gene duplication). A schwannoma is a benign encapsulated tumor originating from a Schwann cell. A case of hereditary neuropathy with liability to pressure palsies (HNPP) concurrent with schwannoma has been previously reported. Although it seems that the co-occurrence of CMT1A and schwannomas in a family would be the result of independent events, we could not completely ignore the possibility that the coincidence of two diseases might be due to a shared genetic background. PMID:19654968

  6. Acute Charcot foot and diabetes: A primer for the vascular nurse.

    PubMed

    Foley, Anne M

    2016-03-01

    The clinical findings of the acute Charcot process includes a swollen, warm, and erythematous foot; although pain may be present, it is often mild and out of proportion to the clinical examination. The diagnosis is confirmed by radiologic imaging, and the diagnosis must be considered in any patient with diabetic neuropathy and unilateral foot swelling. Initial treatment calls for immediate immobilization of the foot. Failure to do so can lead to further foot damage, destruction, and possibly amputation. The patient with acute CN requires referral to a multidisciplinary team experienced in the care of the diabetic patient with this devastating condition. Patient education is a crucial component of the treatment plan when caring for a client with CN. PMID:26897350

  7. The diagnostic criteria for multiple sclerosis: From Charcot to McDonald.

    PubMed

    Gafson, Arie; Giovannoni, Gavin; Hawkes, Christopher H

    2012-01-01

    The history of diagnostic criteria for multiple sclerosis (MS) from Charcot to McDonald is reviewed. Although the criteria have evolved positively with each revision we think there is still room for improvement. It is proposed that the 2010 revision to the McDonald criteria should be used for research or drug trials and comprise two categories: 'MS' and 'Not MS'. McDonald 2010 could be used optionally for routine clinical purposes. The categories 'probable' and 'possible' are permissible for everyday clinical activity, particularly where there is limited access to MRI, but they would not be appropriate for research or drug trials. Future updates should make it mandatory to perform MRI of the brain, and possibly spinal cord, and the definition of 'an attack' should be revised to include information from physical examination or MRI. Finally, we suggest that certain paroxysmal symptoms (e.g. Lhermitte phenomenon) should be incorporated in any further revision. PMID:25876446

  8. Connexin mutations in X-linked Charcot-Marie-Tooth disease

    SciTech Connect

    Bergoffen, J. ); Scherer, S.S.; Wang, S.; Scott, M.; Bone, L.J.; Chen, K.; Lensch, M.W.; Fischbeck, K.H. ); Paul, D.L. ); Change, P.F. )

    1993-12-24

    X-linked Charcot-Marie-Tooth disease (CMTX) is a form of hereditary neuropathy with demyelination. Recently, this disorder was mapped to chromosome Xq13.1. The gene for the gap junction protein connexin32 is located in the same chromosomal segment, which led to its consideration as a candidate gene for CMTX. With the use of Northern (RNA) blot and immunohistochemistry techniques, it was found that connexin32 is normally expressed in myelinated peripheral nerve. Direct sequencing of the connexin32 gene showed seven different mutations in affected persons from eight CMTX families. These findings, a demonstration of inherited defects in a gap junction protein, suggest that connexin32 plays an important role in peripheral nerve.

  9. A rare presentation of multiple dens invaginatus in maxillary dentition

    PubMed Central

    Purani, Jigar M; Purani, Hiral J

    2014-01-01

    Dens invaginatus is a developmental disturbance of the tooth and usually occurs in the maxillary lateral incisor of permanent dentition. In this article, a rare case of dens invaginatus affecting multiple permanent maxillary teeth is described. PMID:25085944

  10. A neurological bias in the history of hysteria: from the womb to the nervous system and Charcot.

    PubMed

    Mota Gomes, Marleide da; Engelhardt, Eliasz

    2014-12-01

    Hysteria conceptions, from ancient Egypt until the 19th century Parisian hospital based studies, are presented from gynaecological and demonological theories to neurological ones. The hysteria protean behavioral disorders based on nervous origin was proposed at the beginning, mainly in Great Britain, by the "enlightenment nerve doctors". The following personages are highlighted: Galen, William, Sydenham, Cullen, Briquet, and Charcot with his School. Charcot who had hysteria and hypnotism probably as his most important long term work, developed his conceptions, initially, based on the same methodology he applied to studies of other neurological disorder. Some of his associates followed him in his hysteria theories, mainly Paul Richer and Gilles de La Tourette who produced, with the master's support, expressive books on Salpêtrière School view on hysteria. PMID:25517645

  11. A literature-based guide to the conservative and surgical management of the acute Charcot foot and ankle

    PubMed Central

    Schade, Valerie L.; Andersen, Charles A.

    2015-01-01

    Acute Charcot neuroarthropathy of the foot and ankle presents with the insidious onset of a unilateral acutely edematous, erythematous, and warm lower extremity. The acute stages are typically defined as Eichenholtz Stage 1, or Stage 0, which was first described by Shibata et al. in 1990. The ultimate goal of treatment is maintenance of a stable, plantigrade foot which can be easily shod, minimizing the risk of callus, ulceration, infection, and amputation. The gold standard of treatment is non-weight-bearing immobilization in a total contact cast. Surgical intervention remains controversial. A review of the literature was performed to provide an evidenced-based approach to the conservative and surgical management of acute Charcot neuroarthropathy of the foot and ankle. PMID:25795102

  12. Charcot Foot

    MedlinePlus

    ... occur in people who have significant nerve damage (neuropathy). The bones are weakened enough to fracture, and ... patients with diabetes—a disease often associated with neuropathy—take preventive measures and seek immediate care if ...

  13. Marguerite Bottard (1822-1906), nurse under Jean-Martin Charcot, portrayed by G. Gilles de la Tourette.

    PubMed

    Walusinski, Olivier

    2011-01-01

    Hospitals in Paris underwent considerable change at the end of the 19th century. As they moved from providing accommodation to care, their mission shifted from helping to healing. The glorification of scientific progress, as opposed to religious obscurantism, affected all of French 'Republican' society, in particular a significant part of the medical profession, led by figures such as D.M. Bourneville, former interne (house officer) under J.M. Charcot and also his publisher. Bourneville helped bring about the creation of nursing schools and the gradual replacement of religious orders by educated secular nurses. Marguerite Bottard, Charcot's chief nurse made famous by A. Brouillet's painting 'Une leçon clinique à La Salpêtrière', would be glorified and decorated as a model for this movement. A letter by G. Gilles de la Tourette to Charcot's successor F. Raymond, never before published, illustrates this progressive current of thought and revisits the struggle to secularise hospitals under the Third Republic in France. At the same time, it renews interest in the exemplary career of a nurse whose name was recently given to a building at La Salpêtrière Hospital. PMID:21487229

  14. Dens Evaginatus: A Problem-Based Approach

    PubMed Central

    Ayer, A.; Vikram, M.; Suwal, P.

    2015-01-01

    Dens evaginatus is an uncommon developmental anomaly of human dentition characterized by the presence of tubercle on the occlusal surface of mandibular premolars and lingual surface of anterior teeth. Due to occlusal trauma this tubercle tends to fracture thus exposing the pathway to the pulp chamber of teeth. This case report is about the presentation of dens evaginatus in mandibular premolars bilaterally; among them tooth 44 was associated with chronic apical periodontitis. Fractured tubercle of three premolars was sealed with composite resin. Root canal treatment was performed with tooth 44. Routine endodontic treatment did not result in remission of infection. Therefore, culture and sensitivity tests were performed to identify the cause and modify treatment plan accordingly. Triple antibiotic paste was used as an intracanal medicament to disinfect the root canal that resulted in remission of infection. PMID:26779353

  15. Alfred Vulpian and Jean-Martin Charcot in each other's shadow? From Castor and Pollux at La Salpêtrière to neurology forever.

    PubMed

    Bogousslavsky, Julien; Walusinski, Olivier; Moulin, Thierry

    2011-01-01

    While Alfred Vulpian (1826-1887) is not completely forgotten, he cannot match the uninterrupted celebrity which Jean-Martin Charcot (1825-1893) still enjoys today. After becoming interne (residents) at the same institute in 1848, both were involved in shaping the cradle of what would become modern neurology. Both started work as chiefs at a La Salpêtrière service on January 1, 1862, making common rounds and studies, with several common publications. While their friendship remained 'for life', as stated by Charcot at Vulpian's funeral, their career paths differed. Vulpian progressed quicker and higher, being appointed full professor and elected at the Académie Nationale de Médecine and the Académie des Sciences several years before Charcot, as well as becoming dean of the Paris Faculty of Medicine. These positions also enabled him to support his friend Charcot in getting appointed full clinical professor and becoming the first holder of the chair of Clinique des Maladies du Système Nerveux in 1882. Before studying medicine, Vulpian had worked in physiology with Pierre Flourens, and his career always remained balanced between physiology and neurology, with remarkable papers. He introduced Charcot to optic microscopy during their La Salpêtrière years, indirectly helping him to become his successor to the chair of pathological anatomy in 1872. While Vulpian succeeded so well in local medical affairs, Charcot spent his time building up a huge clinical service and a teaching 'school' at La Salpêtrière, which he never left for over 31 years until his death. This 'school' progressively became synonymous with clinical neurology itself and perpetuated the master's memory for decades. Vulpian never had such support, although Jules Déjerine was his pupil and Joseph Babinski was his interne before becoming Charcot's chef de clinique (chief of staff) in 1885. This unusual switch in Parisian medicine contributed to Charcot's unaltered celebrity over more than a century

  16. Respiratory dysfunction in Charcot-Marie-Tooth disease type 1A.

    PubMed

    de Carvalho Alcântara, Mônica; Nogueira-Barbosa, Marcello H; Fernandes, Regina Maria França; da Silva, Geruza Alves; Lourenço, Charles Marques; Sander, Heide H; Marques Junior, Wilson

    2015-05-01

    We aimed to investigate the relationship between neurological compromise, respiratory parameters in wakefulness and in sleep, physiology, and morphology of phrenic nerves in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). Sixteen patients with CMT1A were evaluated by spirometry, maximal expiratory and maximal inspiratory pressures (MEP, MIP), polysomnography, phrenic nerve compound muscle action potential (CMAP), and ultrasonography (roots C3,C4,C5 and phrenic nerves). Clinical disability was measured with Charcot-Marie-Tooth neuropathy score (CMT-NS; range 0-36). Two control groups, comprising 30 individuals matched for age, sex, and body mass index, were used for comparison. Ten patients were female (62%), mean age was 37.88 years (range 24-76); and CMT-NS range was 7-34. MIP was reduced in five (31%) and MEP in 12 patients (75%), although only one had restrictive respiratory dysfunction in spirometry. Apnoea-hypopnea index (AHI) was significantly higher in patients (12.01 ± 11.57/h × 5.89 ± 8.36/h; p value = 0.05) and increased in REM sleep compared with NREM (9.94 ± 10.96/h × 19.13 ± 19.93/h; p value = 0.01). There were significant correlations between CMT-NS and AHI (Pearson = 0.69; p value = 0.03); CMT-NS and MIP (Pearson = -0.691, p value = 0.003); and CMT-NS and MEP (Pearson = -0.603, p value = 0.013). Also, AHI showed negative correlation with MIP (Pearson = -0.52, p value = 0.036) and MEP (Pearson = -0.55, p value = 0.026). Phrenic nerves were enlarged in ultrasonography in all patients and presented significant correlations with CMAPs (right: Pearson = -0.554, p value = 0.026; left: Pearson = -0.558, p value = 0.025). We suggest that axonal degeneration of nerves directed to muscles of respiration might explain the high prevalence of respiratory weakness in patients with CMT1A. Clinical manifestations are frequent during sleep, where the diaphragm alone can only partially surpass the overload in breathing apparatus. PMID:25761374

  17. [Phenotypes of Charcot-Marie-Tooth Syndrome and Differential Diagnosis Focused in Inflammatory Neuropathies].

    PubMed

    Iijima, Masahiro

    2016-01-01

    Charcot-Marie-Tooth disease (CMT), the most frequent form of inherited neuropathy, is a genetically heterogeneous syndrome of the peripheral nervous system with a rather homologous clinical phenotype (slowly progressive distal weakness and muscle atrophy, skeletal deformities, and areflexia in each limb). CMT1 is the autosomal-dominant demyelinating form, and CMT1A (mostly PMP22 duplication) is the most frequent subtype, followed by CMTX1, HNPP (hereditary neuropathy with liability to pressure palsies), CMT1B, or CMT2. As CMT is characterized by slowly progressive motor and sensory disturbances in each limb, it could be misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP) occasionally. Some points can distinguish demyelinating CMT from CIDP. CMT1 patients do not show the conduction block that is frequent in CIDP. In addition, ultrasonographic findings are useful because CMT1 suggests diffuse enlargement of peripheral nerves, whereas CIDP is characterized by asymmetrical or focal enlargement of peripheral nerves. Some CMT1 cases show favorable responses to immunomodulating therapeutics such as corticosteroids, IVIg, and plasma exchange. Such CIDP-like CMT1 (especially CMT1B or CMT2A) shows moderate to high levels of cerebrospinal fluid protein and infiltrated inflammatory macrophages. PMID:26764297

  18. Mutation of SIMPLE in Charcot-Marie-Tooth 1C alters production of exosomes.

    PubMed

    Zhu, Hong; Guariglia, Sara; Yu, Raymond Y L; Li, Wenjing; Brancho, Deborah; Peinado, Hector; Lyden, David; Salzer, James; Bennett, Craig; Chow, Chi-Wing

    2013-06-01

    Charcot-Marie-Tooth (CMT) disease is an inherited neurological disorder. Mutations in the small integral membrane protein of the lysosome/late endosome (SIMPLE) account for the rare autosomal-dominant demyelination in CMT1C patients. Understanding the molecular basis of CMT1C pathogenesis is impeded, in part, by perplexity about the role of SIMPLE, which is expressed in multiple cell types. Here we show that SIMPLE resides within the intraluminal vesicles of multivesicular bodies (MVBs) and inside exosomes, which are nanovesicles secreted extracellularly. Targeting of SIMPLE to exosomes is modulated by positive and negative regulatory motifs. We also find that expression of SIMPLE increases the number of exosomes and secretion of exosome proteins. We engineer a point mutation on the SIMPLE allele and generate a physiological mouse model that expresses CMT1C-mutated SIMPLE at the endogenous level. We find that CMT1C mouse primary embryonic fibroblasts show decreased number of exosomes and reduced secretion of exosome proteins, in part due to improper formation of MVBs. CMT1C patient B cells and CMT1C mouse primary Schwann cells show similar defects. Together the data indicate that SIMPLE regulates the production of exosomes by modulating the formation of MVBs. Dysregulated endosomal trafficking and changes in the landscape of exosome-mediated intercellular communications may place an overwhelming burden on the nervous system and account for CMT1C molecular pathogenesis. PMID:23576546

  19. Characteristics of demyelinating Charcot-Marie-Tooth disease with concurrent diabetes mellitus

    PubMed Central

    Yu, Zhiliang; Wu, Xiaohua; Xie, Huijun; Han, Ying; Guan, Yangtai; Qin, Yong; Zheng, Huimin; Jiang, Jianming; Niu, Zhenmin

    2014-01-01

    Purpose: Charcot-Marie-Tooth disease (CMT) is the most common type of inherited peripheral neuropathy and has a high degree of genetic heterogeneity. CMT with concurrent diabetes mellitus (DM) is rare. The purpose of this study is to explore the genetic, clinical and pathological characteristics of the patients with CMT and concurrent DM. Methods: We investigated gene mutations (the peripheral myelin protein 22 gene, myelin protein zero gene, lipopolysaccharide-induced tumor necrosis factor-α factor gene, early growth response gene and the neurofilament light chain gene loci) of a relatively large and typical Chinese family with CMT1 and concurrent DM2. From the literature, we also retrieved all reported families and single cases with CMT and concurrent DM. We comprehensively analyzed the characteristics of total 33 patients with CMT and concurrent DM, and further compared these characteristics with those of patients of diabetic peripheral neuropathy (DPN). Results: Patients with CMT and concurrent DM had some relatively independent characteristics and pathogenic mechanisms. So we designated that kind of characteristic demyelinating CMT which accompanies DM as Yu-Xie syndrome (YXS), a new specific clinical subtype of CMT. Conclusion: CMT is an etiologic factor of DM, even though the intrinsic association between CMT and DM still remains further exploration. PMID:25120817

  20. Intermittent fasting alleviates the neuropathic phenotype in a mouse model of Charcot-Marie-Tooth disease

    PubMed Central

    Madorsky, Irina; Opalach, Katherine; Waber, Amanda; Verrier, Jonathan D.; Solmo, Chelsea; Foster, Thomas; Dunn, William A; Notterpek, Lucia

    2009-01-01

    Charcot-Marie-Tooth type 1A (CMT1A) neuropathies linked to the misexpression of peripheral myelin protein 22 (PMP22) are progressive demyelinating disorders of the peripheral nervous system. In this study we asked whether dietary restriction by intermittent fasting (IF) could alleviate the neuropathic phenotype in the Trembler J (TrJ) mouse model of CMT1A. Our results show that neuropathic mice kept on a five month long IF regimen had improved locomotor performance compared to ad libitum (AL) fed littermates. The functional benefits of this dietary intervention are associated with an increased expression of myelin proteins combined with a thicker myelin sheath, less redundant basal lamina, and a reduction in aberrant Schwann cell proliferation. These morphological improvements are accompanied by a decrease in PMP22 protein aggregates, and enhanced expression of cytosolic chaperones and constituents of the autophagy-lysosomal pathway. These results indicate that dietary restriction is beneficial for peripheral nerve function in TrJ neuropathic mice, as it promotes the maintenance of locomotor performance. PMID:19320048

  1. A compound heterozygous mutation in HADHB gene causes an axonal Charcot-Marie-tooth disease

    PubMed Central

    2013-01-01

    Background Charcot-Marie-Tooth disease (CMT) is a heterogeneous disorder of the peripheral nervous system. So far, mutations in hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), beta subunit (HADHB) gene exhibit three distinctive phenotypes: severe neonatal presentation with cardiomyopathy, hepatic form with recurrent hypoketotic hypoglycemia, and later-onset axonal sensory neuropathy with episodic myoglobinuria. Methods To identify the causative and characterize clinical features of a Korean family with motor and sensory neuropathies, whole exome study (WES), histopathologic study of distal sural nerve, and lower limb MRIs were performed. Results WES revealed that a compound heterozygous mutation in HADHB is the causative of the present patients. The patients exhibited an early-onset axonal sensorimotor neuropathy without episodic myoglobinuria, and showed typical clinical and electrophysiological features of CMT including predominant distal muscle weakness and atrophy. Histopathologic findings of sural nerve were compatible with an axonal CMT neuropathy. Furthermore, they didn’t exhibit any other symptoms of the previously reported HADHB patients. Conclusions These data implicate that mutation in HADHB gene can also cause early-onset axonal CMT instead of typical manifestations in mitochondrial trifunctional protein (MTP) deficiency. Therefore, this study is the first report of a new subtype of autosomal recessive axonal CMT by a compound heterozygous mutation in HADHB, and will expand the clinical and genetic spectrum of HADHB. PMID:24314034

  2. A pilot study of proximal strength training in Charcot-Marie-Tooth disease.

    PubMed

    Ramdharry, Gita M; Pollard, Alexander; Anderson, Cheryl; Laurá, Matilde; Murphy, Sinead M; Dudziec, Magdalena; Dewar, Elizabeth L; Hutton, Elspeth; Grant, Robert; Reilly, Mary M

    2014-12-01

    Gait analysis of people with Charcot-Marie-Tooth (CMT) disease revealed proximal adaptive gait strategies to compensate for foot drop. We previously demonstrated that hip flexor muscle fatigue can limit walking endurance. This pilot study used a single-blinded cross over design to investigate the effect of a 16-week home-based programme of resistance training on hip flexor muscle strength. Measures of walking endurance, gait speed, exertion, fatigue, and general activity were also recorded. The exercise protocol was based on American College of Sports Medicine recommendations. A mixed effects model was used for analysis. Twenty-six people finished the study, with average reported exercise participation of 93%. No negative effects of exercise were observed. Significant increase in hip flexor muscle strength was observed on the left, but not the right. No changes were observed in walking speed and endurance measures. This pilot study of home-based resistance training showed a modest improvement in hip strength but only on one side. The lack of a more significant improvement and no improvement in walking measures suggests that this training protocol may not be optimal for people with CMT and that patients may need to stratified differently for training studies in CMT. PMID:25582960

  3. Hereditary motor and sensory neuropathies or Charcot-Marie-Tooth diseases: an update.

    PubMed

    Tazir, Meriem; Hamadouche, Tarik; Nouioua, Sonia; Mathis, Stephane; Vallat, Jean-Michel

    2014-12-15

    Hereditary motor and sensory neuropathies (HMSN) or Charcot-Marie-Tooth (CMT) diseases are the most common degenerative disorders of the peripheral nervous system. However, the frequency of the different subtypes varies within distinct populations. Although more than seventy clinical and genetic forms are known to date, more than 80% of CMT patients in Western countries have genetic abnormalities associated with PMP22, MPZ, MFN2 and GJB1. Given the considerable genetic heterogeneity of CMT, we emphasize the interest of both clinical and pathological specific features such that focused genetic testing could be performed. In this regard, peripheral nerve lesions in GDAP1 mutations (AR CMT1A), such as mitochondrial abnormalities, have been newly demonstrated. Otherwise, while demyelinating autosomal recessive CMT used to be classified as CMT4 (A, B, C …), we propose a simplified classification such as AR CMT1 (A, B, C …), and AR CMT2 for axonal forms. Also, we stress that next generation sequencing techniques, now considered to be the most efficient methods of genetic testing in CMT, will be helpful in molecular diagnosis and research of new genes involved. Finally, while no effective therapy is known to date, ongoing new therapeutic trials such as PXT3003 (a low dose combination of the three already approved drugs baclofen, naltrexone, and D-sorbitol) give hopes for potential curative treatment. PMID:25454638

  4. Exacerbation of Charcot-Marie-Tooth type 2E neuropathy following traumatic nerve injury.

    PubMed

    Villalón, Eric; Dale, Jeffrey M; Jones, Maria; Shen, Hailian; Garcia, Michael L

    2015-11-19

    Charcot-Marie-Tooth disease (CMT) is the most commonly inherited peripheral neuropathy. CMT disease signs include distal limb neuropathy, abnormal gait, sensory defects, and deafness. We generated a novel line of CMT2E mice expressing hNF-L(E397K), which displayed muscle atrophy of the lower limbs without denervation, proximal reduction in large caliber axons, and decreased nerve conduction velocity. In this study, we challenged wild type, hNF-L and hNF-L(E397K) mice with crush injury to the sciatic nerve. We analyzed functional recovery by measuring toe spread and analyzed gait using the Catwalk system. hNF-L(E397K) mice demonstrated reduced recovery from nerve injury consistent with increased susceptibility to neuropathy observed in CMT patients. In addition, hNF-L(E397K) developed a permanent reduction in their ability to weight bear, increased mechanical allodynia, and premature gait shift in the injured limb, which led to increasingly disrupted interlimb coordination in hNF-L(E397K). Exacerbation of neuropathy after injury and identification of gait alterations in combination with previously described pathology suggests that hNF-L(E397K) mice recapitulate many of clinical signs associated with CMT2. Therefore, hNF-L(E397K) mice provide a model for determining the efficacy of novel therapies. PMID:26423936

  5. Neural and Molecular Features on Charcot-Marie-Tooth Disease Plasticity and Therapy

    PubMed Central

    Juárez, Paula; Palau, Francesc

    2012-01-01

    In the peripheral nervous system disorders plasticity is related to changes on the axon and Schwann cell biology, and the synaptic formations and connections, which could be also a focus for therapeutic research. Charcot-Marie-Tooth disease (CMT) represents a large group of inherited peripheral neuropathies that involve mainly both motor and sensory nerves and induce muscular atrophy and weakness. Genetic analysis has identified several pathways and molecular mechanisms involving myelin structure and proper nerve myelination, transcriptional regulation, protein turnover, vesicle trafficking, axonal transport and mitochondrial dynamics. These pathogenic mechanisms affect the continuous signaling and dialogue between the Schwann cell and the axon, having as final result the loss of myelin and nerve maintenance; however, some late onset axonal CMT neuropathies are a consequence of Schwann cell specific changes not affecting myelin. Comprehension of molecular pathways involved in Schwann cell-axonal interactions is likely not only to increase the understanding of nerve biology but also to identify the molecular targets and cell pathways to design novel therapeutic approaches for inherited neuropathies but also for most common peripheral neuropathies. These approaches should improve the plasticity of the synaptic connections at the neuromuscular junction and regenerate cell viability based on improving myelin and axon interaction. PMID:22745917

  6. Charcot-Marie-Tooth 1A: A narrative review with clinical and anatomical perspectives.

    PubMed

    McGrath, M C

    2016-07-01

    Charcot-Marie-Tooth 1A (CMT1A) is regarded as the most common hereditary peripheral neurodegenerative disorder. This narrative review highlights perspectives around the historically well-established and characteristic anatomical manifestations of CMT1A seen in the feet, legs and hands, in addition to a clinical diagnosis that may be confirmed by electrophysiology, genetic or molecular markers together with the presence of a typical family history. A less well-known perspective is the potential for systemic manifestations and wider complication. The condition is characterised by a progressive clinical picture with unmistakable anatomical and neurological features that have been described since the late 19th century. There remains no cure although supportive, rehabilitative, and surgical regimes may provide helpful management or amelioration of symptoms. Most recently, the emergence of a pleotherapeutic approach suggests distinct promise. Future research focused on a detailed elucidation of the underlying molecular mechanisms underpinning myelin and axonal function may eventually hold the key to successful treatment of CMT1A. Genetic modification would potentially present a cure. Clin. Anat. 29:547-554, 2016. © 2015 Wiley Periodicals, Inc. PMID:26457477

  7. Charcot neuroarthropathy after simultaneous pancreas-kidney transplantation: risk factors, prevalence, and outcome.

    PubMed

    García Barrado, Fernando; Kuypers, Dirk R; Matricali, Giovanni A

    2015-08-01

    We retrospectively analyzed outcome and risk factors of developing Charcot foot (CF) in 100 patients with type 1 diabetes mellitus who underwent a simultaneous pancreas-kidney (SPK) transplantation. Patients who developed CF after SPK transplantation had significantly higher mortality (56% vs. 18%) and more frequently graft failure (44% vs. 13%). Recipients with CF also experienced acute rejections more frequently (78% vs. 41%). They furthermore had higher pre-transplant values of HbA1c , received cyclosporine and azathioprine more often, and had significantly higher cumulative corticosteroid use. Patients transplanted in an earlier era (1992-1998) received cyclosporine and azathioprine more often and had a significantly higher cumulative corticosteroid use with the higher prevalence of CF. Conversely, patients with diabetes transplanted more recently (1999-2012) received lower doses of corticosteroids as part of their tacrolimus-based immunosuppressive therapy, resulting in fewer CF attacks. In conclusion, development of CF after SPK is associated with poor patient and graft outcome. Poor pre-transplant diabetic control and the use of high-dose corticosteroids are risk factors for the development of CF. We recommend reduction in or even total avoidance of corticosteroids after SPK transplantation. Given the importance of the diagnosis of CF on outcome, a systematic examination of SPK patients' feet is recommended. PMID:26033225

  8. Postural stabilization and balance assessment in Charcot-Marie-Tooth 1A subjects.

    PubMed

    Lencioni, T; Rabuffetti, M; Piscosquito, G; Pareyson, D; Aiello, A; Di Sipio, E; Padua, L; Stra, F; Ferrarin, M

    2014-09-01

    The aim of the present study was to assess postural stabilization skill in adult subjects affected by Charcot-Marie-Tooth disease (CMT) type 1A. For this purpose ground reaction force (GRF) was measured by means of a piezoelectric force platform during the sit-to-stand (STS) movement, until a steady state erect posture was achieved. Specific indexes to quantify Centre of Mass acceleration, both during postural stabilization and during quiet standing, were computed using a mathematical model. Forty-seven CMT1A subjects were recruited for the study, and the control group was formed by forty-one age- and sex-matched healthy subjects. The results show that CMT1A subjects are less stable than controls during the quiet stance. Greater difficulty (high values of Yinf, the final instability rate) to maintain erect posture appears to be mainly associated with plantar-flexor muscle weakness, rather than to damage of the proprioceptive system. The worst performances shown by CMT1A subjects in the stabilization phase (high values of I, the global index of postural stabilization performance) seem to be associated with reduced muscle strength and the loss of large sensory nerve fibres. Distal muscle weakness appears to affect both postural stabilization and quiet erect posture. The presented protocol and the analysis of postural stabilization parameters provide useful information on CMT1A balance disorders. PMID:25082324

  9. Coexistence of Charcot-Marie-Tooth disease type 1A and anti-MAG neuropathy.

    PubMed

    Piscosquito, Giuseppe; Salsano, Ettore; Ciano, Claudia; Palamara, Luisa; Morbin, Michela; Pareyson, Davide

    2013-06-01

    At age 35, a man with a genetic diagnosis of Charcot-Marie-Tooth disease type 1A (CMT1A) but no family history of neuropathy and no clinical symptoms developed rapidly progressive loss of balance, distal limb numbness, loss of manual dexterity, and hand tremor. Five years later, he walked with support and had mild pes cavus, marked sensory ataxia, severe leg and hand weakness, absent deep tendon reflexes (DTRs), severe sensory loss, and hand tremor. He had dramatically reduced motor nerve conduction velocity (MNCV), strikingly prolonged motor distal latencies, absent sensory action potentials and lower limb compound muscle action potentials. CMT1A duplication was reconfirmed but the dramatic change in his clinical course suggested a superimposed acquired neuropathy. An IgM-kappa monoclonal gammopathy of uncertain significance (MGUS) with high titer anti-myelin associated glycoprotein (anti-MAG) activity was found. Nerve biopsy showed severe loss of myelinated fibers with onion bulbs, no evidence of uncompacted myelin, and few IgM deposits. Rituximab was given and he improved. It is very likely that this is a chance association of two rare and slowly progressive neuropathies; rapidly worsening course may have been due to a "double hit". Interestingly, there are reports of possible superimposition of dysimmune neuropathies on hereditary ones, and the influence of the immune system on inherited neuropathies is matter for debate. PMID:23781967

  10. A brief review of recent Charcot-Marie-Tooth research and priorities

    PubMed Central

    Ekins, Sean; Litterman, Nadia K.; Arnold, Renée J.G.; Burgess, Robert W.; Freundlich, Joel S.; Gray, Steven J.; Higgins, Joseph J.; Langley, Brett; Willis, Dianna E.; Notterpek, Lucia; Pleasure, David; Sereda, Michael W.; Moore, Allison

    2015-01-01

    This brief review of current research progress on Charcot-Marie-Tooth (CMT) disease is a summary of discussions initiated at the Hereditary Neuropathy Foundation (HNF) scientific advisory board meeting on November 7, 2014. It covers recent published and unpublished in vitro and in vivo research. We discuss recent promising preclinical work for CMT1A, the development of new biomarkers, the characterization of different animal models, and the analysis of the frequency of gene mutations in patients with CMT. We also describe how progress in related fields may benefit CMT therapeutic development, including the potential of gene therapy and stem cell research. We also discuss the potential to assess and improve the quality of life of CMT patients. This summary of CMT research identifies some of the gaps which may have an impact on upcoming clinical trials. We provide some priorities for CMT research and areas which HNF can support. The goal of this review is to inform the scientific community about ongoing research and to avoid unnecessary overlap, while also highlighting areas ripe for further investigation. The general collaborative approach we have taken may be useful for other rare neurological diseases. PMID:25901280

  11. Charcot-Marie-Tooth (CMT) disease 1A with superimposed inflammatory polyneuropathy in children.

    PubMed

    Desurkar, A; Lin, J-P; Mills, K; Al-Sarraj, S; Jan, W; Jungbluth, H; Wraige, E

    2009-04-01

    Charcot-Marie-Tooth (CMT) disease is genetically heterogeneous and subdivided into demyelinating (CMT 1) and axonal (CMT 2) types based on neurophysiology findings. CMT1A, the commonest form associated with duplication of the PMP22 segment on chromosome 17p, often arises in childhood but is generally a slowly progressive disease. We report 2 children presenting with clinical features of an acute inflammatory demyelinating polyneuropathy (AIDP) who were subsequently diagnosed with underlying CMT1A. Both children had neurophysiology and histopathology features consistent with CMT1. Immunoglobulin treatment was initiated considering the evidence of superimposed inflammation and appeared to modify disease progression. Our findings indicate that CMT1A predisposes to a superimposed inflammatory neuropathy. Recognition of this association is difficult, particularly in children without clear family history, but of great importance as immunomodulatory treatment may improve outcome. In addition, we postulate that an underlying genetic polyneuropathy should be suspected if the recovery from AIDP is slower than expected, or incomplete. PMID:19809938

  12. Charcot-Marie-Tooth disease: frequency of genetic subtypes in a Southern Italy population.

    PubMed

    Manganelli, Fiore; Tozza, Stefano; Pisciotta, Chiara; Bellone, Emilia; Iodice, Rosa; Nolano, Maria; Geroldi, Alessandro; Capponi, Simona; Mandich, Paola; Santoro, Lucio

    2014-12-01

    The objective of this study is to assess the genetic distribution of Charcot-Marie-Tooth (CMT) disease in Campania, a region of Southern Italy. We analyzed a cohort of 197 index cases and reported the type and frequency of mutations for the whole CMT population and for each electrophysiological group (CMT1, CMT2, and hereditary neuropathy with susceptibility to pressure palsies [HNPP]) and for familial and isolated CMT cases. Genetic diagnosis was achieved in 148 patients (75.1%) with a higher success rate in HNPP and CMT1 than CMT2. Only four genes (PMP22, GJB1, MPZ, and GDAP1) accounted for 92% of all genetically confirmed CMT cases. In CMT1, PMP22 duplication was the most common mutation while the second gene in order of frequency was MPZ in familial and SH3TC2 in isolated cases. In CMT2, GJB1 was the most frequent mutated gene and GJB1 with GDAP1 accounted for almost 3/4 of genetically defined CMT2 patients. The first gene in order of frequency was GJB1 in familial and GDAP1 in isolated cases. In HNPP, the majority of patients harbored the PMP22 gene deletion. The novelty of our data is the relatively high frequency of SH3TC2 and GDAP1 mutations in demyelinating and axonal forms, respectively. These epidemiological data can help in panel design for our patients' population. PMID:25429913

  13. Genetic Diagnosis of Charcot-Marie-Tooth Disease in a Population by Next-Generation Sequencing

    PubMed Central

    Høyer, Helle; Braathen, Geir J.; Busk, Øyvind L.; Holla, Øystein L.; Svendsen, Marit; Hilmarsen, Hilde T.; Strand, Linda; Skjelbred, Camilla F.; Russell, Michael B.

    2014-01-01

    Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited neuropathy. Today more than 40 CMT genes have been identified. Diagnosing heterogeneous diseases by conventional Sanger sequencing is time consuming and expensive. Thus, more efficient and less costly methods are needed in clinical diagnostics. We included a population based sample of 81 CMT families. Gene mutations had previously been identified in 22 families; the remaining 59 families were analysed by next-generation sequencing. Thirty-two CMT genes and 19 genes causing other inherited neuropathies were included in a custom panel. Variants were classified into five pathogenicity classes by genotype-phenotype correlations and bioinformatics tools. Gene mutations, classified certainly or likely pathogenic, were identified in 37 (46%) of the 81 families. Point mutations in known CMT genes were identified in 21 families (26%), whereas four families (5%) had point mutations in other neuropathy genes, ARHGEF10, POLG, SETX, and SOD1. Eleven families (14%) carried the PMP22 duplication and one family carried a MPZ duplication (1%). Most mutations were identified not only in known CMT genes but also in other neuropathy genes, emphasising that genetic analysis should not be restricted to CMT genes only. Next-generation sequencing is a cost-effective tool in diagnosis of CMT improving diagnostic precision and time efficiency. PMID:25025039

  14. Perk Ablation Ameliorates Myelination in S63del-Charcot-Marie-Tooth 1B Neuropathy.

    PubMed

    Musner, Nicolò; Sidoli, Mariapaola; Zambroni, Desireè; Del Carro, Ubaldo; Ungaro, Daniela; D'Antonio, Maurizio; Feltri, Maria L; Wrabetz, Lawrence

    2016-04-01

    In peripheral nerves, P0 glycoprotein accounts for more than 20% of myelin protein content. P0 is synthesized by Schwann cells, processed in the endoplasmic reticulum (ER) and enters the secretory pathway. However, the mutant P0 with S63 deleted (P0S63del) accumulates in the ER lumen and induces a demyelinating neuropathy in Charcot-Marie-Tooth disease type 1B (CMT1B)-S63del mice. Accumulation of P0S63del in the ER triggers a persistent unfolded protein response. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is an ER stress sensor that phosphorylates eukaryotic initiation factor 2 alpha (eIF2alpha) in order to attenuate protein synthesis. We have shown that increasing phosphophorylated-eIF2alpha (P-eIF2alpha) is a potent therapeutic strategy, improving myelination and motor function in S63del mice. Here, we explore the converse experiment:Perkhaploinsufficiency reduces P-eIF2alpha in S63del nerves as expected, but surprisingly, ameliorates, rather than worsens S63del neuropathy. Motor performance and myelin abnormalities improved in S63del//Perk+/- compared with S63del mice. These data suggest that mechanisms other than protein translation might be involved in CMT1B/S63del neuropathy. In addition,Perkdeficiency in other cells may contribute to demyelination in a non-Schwann-cell autonomous manner. PMID:27095827

  15. Myelin protein zero gene mutated in Charcot-Marie-Tooth type 1B patients

    SciTech Connect

    Su, Ying; Li, Lanying; Lepercq, J.; Lebo, R.V. ); Brooks, D.G.; Ravetch, J.V. ); Trofatter, J.A. )

    1993-11-15

    The autosomal dominant of Charcot-Marie-Tooth disease (CMT), whose gene is type 1B (CMT1B), has slow nerve conduction with demyelinated Schwann cells. In this study the abundant peripheral myelin protein zero (MPZ) gene, MPZ, was mapped 130 kb centromeric to the Fc receptor immunoglobulin gene cluster in band 1q22, and a major MPZ point mutation was found to cosegregate with CMT1B in one large CMT1B family. The MPZ point mutation in 18 of 18 related CMT1B pedigree 1 patients converts a positively charged lysine in codon 96 to a negatively charged glutamate. The same MPZ locus cosegregates with the CMT1B disease gene in a second CMT1B family [total multipoint logarithm of odds (lod) = 11.4 at [theta] = 0.00] with a splice junction mutation. Both mutations occur in MPZ protein regions otherwise conserved identically in human, rat, and cow since these species diverged 100 million years ago. MPZ protein, expressed exclusively in myelinated peripheral nerve Schwann cells, constitutes >50% of myelin protein. These mutations are anticipated to disrupt homophilic MPZ binding and result in CMT1B peripheral nerve demyelination.

  16. Oral Health, Temporomandibular Disorder, and Masticatory Performance in Patients with Charcot-Marie-Tooth Type 2

    PubMed Central

    Rezende, Rejane L. S.; Bonjardim, Leonardo R.; Neves, Eduardo L. A.; Santos, Lidiane C. L.; Nunes, Paula S.; Garcez, Catarina A.; Souza, Cynthia C.; Araújo, Adriano A. S.

    2013-01-01

    Background. The aim of this study was to evaluate the oral health status of temporomandibular disorders (TMD) and bruxism, as well as to measure masticatory performance of subjects with Charcot-Marie-Tooth type 2 (CMT2). Methods and Results. The average number of decayed, missing, and filled teeth (DMFT) for both groups, control (CG) and CMT2, was considered low (CG = 2.46; CMT2 = 1.85, P = 0.227). The OHIP-14 score was considered low (CG = 2.86, CMT2 = 5.83, P = 0.899). The prevalence of self-reported TMD was 33.3% and 38.9% (P = 0.718) in CG and CMT2 respectively and for self-reported bruxism was 4.8% (CG) and 22.2% (CMT2), without significant difference between groups (P = 0.162). The most common clinical sign of TMD was masseter (CG = 38.1%; CMT2 = 66.7%) and temporalis (CG = 19.0%; GCMT2 = 33.3%) muscle pain. The geometric mean diameter (GMD) was not significantly different between groups (CG = 4369; CMT2 = 4627, P = 0.157). Conclusion. We conclude that the CMT2 disease did not negatively have influence either on oral health status in the presence and severity of TMD and bruxism or on masticatory performance. PMID:24391462

  17. Charcot Neuroarthropathy in Patients With Diabetes: An Updated Systematic Review of Surgical Management.

    PubMed

    Schneekloth, Brian J; Lowery, Nicholas J; Wukich, Dane K

    2016-01-01

    Charcot neuroarthropathy (CN) of the foot and ankle is a demanding clinical dilemma, and surgical management can be very complicated. Historically, the evidence guiding surgical management of CN has been small retrospective case series and expert opinions. The purpose of the present report was to provide a systematic review of studies published from 2009 to 2014 and to review the indications for surgery. A Medline search was performed, and a systematic review of studies discussing the surgical management of CN was undertaken. Thirty reports fit the inclusion criteria for our study, including 860 patients who had undergone a surgical procedure for the treatment of CN. The surgical procedures included amputation, arthrodesis, debridement of ulcers, drainage of infections, and exostectomy. The midfoot was addressed in 26.9% of cases, the hindfoot in 41.6%, and the ankle in 38.4%. Of the 30 studies, 24 were retrospective case series (level 4), 4 were controlled retrospective studies (level 3), and 2 were level II studies. The overall amputation rate was 8.9%. The quality of the published data on the surgical management of CN has improved during the past several years. Evidence concerning the timing of treatment and the use of different fixation methods remains inconclusive. PMID:26810129

  18. Severe phenotypes in a Charcot-Marie-Tooth 1A patient with PMP22 triplication.

    PubMed

    Kim, Sung Min; Lee, Jinho; Yoon, Bo Ram; Kim, Ye Jin; Choi, Byung-Ok; Chung, Ki Wha

    2015-02-01

    Charcot-Marie-Tooth disease (CMT) is a genetically and clinically heterogeneous hereditary motor and sensory neuropathy signified by a distal symmetric polyneuropathy. The most frequent subtype is type 1A (CMT1A) caused by duplication in chromosome 17p12 that includes PMP22. This study reports a woman with a family history of CMT1A due to PMP22 duplication. However, she presented with a more severe phenotype than her sibling or ancestors and was found to have a PMP22 triplication instead of the duplication. This was caused by de novo mutation on her affected mother's duplication chromosome. Her lower limb magnetic resonance imaging revealed severe diffused atrophy and fatty replacement. However, her affected sister with typical PMP22 duplication showed almost intact lower limb. Triplication patient's median motor nerve conduction velocity was far lower compared with her sister. Her onset age was faster (8 years) than her sister (42 years). CMT1A triplication might be generated by a female-specific chromosomal rearrangement mechanism that is different from the frequent paternal-originated CMT1A duplication. It also suggests that the wide phenotypic variation of CMT1A might be partly caused by unstable genomic rearrangement, including PMP22 triplication. PMID:25500726

  19. Cerebral involvement in axonal Charcot-Marie-Tooth neuropathy caused by mitofusin2 mutations.

    PubMed

    Brockmann, Knut; Dreha-Kulaczewski, Steffi; Dechent, Peter; Bönnemann, Carsten; Helms, Gunther; Kyllerman, Marten; Brück, Wolfgang; Frahm, Jens; Huehne, Kathrin; Gärtner, Jutta; Rautenstrauss, Bernd

    2008-07-01

    Mutations in the mitofusin 2 (MFN2) gene are a major cause of primary axonal Charcot- Marie-Tooth (CMT) neuropathy. This study aims at further characterization of cerebral white matter alterations observed in patients with MFN2 mutations. Molecular genetic, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) investigations were performed in four unrelated patients aged 7 to 38 years with early onset axonal CMT neuropathy. Three distinct and so far undescribed MFN2 mutations were detected. Two patients had secondary macrocephaly and mild diffuse predominantly periventricular white matter alterations on MRI. In addition, one boy had symmetrical T2-hyperintensities in both thalami. Two patients had optic atrophy, one of them with normal MRI. In three patients proton MRS revealed elevated concentrations of total N-acetyl compounds (neuronal marker), total creatine (found in all cells) and myo-inositol (astrocytic marker) in cerebral white and gray matter though with regional variation. These alterations were most pronounced in the two patients with abnormal MRI. DTI of these patients revealed mild reductions of fractional anisotropy and mild increase of mean diffusivity in white matter. The present findings indicate an enhanced cellular density in cerebral white matter of MFN2 neuropathy which is primarily due to a reactive gliosis without axonal damage and possibly accompanied by mild demyelination. PMID:18425620

  20. Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2.

    PubMed

    Cottenie, Ellen; Kochanski, Andrzej; Jordanova, Albena; Bansagi, Boglarka; Zimon, Magdalena; Horga, Alejandro; Jaunmuktane, Zane; Saveri, Paola; Rasic, Vedrana Milic; Baets, Jonathan; Bartsakoulia, Marina; Ploski, Rafal; Teterycz, Pawel; Nikolic, Milos; Quinlivan, Ros; Laura, Matilde; Sweeney, Mary G; Taroni, Franco; Lunn, Michael P; Moroni, Isabella; Gonzalez, Michael; Hanna, Michael G; Bettencourt, Conceicao; Chabrol, Elodie; Franke, Andre; von Au, Katja; Schilhabel, Markus; Kabzińska, Dagmara; Hausmanowa-Petrusewicz, Irena; Brandner, Sebastian; Lim, Siew Choo; Song, Haiwei; Choi, Byung-Ok; Horvath, Rita; Chung, Ki-Wha; Zuchner, Stephan; Pareyson, Davide; Harms, Matthew; Reilly, Mary M; Houlden, Henry

    2014-11-01

    Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels. PMID:25439726

  1. Behavioural profiling of a murine Charcot-Marie-Tooth disease type 1A model.

    PubMed

    Norreel, J C; Jamon, M; Riviere, G; Passage, E; Fontes, M; Clarac, F

    2001-04-01

    Different features of motor behaviour were studied on a transgenic mouse model of Charcot-Marie-Tooth's disease (CMT). Mutants with 4 or 7 copies of the human PMP22 gene leading to a phenotype significantly close to CMT's disease type 1A were compared with control animals. The aim of the study was to validate this transgenic model and to characterise the impairments occurring in the various lines. Three main types of analysis were performed in 2-month-old mice without any peculiar visible deficit: (i) a study of standardised clinical tests (SHIRPA protocol) demonstrated that only a few motor deficits were expressed; (ii) a measurement of general spontaneous activity by means of a commercial video-tracking system was performed and revealed that the main spontaneous activities were identical in the three lines with, however, some slight localised modifications; and, (iii) by contrast, the three lines respond very differently to the footprints, grip strength, splay test and rotarod test. Even in lines with a significantly limited copy number of the transgene, we observed and quantified impairments. In conclusion, mutants of CMT1A seem to be a very pertinent model of this human pathology and will certainly be useful for therapeutic procedures and for theoretical studies on this disease. PMID:11328356

  2. Charcot-Marie-Tooth type 1A disease from patient to laboratory.

    PubMed

    Perveen, Shazia; Mannan, Shazia; Hussain, Abrar; Kanwal, Sumaira

    2015-02-01

    Charcot-Marie-Tooth (CMT) disease is a well-known neural or spinal type of muscular atrophy. It is the most familiar disease within a group of conditions called Hereditary Motor and Sensory Neuropathies (HMSN). The disease was discovered by three scientists several years ago. Several genes are involved as the causative agents for the disease. Hundreds of causative mutations have been found and research work for the identification of a novel locus and for the treatment of CMT1A is going on. This review article was planned to gather information on CMT disease and updates on its treatment.National Center for Biotechnology Information (NCBI) and PubMed were searched for data retrieval. Molgen database, which is the exclusive site for CMT mutation, was the other source of articles. Different aspects of the CMT disease were compared.Advancements in the finding of the causative gene, discovery of the novel Loci are the current issues in this regard.CMT disease is incurable, but researchers are trying to get some benefits from different natural compounds and several therapeutic agents.Various groups are working on the treatment projects of CMT1A. Major step forward in CMT research was taken in 2004 when ascorbic acid was used for transgenic mice treatment. Gene therapy for constant neurotrophin-3 (NT- 3) delivery by secretion by muscle cells for the CMT1A is also one of the possible treatments under trial. PMID:25842560

  3. [Treatment for Patients with Charcot-Marie-Tooth Disease: Orthopaedic Aspects].

    PubMed

    Watanabe, Kota

    2016-01-01

    The orthopedic manifestations in patients with Charcot-Marie-Tooth disease include deformity and dysfunction of the extremities and spine. Conservative treatment is the first choice. Orthosis and rehabilitation can improve function, and are important for the prevention of joint contractures. Foot problems are most commonly observed and require surgical treatment. Foot deformities include pes cavus, cavovarus, claw toes, or drop foot. Single or combined surgeries selected for soft tissues are plantar release, tendon transfer, or Achilles tendon lengthening, and those for bones are osteotomies and joint fusions. The upper limb initially demonstrates loss of power of the intrinsic hand muscles followed by symmetrical atrophy of the forearm muscle groups. The typical hand deformity is claw hand. Tendon transfer, joint fusion, soft tissue release, or nerve decompression procedures are performed for correction of hand deformities. Acetabular dysplasia in the hip joints is sometimes observed and osteotomy is selected as surgical treatment in such cases. The associated spinal deformity is scoliosis with or without kyphosis. Similar to treatment of idiopathic scoliosis, posterior spinal fusion is performed in patients with progressive spinal deformities. PMID:26764299

  4. A Mutation in PMP2 Causes Dominant Demyelinating Charcot-Marie-Tooth Neuropathy

    PubMed Central

    Hyun, Young Se; Kwak, Geon; Choi, Yu-Ri; Yeo, Ha Kyung; Jwa, Dong Hwan; Kim, Eun Ja; Mo, Won Min; Nam, Soo Hyun; Kim, Sung Min; Yoo, Jeong Hyun; Koo, Heasoo; Park, Hwan Tae; Chung, Ki Wha; Choi, Byung-Ok

    2016-01-01

    Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of peripheral neuropathies with diverse genetic causes. In this study, we identified p.I43N mutation in PMP2 from a family exhibiting autosomal dominant demyelinating CMT neuropathy by whole exome sequencing and characterized the clinical features. The age at onset was the first to second decades and muscle atrophy started in the distal portion of the leg. Predominant fatty replacement in the anterior and lateral compartment was similar to that in CMT1A caused by PMP22 duplication. Sural nerve biopsy showed onion bulbs and degenerating fibers with various myelin abnormalities. The relevance of PMP2 mutation as a genetic cause of dominant CMT1 was assessed using transgenic mouse models. Transgenic mice expressing wild type or mutant (p.I43N) PMP2 exhibited abnormal motor function. Electrophysiological data revealed that both mice had reduced motor nerve conduction velocities (MNCV). Electron microscopy revealed that demyelinating fibers and internodal lengths were shortened in both transgenic mice. These data imply that overexpression of wild type as well as mutant PMP2 also causes the CMT1 phenotype, which has been documented in the PMP22. This report might expand the genetic and clinical features of CMT and a further mechanism study will enhance our understanding of PMP2-associated peripheral neuropathy. PMID:26828946

  5. Two Novel De Novo GARS Mutations Cause Early-Onset Axonal Charcot-Marie-Tooth Disease

    PubMed Central

    Liao, Yi-Chu; Liu, Yo-Tsen; Tsai, Pei-Chien; Chang, Chia-Ching; Huang, Yen-Hua; Soong, Bing-Wen; Lee, Yi-Chung

    2015-01-01

    Background Mutations in the GARS gene have been identified in a small number of patients with Charcot-Marie-Tooth disease (CMT) type 2D or distal spinal muscular atrophy type V, for whom disease onset typically occurs during adolescence or young adulthood, initially manifesting as weakness and atrophy of the hand muscles. The role of GARS mutations in patients with inherited neuropathies in Taiwan remains elusive. Methodology and Principal Findings Mutational analyses of the coding regions of GARS were performed using targeted sequencing of 54 patients with molecularly unassigned axonal CMT, who were selected from 340 unrelated CMT patients. Two heterozygous mutations in GARS, p.Asp146Tyr and p.Met238Arg, were identified; one in each patient. Both are novel de novo mutations. The p.Asp146Tyr mutation is associated with a severe infantile-onset neuropathy and the p.Met238Arg mutation results in childhood-onset disability. Conclusion GARS mutations are an uncommon cause of CMT in Taiwan. The p.Asp146Tyr and p.Met238Arg mutations are associated with early-onset axonal CMT. These findings broaden the mutational spectrum of GARS and also highlight the importance of considering GARS mutations as a disease cause in patients with early-onset neuropathies. PMID:26244500

  6. Linkage localization of X-linked Charcot-Marie-Tooth disease.

    PubMed Central

    Bergoffen, J; Trofatter, J; Pericak-Vance, M A; Haines, J L; Chance, P F; Fischbeck, K H

    1993-01-01

    Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of slowly progressive, degenerative disorders of peripheral nerve. X-linked CMT (CMTX) (McKusick 302800), a subdivision of type I, or demyelinating, CMT is an X-linked dominant condition with variable penetrance. Previous linkage analysis using RFLPs demonstrated linkage to markers on the proximal long and short arms of the X chromosome, with the more likely localization on the proximal long arm of the X chromosome. Available variable simple-sequence repeats (VSSRs) broaden the possibilities for linkage analysis. This paper presents new linkage data and recombination analysis derived from work with four VSSR markers--AR, PGKP1, DXS453, and DXYS1X--in addition to analysis using RFLP markers described elsewhere. These studies localize the CMTX gene to the proximal Xq segment between PGKP1 (Xq11.2-12) and DXS72 (Xq21.1), with a combined maximum multipoint lod score of 15.3 at DXS453 (theta = 0). PMID:8430694

  7. Vestibular impairment in Charcot-Marie-Tooth disease type 4C.

    PubMed

    Pérez-Garrigues, Herminio; Sivera, Rafael; Vílchez, Juan Jesús; Espinós, Carmen; Palau, Francesc; Sevilla, Teresa

    2014-07-01

    Charcot-Marie-Tooth disease type 4C (CMT4C) is a hereditary neuropathy with prominent unsteadiness. The objective of the current study is to determine whether the imbalance in CMT4C is caused only by reduced proprioceptive input or if vestibular nerve involvement is an additional factor. We selected 10 CMT4C patients and 10 age-matched and sex-matched controls. We performed a comprehensive evaluation of the vestibular system, including video Head Impulse Test, bithermal caloric test, galvanic stimulation test and skull vibration-induced nystagmus test. None of the patients experienced dizziness, spontaneous or gaze-evoked nystagmus, but all had significant vestibular impairment when tested when compared to controls. Seven had completely unexcitable vestibular systems and abnormal vestibuloocular reflex. There was no correlation between the degree of vestibulopathy and age or clinical severity. Significant vestibular impairment is a consistent finding in CMT4C and is present early in disease evolution. The profound imbalance that is so disabling in these patients may result from a combination of proprioceptive loss and vestibular neuropathy, and this would modify the recommended rehabilitation strategies. PMID:24614092

  8. Charcot osteoarthropathy in diabetes: A brief review with an emphasis on clinical practice

    PubMed Central

    Gouveri, Evanthia; Papanas, Nikolaos

    2011-01-01

    Charcot osteoarthropathy (COA) is a potentially limbthreatening condition that mainly affects diabetic patients with neuropathy. In everyday practice, it presents as a red, hot, swollen foot, usually painless, and is frequently triggered by trivial injury. Its etiology is traditionally attributed to impairment of either the autonomic nervous system, leading to increased blood flow and bone resorption, or of the peripheral nervous system, whereby loss of pain and protective sensation render the foot susceptible to repeated injury. More recently, excessive local inflammation is thought to play a decisive role. Diagnosis is based on clinical manifestation and imaging studies (plain X-rays, bone scan, Magnetic Resonance Imaging). The mainstay of management is immediate off-loading, while surgery is usually reserved for chronic cases with irreversible deformities and/or joint instability. The aim of this review is to provide an overview of COA in terms of pathogenesis, classification and clinical presentation, diagnosis and treatment, with an emphasis on the high suspicion required by clinicians for timely recognition to avoid further complications. PMID:21691556

  9. How do Mutations in GJB1 Cause X-linked Charcot-Marie-Tooth Disease?

    PubMed Central

    Kleopa, Kleopas A.; Abrams, Charles K.; Scherer, Steven S.

    2012-01-01

    The X-linked form of Charcot-Marie-Tooth disease (CMT1X) is the second most common form of hereditary motor and sensory neuropathy. The clinical phenotype is characterized by progressive weakness, atrophy, and sensory abnormalities that are most pronounced in the distal extremities. Some patients have CNS manifestations. Affected males have moderate to severe symptoms, whereas heterozygous females are usually less affected. Neurophysiology shows intermediate slowing of conduction and length-dependent axonal loss. Nerve biopsies show more prominent axonal degeneration than de/remyelination. Mutations in GJB1, the gene that encodes the gap junction (GJ) protein connexin32 (Cx32) cause CMT1X; more than 400 different mutations have been described. Many Cx32 mutants fail to form functional GJs, or form GJs with abnormal biophysical properties. Schwann cells and oligodendrocytes express Cx32, and the GJs formed by Cx32 play an important role in the homeostasis of myelinated axons. Animal models of CMT1X demonstrate that loss of Cx32 in myelinating Schwann cells causes a demyelinating neuropathy. Effective therapies remain to be developed. PMID:22771394

  10. Linkage localization of X-linked Charcot-Marie-Tooth disease

    SciTech Connect

    Bergoffen, J. Univ. of Pennsylvania, Philadelphia ); Trofatter, J.; Haines, J.L. ); Pericak-Vance, M.A. ); Chance, P.F. ); Fischbeck, K.H. )

    1993-02-01

    Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of slowly progressive, degenerative disorders of peripheral nerve. X-linked CMT (CMTX) (McKusick 302800), a subdivision of type I, or demyelinating, CMT is an X-linked dominant condition with variable penetrance. Previous linkage analysis using RFLPs demonstrated linkage to markers on the proximal long and short arms of the X chromosome, with the more likely localization on the proximal long arm of the X chromosome. Available variable simple-sequence repeats (VSSRs) broaden the possibilities for linkage analysis. This paper presents new linkage data and recombination analysis derived from work with four VSSR markers - AR, PGKP1, DXS453, and DXYS1X - in addition to analysis using RFLP markers described elsewhere. These studies localize the CMTX gene to the proximal Xq segment between PGKP1 (Xq11.2-12) and DXS72 (Xq21.1), with a combined maximum multipoint lod score of 15.3 at DXS453 ([theta] = 0). 32 refs., 3 figs., 2 tabs.

  11. Mutational studies in X-linked Charcot-Marie-Tooth disease (CMTX)

    SciTech Connect

    Cherryson, A.K.; Yeung, L.; Kennerson, M.L.; Nicholson, G.A.

    1994-09-01

    Charcot-Marie-Tooth disease, also known as hereditary motor and sensory neuropathy (HMSN), is a heterogeneous group of slowly progressive disorders of the peripheral nerve. X-linked CMT (CMTX) is characterized by slow motor nerve conduction velocities in affected males and the presence of mildly affected or normal carrier females with intermediate or normal nerve conduction velocities. CMTX, which has an incidence of 3.1 per 100,000 and accounts for approximately 10% of CMT cases, has been mapped to Xq13. One of the genes lying in this region, connexin 32, has been found to contain alterations in individuals affected with X-linked CMT. We have identified our X-linked families from dominant type 1 CMT families using the clinical criteria given above. These families were screened for point mutations in connexin 32. We have identified three missense mutations, a G{r_arrow}A transition at amino acid 35 (valine to methionine), a C{r_arrow}G transition at amino acid 158 (proline to alanine) and a T{r_arrow}A transition at amino acid 182 (serine to threonine). Another family showed a 18 bp deletion, which removed the amino acid 111 to 116 inclusive (histidine, glycine, aspartic acid, proline, leucine, histidine).

  12. Quantum dot-based diabetic foot mapping for diagnosing osteomyelitis and Charcot neuroarthropathy.

    PubMed

    Yousefi, Farzaneh; Nabipour, Iraj; Kalantarhormozi, Mohammadreza; Assadi, Tahereh; Raeisi, Alireza; Assadi, Majid

    2015-07-01

    The location of osteomyelitis is very important in Charcot neuroarthropathy (CN), especially when a physician is considering amputation of the affected extremity. In diabetic CN, the presence of osteomyelitis is likely. Thus, to identify the infected tissue that needs to be removed, the specific area of infection must be correctly identified. Both CN and osteomyelitis have high mortality rates, but osteomyelitis is more life threatening and needs aggressive treatment. We propose a QD-based method for distinguishing CN with sterile inflammation from osteomyelitis that does not require multiple and frequent imaging modalities. The method utilizes two different colored QDs (i.e., red and green). The red QD is attached to a UBI, an antimicrobial peptide, which attaches to bacteria, enabling their detection. The green QD is attached to MDP, which accumulates in areas of inflammation. When these QDs are injected intravenously at the same time, the red QD-UBI accumulates in infected areas and attaches to bacteria, and the green QD-MDP accumulates both in areas with sterile inflammation and infected areas. The accumulation of only green QDs in the suspect extremity signifies a sterile inflammation process (CN). However, the accumulation of both the red and green QDs signify infectious and inflammation processes (i.e., osteomyelitis or a soft tissue infection, depending on the location). In the latter case, the treatment needs to be more intensive, with even amputation considered. PMID:25801484

  13. Denning behaviour of non-gravid wolves, Canis lupus

    USGS Publications Warehouse

    Mech, L.D.; Phillips, M.K.; Smith, D.W.; Kreeger, T.J.

    1996-01-01

    Wild wolves (Canis lupus) that had produced pups in earlier years but were not currently pregnant, and ovariectomized captive wolves, dug dens during and after the whelping season even though they produced no pups. These observations suggest that den digging is not a function of pregnancy or of ovarian estrogen or progesterone. We hypothesize that increasing prolactin in spring elicits or mediates den-digging behavior.

  14. Jean Martin Charcot (1825-93) and John Hughlings Jackson (1835-1911): neurology in France and England in the 19th century.

    PubMed

    Silvester, Alexander

    2009-11-01

    In 1862 Jean Martin Charcot was appointed Physician at the Salpêtrière Hospital in Paris, and simultaneously John Hughlings Jackson was appointed as assistant physician at the National Hospital for the Paralysed and Epileptic, Queen Square, London. Both men made significant contributions to the development of neurology, many of which remain important to contemporary neurologists. The achievements and the work of Charcot and Hughlings Jackson are considered in the light of their respective localities and medical education, and the structure of hospital institutions and political allegiances are compared in the late 19th century in France and Britain. PMID:20029079

  15. Minimally Invasive Early Operative Treatment of Progressive Foot and Ankle Deformity Associated With Charcot-Marie-Tooth Disease.

    PubMed

    Boffeli, Troy J; Tabatt, Jessica A

    2015-01-01

    Charcot-Marie-Tooth disease is a neuromuscular disorder that commonly results in a predictable pattern of progressive bilateral lower extremity weakness, numbness, contracture, and deformity, including drop foot, loss of ankle eversion strength, dislocated hammertoes, and severe cavus foot deformity. Late stage reconstructive surgery will be often necessary if the deformity becomes unbraceable or when neuropathic ulcers have developed. Reconstructive surgery for Charcot-Marie-Tooth deformity is generally extensive and sometimes staged. Traditional reconstructive surgery involves a combination of procedures, including tendon lengthening or transfer, osteotomy, and arthrodesis. The described technique highlights our early surgical approach, which involves limited intervention before the deformity becomes rigid, severe, or disabling. We present 2 cases to contrast our early minimally invasive technique with traditional late stage reconstruction. Charcot-Marie-Tooth disease affects different muscles at various stages of disease progression. As 1 muscle becomes weak, the antagonist will overpower it and cause progressive deformity. The focus of the early minimally invasive approach is to decrease the forces that cause progressive deformity yet maintain function, where possible. Our goal has been to maintain a functional and braceable foot and ankle, with the hope of avoiding or limiting the extent of future major reconstructive surgery. The presented cases highlight the patient selection criteria, the ideal timing of early surgical intervention, the procedure selection criteria, and operative pearls. The early minimally invasive approach includes plantar fasciotomy, Achilles tendon lengthening, transfer of the peroneus longus to the fifth metatarsal, Hibbs and Jones tendon transfer, and hammertoe repair of digits 1 to 5. PMID:25131389

  16. Diabetic Charcot neuroarthropathy: The diagnosis must be considered in all diabetic neuropathic patients presenting with a hot, swollen foot.

    PubMed

    Al-Busaidi, Ibrahim S; Mason, Rhett; Lunt, Helen

    2015-10-16

    The diagnosis of diabetic Charcot neuroarthropathy (CN) is challenging. This is especially true early in the disease process, when its classical presentation of an acutely inflamed foot may masquerade as other more common lower limb conditions. Prompt diagnosis and appropriate treatment reduces the risk of CN causing permanent incapacitating foot deformity or amputation. We report two cases in which the diagnosis was delayed, resulting in long-term sequelae. These cases highlight the importance of considering CN in patients with diabetic peripheral neuropathy, who present with a red, hot, and swollen foot. PMID:26645758

  17. Misunderstanding of foot drop in a patient with charcot-marie-tooth disease and lumbar disk herniation.

    PubMed

    Han, Youngmin; Kim, Kyoung-Tae; Cho, Dae-Chul; Sung, Joo-Kyung

    2015-04-01

    We report the case of 57-year-old woman diagnosed with Charcot-Marie-Tooth (CMT) disease and lumbar disk herniation (LDH). She had left leg weakness and foot numbness, foot deformity (muscle atrophy, high arch, and clawed toes). The lumbar spine MRI showed LDH at L4-5. Additionally, electrophysiology results were consistent with chronic peripheral motor-sensory polyneuropathy (axonopathy). In genetic testing, 17p11.2-p12 duplication/deletions characteristic of CMT disease were observed. We confirmed the patient's diagnosis as CMT disease and used conservative treatment. PMID:25932299

  18. Dens in dente in a six year old doberman pinscher.

    PubMed

    DeForge, D H

    1992-09-01

    Developmental abnormalities of tooth shape and form are rare. Identification of dens in dente is made by radiographic and clinical examination. Pulpitis, pulp necrosis and periapical inflammation can be associated with this abnormality. The tooth should be evaluated for endodontic therapy. A review of the literature related to dens in dente is described with the findings in a doberman pinscher. PMID:1290603

  19. View east along Wolf Den Road showing residences on the ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View east along Wolf Den Road showing residences on the north side of the road - Brooklyn Green, North Green, South Green, & West Green, parts of Brown Road, Canterbury Road (Route 169), Hartford Road (Route 6), Hyde Road, Pomfret Road (Route 169), Prince Hill Road, Providence Road (Route 6), Wauregan Road (Routes 169 & 205), & Wolf Den Road, Brooklyn, Windham County, CT

  20. View northwest along Wolf Den Road showing residences on the ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View northwest along Wolf Den Road showing residences on the north side of the road - Brooklyn Green, North Green, South Green, & West Green, parts of Brown Road, Canterbury Road (Route 169), Hartford Road (Route 6), Hyde Road, Pomfret Road (Route 169), Prince Hill Road, Providence Road (Route 6), Wauregan Road (Routes 169 & 205), & Wolf Den Road, Brooklyn, Windham County, CT

  1. Prevalence of Peripheral Arterial Disease in Patients With Diabetic Charcot Neuroarthropathy.

    PubMed

    Wukich, Dane K; Raspovic, Katherine M; Suder, Natalie C

    2016-01-01

    Charcot neuroarthropathy (CN) is a serious complication of diabetes mellitus (DM) that can lead to pedal ulceration, infection, hospitalization, and amputation. Peripheral arterial disease (PAD) is also found in patients with diabetic foot disease; however, its prevalence in patients with CN has not been extensively evaluated. The aim of the present study was to evaluate the prevalence of PAD in a group of patients with CN (with and without ulceration) and compare this to a group of patients with diabetic foot ulceration (DFU) and no CN. We compared the lower extremity noninvasive arterial testing results of 85 patients with DM and CN with those from a group of 126 patients with DFU and no CN. No statistically significant differences were found in age, gender, type of DM (1 versus 2), insulin use, duration of DM, or history of dialysis between our study and control groups. The prevalence of PAD in the patients with CN was 40%. Compared with patients with DFUs, the patients with CN were less likely to have PAD (odds ratio 0.48, 95% confidence interval 0.28 to 0.85; p = .0111), ischemia (odds ratio 0.33, 95% confidence interval 0.16 to 0.69; p = .0033), or the need for revascularization (odds ratio 0.27, 95% confidence interval 0.10 to 0.73; p = .0097). Critical limb ischemia (great toe pressure <30 mm Hg) was 82% less likely in patients with CN than in patients with DFU. PAD in patients with CN is not uncommon; however, ischemia and the need for revascularization were significantly less likely than in patients with DFU without CN. PMID:27020760

  2. Innovative quantitative testing of hand function in Charcot-Marie-Tooth neuropathy.

    PubMed

    Alberti, Maria A; Mori, Laura; Francini, Luca; Poggi, Ilaria; Monti Bragadin, Margherita; Bellone, Emilia; Grandis, Marina; Maggi, Giovanni; Reni, Lizia; Sormani, Maria P; Tacchino, Andrea; Padua, Luca; Prada, Valeria; Bove, Marco; Schenone, Angelo

    2015-12-01

    To describe a new test to quantitatively evaluate hand function in patients affected by Charcot-Marie-Tooth neuropathy (CMT). The sensor-engineered glove test (SEGT) was applied to CMT patients (N: 26) and compared with a cohort of healthy controls (HC, N: 26). CMT patients were further divided into subjects with clinically normal (group 1) or impaired hand (group 2) function. The SEGT parameters evaluated were touch duration, inter-tapping interval, and movement rate parameters of two different sequences: finger tapping (FT) and index-medium-ring-little (IMRL) performed at self-paced mode (SPM) and maximum velocity (MV). Hand function and strength were assessed by the 9-hole peg test (9HPT) and dynamometry. Disability of patients was measured by the CMT neuropathy score. CMT patients had significantly worst performances at SEGT than controls regarding the rate of execution of both FT (at MV) and IMRL sequences (at SPM and MV). The rate parameter at MV in IMRL sequence showed a significant trend of decreasing in its average between HC (n: 26, rate = 3.08 ± 0.52 Hz), group 1 (n: 9, rate = 2.64 ± 0.66 Hz) and group 2 (n: 17, rate = 2.19 ± 0.45 Hz) (p for trend <0.001). No correlations were found with either 9HPT, dynamometry, electrophysiology, and the CMT neuropathy score. The SEGT test is sensitive to show hand dysfunction in CMT patients, with and without clinically impaired hands. PMID:26456943

  3. Clinical, neurophysiological and morphological study of dominant intermediate Charcot-Marie-Tooth type C neuropathy.

    PubMed

    Thomas, Florian P; Guergueltcheva, Velina; Gondim, Francisco A A; Tournev, Ivailo; Rao, Chitharanjan V; Ishpekova, Boryana; Kinsella, Laurence J; Pan, Yi; Geller, Thomas J; Litvinenko, Ivan; De Jonghe, Peter; Scherer, Steven S; Jordanova, Albena

    2016-03-01

    Dominant intermediate Charcot-Marie-Tooth neuropathy subtype C (DI-CMTC) was associated with mutations in the YARS gene, encoding tyrosyl-tRNA synthetase, in two large unrelated Bulgarian and US pedigrees and one sporadic case. Here for the first time we describe the clinical, neurophysiological and histopathological features, and phenotypic differences between these two DI-CMTC families. Twenty-one affected individuals from the US family and 27 from the Bulgarian family were evaluated. The mean age of onset in US subjects was 10.7 years in men and 7.3 years in women, while in the Bulgarian participants it was 18.2 years in men and 33.7 years in women. The course was slowly progressive. Extensor digitorum brevis atrophy was uniform. Atrophy and/or weakness of upper and lower limb muscles were found in over 50 % of the subjects. Nerve conduction studies (NCS) were abnormal in all US adults and five of six children and all Bulgarian patients except one asymptomatic 25-year-old man. Median motor NCS were in the range of 29.5-45.6 m/s in the US family and 24.7-57.8 m/s in the Bulgarian family. Sural sensory nerve action potentials were absent in 14/21 and 4/12 NCS from adult US and Bulgarian participants, respectively. Analysis of sural nerve biopsies from US patients revealed age-dependent morphological changes of axonal degeneration, absence of onion bulbs, and <10 % fibers with segmental remyelination. Our findings provide further insights into the diagnosis and pathology of intermediate CMT. They also extend the phenotypic spectrum of peripheral neuropathies associated with aminoacyl-tRNA synthetase mutations. PMID:26725087

  4. Clinical and genetic spectra in a series of Chinese patients with Charcot-Marie-Tooth disease.

    PubMed

    Wang, Rui; He, Jin; Li, Jin-Jing; Ni, Wang; Wu, Zhi-Ying; Chen, Wan-Jin; Wang, Yi

    2015-12-01

    The aim of this study was to determine the clinical features and frequencies of genetic subtypes in a series of patients with Charcot-Marie-Tooth (CMT) disease from Eastern China. Patients were divided into three subtypes, CMT1, CMT2 and hereditary neuropathy with liability to pressure palsy (HNPP), according to their electrophysiological manifestations. Multiplex ligation-dependent probe analysis (MLPA) was performed to detect duplications/deletions in the PMP22 gene. The coding regions and splice sites of the GJB1, MPZ, MFN2 and GDAP-1 genes were determined by direct sequencing. Among the 148 patients in the study, 37.2% of the cases had mutations in genes assessed. The mutation detection rate was higher in patients with family histories than in spontaneous cases. PMP22 duplication (13.5%) was predominant in this group of patients, followed by PMP22 deletion (11.5%), and point mutations in GJB1 (8.8%), MPZ (2.0%) and MFN2 (0.7%). Three novel mutations (c.151T>C and c.310 A>G in GJB1 and c.1516 C>G in MFN2) were detected. A small deletion in PMP22 exon 4 was detected in a patient with severe CMT1. Genetic tests have great value in CMT patients with family histories. The frequency of PMP22 duplications was lower in Asian patients than in others. We suggest that genetic testing strategies in CMT patients should be primarily based on electromyography data. PMID:26454100

  5. Myelin protein zero gene sequencing diagnoses Charcot-Marie-Tooth Type 1B disease

    SciTech Connect

    Su, Y.; Zhang, H.; Madrid, R.

    1994-09-01

    Charcot-Marie-Tooth disease (CMT), the most common genetic neuropathy, affects about 1 in 2600 people in Norway and is found worldwide. CMT Type 1 (CMT1) has slow nerve conduction with demyelinated Schwann cells. Autosomal dominant CMT Type 1B (CMT1B) results from mutations in the myelin protein zero gene which directs the synthesis of more than half of all Schwann cell protein. This gene was mapped to the chromosome 1q22-1q23.1 borderline by fluorescence in situ hybridization. The first 7 of 7 reported CMT1B mutations are unique. Thus the most effective means to identify CMT1B mutations in at-risk family members and fetuses is to sequence the entire coding sequence in dominant or sporadic CMT patients without the CMT1A duplication. Of the 19 primers used in 16 pars to uniquely amplify the entire MPZ coding sequence, 6 primer pairs were used to amplify and sequence the 6 exons. The DyeDeoxy Terminator cycle sequencing method used with four different color fluorescent lables was superior to manual sequencing because it sequences more bases unambiguously from extracted genomic DNA samples within 24 hours. This protocol was used to test 28 CMT and Dejerine-Sottas patients without CMT1A gene duplication. Sequencing MPZ gene-specific amplified fragments identified 9 polymorphic sites within the 6 exons that encode the 248 amino acid MPZ protein. The large number of major CMT1B mutations identified by single strand sequencing are being verified by reverse strand sequencing and when possible, by restriction enzyme analysis. This protocol can be used to distringuish CMT1B patients from othre CMT phenotypes and to determine the CMT1B status of relatives both presymptomatically and prenatally.

  6. Proximal nerve magnetization transfer MRI relates to disability in Charcot-Marie-Tooth diseases

    PubMed Central

    Dethrage, Lindsey M.; Gore, John C.; Smith, Seth A.; Li, Jun

    2014-01-01

    Objective: The objectives of this study were (1) to develop a novel magnetization transfer ratio (MTR) MRI assay of the proximal sciatic nerve (SN), which is inaccessible via current tools for assessing peripheral nerves, and (2) to evaluate the resulting MTR values as a potential biomarker of myelin content changes in patients with Charcot-Marie-Tooth (CMT) diseases. Methods: MTR was measured in the SN of patients with CMT type 1A (CMT1A, n = 10), CMT type 2A (CMT2A, n = 3), hereditary neuropathy with liability to pressure palsies (n = 3), and healthy controls (n = 21). Additional patients without a genetically confirmed subtype (n = 4), but whose family histories and electrophysiologic tests were consistent with CMT, were also included. The relationship between MTR and clinical neuropathy scores was assessed, and the interscan and inter-rater reliability of MTR was estimated. Results: Mean volumetric MTR values were significantly decreased in the SN of patients with CMT1A (33.8 ± 3.3 percent units) and CMT2A (31.5 ± 1.9 percent units) relative to controls (37.2 ± 2.3 percent units). A significant relationship between MTR and disability scores was also detected (p = 0.01 for genetically confirmed patients only, p = 0.04 for all patients). From interscan and inter-rater reliability analyses, proximal nerve MTR values were repeatable at the slicewise and mean volumetric levels. Conclusions: MTR measurements may be a viable biomarker of proximal nerve pathology in patients with CMT. PMID:25253751

  7. Balance and muscle power of children with Charcot-Marie-Tooth

    PubMed Central

    Silva, Tais R.; Testa, Amanda; Baptista, Cyntia R. J. A.; Marques, Wilson; Mattiello-Sverzut, Ana C.

    2014-01-01

    BACKGROUND: In certain diseases, functional constraints establish a greater relationship with muscle power than muscle strength. However, in hereditary peripheral polyneuropathies, no such relationship was found in the literature. OBJECTIVE: In children with Charcot-Marie-Tooth (CMT), to identify the impact of muscle strength and range of movement on the static/dynamic balance and standing long jump based on quantitative and functional variables. METHOD: The study analyzed 19 participants aged between 6 and 16 years, of both genders and with clinical diagnoses of CMT of different subtypes. Anthropometric data, muscle strength of the lower limbs (hand-held dynamometer), ankle and knee range of movement, balance (Pediatric Balance Scale) and standing long jump distance were obtained by standardized procedures. For the statistical analysis, Pearson and Spearman correlation coefficients were used. RESULTS: There was a strong positive correlation between balance and the muscle strength of the right plantar flexors (r=0.61) and dorsiflexors (r=0.59) and a moderate correlation between balance and the muscle strength of inversion (r=0.41) and eversion of the right foot (r=0.44). For the long jump and range of movement, there was a weak positive correlation with right and left plantar flexion (r=0.20 and r=0.12, respectively) and left popliteal angle (r=0.25), and a poor negative correlation with left dorsiflexion (r=-0.15). CONCLUSIONS: The data on the patients analyzed suggests that the maintenance of distal muscle strength favors performance during balance tasks, while limitations in the range of movement of the legs seem not to be enough to influence the performance of the horizontal long jump. PMID:25076001

  8. Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy

    PubMed Central

    Sames, Lori; Moore, Allison; Arnold, Renee; Ekins, Sean

    2014-01-01

    Approximately 1 in 2500 Americans suffer from Charcot-Marie-Tooth (CMT) disease. The underlying disease mechanisms are unique in most forms of CMT, with many point mutations on various genes causing a toxic accumulation of misfolded proteins. Symptoms of the disease often present within the first two decades of life, with CMT1A patients having reduced compound muscle and sensory action potentials, slow nerve conduction velocities, sensory loss, progressive distal weakness, foot and hand deformities, decreased reflexes, bilateral foot drop and about 5% become wheelchair bound. In contrast, the ultra-rare disease Giant Axonal Neuropathy (GAN) is frequently described as a recessively inherited condition that results in progressive nerve death. GAN usually appears in early childhood and progresses slowly as neuronal injury becomes more severe and leads to death in the second or third decade. There are currently no treatments for any of the forms of CMTs or GAN. We suggest that further clinical studies should analyse electrical impedance myography as an outcome measure for CMT. Further, additional quality of life (QoL) assessments for these CMTs are required, and we need to identify GAN biomarkers as well as develop new genetic testing panels for both diseases. We propose that using the Global Registry of Inherited Neuropathy (GRIN) could be useful for many of these studies. Patient advocacy groups and professional organizations (such as the Hereditary Neuropathy Foundation (HNF), Hannah's Hope Fund (HHF), The Neuropathy Association (TNA) and the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) can play a central role in educating clinicians and patients. Undertaking these studies will assist in the correct diagnosis of disease recruiting patients for clinical studies, and will ultimately improve the endpoints for clinical trials. By addressing obstacles that prevent industry investment in various forms of inherited neuropathies, we can

  9. Rapid genetic screening of Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies patients★

    PubMed Central

    Li, Xiaobo; Zi, Xiaohong; Li, Lin; Zhan, Yajing; Huang, Shunxiang; Li, Jin; Li, Xuning; Li, Xigui; Hu, Zhengmao; Xia, Kun; Tang, Beisha; Zhang, Ruxu

    2012-01-01

    We used the allele-specific PCR-double digestion method on peripheral myelin protein 22 (PMP22) to determine duplication and deletion mutations in the proband and family members of one family with Charcot-Marie-Tooth disease type 1 and one family with hereditary neuropathy with liability to pressure palsies. The proband and one subclinical family member from the Charcot-Marie-Tooth disease type 1 family had a PMP22 gene duplication; one patient from the hereditary neuropathy with liability to pressure palsies family had a PMP22 gene deletion. Electron microscopic analysis of ultrathin sections of the superficial peroneal nerve from the two probands demonstrated demyelination and myelin sheath hyperplasia, as well as an ‘onion-like’ structure in the Charcot-Marie-Tooth disease type 1A patient. We observed an irregular thickened myelin sheath and ‘mouse-nibbled’-like changes in the patient with hereditary neuropathy with liability to pressure palsies. In the Charcot-Marie-Tooth disease type 1A patient, nerve electrophysiological examination revealed moderate-to-severe reductions in the motor and sensory conduction velocities of the bilateral median nerve, ulnar nerve, tibial nerve, and sural nerve. Moreover, the compound muscle action potential amplitude was decreased. In the patient with hereditary neuropathy with liability to pressure palsies, the nerve conduction velocity of the bilateral tibial nerve and sural nerve was moderately reduced, and the nerve conduction velocity of the median nerve and ulnar nerve of both upper extremities was slightly reduced. PMID:25337104

  10. Late Corrective Arthrodesis in Nonplantigrade Diabetic Charcot Midfoot Disease Is Associated with High Complication and Reoperation Rates

    PubMed Central

    Wussow, Annekatrin

    2015-01-01

    Introduction. Charcot arthropathy may lead to a loss of osteoligamentous foot architecture and consequently loss of the plantigrade alignment. In this series of patients a technique of internal corrective arthrodesis with maximum fixation strength was provided in order to lower complication rates. Materials/Methods. 21 feet with severe nonplantigrade diabetic Charcot deformity Eichenholtz stages II/III (Sanders/Frykberg II/III/IV) and reconstructive arthrodesis with medial and additional lateral column support were retrospectively enrolled. Follow-up averaged 4.0 years and included a clinical (AOFAS score/PSS), radiological, and complication analysis. Results. A mean of 2.4 complications/foot occurred, of which 1.5/foot had to be solved surgically. 76% of feet suffered from soft tissue complications; 43% suffered hardware-associated complications. Feet with only 2 out of 5 high risk criteria according to Pinzur showed significantly lower complication counts. Radiographs revealed a correct restoration of all foot axes postoperatively with superior fixation strength medially. Conclusion. Late corrective arthrodesis with medial and lateral column stabilization in the nonplantigrade stages of neuroosteoarthropathy can provide reasonable reconstruction of the foot alignment. Nonetheless, overall complication/reoperation rates were high. With separation into low/high risk criteria a helpful guide in treatment choice is provided. This trial is registered with German Clinical Trials Register (DRKS) under number DRKS00007537. PMID:26000309

  11. The chair of mental and brain diseases: Charcot's pupils--Benjamin Ball, Alix Joffroy and Gilbert Ballet.

    PubMed

    Tiberghien, Denis

    2011-01-01

    Benjamin Ball (1833-1893), Alix Joffroy (1844-1908) and Gilbert Ballet (1853-1916) were three pupils of the great Charcot (1825-1893). They were successive holders of the chair for mental illness and encephalon at its creation in 1877 until the First World War: Benjamin Ball from 1877 to 1893, Alix Joffroy from 1893 to 1908, and Gilbert Ballet from 1908 to 1916. After describing the context surrounding the creation of this chair and the choice of its representative and successors, we will examine their neurological work on the brain derived from a method influenced by a current of thought careful to list the symptoms of the disease and to look for the anatomical causes in the brain. The renowned 19th century French neurologist Jean-Martin Charcot was a huge influence. With their acquired experience and progress in the fields of morphology and histology and cerebral cortex functioning, they greatly contributed to the evolution of neurological, clinical anatomical and psychological-physiological findings--thus allowing certain pathologies to be considered as organic diseases rather than neurotic symptoms--while all the time recognizing the importance of the cortical cell in mental illness. PMID:20938145

  12. Dens evaginatus: case reports and review of the literature.

    PubMed

    Ponnambalam, Yoganathan; Love, Robert M

    2006-06-01

    Dens evaginatus is a developmental anomaly that produces a tubercle on the occlusal or palatal or lingual surfaces of teeth. The tubercle, which often contains pulp tissue, can cause occlusal interference, and pulpal pathology is a common sequel of attrition or fracture of the evagination. It affects a number of tooth types, but most commonly the premolar teeth of people of oriental ethnicity. Early diagnosis and management of dens evaginatus are important to maintain pulp vitality. This article describes three cases of dens evaginatus with different presentations. PMID:16773794

  13. Dens invaginatus: review, relevance, and report of 3 cases.

    PubMed

    Khan, Suleman Abbas; Khan, Saima Yunus; Bains, Vivek K; Bains, Rhythm; Loomba, Kapil

    2012-01-01

    Dens invaginatus is a rare developmental morphoanatomical variation resulting from the infolding of the dental papilla before biological mineralization that allows the invagination of inner dental epithelium. Permanent maxillary lateral incisors are most commonly affected, and the condition is frequently bilateral, but it may also prevail in permanent maxillary central incisors. The purpose of this paper was to provide an overview of the etiopathogenesis, frequency of occurrence, and clinical and radiographic features and to discuss 3 dens invaginatus cases. PMID:23433617

  14. Patterns of den occupation by the spotted hyaena (Crocuta crocuta)

    USGS Publications Warehouse

    Boydston, E.E.; Kapheim, K.M.; Holekamp, K.E.

    2006-01-01

    Spotted hyaenas utilize isolated natal dens (NDs) and communal dens (CDs) for rearing their cubs. Here we describe patterns of natal and CD occupation by hyaenas belonging to one well-studied clan in the Maasai Mara National Reserve during a 10-year period. Locations of 98 den sites that were used as natal or CDs by hyaenas in the study clan were digitized in a Geographic Information System, and the duration of use of each den site, frequency of re-use, and distances involved in den moves were quantified. Hyaenas moved their CD monthly on average. Most CD sites were occupied only once during the study, but several sites were used repeatedly. On rare occasions, the movement of hyaenas to a new den site could be attributed to a disturbance event at the CD, but factors regularly prompting hyaenas to move to new CD sites were unclear. High-ranking female hyaenas were more likely to rear their cubs from birth in a CD than low-ranking females. Low-ranking females almost always utilized isolated NDs for the first few weeks of a litter's development, and low-ranking females transferred their cubs over longer distances than did high-ranking females. ?? 2006 East African Wild Life Society.

  15. Charcot-Marie-Tooth syndrome and neurofibromatosis type 1 with multiple neurofibromas of the entire spinal nerve roots

    PubMed Central

    Onu, David O; Hunn, Andrew W; Peters-Willke, Jens

    2013-01-01

    The coexistence of polyneuropathy which has the definite clinical and electromyographical findings consistent with Charcot-Marie-Tooth (CMT) syndrome and neurofibromatosis type 1 (NF1) has infrequently been reported. We describe a patient with both CMT and NF1, who had multiple neurofibromas involving the entire spinal neural axis. In addition, he had multiple neurofibromas distributed within the ileopsoas and gluteus muscles and subcutaneous tissues. These lesions were detected readily by MRI and the patient underwent successful surgical resection of the largest tumours compressing bilateral C2 nerve roots. To our knowledge, this is the first reported case of CMT syndrome coexisting with NF1 in which multiple neurofibromas involved the entire spinal nerve roots. We discuss the diagnostic and therapeutic challenges, emphasising the role of MRI and electrophysiology in such cases and provide a literature review. PMID:23853192

  16. Charcot-Marie-Tooth syndrome and neurofibromatosis type 1 with multiple neurofibromas of the entire spinal nerve roots.

    PubMed

    Onu, David O; Hunn, Andrew W; Peters-Willke, Jens

    2013-01-01

    The coexistence of polyneuropathy which has the definite clinical and electromyographical findings consistent with Charcot-Marie-Tooth (CMT) syndrome and neurofibromatosis type 1 (NF1) has infrequently been reported. We describe a patient with both CMT and NF1, who had multiple neurofibromas involving the entire spinal neural axis. In addition, he had multiple neurofibromas distributed within the ileopsoas and gluteus muscles and subcutaneous tissues. These lesions were detected readily by MRI and the patient underwent successful surgical resection of the largest tumours compressing bilateral C2 nerve roots. To our knowledge, this is the first reported case of CMT syndrome coexisting with NF1 in which multiple neurofibromas involved the entire spinal nerve roots. We discuss the diagnostic and therapeutic challenges, emphasising the role of MRI and electrophysiology in such cases and provide a literature review. PMID:23853192

  17. Coexistent Charcot-Marie-Tooth type 1A and type 2 diabetes mellitus neuropathies in a Chinese family

    PubMed Central

    Sun, A-ping; Tang, Lu; Liao, Qin; Zhang, Hui; Zhang, Ying-shuang; Zhang, Jun

    2015-01-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by duplication of the peripheral myelin protein 22 (PMP22) gene on chromosome 17. It is the most common inherited demyelinating neuropathy. Type 2 diabetes mellitus is a common metabolic disorder that frequently causes predominantly sensory neuropathy. In this study, we report the occurrence of CMT1A in a Chinese family affected by type 2 diabetes mellitus. In this family, seven individuals had duplication of the PMP22 gene, although only four had clinical features of polyneuropathy. All CMT1A patients with a clinical phenotype also presented with type 2 diabetes mellitus. The other three individuals had no signs of CMT1A or type 2 diabetes mellitus. We believe that there may be a genetic link between these two diseases. PMID:26692872

  18. A chronic leg ulcer presenting with Charcot-Marie-Tooth disease and type 2 diabetes: a case report.

    PubMed

    Ren, Haitao; You, Chuangang; Han, Chunmao

    2013-03-01

    Charcot-Marie-Tooth (CMT) disease is characterized by hereditary sensorimotor polyneuropathy with foot deformity, sensorineural hearing loss, moderate developmental delay, and gait disturbance. CMT presenting with type 2 diabetes and an ulcer has not been reported. This article reports a man who presented with the symptoms mentioned above and also with a leg ulcer and type 2 diabetes. He was diagnosed with CMT disease based on family history and genetic testing. A skin defect in the left leg had manifested for more than 1 year, and results of initial fasting plasma glucose revealed type 2 diabetes. The evolution of these manifestations, coupled with a slowly progressive weakness, numbness, muscular wasting, and sensory impairment, strongly suggested the co-occurrence of 3 different diseases in the same individual. PMID:23446367

  19. The first de novo mutation of the connexin 32 gene associated with X linked Charcot-Marie-Tooth disease.

    PubMed Central

    Meggouh, F; Benomar, A; Rouger, H; Tardieu, S; Birouk, N; Tassin, J; Barhoumi, C; Yahyaoui, M; Chkili, T; Brice, A; LeGuern, E

    1998-01-01

    X linked Charcot-Marie-Tooth disease (CMTX) is a hereditary motor and sensory neuropathy caused by mutations in the connexin 32 gene (Cx32). Using the SSCP technique and direct sequencing of PCR amplified genomic DNA fragments of the Cx32 gene from a Moroccan patient and her relatives, we identified the first de novo mutation of the Cx32 gene, consisting of a deletion of a G residue at position 499 in the Cx32 open reading frame. This previously unreported mutation produces a frameshift at position 147 in the protein and introduces a premature stop codon (TAG) at nucleotide 643, which results in the production of a truncated Cx32 molecule. This mutation illustrates the risk of an erroneous diagnosis of autosomal recessive CMT, especially in populations where consanguineous unions are frequent, and its consequences for genetic counselling, which can be avoided by molecular analysis. Images PMID:9541114

  20. Coexistent Charcot-Marie-Tooth type 1A and type 2 diabetes mellitus neuropathies in a Chinese family.

    PubMed

    Sun, A-Ping; Tang, Lu; Liao, Qin; Zhang, Hui; Zhang, Ying-Shuang; Zhang, Jun

    2015-10-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by duplication of the peripheral myelin protein 22 (PMP22) gene on chromosome 17. It is the most common inherited demyelinating neuropathy. Type 2 diabetes mellitus is a common metabolic disorder that frequently causes predominantly sensory neuropathy. In this study, we report the occurrence of CMT1A in a Chinese family affected by type 2 diabetes mellitus. In this family, seven individuals had duplication of the PMP22 gene, although only four had clinical features of polyneuropathy. All CMT1A patients with a clinical phenotype also presented with type 2 diabetes mellitus. The other three individuals had no signs of CMT1A or type 2 diabetes mellitus. We believe that there may be a genetic link between these two diseases. PMID:26692872

  1. Correlation between connexin 32 gene mutations and clinical phenotype in X-linked dominant Charcot-Marie-Tooth neuropathy

    SciTech Connect

    Ionasescu, V.; Ionasescu, R.; Searby, C.

    1996-06-14

    We studied the relationship between the genotype and clinical phenotype in 27 families with dominant X-linked Charcot-Marie-Tooth (CMTX1) neuropathy. Twenty-two families showed mutations in the coding region of the connexin32 (cx32) gene. The mutations include four nonsense mutations, eight missense mutations, two medium size deletions, and one insertion. Most missense mutations showed a mild clinical phenotype (five out of eight), whereas all nonsense mutations, the larger of the two deletions, and the insertion that produced frameshifts showed severe phenotypes. Five CMTX1 families with mild clinical phenotype showed no point mutations of the cx32 gene coding region. Three of these families showed positive genetic linkage with the markers of the Xq13.1 region. The genetic linkage of the remaining two families could not be evaluated because of their small size. 25 refs., 1 fig., 1 tab.

  2. Jean-Martin Charcot, father of modern neurology: an homage 120 years after his death.

    PubMed

    Gomes, Marleide da Mota; Engelhardt, Eliasz

    2013-10-01

    Jean-Martin Charcot was a pioneer in a variety of subjects, including nervous system diseases; anatomy; physiology; pathology; and diseases of ageing, joints, and lungs. His medical achievements were mainly based on his anatomopathological proficiency, his observation, and his personal thoroughness that favored the delineation of the nosology of the main neurological diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, peroneal muscular atrophy, and hysteria/epilepsy. The link of this anatomoclinical method with iconographic representations and theatrical lessons, and the rich bibliographical documentations, carried out in a crowded barn for diseased people--Salpetrière Hospital, were the basis of his achievements, which are still discussed 120 years after his death. PMID:24212522

  3. Den use by arctic foxes (Alopex lagopus) in a subarctic region of western Alaska

    USGS Publications Warehouse

    Anthony, R.M.

    1996-01-01

    Distribution, abundance, and use of arctic fox dens located in coastal tundra communities of the Yukon-Kuskokwim delta were determined in studies from 1985 to 1990. Dens were denser and less complex than those described in studies conducted above the Arctic Circle. Eighty-three dens of varying complexity were found in the 52-km2 study area. Nineteen dens were used by arctic foxes for whelping or rearing pups. Three females relocated litters to multiple dens; a maximum of four dens were used concurrently by pups from one litter. Although red foxes were common in the region, their use of dens in the study area was minimal. Differences in vegetation at den sites and nearby unoccupied sites were minimal. Furthermore, den sites could not be distinguished from non-den sites during aerial surveys.

  4. Denning chronology and design of effective bear management units

    USGS Publications Warehouse

    Inman, R.M.; Costello, C.M.; Jones, D.E.; Inman, K.H.; Thompson, B.C.; Quigley, H.B.

    2007-01-01

    Reports on the effectiveness of using late fall hunting seasons to reduce the proportion of female black bears (Ursus americanus) in the harvest are limited, and the geographic scale over which the technique functions as intended has not been examined. During 1992-2000, we radio-equipped black bears in New Mexico, USA, obtained estimates of 175 den entry and 137 den emergence dates, and used New Mexico Department of Game and Fish harvest data (1985-2000) to test for differences in proportion of females in the harvest relative to denning chronology. Bears in northern New Mexico entered dens earlier and emerged later than bears in southern New Mexico (P ??? 0.001). In northern New Mexico bears displayed the typical pattern of earlier entry and later emergence by reproductive females, proportion of females in the harvest varied over time as expected, and late fall seasons were effective (P ??? 0.10). In contrast, denning chronology did not differ by sex in southern New Mexico, proportion of females in the harvest did not change over time, and late fall seasons were not effective (P ??? 0.18). Manipulation of hunting season dates to influence female mortality can be an effective tool, however our study provides an example of an area where denning chronology did not differ by sex and late seasons were not effective. We also observed regional differences in timing of entrance and emergence, which suggest that scale of application may be key. In management jurisdictions that encompass ecologically distinct areas, cover a wide range of latitudes, or are mountainous, successful use of the technique may depend on knowledge of denning chronology at multiple locations and appropriate designation of hunting unit boundaries, season dates, and data analysis units.

  5. Crime, hysteria and belle époque hypnotism: the path traced by Jean-Martin Charcot and Georges Gilles de la Tourette.

    PubMed

    Bogousslavsky, Julien; Walusinski, Olivier; Veyrunes, Denis

    2009-01-01

    Hysteria and hypnotism became a favorite topic of studies in the fin de siècle neurology that emerged from the school organized at La Salpêtrière by Jean-Martin Charcot, where he had arrived in 1861. Georges Gilles de la Tourette started working with Charcot in 1884 and probably remained his most faithful student, even after his mentor's death in 1893. This collaboration was particularly intense on 'criminal hypnotism', an issue on which Hippolyte Bernheim and his colleagues from the Nancy School challenged the positions taken by the Salpêtrière School. Bernheim claimed that hypnotism was not a diagnostic feature of hysteria and that there were real-life examples of murders suggested under hypnosis, while hypnosis susceptibility was identified with hysteria by Charcot and Gilles de la Tourette, who saw rape as the only crime associated with hypnotism. The quarrel was particularly virulent during a series of famous criminal cases which took place between 1888 and 1890. At the time, it was considered that La Salpêtrière had succeeded over Nancy, since the role of hypnotism was discarded during these famous trials. However, the theories of Charcot and Gilles de la Tourette were also damaged by the fight, which probably triggered the conceptual evolution leading to Joseph Babinski's revision of hysteria in 1901. Gilles de la Tourette's strong and public interest in hypnotism nearly cost him his life, when a young woman who claimed to have been hypnotized against her will shot him in the head at his own home in 1893. It was subsequently shown that hypnotism had nothing to do with it. The delusional woman was interned at Sainte-Anne for mental disturbance, thus escaping trial. Ironically, Gilles de la Tourette may have been partly responsible, since he had been one of the strongest proponents of placing mentally-ill criminals in asylums instead of prisons. PMID:19602893

  6. Who was first to diagnose and report neuropathic arthropathy of the foot and ankle: Jean-Martin Charcot or Herbert William Page?

    PubMed

    Sanders, Lee J; Edmonds, Michael E; Jeffcoate, William J

    2013-09-01

    In November 1883, Jean-Martin Charcot and Charles Féré reported on bone and joint disease of the foot in cases of tabes dorsalis, and referred to the condition as 'pied tabétique'--a disabling neuropathic osteoarthropathy that we usually now refer to as the Charcot foot. Charcot had originally described neuropathic osteoarthropathy in more proximal joints in 1868, and in his 1883 paper with Féré stated that involvement of the short bones and small joints of the foot had not yet been described. They emphasised in the paper that one of their cases was the first ever observed, two years earlier, in 1881. It is relevant, however, that it was in this same year that involvement of the foot by tabetic arthropathy was presented to the International Medical Congress in London by an English surgeon, Herbert William Page. We believe that Page was the first to diagnose and to report a case of tabetic neuropathic osteoarthropathy in which the bones of the foot and ankle were involved. He was also the first to propose a link between the tabetic foot and disease of the peripheral nerves, as opposed to the central nervous system. PMID:23765185

  7. Remote identification of polar bear maternal den habitat in northern Alaska

    USGS Publications Warehouse

    Durner, G.M.; Amstrup, Steven C.; Ambrosius, K.J.

    2001-01-01

    Polar bears (Ursus maritimus) give birth in dens of ice and snow to protect their altricial young. During the snow-free season, we visited 25 den sites located previously by radiotelemetry and characterized the den site physiognomy. Seven dens occurred in habitats with minimal relief. Eighteen dens (72%) were in coastal and river banks. These "banks" were identifiable on aerial photographs. We then searched high-resolution aerial photographs (n = 3000) for habitats similar to those of the 18 dens. On aerial photos, we mapped 1782 km of bank habitats suitable for denning. Bank habitats comprised 0.18% of our study area between the Colville River and the Tamayariak River in northern Alaska. The final map, which correctly identified 88% of bank denning habitat in this region, will help minimize the potential for disruptions of maternal dens by winter petroleum exploration activities.

  8. American black bear denning behavior: Observations and applications using remote photography

    USGS Publications Warehouse

    Bridges, A.S.; Fox, J.A.; Olfenbuttel, C.; Vaughan, M.B.

    2004-01-01

    Researchers examining American black bear (Ursus americanus) denning behavior have relied primarily on den-site visitation and radiotelemetry to gather data. Repeated den-site visits are time-intensive and may disturb denning bears, possibly causing den abandonment, whereas radiotelemetry is sufficient only to provide gross data on den emergence. We used remote cameras to examine black bear denning behavior in the Allegheny Mountains of western Virginia during March-May 2003. We deployed cameras at 10 den sites and used 137 pictures of black bears. Adult female black bears exhibited greater extra-den activity than we expected prior to final den emergence, which occurred between April 12 and May 6, 2003. Our technique provided more accurate den-emergence estimation than previously published methodologies. Additionally, we observed seldom-documented behaviors associated with den exits and estimated cub age at den emergence. Remote cameras can provide unique insights into denning ecology, and we describe their potential application to reproductive, survival, and behavioral research.

  9. Detecting denning polar bears with Forward-Looking Infrared (FLIR) imagery

    USGS Publications Warehouse

    Amstrup, Steven C.; York, G.; McDonald, T.L.; Nielson, R.; Simac, K.

    2004-01-01

    Polar bears give birth in snow dens in midwinter and remain in dens until early spring. The survival and development of cubs is dependent on a stable environment within the maternal den. To mitigate potential disruption of polar bear denning by existing and proposed petroleum activities, we used forward-looking infrared (FLIR) viewing to try to detect heat rising from dens.We flew transects over dens of radio-collared females with FLIR imager-equipped aircraft, recorded weather conditions at each observation, and noted whether the den was detected.We surveyed 23 dens on 67 occasions (1 to 7 times each). Nine dens were always detected, and 10 dens visited more than once were detected on some flights but not on others. Four dens were never detected (17 percent), but three of those were visited only under marginal conditions. The odds of detecting a den were 4.8 times greater when airborne moisture (snow, blowing snow, fog, etc.) was absent than when it was present, and they increased 3-fold for every 1?C increase in temperature-dew point spread. The estimated probability of detecting dens in sunlight was 0. Data suggested that FLIR surveys conducted during optimal conditions for detection can produce detection rates approaching 90 percent and thus can be an important management and mitigation tool. polar bear, infrared imagery, maternal denning, human impacts, management

  10. Habitat characteristics of polar bear terrestrial maternal den sites in northern Alaska

    USGS Publications Warehouse

    Durner, G.M.; Amstrup, Steven C.; Fischbach, Anthony S.

    2003-01-01

    Polar bears (Ursus maritimus) give birth to and nurture their young in dens of ice and snow. During 1999-2001, we measured the structure of 22 dens on the coastal plain of northern Alaska after polar bear families had evacuated their dens in the spring. During the summers of 2001 and 2002, we revisited the sites of 42 maternal and autumn exploratory dens and recorded characteristics of the under-snow habitat. The structure of polar bear snow dens was highly variable. Most were simple chambers with a single entrance/egress tunnel. Others had multiple chambers and additional tunnels. Thickness of snow above and below dens was highly variable, but most dens were overlain by less than 1 m of snow. Dens were located on, or associated with, pronounced landscape features (primarily coastal and river banks, but also a lake shore and an abandoned oil field gravel pad) that are readily distinguished from the surrounding terrain in summer and catch snow in early winter. Although easily identified, den landforms in northern Alaska were more subtle than den habitats in many other parts of the Arctic. The structure of polar bear dens in Alaska was strikingly similar to that of dens elsewhere and has remained largely unchanged in northern Alaska for more than 25 years. Knowledge of den structure and site characteristics will allow resource managers to identify habitats with the greatest probability of holding dens. This information may assist resource managers in preventing negative impacts of mineral exploration and extraction on polar bears.

  11. Prophylactic treatment of dens evaginatus using mineral trioxide aggregate.

    PubMed

    Koh, E T; Ford, T R; Kariyawasam, S P; Chen, N N; Torabinejad, M

    2001-08-01

    Two case reports with dens evaginatus are presented. Each patient had one tooth affected. There was a prominent tubercle on the occlusal surface of the mandibular second premolar. Under local anesthesia and rubber dam isolation a partial pulpotomy was conducted and mineral trioxide aggregate was placed. After 6 months the teeth were removed as part of planned orthodontic treatment. Histological examination of these teeth showed an apparent continuous dentin bridge formation in both teeth, and the pulps were free of inflammation. These cases show that mineral trioxide aggregate can be used as an alternative to existing materials in the proplylactic treatment of dens evaginatus. PMID:11501594

  12. Denning habits of free-ranging dogs reveal preference for human proximity

    PubMed Central

    Sen Majumder, Sreejani; Paul, Manabi; Sau, Shubhra; Bhadra, Anindita

    2016-01-01

    Dens are crucial in the early development of many mammals, making den site selection an important component of parental care in such species. Resource availability and shelter from predators primarily govern den selection. Species inhabiting human-dominated landscapes typically den away from human disturbance, often shifting dens to avoid humans during the early life of their young. Domesticated dogs have evolved in human proximity over centuries, being bred and reared in human homes for generations. While pets rely on their owners for shelter and care, free-ranging dogs roam uncared, and typically whelp in dens. We conducted a study on 148 free-ranging dog dens in India to understand their denning habits. Distance from resources influenced den choice, but anthropogenic disturbance did not. Dens were found in areas of high human activity, and begging from humans was preferred over scavenging. A study on 15 pregnant females revealed that females actively searched for denning sites, rejecting several intermediate ones before selecting the final den. We propose that the obvious preference of dogs for denning close to humans is a behavioural adaptation that helps them to survive in the urban landscape, in spite of the high human induced mortality during the early life of pups. PMID:27535214

  13. Denning habits of free-ranging dogs reveal preference for human proximity.

    PubMed

    Sen Majumder, Sreejani; Paul, Manabi; Sau, Shubhra; Bhadra, Anindita

    2016-01-01

    Dens are crucial in the early development of many mammals, making den site selection an important component of parental care in such species. Resource availability and shelter from predators primarily govern den selection. Species inhabiting human-dominated landscapes typically den away from human disturbance, often shifting dens to avoid humans during the early life of their young. Domesticated dogs have evolved in human proximity over centuries, being bred and reared in human homes for generations. While pets rely on their owners for shelter and care, free-ranging dogs roam uncared, and typically whelp in dens. We conducted a study on 148 free-ranging dog dens in India to understand their denning habits. Distance from resources influenced den choice, but anthropogenic disturbance did not. Dens were found in areas of high human activity, and begging from humans was preferred over scavenging. A study on 15 pregnant females revealed that females actively searched for denning sites, rejecting several intermediate ones before selecting the final den. We propose that the obvious preference of dogs for denning close to humans is a behavioural adaptation that helps them to survive in the urban landscape, in spite of the high human induced mortality during the early life of pups. PMID:27535214

  14. Den-site characteristics of black bears in Rocky Mountain National Park, Colorado

    USGS Publications Warehouse

    Baldwin, R.A.; Bender, L.C.

    2008-01-01

    We compared historic (1985-1992) and contemporary (2003-2006) black bear (Ursus americanus) den locations in Rocky Mountain National Park (RMNP), Colorado, USA, for habitat and physiographic attributes of den sites and used maximum entropy modeling to determine which factors were most influential in predicting den-site locations. We observed variability in the relationship between den locations and distance to trails and elevation over rime. Locations of historic den sites were most associated with slope, elevation, and covertype, whereas contemporary sites were associated with slope, distance to roads, aspect, and canopy height. Although relationships to covariates differed between historic and contemporary periods, preferred den-site characteristics consistently included steep slopes and factors associated with greater snow depth. Distribution of den locations shifted toward areas closer to human developments, indicating little negative influence of this factor on den-site selection by black bears in RMNP.

  15. PMP22 messenger RNA levels in skin biopsies: testing the effectiveness of a Charcot-Marie-Tooth 1A biomarker.

    PubMed

    Nobbio, Lucilla; Visigalli, Davide; Radice, Davide; Fiorina, Elisabetta; Solari, Alessandra; Lauria, Giuseppe; Reilly, Mary M; Santoro, Lucio; Schenone, Angelo; Pareyson, Davide

    2014-06-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with increased gene dosage for PMP22. Therapeutic approaches are currently aiming at correcting PMP22 over-expression. It is unknown whether PMP22 can be used as a biological marker of disease progression and therapy efficacy. We performed quantitative real-time polymerase chain reaction on skin biopsies of 45 patients with CMT1A, obtained at study entry and after 24-months of treatment either with ascorbic acid or placebo. Data of a subgroup of patients were also compared with matched healthy subjects. Finally, we analysed PMP22 messenger RNA levels in sural nerve biopsies. We did not find significant differences in the levels of any known PMP22 transcripts in treated or untreated patients with CMT1A, thus confirming that ascorbic acid does not impact on the molecular features of CMT1A. Most importantly, we did not observe any correlation between PMP22 messenger RNA levels and the different clinical and electrophysiological outcome measures, underscoring the weakness of PMP22 to mirror the phenotypic variability of patients with CMT1A. We did not find increased PMP22 messenger RNA levels in skin and sural nerve biopsies of patients with CMT1A compared with relative controls. In conclusion, this study shows that ascorbic acid does not impact on PMP22 transcriptional regulation and PMP22 is not a suitable biomarker for CMT1A. PMID:24812204

  16. A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.

    PubMed

    Tamiya, Gen; Makino, Satoshi; Hayashi, Makiko; Abe, Akiko; Numakura, Chikahiko; Ueki, Masao; Tanaka, Atsushi; Ito, Chizuru; Toshimori, Kiyotaka; Ogawa, Nobuhiro; Terashima, Tomoya; Maegawa, Hiroshi; Yanagisawa, Daijiro; Tooyama, Ikuo; Tada, Masayoshi; Onodera, Osamu; Hayasaka, Kiyoshi

    2014-09-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy characterized by clinical and genetic heterogeneity. Although more than 30 loci harboring CMT-causing mutations have been identified, many other genes still remain to be discovered for many affected individuals. For two consanguineous families with CMT (axonal and mixed phenotypes), a parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb region on 12q24 showing a maximum multipoint LOD score of 4.23. Subsequent whole-genome sequencing study in one of the probands, followed by mutation screening in the two families, revealed a disease-specific 5 bp deletion (c.247-10_247-6delCACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV (cytochrome c oxidase [COX]), within the autozygous linkage region. Functional analysis showed that expression of COX6A1 in peripheral white blood cells from the affected individuals and COX activity in their EB-virus-transformed lymphoblastoid cell lines were significantly reduced. In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking. Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT. PMID:25152455

  17. A Mutation of COX6A1 Causes a Recessive Axonal or Mixed Form of Charcot-Marie-Tooth Disease

    PubMed Central

    Tamiya, Gen; Makino, Satoshi; Hayashi, Makiko; Abe, Akiko; Numakura, Chikahiko; Ueki, Masao; Tanaka, Atsushi; Ito, Chizuru; Toshimori, Kiyotaka; Ogawa, Nobuhiro; Terashima, Tomoya; Maegawa, Hiroshi; Yanagisawa, Daijiro; Tooyama, Ikuo; Tada, Masayoshi; Onodera, Osamu; Hayasaka, Kiyoshi

    2014-01-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy characterized by clinical and genetic heterogeneity. Although more than 30 loci harboring CMT-causing mutations have been identified, many other genes still remain to be discovered for many affected individuals. For two consanguineous families with CMT (axonal and mixed phenotypes), a parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb region on 12q24 showing a maximum multipoint LOD score of 4.23. Subsequent whole-genome sequencing study in one of the probands, followed by mutation screening in the two families, revealed a disease-specific 5 bp deletion (c.247−10_247−6delCACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV (cytochrome c oxidase [COX]), within the autozygous linkage region. Functional analysis showed that expression of COX6A1 in peripheral white blood cells from the affected individuals and COX activity in their EB-virus-transformed lymphoblastoid cell lines were significantly reduced. In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking. Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT. PMID:25152455

  18. The genomic structure of the human Charcot-Leyden crystal protein gene is analogous to those of the galectin genes

    SciTech Connect

    Dyer, K.D. |; Handen, J.S.; Rosenberg, H.F.

    1997-03-01

    The Charcot-Leyden crystal (CLC) protein, or eosinophil lysophospholipase, is a characteristic protein of human eosinophils and basophils; recent work has demonstrated that the CLC protein is both structurally and functionally related to the galectin family of {beta}-galactoside binding proteins. The galectins as a group share a number of features in common, including a linear ligand binding site encoded on a single exon. In this work, we demonstrate that the intron-exon structure of the gene encoding CLC is analogous to those encoding the galectins. The coding sequence of the CLC gene is divided into four exons, with the entire {beta}-galactoside binding site encoded by exon III. We have isolated CLC {beta}-galactoside binding sites from both orangutan (Pongo pygmaeus) and murine (Mus musculus) genomic DNAs, both encoded on single exons, and noted conservation of the amino acids shown to interact directly with the {beta}-galactoside ligand. The most likely interpretation of these results suggests the occurrence of one or more exon duplication and insertion events, resulting in the distribution of this lectin domain to CLC as well as to the multiple galectin genes. 35 refs., 3 figs.

  19. NEFL E396K mutation is associated with a novel dominant intermediate Charcot-Marie-Tooth disease phenotype.

    PubMed

    Berciano, José; García, Antonio; Peeters, Kristien; Gallardo, Elena; De Vriendt, Els; Pelayo-Negro, Ana L; Infante, Jon; Jordanova, Albena

    2015-05-01

    The purpose of the study was to describe a pedigree with NEFL E396K mutation associated with a novel dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) phenotype. The pedigree comprised four patients over two generations, aged between 35 and 59 years, who have been serially evaluated since 1993. Their clinical picture was characterized by pes cavus, sensorimotor neuropathy and spastic gait. Both older patients showed ascending leg weakness to involve pelvic musculature. CMT neuropathy score ranged from 14 to 26 (moderate to severe disease). Electrophysiology showed uniform nerve conduction slowing in the intermediate range, both in distal and proximal nerve segments. Multimodal evoked potential and blink reflex studies revealed abnormalities indicative of central sensorimotor pathway dysfunction. On imaging studies of lower-limb musculature, there was massive atrophy of intrinsic foot muscles and to a lesser degree of calves and thighs predominating in muscles innervated by tibial and sciatic nerves. In both patients exhibiting waddling gait, there was atrophy of pelvic muscles mainly involving gluteus medius, gluteus minimus and piriformis. We conclude that NEFL E396K mutation may manifest with a novel DI-CMT phenotype, characterized by simultaneous involvement of the peripheral and central nervous system. PMID:25877835

  20. Steroid-dependent sensorineural hearing loss in a patient with Charcot-Marie-Tooth disease showing auditory neuropathy.

    PubMed

    Maeda, Yukihide; Kataoka, Yuko; Sugaya, Akiko; Kariya, Shin; Kobayashi, Katsuhiro; Nishizaki, Kazunori

    2015-06-01

    Charcot-Marie-Tooth disease (CMT) is the most common form of hereditary sensorimotor neuropathy and sometimes involves disorders of the peripheral auditory system. We present a case of steroid-dependent auditory neuropathy associated with CMT, in which the patient experienced 3 episodes of acute exacerbation of hearing loss and successful rescue of hearing by prednisolone. An 8-year-old boy was referred to the otolaryngology department at the University Hospital. He had been diagnosed with CMT type 1 (demyelinating type) at the Child Neurology Department and was suffering from mild hearing loss due to auditory neuropathy. An audiological diagnosis of auditory neuropathy was confirmed by auditory brainstem response and distortion-product otoacoustic emissions. At 9 years and 0 months old, 9 years and 2 months old, and 10 years and 0 months old, he had experienced acute exacerbations of hearing loss, each of which was successfully rescued by intravenous or oral prednisolone within 2 weeks. Steroid-responsive cases of CMT have been reported, but this is the first case report of steroid-responsive sensorineural hearing loss in CMT. The present case may have implications for the mechanisms of action of glucocorticoids in the treatment of sensorineural hearing loss. PMID:25440412

  1. Charcot-Marie-Tooth disease-associated mutants of GDAP1 dissociate its roles in peroxisomal and mitochondrial fission

    PubMed Central

    Huber, Nina; Guimaraes, Sofia; Schrader, Michael; Suter, Ueli; Niemann, Axel

    2013-01-01

    Mitochondria and peroxisomes can be fragmented by the process of fission. The fission machineries of both organelles share a set of proteins. GDAP1 is a tail-anchored protein of mitochondria and induces mitochondrial fragmentation. Mutations in GDAP1 lead to Charcot-Marie-Tooth disease (CMT), an inherited peripheral neuropathy, and affect mitochondrial dynamics. Here, we show that GDAP1 is also targeted to peroxisomes mediated by the import receptor Pex19. Knockdown of GDAP1 leads to peroxisomal elongation that can be rescued by re-expressing GDAP1 and by missense mutated forms found in CMT patients. GDAP1-induced peroxisomal fission is dependent on the integrity of its hydrophobic domain 1, and on Drp1 and Mff, as is mitochondrial fission. Thus, GDAP1 regulates mitochondrial and peroxisomal fission by a similar mechanism. However, our results reveal also a more critical role of the amino-terminal GDAP1 domains, carrying most CMT-causing mutations, in the regulation of mitochondrial compared to peroxisomal fission. PMID:23628762

  2. Recurrent Episodes of Stroke-Like Symptoms in a Patient with Charcot-Marie-Tooth Neuropathy X Type 1

    PubMed Central

    Wu, Ning; Said, Sarita; Sabat, Shyamsunder; Wicklund, Matthew; Stahl, Mark C.

    2015-01-01

    Charcot-Marie-Tooth disease (CMT), also known as hereditary motor sensory neuropathy, is a heterogeneous group of disorders best known for causing inherited forms of peripheral neuropathy. The X-linked form, CMTX1, is caused by mutations in the gap junction protein beta 1 (GJB1) gene, expressed both by peripheral Schwann cells and central oligodendrocytes. Central manifestations are known but are rare, and there are few case reports of leukoencephalopathy with transient or persistent neurological deficits in patients with this CMT subtype. Here, we report the case of a man with multiple male and female family members affected by neuropathy who carries a pathologic mutation in GJB1. He has experienced three transient episodes with variable neurological deficits over the course of 7 years with corresponding changes on magnetic resonance imaging (MRI). This case illustrates CMT1X as a rare cause of transient neurological deficit and demonstrates the evolution of associated reversible abnormalities on MRI over time. To the best of our knowledge, this report provides the longest period of serial imaging in a single patient with this condition in the English language literature. PMID:26955336

  3. Mechanism, Prevalence, and More Severe Neuropathy Phenotype of the Charcot-Marie-Tooth Type 1A Triplication

    PubMed Central

    Liu, Pengfei; Gelowani, Violet; Zhang, Feng; Drory, Vivian E.; Ben-Shachar, Shay; Roney, Erin; Medeiros, Adam C.; Moore, Rebecca J.; DiVincenzo, Christina; Burnette, William B.; Higgins, Joseph J.; Li, Jun; Orr-Urtreger, Avi; Lupski, James R.

    2014-01-01

    Copy-number variations cause genomic disorders. Triplications, unlike deletions and duplications, are poorly understood because of challenges in molecular identification, the choice of a proper model system for study, and awareness of their phenotypic consequences. We investigated the genomic disorder Charcot-Marie-Tooth disease type 1A (CMT1A), a dominant peripheral neuropathy caused by a 1.4 Mb recurrent duplication occurring by nonallelic homologous recombination. We identified CMT1A triplications in families in which the duplication segregates. The triplications arose de novo from maternally transmitted duplications and caused a more severe distal symmetric polyneuropathy phenotype. The recombination that generated the triplication occurred between sister chromatids on the duplication-bearing chromosome and could accompany gene conversions with the homologous chromosome. Diagnostic testing for CMT1A (n = 20,661 individuals) identified 13% (n = 2,752 individuals) with duplication and 0.024% (n = 5 individuals) with segmental tetrasomy, suggesting that triplications emerge from duplications at a rate as high as ∼1:550, which is more frequent than the rate of de novo duplication. We propose that individuals with duplications are predisposed to acquiring triplications and that the population prevalence of triplication is underascertained. PMID:24530202

  4. Autosomal recessive MFN2-related Charcot-Marie-Tooth disease with diaphragmatic weakness: Case report and literature review.

    PubMed

    Tan, Christopher A; Rabideau, Marina; Blevins, Amy; Westbrook, Marjorie Jody; Ekstein, Tali; Nykamp, Keith; Deucher, Anne; Harper, Amy; Demmer, Laurie

    2016-06-01

    Pathogenic variants in the mitofusin 2 gene (MFN2) are the most common cause of autosomal dominant Charcot-Marie-Tooth (CMT2) disease, which is typically characterized by axonal sensorimotor neuropathy. We report on a 7-month-old white female with hypotonia, motor delay, distal weakness, and motor/sensory axonal neuropathy in which next-generation sequencing analysis identified compound heterozygous pathogenic variants (c.2054_2069_1170del and c.392A>G) in MFN2. A review of the literature reveals that sporadic and familial cases of compound heterozygous or homozygous pathogenic MFN2 variants have been infrequently described, which indicates that MFN2 can also be inherited in a recessive manner. This case highlights several clinical findings not typically associated with MFN2 pathogenic variants, including young age of onset and rapidly progressing diaphragmatic paresis that necessitated tracheostomy and mechanical ventilation, and adds to the growing list of features identified in autosomal recessive MFN2-related CMT2. Our patient with MFN2-related CMT2 expands the clinical and mutational spectrum of individuals with autosomal recessive CMT2 and identifies a new clinical feature that warrants further observation. © 2016 Wiley Periodicals, Inc. PMID:26955893

  5. An essential role of MAG in mediating axon-myelin attachment in Charcot-Marie-Tooth 1A disease

    PubMed Central

    Kinter, Jochen; Lazzati, Thomas; Schmid, Daniela; Zeis, Thomas; Erne, Beat; Lützelschwab, Roland; Steck, Andreas J.; Pareyson, Davide; Peles, Elior; Schaeren-Wiemers, Nicole

    2012-01-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary demyelinating peripheral neuropathy caused by the duplication of the PMP22 gene. Demyelination precedes the occurrence of clinical symptoms that correlate with axonal degeneration. It was postulated that a disturbed axon-glia interface contribute to altered myelination consequently leading to axonal degeneration. In this study, we examined the expression of MAG and Necl4, two critical adhesion molecules that are present at the axon-glia interface, in sural nerve biopsies of CMT1A patients and in peripheral nerves of mice overexpressing human PMP22, an animal model for CMT1A. We show an increase in the expression of MAG and a strong decrease of Necl4 in biopsies of CMT1A patients as well as in CMT1A mice. Expression analysis revealed that MAG is strongly upregulated during peripheral nerve maturation, whereas Necl4 expression remains very low. Ablating MAG in CMT1A mice results in separation of axons from their myelin sheath. Our data show that MAG is important for axon-glia contact in a model for CMT1A, and suggest that its increased expression in CMT1A disease has a compensatory role in the pathology of the disease. Thus, we demonstrate that MAG together with other adhesion molecules such as Necl4 is important in sustaining axonal integrity. PMID:22940629

  6. PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease.

    PubMed

    Azzedine, Hamid; Zavadakova, Petra; Planté-Bordeneuve, Violaine; Vaz Pato, Maria; Pinto, Nuno; Bartesaghi, Luca; Zenker, Jennifer; Poirot, Olivier; Bernard-Marissal, Nathalie; Arnaud Gouttenoire, Estelle; Cartoni, Romain; Title, Alexandra; Venturini, Giulia; Médard, Jean-Jacques; Makowski, Edward; Schöls, Ludger; Claeys, Kristl G; Stendel, Claudia; Roos, Andreas; Weis, Joachim; Dubourg, Odile; Leal Loureiro, José; Stevanin, Giovanni; Said, Gérard; Amato, Anthony; Baraban, Jay; LeGuern, Eric; Senderek, Jan; Rivolta, Carlo; Chrast, Roman

    2013-10-15

    Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4. Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles. Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families. Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance. Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cells. PMID:23777631

  7. Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach

    PubMed Central

    Zimoń, Magdalena; Battaloǧlu, Esra; Parman, Yesim; Erdem, Sevim; Baets, Jonathan; De Vriendt, Els; Atkinson, Derek; Almeida-Souza, Leonardo; Deconinck, Tine; Ozes, Burcak; Goossens, Dirk; Cirak, Sebahattin; Van Damme, Philip; Shboul, Mohammad; Voit, Thomas; Van Maldergem, Lionel; Dan, Bernard; El-Khateeb, Mohammed S.; Guergueltcheva, Velina; Lopez-Laso, Eduardo; Goemans, Nathalie; Masri, Amira; Züchner, Stephan; Timmerman, Vincent; Topaloǧlu, Haluk; De Jonghe, Peter

    2016-01-01

    Autosomal recessive forms of Charcot-Marie-Tooth disease (ARCMT) are rare but severe disorders of the peripheral nervous system. Their molecular basis is poorly understood due to the extensive genetic and clinical heterogeneity, posing considerable challenges for patients, physicians, and researchers. We report on the genetic findings from a systematic study of a large collection of 174 independent ARCMT families. Initial sequencing of the three most common ARCMT genes (ganglioside-induced differentiation protein 1—GDAP1, SH3 domain and tetratricopeptide repeats-containing protein 2—SH3TC2, histidine-triad nucleotide binding protein 1—HINT1) identified pathogenic mutations in 41 patients. Subsequently, 87 selected nuclear families underwent single nucleotide polymorphism (SNP) genotyping and homozygosity mapping, followed by targeted screening of known ARCMT genes. This strategy provided molecular diagnosis to 22 % of the families. Altogether, our unbiased genetic approach identified pathogenic mutations in ten ARCMT genes in a total of 41.3 % patients. Apart from a newly described founder mutation in GDAP1, the majority of variants constitute private molecular defects. Since the gene testing was independent of the clinical phenotype of the patients, we identified mutations in patients with unusual or additional clinical features, extending the phenotypic spectrum of the SH3TC2 gene. Our study provides an overview of the ARCMT genetic landscape and proposes guidelines for tackling the genetic heterogeneity of this group of hereditary neuropathies. PMID:25231362

  8. Genetics of Charcot-Marie-Tooth (CMT) Disease within the Frame of the Human Genome Project Success

    PubMed Central

    Timmerman, Vincent; Strickland, Alleene V.; Züchner, Stephan

    2014-01-01

    Charcot-Marie-Tooth (CMT) neuropathies comprise a group of monogenic disorders affecting the peripheral nervous system. CMT is characterized by a clinically and genetically heterogeneous group of neuropathies, involving all types of Mendelian inheritance patterns. Over 1,000 different mutations have been discovered in 80 disease-associated genes. Genetic research of CMT has pioneered the discovery of genomic disorders and aided in understanding the effects of copy number variation and the mechanisms of genomic rearrangements. CMT genetic study also unraveled common pathomechanisms for peripheral nerve degeneration, elucidated gene networks, and initiated the development of therapeutic approaches. The reference genome, which became available thanks to the Human Genome Project, and the development of next generation sequencing tools, considerably accelerated gene and mutation discoveries. In fact, the first clinical whole genome sequence was reported in a patient with CMT. Here we review the history of CMT gene discoveries, starting with technologies from the early days in human genetics through the high-throughput application of modern DNA analyses. We highlight the most relevant examples of CMT genes and mutation mechanisms, some of which provide promising treatment strategies. Finally, we propose future initiatives to accelerate diagnosis of CMT patients through new ways of sharing large datasets and genetic variants, and at ever diminishing costs. PMID:24705285

  9. Misclassification and linkage of hereditary sensory and autonomic neuropathy type 1 as Charcot-Marie-Tooth disease, Type 2B

    SciTech Connect

    Vance, J.M.; Speer, M.C.; Stajich, J.M.

    1996-07-01

    Recently Kwon et al. published in the Journal their work describing linkage of a single large family with an inherited axonal neuropathy to chromosome 3, which they suggest is a second locus for Charcot-Marie-Tooth (CMT) type 2 and subsequently named {open_quotes}CMT2B.{close_quotes} We think that the diagnostic classification of this family as CMT2 is incorrect, since the subjects have a severe sensory neuropathy that fits within the hereditary sensory and autonomic neuropathy (HSAN) type 1 classification of Dyck (1993). Abnormal sensory findings in CMT2 separate it from distal spinal muscular atrophy but are a minor component of clinical symptoms in most CMT patients, as CMT is primarily a motor neuropathy. When Kwon et al. state that {open_quotes}all [patients] had characteristic findings in their physical examinations, including... evidence of foot sores that were slow to heal, or amputated limbs related to the poorly healing foot ulcers,{close_quotes} it suggests that a different diagnosis is more appropriate. In our experience collecting data on >950 individuals in >60 CMT1, CMT2, CMTX and CMT4 families, we have not seen foot ulcers, osteomyelitis, or amputations. Ulcerations leading to osteomyelitis and amputations are usually associated with severe sensory neuropathies. 16 refs., 1 tab.

  10. DGAT2 Mutation in a Family with Autosomal-Dominant Early-Onset Axonal Charcot-Marie-Tooth Disease.

    PubMed

    Hong, Young Bin; Kang, Junghee; Kim, Ji Hyun; Lee, Jinho; Kwak, Geon; Hyun, Young Se; Nam, Soo Hyun; Hong, Hyun Dae; Choi, Yu-Ri; Jung, Sung-Chul; Koo, Heasoo; Lee, Ji Eun; Choi, Byung-Ok; Chung, Ki Wha

    2016-05-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy and is a genetically and clinically heterogeneous disorder. We examined a Korean family in which two individuals had an autosomal-dominant axonal CMT with early-onset, sensory ataxia, tremor, and slow disease progression. Pedigree analysis and exome sequencing identified a de novo missense mutation (p.Y223H) in the diacylglycerol O-acyltransferase 2 (DGAT2) gene. DGAT2 encodes an endoplasmic reticulum-mitochondrial-associated membrane protein, acyl-CoA:diacylglycerol acyltransferase, which catalyzes the final step of the triglyceride (TG) biosynthesis pathway. The patient showed consistently decreased serum TG levels, and overexpression of the mutant DGAT2 significantly inhibited the proliferation of mouse motor neuron cells. Moreover, the variant form of human DGAT2 inhibited the axonal branching in the peripheral nervous system of zebrafish. We suggest that mutation of DGAT2 is the novel underlying cause of an autosomal-dominant axonal CMT2 neuropathy. This study will help provide a better understanding of the pathophysiology of axonal CMT and contribute to the molecular diagnostics of peripheral neuropathies. PMID:26786738

  11. Occurrence of Optic Neuritis and Cervical Cord Schwannoma with Charcot-Marie-Tooth Type 4B1 Disease

    PubMed Central

    Scott, Patrick; Bruwer, Zandre; Al-Kharusi, Khalsa; Meftah, Douja; Al-Murshedi, Fathiya

    2016-01-01

    Charcot-Marie-Tooth neuropathy type 4B1 (CMT4B1) disease is a rare subtype of CMT4 with reported association of facial weakness, vocal cord paresis, chest deformities, and claw hands. We report the unusual occurrence of optic neuritis and cervical cord schwannoma in a male individual with confirmed CMT4B1 disease. Sequencing of the MTMR2 gene revealed a novel nonsense homozygous mutation c.1768C>T (p.Gln590*). The mutation was identified in affected relatives of the proband and a second, apparently unrelated, family. The rare association of optic neuritis or schwannoma with genetically confirmed CMT1A has been individually observed, but never with recessive CMT. To the best of our knowledge, the occurrence of optic neuritis and cervical cord schwannoma in the same patient has never been reported with any form of CMT including CMT4B1. In similar cases, we recommend immediate medical attention to rule out the possibility of schwannomas in patients with all demyelinating CMT subtypes in case of the development of focal neurological signs or acute worsening of clinical status. PMID:27162595

  12. Bicyclic-Capped Histone Deacetylase 6 Inhibitors with Improved Activity in a Model of Axonal Charcot-Marie-Tooth Disease.

    PubMed

    Shen, Sida; Benoy, Veronick; Bergman, Joel A; Kalin, Jay H; Frojuello, Mariana; Vistoli, Giulio; Haeck, Wanda; Van Den Bosch, Ludo; Kozikowski, Alan P

    2016-02-17

    Charcot-Marie-Tooth (CMT) disease is a disorder of the peripheral nervous system where progressive degeneration of motor and sensory nerves leads to motor problems and sensory loss and for which no pharmacological treatment is available. Recently, it has been shown in a model for the axonal form of CMT that histone deacetylase 6 (HDAC6) can serve as a target for the development of a pharmacological therapy. Therefore, we aimed at developing new selective and activity-specific HDAC6 inhibitors with improved biochemical properties. By utilizing a bicyclic cap as the structural scaffold from which to build upon, we developed several analogues that showed improved potency compared to tubastatin A while maintaining excellent selectivity compared to HDAC1. Further screening in N2a cells examining both the acetylation of α-tubulin and histones narrowed down the library of compounds to three potent and selective HDAC6 inhibitors. In mutant HSPB1-expressing DRG neurons, serving as an in vitro model for CMT2, these inhibitors were able to restore the mitochondrial axonal transport deficits. Combining structure-based development of HDAC6 inhibitors, screening in N2a cells and in a neuronal model for CMT2F, and preliminary ADMET and pharmacokinetic profiles, resulted in the selection of compound 23d that possesses improved biochemical, functional, and druglike properties compared to tubastatin A. PMID:26599234

  13. Mapping of the chromosome 1p36 region surrounding the Charcot-Marie-Tooth disease type 2A locus

    SciTech Connect

    Denton, P.; Gere, S.; Wolpert, C.

    1994-09-01

    Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy. Although CMT2 is clinically indistinguishable from CMT1, the two forms can be differentiated by pathological and neurophysiological methods. We have established one locus, CMT2A on chromosome 1p36, and have established genetic heterogeneity. This locus maps to the region of the deletions associated with neuroblastoma. We have now identified an additional 11 CMT2 families. Three families are linked to chromosome 1p36 while six families are excluded from this region. Another six families are currently under analysis and collection. To date the CMT2A families represent one third of those CMT2 families examined. We have established a microdissection library of the 1p36 region which is currently being characterized for microsatellite repeats and STSs using standard hybridization techniques and a modified degenerate primer method. In addition, new markers (D1S253, D1S450, D1S489, D1S503, GATA27E04, and GATA4H04) placed in this region are being mapped using critical recombinants in the CEPH reference pedigrees. Fluorescent in situ hybridization (FISH) has been used to confirm mapping. A YAC contig is being assembled from the CEPH megabase library using STSs to isolate key YACs which are extended by vectorette end clone and Alu-PCR. These findings suggest that the CMT2 phenotype is secondary to at least two different genes and demonstrates further heterogeneity in the CMT phenotype.

  14. Grizzly bear denning chronology and movements in the Greater Yellowstone Ecosystem

    USGS Publications Warehouse

    Haroldson, Mark A.; Ternent, Mark A.; Gunther, Kerry A.; Schwartz, Charles C.

    2002-01-01

    Den entrance and emergence dates of grizzly bears (Ursus arctos) in the Greater Yellowstone Ecosystem are important to management agencies that wish to minimize impacts of human activities on bears. Current estimates for grizzly bear denning events use data that were collected from 1975–80. We update these estimates by including data obtained from 1981–99. We used aerial telemetry data to estimate week of den entry and emergence by determining the midpoint between the last known active date and the first known date denned, as well as the last known date denned and the first known active date. We also investigated post emergence movement patterns relative to den locations. Mean earliest and latest week of den entry and emergence were also determined. Den entry for females began during the fourth week in September, with 90% denned by the fourth week of November. Earliest den entry for males occurred during the second week of October, with 90% denned by the second week of December. Mean week of den entry for known pregnant females was earlier than males. Earliest week of den entry for known pregnant females was earlier than other females and males. Earliest den emergence for males occurred during the first week of February, with 90% of males out of dens by the fourth week of April. Earliest den emergence for females occurred during the third week of March; by the first week of May, 90% of females had emerged. Male bears emerged from dens earlier than females. Denning period differed among classes and averaged 171 days for females that emerged from dens with cubs, 151 days for other females, and 131 days for males. Known pregnant females tended to den at higher elevations and, following emergence, remained at higher elevation until late May. Females with cubs remained relatively close (<3 km) to den sites until the last 2 weeks in May. Timing of denning events was similar to previous estimates for this and other grizzly bear populations in the southern Rocky

  15. Assessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy.

    PubMed

    Lupo, Vincenzo; García-García, Francisco; Sancho, Paula; Tello, Cristina; García-Romero, Mar; Villarreal, Liliana; Alberti, Antonia; Sivera, Rafael; Dopazo, Joaquín; Pascual-Pascual, Samuel I; Márquez-Infante, Celedonio; Casasnovas, Carlos; Sevilla, Teresa; Espinós, Carmen

    2016-03-01

    Charcot-Marie-Tooth disease is characterized by broad genetic heterogeneity with >50 known disease-associated genes. Mutations in some of these genes can cause a pure motor form of hereditary motor neuropathy, the genetics of which are poorly characterized. We designed a panel comprising 56 genes associated with Charcot-Marie-Tooth disease/hereditary motor neuropathy. We validated this diagnostic tool by first testing 11 patients with pathological mutations. A cohort of 33 affected subjects was selected for this study. The DNAJB2 c.352+1G>A mutation was detected in two cases; novel changes and/or variants with low frequency (<1%) were found in 12 cases. There were no candidate variants in 18 cases, and amplification failed for one sample. The DNAJB2 c.352+1G>A mutation was also detected in three additional families. On haplotype analysis, all of the patients from these five families shared the same haplotype; therefore, the DNAJB2 c.352+1G>A mutation may be a founder event. Our gene panel allowed us to perform a very rapid and cost-effective screening of genes involved in Charcot-Marie-Tooth disease/hereditary motor neuropathy. Our diagnostic strategy was robust in terms of both coverage and read depth for all of the genes and patient samples. These findings demonstrate the difficulty in achieving a definitive molecular diagnosis because of the complexity of interpreting new variants and the genetic heterogeneity that is associated with these neuropathies. PMID:26752306

  16. Duchenne, Charcot and Babinski, three neurologists of La Salpetrière Hospital, and their contribution to concepts of the central organization of motor synergy.

    PubMed

    Clarac, François; Massion, Jean; Smith, Allan M

    2009-11-01

    Many currently accepted notions of motor control originate from a few seminal concepts developed in the latter half of the 19th century (see Bennett and Hacker, 2002). The goal of this review is to retrace some current ideas about motor control back to the thought of three French neurologists of Hospital of the Salpetrière hospital in Paris during the latter half of the 19th century and early 20th century (Fig. 1): Guillaume Duchenne de Boulogne (1806-1875), Jean-Martin Charcot (1825-1893), and Joseph Babinski (1857-1932). A common theoretical and methodological thread unites these three men as Charcot was taught neurology by Duchenne, and Babinski was trained by Charcot. The influential concepts developed by these pioneering French neurologists have been neglected for nearly a century and only rediscovered recently. We intend to highlight how these astute clinicians used their meticulous clinical observations of patients to reveal novel and original perspectives of motor co-ordination. Between 1850 and 1930, all three men played a major role in developing and shaping the entire field of normal and pathological motor control in addition to making important contributions to three major scientific issues; the centralist view of muscle sense, the emerging concept of muscle synergy in voluntary movements and in locomotion and finally the specific role of the cerebellum in muscle synergy. The important contributions of these men will be considered in the context of other significant schools of neurology from other countries. Finally, the concept of cerebellar asynergy as proposed by Babinski anticipated the development of the internal models which much later were able to provide a theoretical basis for understanding the mechanism of learned motor co-ordination involving the cerebellum. PMID:19766718

  17. Raccoon (Procyon lotor) diurnal den use within an intensively managed forest in central West Virginia

    USGS Publications Warehouse

    Owen, Sheldon F.; Berl, Jacob L.; Edwards, John W.; Ford, W. Mark; Wood, Petra Bohall

    2015-01-01

    Intensive forest management may influence the availability of suitable den sites for large den-seeking species, such as Procyon lotor (Raccoon). As part of a Raccoon ecology study on an industrial forest in the Allegheny Mountains of central West Virginia, we radio-tracked 32 Raccoons to 175 diurnal den sites to determine relative use of dens that included cavity trees, rock dens, log piles, slash piles, and exposed limbs. Patterns of den use significantly differed between sexes and among seasons. Overall, we recorded 58 cavity dens in 12 tree species with 7 maternal dens found in 5 tree species. Raccoons selected larger-diameter den trees than available cavity trees and non-cavity trees. Because the abundance of suitable tree cavities is known to influence Raccoon densities and recruitment at fine spatial scales and female Raccoons in this study used tree cavities as maternal den sites, the continued harvest of large-diameter trees (i.e., those capable of developing den cavities) without replacement may impact Raccoon recruitment within intensively managed forests throughout the central Appalachians.

  18. Selection of den sites by black bears in the southern Appalachians

    USGS Publications Warehouse

    Reynolds-Hogland, M. J.; Mitchell, M.S.; Powell, R.A.; Brown, D.C.

    2007-01-01

    We evaluated selection of den sites by American black bears (Ursus americanus) in the Pisgah Bear Sanctuary, western North Carolina, by comparing characteristics of dens at 53 den sites with availability of habitat characteristics in annual home ranges of bears and in the study area. We also tested whether den-site selection differed by sex, age, and reproductive status of bears. In addition, we evaluated whether the den component of an existing habitat model for black bears predicted where bears would select den sites. We found bears selected den sites far from gravel roads, on steep slopes, and at high elevations relative to what was available in both annual home ranges and in the study area. Den-site selection did not differ by sex or age, but it differed by reproductive status. Adult females with cubs preferred to den in areas that were relatively far from gravel roads, but adult females without cubs did not. The habitat model overestimated the value of areas near gravel roads, underestimated the value of moderately steep areas, and did not include elevation as a predictor variable. Our results highlight the importance of evaluating den selection in terms of both use and availability of den characteristics. ?? 2007 American Society of Mammalogists.

  19. A female black bear denning habitat model using a geographic information system

    USGS Publications Warehouse

    Clark, J.D.; Hayes, S.G.; Pledger, J.M.

    1998-01-01

    We used the Mahalanobis distance statistic and a raster geographic information system (GIS) to model potential black bear (Ursus americanus) denning habitat in the Ouachita Mountains of Arkansas. The Mahalanobis distance statistic was used to represent the standard squared distance between sample variates in the GIS database (forest cover type, elevation, slope, aspect, distance to streams, distance to roads, and forest cover richness) and variates at known bear dens. Two models were developed: a generalized model for all den locations and another specific to dens in rock cavities. Differences between habitat at den sites and habitat across the study area were represented in 2 new GIS themes as Mahalanobis distance values. Cells similar to the mean vector derived from the known dens had low Mahalanobis distance values, and dissimilar cells had high values. The reliability of the predictive model was tested by overlaying den locations collected subsequent to original model development on the resultant den habitat themes. Although the generalized model demonstrated poor reliability, the model specific to rock dens had good reliability. Bears were more likely to choose rock den locations with low Mahalanobis distance values and less likely to choose those with high values. The model can be used to plan the timing and extent of management actions (e.g., road building, prescribed fire, timber harvest) most appropriate for those sites with high or low denning potential. 

  20. Efficacy of focal mechanic vibration treatment on balance in Charcot-Marie-Tooth 1A disease: a pilot study.

    PubMed

    Pazzaglia, Costanza; Camerota, F; Germanotta, M; Di Sipio, E; Celletti, C; Padua, L

    2016-07-01

    Patients affected by Charcot-Marie-Tooth (CMT) disease experience an impaired balance. Although the causes of the postural instability are not fully understood, somatosensory system seems to play a key role. Mechanical vibration seems to act on the somatosensory system and to improve its function. The aim of our study was to evaluate the effects of focal mechanical vibration (fMV) on the balance of CMT 1A patients. We enrolled 14 genetically confirmed CMT 1A patients (8 female and 6 male, mean age 492 years, range 32-74, mean duration of disease: 13 years, range 1-30). Patients underwent a 3-day fMV treatment on quadriceps and triceps surae and were evaluated before the treatment as well as 1 week and 1 month after the end of the treatment. The primary outcome measure was the Berg Balance Scale (BBS) and the secondary were the Dynamic Gait Index (DGI), the 6 Min Walking Test (6MWT), the muscular strength of lower limbs, the Quality of Life (QoL) questionnaire and the stabilometric variables. The statistical analysis showed a significant modification of the BBS due to the effect of treatment (p < 0.05). A significant modification was also found in the DGI (p < 0.05). Concerning the stabilometric variables we found significant changes only for the eyes closed condition; in particular, a significant decrease was found in VelocityML (p < 0.05) and Sway path length (p < 0.05). The fMV treatment applied on lower limbs of CMT 1A patients determined an improvement of balance as detected by the BBS. The concurrent improvement of stabilometric variables in the eyes closed condition only suggests that fMV acts mostly on somatosensory afferences. Further studies are needed to confirm these data on a larger sample of CMT patients. PMID:27177999

  1. Exome Sequencing Identifies GNB4 Mutations as a Cause of Dominant Intermediate Charcot-Marie-Tooth Disease

    PubMed Central

    Soong, Bing-Wen; Huang, Yen-Hua; Tsai, Pei-Chien; Huang, Chien-Chang; Pan, Hung-Chuan; Lu, Yi-Chun; Chien, Hsin-Ju; Liu, Tze-Tze; Chang, Ming-Hong; Lin, Kon-Ping; Tu, Pang-Hsien; Kao, Lung-Sen; Lee, Yi-Chung

    2013-01-01

    Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of inherited neuropathies. Mutations in approximately 45 genes have been identified as being associated with CMT. Nevertheless, the genetic etiologies of at least 30% of CMTs have yet to be elucidated. Using a genome-wide linkage study, we previously mapped a dominant intermediate CMT to chromosomal region 3q28–q29. Subsequent exome sequencing of two affected first cousins revealed heterozygous mutation c.158G>A (p.Gly53Asp) in GNB4, encoding guanine-nucleotide-binding protein subunit beta-4 (Gβ4), to cosegregate with the CMT phenotype in the family. Further analysis of GNB4 in an additional 88 unrelated CMT individuals uncovered another de novo mutation, c.265A>G (p.Lys89Glu), in this gene in one individual. Immunohistochemistry studies revealed that Gβ4 was abundant in the axons and Schwann cells of peripheral nerves and that expression of Gβ4 was significantly reduced in the sural nerve of the two individuals carrying the c.158G>A (p.Gly53Asp) mutation. In vitro studies demonstrated that both the p.Gly53Asp and p.Lys89Glu altered proteins impaired bradykinin-induced G-protein-coupled-receptor (GPCR) signaling, which was facilitated by the wild-type Gβ4. This study identifies GNB4 mutations as a cause of CMT and highlights the importance of Gβ4-related GPCR signaling in peripheral-nerve function in humans. PMID:23434117

  2. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies

    PubMed Central

    2014-01-01

    PMP22 related neuropathies comprise (1) PMP22 duplications leading to Charcot-Marie-Tooth disease type 1A (CMT1A), (2) PMP22 deletions, leading to Hereditary Neuropathy with liability to Pressure Palsies (HNPP), and (3) PMP22 point mutations, causing both phenotypes. Overall prevalence of CMT is usually reported as 1:2,500, epidemiological studies show that 20-64% of CMT patients carry the PMP22 duplication. The prevalence of HNPP is not well known. CMT1A usually presents in the first two decades with difficulty walking or running. Distal symmetrical muscle weakness and wasting and sensory loss is present, legs more frequently and more severely affected than arms. HNPP typically leads to episodic, painless, recurrent, focal motor and sensory peripheral neuropathy, preceded by minor compression on the affected nerve. Electrophysiological evaluation is needed to determine whether the polyneuropathy is demyelinating. Sonography of the nerves can be useful. Diagnosis is confirmed by finding respectively a PMP22 duplication, deletion or point mutation. Differential diagnosis includes other inherited neuropathies, and acquired polyneuropathies. The mode of inheritance is autosomal dominant and de novo mutations occur. Offspring of patients have a chance of 50% to inherit the mutation from their affected parent. Prenatal testing is possible; requests for prenatal testing are not common. Treatment is currently symptomatic and may include management by a rehabilitation physician, physiotherapist, occupational therapist and orthopaedic surgeon. Adult CMT1A patients show slow clinical progression of disease, which seems to reflect a process of normal ageing. Life expectancy is normal. PMID:24646194

  3. Novel mutations in the connexin 32 gene associated with X-linked Charcot-Marie-Tooth disease

    SciTech Connect

    Tan, C.; Ainsworth, P. |

    1994-09-01

    Charcot-Marie-Tooth disease is a pathologically and genetically hetergenous group of disorders that cause a progressive neuropathy, defined pathologically by degeneration of the myelin (CMT 1) of the axon (CMT 2) of the peripheral nerves. An X-linked type of the demyelinating form of this disorder (CMT X) has recently been linked to mutations in the connexin 32 (Cx32) gene, which codes for a 284 amino acid gap junction protein found in myelinated peripheral nerve. To date some 7 different mutations in this gene have been identified as being responsible for CMT X. The majority of these predict nonconservative amino acid substitutions, while one is a frameshift mutation which predicts a premature stop at codon 21. We report the results of molecular studies on three further local CMT X kindreds. The Cx32 gene was amplified by PCR in three overlapping fragments 300-450 bp in length using leukocyte-derived DNA as template. These were either sequenced directly using a deaza dGTP sequencing protocol, or were cloned and sequenced using a TA vector. In two of the kindreds the affected members carried a point mutation which was predicted to effect a non-conservative amino acid change within the first transmembrane domain. Both of these mutations caused a restriction site alteration (the loss of an Nla III and the creation of a Pvu II, respectively), and the former mutation was observed to segregate with the clinicial phenotype in affected family members. Affected members of the third kindred, which was a very large multigenerational family that had been extensively studied previously, were shown to carry a point mutation predicted to cause a premature truncation of the Cx32 gene product in the intracellular carboxy terminus. This mutation obliterated an Rsa I site which allowed a rapid screen of several other family members.

  4. The 5' regulatory sequence of the PMP22 in the patients with Charcot-Marie-Tooth disease.

    PubMed

    Sinkiewicz-Darol, Elena; Kabzińska, Dagmara; Moszyńska, Izabela; Kochański, Andrzej

    2010-01-01

    Little is known about the molecular background of clinical variability of Charcot-Marie-Tooth type 1A (CMT1A) disease and hereditary neuropathy with liability to pressure palsies (HNPP). The CMT1A and HNPP disorders result from duplication and deletion of the PMP22 gene respectively. In a series of studies performed on affected animal transgenic models of CMT1A disease, expression of the PMP22 gene (gene dosage) was shown to correlete with severity of CMT course (gene dosage effect). In this study we hypothesized that single nucleotide polymorphisms (SNPs) located within the 5' regulatory sequence of PMP22 gene may be responsible for the CMT1A/HNPP clinical variability. We have sequenced the PMP22 5' upstream regulatory sequence in a group of 45 CMT1A/HNPP patients harboring the PMP22 duplication (37) /deletion (8). We have identified five SNPs in the regulatory sequence of the PMP22 gene. Three of them i.e. -819C>T, -4785G>T, -4800C>T were detected both in the patients and in the control group. Thus, their pathogenic role in the regulation of the expression of the PMP22 gene seems not to be significant. Two SNPs i.e. -4210T>C and -4759T>A were found only in the CMT patients. Their role in the regulation of the PMP22 gene expression can not be excluded. Additionally we have detected the Thr118Met variant in exon 4 of the PMP22 gene, which was previously reported by other authors, in one patient. We conclude that the 5' regulatory sequence of the PMP22 gene is conserved at the nucleotiode level, however rarely occurring SNPs variant in the PMP22 regulatory sequence may be associated with the gene dosage effect. PMID:20842290

  5. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies.

    PubMed

    van Paassen, Barbara W; van der Kooi, Anneke J; van Spaendonck-Zwarts, Karin Y; Verhamme, Camiel; Baas, Frank; de Visser, Marianne

    2014-01-01

    PMP22 related neuropathies comprise (1) PMP22 duplications leading to Charcot-Marie-Tooth disease type 1A (CMT1A), (2) PMP22 deletions, leading to Hereditary Neuropathy with liability to Pressure Palsies (HNPP), and (3) PMP22 point mutations, causing both phenotypes. Overall prevalence of CMT is usually reported as 1:2,500, epidemiological studies show that 20-64% of CMT patients carry the PMP22 duplication. The prevalence of HNPP is not well known. CMT1A usually presents in the first two decades with difficulty walking or running. Distal symmetrical muscle weakness and wasting and sensory loss is present, legs more frequently and more severely affected than arms. HNPP typically leads to episodic, painless, recurrent, focal motor and sensory peripheral neuropathy, preceded by minor compression on the affected nerve. Electrophysiological evaluation is needed to determine whether the polyneuropathy is demyelinating. Sonography of the nerves can be useful. Diagnosis is confirmed by finding respectively a PMP22 duplication, deletion or point mutation. Differential diagnosis includes other inherited neuropathies, and acquired polyneuropathies. The mode of inheritance is autosomal dominant and de novo mutations occur. Offspring of patients have a chance of 50% to inherit the mutation from their affected parent. Prenatal testing is possible; requests for prenatal testing are not common. Treatment is currently symptomatic and may include management by a rehabilitation physician, physiotherapist, occupational therapist and orthopaedic surgeon. Adult CMT1A patients show slow clinical progression of disease, which seems to reflect a process of normal ageing. Life expectancy is normal. PMID:24646194

  6. Pedal bone density, strength, orientation, and plantar loads preceding incipient metatarsal fracture after Charcot neuroarthropathy: 2 case reports

    PubMed Central

    Gutekunst, David J.; Sinacore, David R.

    2014-01-01

    Study Design Case reports Background Charcot neuroarthropathy (CN) is a progressive, non-infective, inflammatory destruction of bones and joints leading to foot deformities and plantar ulceration. Though individuals with CN typically have low areal bone mineral density (aBMD), little is known regarding changes in volumetric bone mineral density (vBMD), bone geometry, joint mal-alignment, and biomechanical loads preceding fracture. Case Description Two females, aged 45 and 54 years at the onset of an acute non-fracture CN event, received regular physical therapy with wound care and total contact casting. Both enrolled in a larger research study that included plantar pressure assessment and quantitative computed tomography (QCT) at enrollment and 3, 6, and 12 months later. The women sustained mid-diaphyseal fifth metatarsal fracture 10–11 months after enrollment. QCT image analysis techniques were used to measure vBMD; bone geometric indices reflecting strength in compression, bending, and cortical buckling; and 3-dimensional bone-to-bone orientation angles reflecting foot deformity. Outcomes Fifth metatarsal mid-diaphyseal vBMD decreased during off-loading treatment from 0 to 3 months, then increased to above baseline levels by 6 months. All geometric strength indices improved from baseline through 6 months. Plantar loading in the lateral midfoot increased preceding fracture, concomitant with alterations in bone orientation angles which suggest progressive development of metatarsus adductus and equinovarus foot deformity. Discussion Fractures may occur when bone strength decreases or when biomechanical loading increases. Incipient fracture was preceded by increased loading in the lateral midfoot, but not by reductions in vBMD or geometric strength indices, suggesting that loading played a greater role in fracture. Moreover, the progression of foot deformities may be causally linked to the increased plantar loading. Level of evidence Therapy, level 4 PMID:24256173

  7. [An autopsy case of neuronal type Charcot-Marie-Tooth disease (HMSN type II) with nerve deafness and psychiatric symptoms].

    PubMed

    Yoshimura, I; Yoshimura, N; Hanazono, T; Usutani, S; Muramoto, Y; Fukushima, Y

    1992-06-01

    The clinical and pathological findings of a 41-year-old male patient with atypical Charcot-Marie-Tooth disease were reported. There were 3 cases of subarachnoid haemorrhage, 2 nerve deafness and 2 hereditary motor and sensory neuropathy (HMSN) in his family. He had suffered from progressive nerve deafness since 5 years old and gait disturbance since 37 years old. He had been admitted to the psychiatric hospital 3 times because of hallucinatory-delusional state and behavior abnormalities. Neurological examinations at 39 years old revealed that he had mental deterioration (IQ 66), nerve deafness, diffuse muscle atrophy, most marked distally, sensory disturbance, areflexia, positive Romberg's sign, orthostatic hypotension, dysphagia and slurred speech. MCV of median nerve was 27.8 m/sec, and SCV was not evoked. EEG revealed nonspecific dysfunction of the brain. He died of ileus-like condition at 41 years old. General autopsy showed haemorrhagic infarction of the jejunum and ileum due to compression of the superior mesenteric artery and vein by an adhesion band of connective tissue formed after previous appendectomy. Neuropathological examinations revealed axonal degeneration and loss of myelinated fibers with schwannosis of anterior and posterior spinal nerve roots as well as peripheral nerves. The posterior roots were more severely affected than the anterior ones. Ganglion cells of the posterior root ganglia showed remarkable degeneration and loss. There was severe degeneration of the posterior columns, especially in the gracilis, of the spinal cord. Nerve cells in the anterior horns and Clarke's columns also displayed conspicuous atrophy or central chromatolysis followed by gliosis. There was slight degeneration of the posterior spinocerebellar tracts.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1389565

  8. Mutational analysis of the myelin protein zero (MPZ) gene associated with Charcot-Marie-Tooth neuropathy type 1B

    SciTech Connect

    Roa, B.B.; Warner, L.E.; Lupski, J.R.

    1994-09-01

    The MPZ gene that maps to chromosome 1q22q23 encodes myelin protein zero, which is the most abundant peripheral nerve myelin protein that functions as a homophilic adhesion molecule in myelin compaction. Association of the MPZ gene with the dysmyelinating peripheral neuropathies Charcot-Marie-Tooth disease type 1B (CMT1B) and the more severe Dejerine-Sottas syndrome (DSS) was previously demonstrated by MPZ mutations identified in CMT1B and in rare DSS patients. In this study, the coding region of the MPZ gene was screened for mutations in a cohort of 74 unrelated patients with either CMT type 1 or DSS who do not carry the most common CMT1-associated molecular lesion of a 1.5 Mb DNA duplication on 17p11.2-p12. Heteroduplex analysis detected base mismatches in ten patients that were distributed over three exons of MPZ. Direct sequencing of PCR-amplified genomic DNA identified a de novo MPZ mutation associated with CMT1B that predicts an Ile(135)Thr substitution. This finding further confirms the role of MPZ in the CMT1B disease process. In addition, two polymorphisms were identified within the Gly(200) and Ser(228) codons that do not alter the respective amino acid residues. A fourth base mismatch in MPZ exon 3 detected by heteroduplex analysis is currently being characterized by direct sequence determination. Previously, four unrelated patients in this same cohort were found to have unique point mutations in the coding region of the PMP22 gene. The collective findings on CMT1 point mutations could suggest that regulatory region mutations, and possibly mutations in CMT gene(s) apart from the MPZ, PMP22 and Cx32 genes identified thus far, may prove to be significant for a number of CMT1 cases that do not involve DNA duplication.

  9. Peripheral myelin protein 22 gene duplication with atypical presentations: a new example of the wide spectrum of Charcot-Marie-Tooth 1A disease.

    PubMed

    Mathis, Stéphane; Corcia, Philippe; Tazir, Meriem; Camu, William; Magdelaine, Corinne; Latour, Philippe; Biberon, Julien; Guennoc, Anne-Marie; Richard, Laurence; Magy, Laurent; Funalot, Benoît; Vallat, Jean-Michel

    2014-06-01

    Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are both autosomal-dominant disorders linked to peripheral myelin anomalies. CMT1A is associated with a Peripheral Myelin Protein 22 (PMP22) duplication, whereas HNPP is due to a PMP22 deletion on chromosome 17. In spite of this crucial difference, we report three observations of patients with the 1.4 megabase CMT1A duplication and atypical presentation (electrophysiological, clinical or pathological): a 10 year-old girl with tomaculous lesions on nerve biopsy; a 26 year-old woman with recurrent paresthesiae and block conduction on the electrophysiological study; a 46 year-old woman with transient recurrent nerve palsies mimicking HNPP. These observations highlight the wide spectrum of CMT1A and the overlap between CMT1A and HNPP (both linked to the PMP22 gene), and finally illustrate the complexity of the genotype-phenotype correlations in Charcot-Marie-Tooth diseases. PMID:24792522

  10. Long-term analyses of innervation and neuromuscular integrity in the Trembler-J mouse model of Charcot-Marie-Tooth disease.

    PubMed

    Nicks, Jessica Renee; Lee, Sooyeon; Kostamo, Kathryne Ann; Harris, Andrew Benford; Sookdeo, Amanda M; Notterpek, Lucia

    2013-10-01

    A large fraction of hereditary demyelinating neuropathies, classified as Charcot-Marie-Tooth disease type 1A, is associated with misexpression of peripheral myelin protein 22. In this study, we characterized morphologic and biochemical changes that occur with diseaseprogression in neuromuscular tissue of Trembler-J mice, a spontaneous rodent model of Charcot-Marie-Tooth disease type 1A. Using age-matched, 2- and 10-month-old, wild-type and Trembler-J mice, we observed neuromuscular deficits that progress from distal to proximal regions. The impairments in motor performance are underlined by degenerative events at distal nerve segments and structural alterations at nerve-muscle synapses. Furthermore, skeletal muscle of affected mice showed reduced myofiber diameter, increased expression of the muscle atrophy marker muscle ring-finger protein 1, and fiber type switching. A dietary intervention of intermittent fasting attenuated these progressive changes and supported distal nerve myelination and neuromuscular junction integrity. In addition to the well-characterized demyelination aspects of this model, our investigations identified distinct degenerative events in distal nerves and muscle of affected neuropathic mice. Therefore, therapeutic studies aimed at slowing or reversing the neuropathic features of these disorders should include the examination of muscle tissue, as well as neuromuscular contact sites. PMID:24042197