The studies presented in this thesis were undertaken to investigate the cellular and molecular mechanisms responsible for sympathetic hyperactivity that is observed in the Spontaneous Hypertensive Rat (SHR) and whether these abnormalities arise even before the onset of hypertension. Moreover, selected molecular candidates related to oxidative state in cardiac autonomic signalling have been explored for their potential therapeutic effects. <b>Chapter One</b> is an overview of (i) the relevance of autonomic dysfunction in cardiovascular disease in both human and animal models, (ii) the physiological basis of cardiac sympathetic neurotransmission, (iii) the neuromodulators of peripheral cardiac sympathetic-vagal balance discussed along with how they may be involved in cardiac adrenergic control of neurotransmission and NO-cGMP signalling. This develops the formulation of the specific aims of the thesis. <b>Chapter Two</b> outlines a detailed rationale for the experimental approach taken to (i) characterise protein expression in the pre-hypertensive animal model with immunohistochemistry and Western blotting, (ii) manipulate selected gene expression to amplify NO-cGMP signalling in vivo and in vitro via viral gene transfer, (iii) investigate calcium handling in cardiac sympathetic stellate neurons with calcium imaging , (iv) measure cardiac noradrenergic neurotransmission from double atria using radioactive-labelled [³H]-noradrenaline. <b>Chapter Three</b> demonstrated abnormal NO-cGMP signalling in pre-hypertensive SHRs. Endogenous nNOS protein residing in both cardiac parasympathetic and sympathetic neurons was significantly lower in the pre-hypertensive SHR compared to aged-matched WKYs. This was associated with lower cGMP levels. An enhanced depolarization evoked [Ca²⁺]i transient was observed in cardiac stellate neurons from pre-hypertensive SHR when compared with the WKY, an effect that was reversed by nNOS or sGC inhibition. <b>Chapter Four</b> investigated the role of nNOS and brain natriuretic peptide (BNP) in cGMP signalling pathways. Gene transfer of nNOS via adenoviral vector in SHR cardiac sympathetic neurons increased cGMP concentration and normalised neuronal calcium handling during depolarization. BNP significantly reduces [3H]- noradrenaline release. Overexpression of PDE2 which facilitates the breakdown of cGMP caused an increase in [³H]- noradrenaline release in response to field stimulation and also prevented the inhibitory action of BNP. <b>Chapter Five</b> examined the role of the nNOS adaptor protein, CAPON in NO-cGMP signalling. Endogenous CAPON protein is present in cardiac sympathetic neurons in the WKY, and is significantly reduced in pre-hypertensive SHR cardiac neurons. Artificial up-regulation of cardiac sympathetic CAPON via targeted gene transfer directly attenuated neuronal Ca²⁺ transients, resulting in decreased noradrenaline release in the SHR. <b>Chapter Six</b> is a concluding discussion summarising the main findings from this thesis, placing them in a physiological context and discussing avenues for further research.

Postural orthostatic tachycardia syndrome (POTS) is a common yet frequently misdiagnosed dysautonomia characterized by a significant increase in heart rate upon standing. POTS patients experience severe fatigue, dizziness, pre-syncope, and a diminished quality of life. The intent of this thesis is to investigate factors contributing to POTS misdiagnosis and develop a proposal for improving diagnostic procedures. The first part of this thesis presents an overview of other frequently misdiagnosed conditions, providing an understanding of the basis for the diagnostic problems in POTS and methods to combat such difficulties. The second part of this thesis details a meta-analysis performed on POTS clinical studies since its classification in 1993, in an attempt to synthesize current knowledge and potential deficits in research. Results show the misdiagnosis rates for POTS are understandably high, as POTS shares many characteristics with other misdiagnosed conditions. Analysis of these conditions demonstrates the need for easier in-clinic diagnostic tests for POTS. The meta-analysis results demonstrate misunderstanding about POTS remains within the scientific community. The final recommendations to reduce POTS misdiagnosis include using a blood pressure/heart rate screening test to identify patients sooner and shifting research efforts from etiology and treatment to prevalence and diagnostic procedures.

Background: Postural Orthostatic Tachycardia Syndrome (POTS) is a disorder of the autonomic nervous system that has high association with chronic pain syndromes such as fibromyalgia, migraine disorders, and chronic abdominal pain in adolescents with the diagnosis. Many of these disorders are characterized as central sensitization disorders, or pathological pain memory mediated by neural plasticity. Ehlers Danlos Syndrome Type 3 (EDS-3), also called joint hypermobility syndrome (JHS) is a genetic disorder of the connective tissue that causes joint laxity and is also highly associated with chronic pain syndromes as well as POTS. Methods: This study proposed to characterize POTS as a disorder of central sensitization. The hypothesis, presented within the proposed theoretical model, demonstrates that JHS leads to chronic pain that results in central sensitization and autonomic nervous system dysfunction (POTS). Other factors that were evaluated were anxiety and function. A sample size of 40 adolescents between the ages of 12 and 19 years were recruited from the cardiology and pain clinics at Children’s National Medical Center. Analysis of data utilizing Wilcoxon, Chi square, Pearson correlation, and logistic regression tests were completed using SAS 9.3. Results: In comparison to those without POTS, there were no significant associations found between having the diagnosis of POTS and any other variable studied in the model. JHS had a stronger correlation with anxiety, central sensitization, both subjectively, and objectively with hyperalgesia on Aδ sensory nerve fiber when compared to those without JHS. Subjective central sensitization was highly correlated with anxiety, function, age, and female gender. Function and central sensitization had a significant association even when removing anxiety as a covariate. Conclusions: These findings suggest that joint hypermobility may be a factor that contributes to the development of central sensitization in individuals with chronic pain. Dysautonomia is likely not a disorder of central sensitization, but rather a variable related to joint hypermobility and chronic pain in ways yet to be discovered. As previously discussed in other literature, anxiety has strong associations with central sensitization and functional disability in chronic pain syndromes, and when treated effectively may increase function in those that suffer with these disorders.

Mutations found in genes encoding human Elongator complex subunits have been linked to neurodevelopmental disorders such as familial dysautonomia (FD), rolandic epilepsy and amyotrophic lateral sclerosis. In addition, loss-of-function mutations in genes encoding Elongator complex subunits cause defects in neurodevelopment and reduced neuronal function in both mice and nematodes. The Elongator complex is a conserved protein complex comprising six subunits (Elp1p-Elp6p) found in eukaryotes. The primary function of this complex in yeast is formation of the 5-methoxycarbonylmethyl (mcm5) and 5-carbamoylmethyl (ncm5) side chains found on wobble uridines (U34) in tRNAs. The aim of this thesis is to investigate the physiological consequences of Elongator complex inactivation in humans and in the yeast Saccharomyces cerevisiae. Inactivation of the Elongator complex causes widespread defects in a multitude of different cellular processes in S. cerevisiae. Thus, we investigated metabolic alterations resulting from Elongator complex inactivation. We show that deletion of the S. cerevisiae ELP3 gene leads to widespread metabolic alterations. Moreover, all global metabolic alterations observed in the elp3Δ strain are not restored in the presence of elevated levels of hypomodified tRNAs that normally have the modified nucleoside mcm5s2U. Collectively, we show that modified wobble nucleosides in tRNAs are required for metabolic homeostasis. Elongator mutants display sensitivity to DNA damage agents, but the underlying mechanism explaining this sensitivity remains elusive. We demonstrate that deletion of the S. cerevisiae ELP3 gene results in post-transcriptional reduction of Ixr1p levels. Further, we show that the reduced Ixr1p levels prevent adequate Rnr1p levels upon treatment with DNA damage agents. These findings suggest that reduced Ixr1p levels could in part explain why Elongator mutants are sensitive to DNA damage agents. Depletion of Elongator complex subunits results in loss of wobble uridine modifications in plants, nematodes, mice and yeast. Therefore, we investigated whether patients with the neurodegenerative disease familial dysautonomia (FD), who have lower levels of the ELP1 protein, display reduced amounts of modified wobble uridine nucleosides. We show that tRNA isolated from brain tissue and fibroblast cell lines derived from FD patients have 64–71% of the mcm5s2U nucleoside levels observed in total tRNA from non-FD brain tissue and non-FD fibroblasts. Overall, these results suggest that the cause for the neurodegenerative nature of FD could be translation impairment caused by reduced levels of modified wobble uridine nucleosides in tRNAs. Thus, our results give new insight on the importance of modified wobble uridine nucleosides for neurodevelopment.

Characterization of IKAP/hELP1-dependent pathways. Abstract An extensive characterization of the signal transduction pathways is required to better understand how cells respond to various stimuli. While the human genome is completely sequenced, it is still necessary to combine those informations with a full knowledge of the biological roles played by the proteins. Importantly, a deregulation of the signal transduction pathways underlie a variety of human diseases such as cancer or neurodegenerative disorders. IKAP/hELP1 is the largest subunit of Elongator and is required for the functional integrity of this complex. The histone acetyltransferase activity of Elongator helps the transcriptional machinery to move on the template of still poorly characterized genes to transcribe. In yeast, Elongator has also been involved in tRNA modifications as well as in exocytosis. In humans, Familial dysautonomia, an autosomal recessive disease characterized by defects in the development and maintenance of neurons of the autonomic and sensory systems, results from a loss-of-function of IKAP/hELP1. Recent work in our laboratory linked this disease to a cell migration defect of IKAP/hELP1 depleted cells. The aim of this work is to investigate the role of Elongator in signal transduction. In the first part, we wanted to know whether Elongator was required for the regulation of gene expression in response to DNA damage. We demonstrated that some p53-dependent genes were aberrantly expressed upon Elongator deficiency in colon cancer-derived cells. Moreover, we showed that these IKAP/hELP1 depleted cells were not more sensitive to apoptosis in response to persistent DNAdamage. In the second part of this work, to better characterize IKAP/hELP1, we tried to validate its potential interaction with the RanBP2 nucleoporin which is a component of the nuclear pore complex. Given its mainly cytoplasmic localization and its role in the nucleus, we studied the translocation of IKAP/hELP1 between both of these cellular compartments. We determined a potential nuclear export signal on the C-terminal part of IKAP/hELP1. This might allow us to further explore the link between the distinct roles and the localization of the Elongator complex. / Caractérisation des mécanismes moléculaires impliquant la protéine IKAP/hELP1 et le complexe Elongator. Résumé Létude des voies de signalisation permet de mieux comprendre comment une cellule réagit face à divers stimuli. Alors que le génome humain est complètement séquencé, la caractérisation des différentes voies de signalisation cellulaire est à ce jour toujours incomplète et nécessite une meilleure connaissance de leurs principaux acteurs, les protéines. Ceci est dautant plus important quun dérèglement de lactivation de ces voies de signalisation peut conduire à des pathologies aussi diverses que le cancer ou des maladies neurodégénératives. IKAP/hELP1 est la plus grande sous-unité du complexe Elongator et est essentielle pour lassemblage fonctionnel de celui-ci. Le complexe Elongator grâce à son activité dacétylation des histones qui permet laccès à la chromatine, participe à lélongation de la transcription de gènes, ceux-ci restant à ce jour peu caractérisés. Récemment chez la levure, Elongator a été décrit comme prenant part à dautres évènements cellulaires aussi divers que la modification des ARNs de transfert qui permet une traduction fidèle des protéines, ou que lexocytose. Chez lhomme, une neuropathologie génétique, la dysautonomie familiale, est la conséquence directe dune perte de fonction de la protéine IKAP/hELP1. Notre laboratoire a récemment fait le lien entre cette maladie qui affecte le développement et la survie du système nerveux autonome et sensoriel, et un déficit des capacités migratoires de cellules exprimant trop faiblement la protéine IKAP/hELP1. Le but de ce travail est de poursuivre la caractérisation des rôles biologiques du complexe Elongator. Dans la première partie de ce travail, nous avons examiné le rôle dElongator dans la modulation de lexpression de gènes suite à un dommage à lADN. Nous avons pu mettre en évidence une altération du profil dexpression de plusieurs gènes connus pour être sous la dépendance de p53, une protéine activée en réponse à divers signaux de stress, dans des cellules dérivées de cancers du colon et déficientes pour Elongator. De plus, nous avons déterminé que ces cellules déplétées pour IKAP/hELP1 nétaient pas plus sensibles à lapoptose, en réponse ou non à des dommages persistants à lADN. Dans la deuxième partie, nous avons tenté de valider, sur base de résultats obtenus chez la levure, son interaction potentielle avec une protéine du pore nucléaire, RanBP2. Etant donné sa localisation majoritairement cytoplasmique et sa fonction dans le compartiment nucléaire, nous avons étudié le transport dIKAP/hELP1 entre le noyau et le cytoplasme. Nous avons pu déterminer un site dexport nucléaire potentiel sur lextrémité C-terminale dIKAP/hELP1 qui nous permettra dexplorer le lien entre les différentes fonctions et la localisation du complexe Elongator.

La dysautonomie familiale (FD) est une neuropathie causée par une mutation du gène IKBKAP induisant un épissage alternatif du pré-ARNm et une déficience de la protéine IKAP/hELP1. La compréhension des mécanismes moléculaires à l'origine de la spécificité tissulaire et le développement de thérapies curatives nous ont amené à identifier une signature des microARN caractéristique de la FD reliée au facteur d'épissage neurone-spécifique NOVA1, à partir de cellules souches olfactives humaines ecto-mésenchymateuses d'individus sains ou de patients FD. De plus, nous avons identifié le protéasome 26S comme étant suractivé chez les patients et dont le blocage corrige l'épissage aberrant du pré-ARNm d'IKBKAP tout en augmentant l’expression d’IKAP/hELP1. Ainsi, l'ensemble de ce travail apporte des perspectives de recherche novatrices pour de nombreuses pathologies neurodégénératives.Nous avons mené un projet de recherche secondaire concernant l’identification de biomarqueurs sanguins pour une maladie très fréquente, la dépression. Nous avons conduit une étude translationnelle à l'aide d'un modèle animal de stress chronique (UCMS) et identifié des signatures transcriptionnelles communes entre le sang et deux régions cérébrales, le gyrus cingulaire et le gyrus dentelé. Plusieurs biomarqueurs candidats ont été validés sur des échantillons sanguins chez la Souris et l'Homme, avec une corrélation entre la variation d'expression d'ACSL1, RALGPS1 et MPP1 et l'évolution du score clinique des patients. En conclusion, ce travail identifie de nouveaux biomarqueurs potentiels de la dépression et renforce la légitimité d'analyser des tissus périphériques dans le cadre d'une pathologie mentale. / Familial dysautonomia (FD) is a neuropathy caused by a mutation in the IKBKAP gene inducing an alternative pre-mRNA splicing and a deficiency of the protein IKAP/hELP1. The understanding of molecular mechanisms underlying tissue specificity and the development of curative therapies led us to identify a particular microRNA signature in FD associated to the neuron-spécific splicing factor NOVA1, from human olfactory ecto-mesenchymal stem cells of control individuals and FD patients. Moreover, we identified the 26S proteasome as being overactived in patients and whose inhibition corrects aberrant IKBKAP pre-mRNA splicing concomitantly to an increase of IKAP/hELP1 expression level. Taken together, these results bring innovative research perspectives for many neurodegenerative diseases.We conducted a secondary project concerning the identification of blood biomarker for a very prevalent disease, major depression. We conducted a translational study using animal model of chronic stress (UCMS) and identified common transcriptional signatures between blood and two brain regions, cingulate gyrus and dentate gyrus. Several candidate biomarkers were validated as similarly dysregulated in blood of mice and men, with correlation of expression variation of ACSL1, RALGPS1 and MPP1 in relation to clinical score evolution. In conclusion, this work identifies new potential biomarkers for depression and reinforces the legitimacy to analyze peripheral tissues in the context of mental disorders.

The relationship between autonomic dysfunction and primary headache disorders has been established in the adult population. The aim of this retrospective study was to elucidate if there was a similar association in the pediatric primary headache population. Three groups were compared - migraine patients, tension-type headache patients and idiopathic scoliosis patients as a control group. Utilizing clinical data collected during patients' initial visits, prevalence of autonomic dysfunction symptoms were quantified. The headache groups also filled out the Functional Disability Index (FDI) as well as the Children's Depression Inventory (CDI) to help elucidate if there was a relationship between function disability, psychiatric state and primary headaches and/or autonomic dysfunction symptoms. It was found that the headache groups had significantly greater dysautonomia as compared to the control group. Only slight differences were found between the migraine and tension-type patients in regards to dysautonomia. No significant differences were found in total FDI or CDI scores. These results illuminate a relationship between autonomic nervous system dysfunction and primary headache disorders in the pediatric population studied. Prospective studies and the development of standardized dysautonomia questionnaires will allow a more detailed autonomic dysfunction profile to be built for this population.

Introduction - Pure autonomic failure is a rare disorder characterized by orthostatic hypotension, absence of a compensatory rise in heart rate, and abnormal autonomic functions. In most cases, supine hypertension is seen coupled with orthostatic hypotension, making the management of these patients a big challenge. We present the case of a 74-year-old gentleman, who presented to the ED with altered mental status for a day; weakness, and falls for 3 weeks. The patient had a past medical history of Hypertension, alcoholism, and REM sleep disorder. He was being treated for erectile dysfunction for the last 10 years and had a family history of Parkinson's disease in his mother and sister. The patient was compliant with Lisinopril 40 mg, Amlodipine, and Rosuvastatin, Tamsulosin 0.4 mg. His blood pressure(BP) on presentation was ranging between 109/74-194/76 mm of Hg. Systolic BP dropped by 30mmHg after tilting the angle of the bed to 45 degrees for 1 minute with no change in HR and the patient became symptomatic in this position. Orthostatic vitals showed a dramatic drop in Systolic BP of >80mmHg with no change in heart rate. MRA and MRI showed chronic microvascular changes. The Echocardiogram, Cortisol, and TSH levels were all normal. All anti-hypertensives were discontinued and supportive treatment was started with Midodrine, Droxidopa, and Pyridostigmine, thigh-high TED hose and abdominal binders at bedtime, and Nitroglycerin patch at night for hypertension. The patient was started on fludrocortisone as he continued to drop his BP by 80 mmHg on standing. The use of TED stockings and bed tilting improved the issue of uncontrolled supine hypertension at night. Conclusion- Treatment of autonomic dysfunction continues to be challenging. There are no definitive guidelines and management is largely individualized. Both pharmacological and non-pharmacological measures are used.

Les fonctions cardiovasculaires doivent répondre à des stimulations physiologiques importantes et différentes lors de l'exercice physique, de l'exposition à la haute altitude ou de tests de stimulation spécifiques du système nerveux autonome. Nous avons dans ce travail de thèse, étudié les modulations autonomiques consécutives à l'exercice (entraînements / compétition ou réentraînement), à l'hypoxie ou à des tests de stimulation adrénergiques afin de faire le lien avec la fatigue et/ou la limitation à l'effort. Le suivi de coureurs à pieds séniors nous a permis d'observer une majoration de l'activité sympathique ainsi qu'une diminution du tonus parasympathique sous l'effet de l'entraînement, et plus encore de la compétition. Dans un second temps, nous avons analysé les réponses adaptatives de sujets exposés à une hypoxie brutale par le biais de tests d'orthostatisme, et mis en évidence une dysautonomie transitoire les deux premiers jours d'exposition à l'altitude, suivie d'un retour vers des valeurs basales le quatrième jour. Notre troisième protocole a montré que les fibromyalgiques présentent une qualité de vie et une capacité d'exercice altérées ainsi que des réponses autonomiques à l'orthostatisme émoussées comparées à des sujets témoins. Cependant, un entraînement en endurance de 12 semaines à intensité modérée, semble bénéfique sur la qualité de vie des patientes, et améliore les paramètres d'exercice et de modulation de l'activité du système nerveux. Enfin, nous avons confirmé que les sujets trisomiques présentaient une capacité d'exercice ainsi qu'une fonction cardio-respiratoire altérées par rapport à des sujets contrôles appariés en âge. Les tests de stimulations du système nerveux autonome montrent aussi une dysautonomie marquée, avec des réponses autonomiques émoussées qui peuvent être mises en lien avec une capacité d'effort limitée et/ou l'apparition d'une fatigue précoce à l'effort chez les trisomiques 21. Notre travail, par l'analyse de la variabilité cardiaque, a donc permis de mettre en évidence des altérations de l'activité autonomique qui peuvent être durables ou transitoires, selon l'environnement, selon le niveau d'activité ou l'existence de pathologies. / Cardiovascular functions have to answer to important physiological stimulations during physical activity, high altitude exposure, or specific stimulation tests of the autonomic nervous system. In this thesis work, we studied autonomic modulations after exercise (training/competition or retraining), hypoxia or adrenergic stimulation tests in order to link them with fatigue and/or effort limitation. Senior runners' follow-up allowed us to observe an increase in sympathetic activity and also a decrease in parasympathetic tone with training and particularly competition. In a second time, we analyzed the adaptive responses of subjects exposed to rough hypoxia through orthostatic tests and we highlighted a transitional dysautonomia during the first two days of altitude exposure followed by a return to basal values on the fourth day. Our third protocol has demonstrated that fibromyalgic patients show altered life quality and exercise capacity and also blunted autonomic responses to orthostatism compared to control subjects. However, twelve weeks of endurance training in moderate intensity seems to be beneficial on patients' life quality and improves exercise parameters and modulation of the activity of the nervous system. Finally, we have confirmed that subjects with Down syndrome showed altered exercise capacity and cardio-respiratory function in comparison to aged matched control subjects. Stimulation tests of the autonomic nervous system also show a marked dysautonomia with blunted autonomic responses, which can be linked to a limited effort capacity and/or to the appearance of an early fatigue to exercise in subjects with Down syndrome. Our work, thanks to cardiac variability analysis highlighted alterations in autonomic activity, which could be lasting or transient, depending on the environment, the activity level or the existence of pathologies.

Les neuropathies des petites fibres (NPF), ou neuropathies douloureuses, se caractérisent par des douleurs neuropathiques et une dysautonomie, symptômes particulièrement invalidant et dont la prise en charge thérapeutique actuelle n’est pas satisfaisante. La biopsie cutanée, actuel examen « gold standard » dans le diagnostic des NPF, est un outil intéressant du fait de sa simplicité de réalisation sans séquelle, et de son accessibilité. Cependant, son interprétation actuelle est limitée, n’apportant qu’une information quantitative sur l’existence ou non d’une perte en fibres intra-épidermiques, résultante des NPF plus qu’une explication de la symptomatologie. Dans une première étude nous avons comparé la quantification des fibres de la biopsie cutanée à leur analyse fonctionnelle explorée par le SUDOSCAN®, ne retrouvant qu’une faible corrélation entre les deux outils et confirmant le mauvais reflet de la fonctionnalité des fibres dans la biopsie cutanée. De plus, dans une deuxième étude sur les patients Charcot-Marie-Tooth 1A, nous n’avons pas mis en évidence de corrélation entre la biopsie cutanée et les symptômes (sauf la sensibilité à la piqûre), soulignant une nouvelle faiblesse de cet examen. Concernant les biomarqueurs cutanées, l’analyse des cellules de Langherans dans différentes neuropathies a retrouvé une augmentation de celles-ci chez les patients diabétiques et une densité plus faible chez les sujets sains, mais également une diminution chez le patient CMT1A, sans jamais aucune corrélation avec la densité des petites fibres. Enfin, dans une troisième partie étudiant le syndrome POEMS, nous avons mise en évidence que la vascularisation cutanée, significativement plus élevée dans le POEMS, serait un biomarqueur candidat intéressant à visée diagnostique étiologique. La recherche de biomarqueurs cutanés, afin d’augmenter la puissance diagnostique, de mieux comprendre la physiopathologie de la perte en fibres pour de trouver des cibles thérapeutiques et améliorer la prise en charge de ces patients, parait essentielle. Des études supplémentaires sont nécessaires, et certaines sont en cours dans la continuité de ce travail. / Small-fiber neuropathies (SFN), or painful neuropathies, are characterized by neuropathic pain and autonomic dysfunction, which are particularly disabling symptoms and whose current therapeutic management is not satisfactory. The skin biopsy, which is the "gold standard" in the SFN diagnosis, is an interesting easy to do and accessible. However, its current interpretation is limited, bringing only a quantitative information: there is a loss of intraepidermic nerve fibers, resulting from SFN more than an explanation of the symptomatology. In a first study, we compared the quantification of skin biopsy fibers with their functional analysis explored by SUDOSCAN®. We found a weak correlation between the two tools, confirming that skin biopsy is not a good reflet of fibers function. Nevertheless, in a second study on Charcot-Marie-Tooth 1A patients, we found a correlation between cutaneous biopsy and sensitivity to sting, sensitivity transmitted by small fibers. Regarding cutaneous biomarkers, analysis of Langherans cells in different neuropathies found an increase in these in diabetic patients and a lower density in healthy subjects, but also a decrease in patients affected with CMT1A, without ever having any correlation with small nerve fibers density. Finally, in a third part studying the POEMS syndrome, we found that the dermal vascularization, which is significantly higher in POEMS, would be an interesting candidate biomarker for etiological diagnostic purposes. The search for skin biomarkers to improve the diagnosis and to better understand the pathophysiology of fiber loss in order to find therapeutic targets to improve the management of these patients seems essential. Additional studies are needed, and some are ongoing as a continuation of this work.