Friedreichs ataxia (FRDA) is a progressive spinocerebellar ataxia (SCA) inherited as an autosomal recessive trait. The neurodegeneration, cardiomyopathy, diabetes mellitus and skeletal deformities characteristic to FRDA result from a deficiency in the mitochondrial protein frataxin. Frataxin chaperones iron to heme and iron-sulfur clusters and its deficiency causes mitochondrial iron accumulation and oxidative stress.<p> To address the effect of frataxin deficiency on mitochondrial iron chemistry, mitochondria were isolated from FRDA and control fibroblasts. X-ray absorption spectroscopy showed that ferrihydrite was the predominant form of iron in both. Near edge analysis showed that the ferrihydrite in the FRDA mitochondria resembled the highly organized ferrihydrite of ferritin. Western blotting confirmed that FRDA mitochondria had 3-fold more holoferritin containing stainable iron. I conclude that mitochondria from FRDA fibroblasts mineralize excess iron as ferrihydrite within mitochondrial ferritin.<p> To address how cellular iron dysregulation affected metal distribution in brain and spinal cord, a new synchrotron imaging technique, rapid-scanning x-ray fluorescence (RS-XRF) was employed and validated. Brain structures were readily identified by their unique metal content and distribution. This showed that RS-XRF could be used to reveal metal pathologies associated with diseases of metal metabolism such as FRDA. Since human FRDA tissues were not available for a detailed study, RS-XRF was employed to study the distribution of metals in normal cerebellum, a major site of FRDA-associated neurodegeneration, and to localize and quantify metals in the brain and spinal cord from a patient with a SCA of unknown aetiology. The motivation for this work is the prospect of future systematic studies on metal pathology in neurodegenerative diseases with direct application to FRDA. Novel findings arising from this work were the metal segmentation of the dentate nucleus, the high copper content of the olivary region and the different metal content of lesions at different stages of neurodegeneration. My results suggest that not only iron, but also copper and zinc may play a role in the physiopathology of neurodegeneration. Therefore, all three metals should be investigated in FRDA and other SCA of both known and unknown aetiologies to identify possible new therapeutic targets.

Friedreichs ataxia (FRDA) is a progressive spinocerebellar ataxia (SCA) inherited as an autosomal recessive trait. The neurodegeneration, cardiomyopathy, diabetes mellitus and skeletal deformities characteristic to FRDA result from a deficiency in the mitochondrial protein frataxin. Frataxin chaperones iron to heme and iron-sulfur clusters and its deficiency causes mitochondrial iron accumulation and oxidative stress.<p> To address the effect of frataxin deficiency on mitochondrial iron chemistry, mitochondria were isolated from FRDA and control fibroblasts. X-ray absorption spectroscopy showed that ferrihydrite was the predominant form of iron in both. Near edge analysis showed that the ferrihydrite in the FRDA mitochondria resembled the highly organized ferrihydrite of ferritin. Western blotting confirmed that FRDA mitochondria had 3-fold more holoferritin containing stainable iron. I conclude that mitochondria from FRDA fibroblasts mineralize excess iron as ferrihydrite within mitochondrial ferritin.<p> To address how cellular iron dysregulation affected metal distribution in brain and spinal cord, a new synchrotron imaging technique, rapid-scanning x-ray fluorescence (RS-XRF) was employed and validated. Brain structures were readily identified by their unique metal content and distribution. This showed that RS-XRF could be used to reveal metal pathologies associated with diseases of metal metabolism such as FRDA. Since human FRDA tissues were not available for a detailed study, RS-XRF was employed to study the distribution of metals in normal cerebellum, a major site of FRDA-associated neurodegeneration, and to localize and quantify metals in the brain and spinal cord from a patient with a SCA of unknown aetiology. The motivation for this work is the prospect of future systematic studies on metal pathology in neurodegenerative diseases with direct application to FRDA. Novel findings arising from this work were the metal segmentation of the dentate nucleus, the high copper content of the olivary region and the different metal content of lesions at different stages of neurodegeneration. My results suggest that not only iron, but also copper and zinc may play a role in the physiopathology of neurodegeneration. Therefore, all three metals should be investigated in FRDA and other SCA of both known and unknown aetiologies to identify possible new therapeutic targets.

This study employed spectral analyses for acoustic measures of sustained vowel productions from a group of 20 adolescents and young adults with Friedreich's Ataxia (FA) and compared findings with a group of 20 age-equivalent and gender-matched normal control participants. State-of-the art spectral analyses from the Analysis of Dysphonia in Speech and Voice (ADSV) program, developed for various voice disorders from Kay Elemetrics, were applied to initial 2 second sustained vowel segments of the vowels /a/, /i/, and /o/. Spectral analyses included averages and standard deviations of Cepstral Peak Prominence (CPP), Cepstral Peak Prominence Standard Deviation (CPP SD), Low/High Spectral Ratio (L/H Ratio), Low/High Spectral Ratio Standard Deviation (L/H Ratio SD), Cepstral/Spectral Index of Dysphonia (CSID), and Mean Cepstral Peak Prominence Fundamental Frequency (Mean CPP F0). Statistical analyses revealed significant differences between the spectral analyses of voice characteristics of individuals with FA and those of normal controls for all measures except for CPP SD. The aim of these analyses was to determine spectral differences evident in vowel productions of individuals with FA using new cepstral-derived measures that characterize the phonatory instability and dis-coordination present in this disorder. Such research may not only help develop early non-invasive indicators of ataxia and track disease progression, but also serve to stimulate research into alleviating the symptoms of this devastating disease.

The purpose of this study was to conduct perceptual analyses, using the initial two-second portions, of prolonged vowels /a/, /i/, and /o/. Two groups of adolescents and young adults were analyzed- one group consisting of 20 individuals with Friedreich's ataxia who were compared to 20 individuals with normal voice (control participants). A trained group of 10 graduate students listened to 132 vowel samples (3 vowels X 40 participants, + 12 samples (10%) for reliability purposes) for a total of 132 perceptual judgments. The students listened to the samples which were randomized onto Dell computers (Optiplex 755) and played through headphones that were set at a comfortable level by the listeners prior to analyzing the voice samples. Listeners used a modified version of the Consensus-Auditory Perceptual Evaluation of Voice (CAPE-VM) to rate the vocal qualities of 'roughness', 'breathiness', and 'strain' in the samples on a 100 millimeter visual analog scale with 0 representing a perception of no roughness, breathiness, or strain, and 100 indicating the most extreme amount of variance from normal voice quality. Statistical analyses were conducted to determine if perceptual measures were significantly different between the two groups. Values on these analyses were expected to be larger for individuals with Friedreich's ataxia than those with normal voice. Results revealed that all three measures were significantly different between the two groups, with those in the Friedreich's ataxia group reported as having increased rough, breathy, and strained components in their voice quality as compared to normal voiced peers. Findings support perceptual measures as useful indicators for reporting changes in the phonatory system due to Friedreich's ataxia.

Background: Technological advancements in speech acoustic analysis have led to the development of spectral/cepstral analyses due to questions regarding the validity of traditional time-based measures (i.e., Jitter, Shimmer, and Harmonics-to-Noise-Ratio) in objectifying perturbations in dysphonic voices. Aim: This study investigated the validity of time-based measures in discriminating those with Friedreich’s ataxia (FA) from normal voiced (NV) peers when compared to cepstral-spectral measures. Method: A total of 120 sustained vowel phonations from an existing database of 40 participants (20 FA; 20 NV) of the vowels /ɑ/, /i/, and /o/ were analyzed to determine which set of variables (i.e., time-based vs. cepstral-spectral) better predicted group membership. Four variables of time-based measures (Jitter Local %, Jitter RAP, Shimmer Local %, Shimmer APQ11, and HNR) were analyzed via the freeware program PRAAT and compared to four cepstral-spectral measures (Cepstral Peak Prominence, Cepstral Peak Prominence Standard Deviation, Low/High Ratio Standard Deviation, and the Cepstral/ Spectral Index of Dysphonia) extracted from the Analysis of Dysphonia in Speech and Voice (ADSV) software program. Results: Findings from a discriminant analysis showed sensitivity and specificity results to be better for ADSV measures; 100% of those in the FA group were classified correctly (sensitivity), and 95% of members in the NV group were correctly identified (specificity) as compared to PRAAT (70% sensitivity and 85% specificity). Conclusions: Cepstral-spectral measures are much more accurate in discriminating between those with FA and NV peers as compared to time-based estimates.

In 1996, scientists discovered a connection between the gene for the human protein frataxin (FXN) and the neurodegenerative disease Friedreich’s ataxia (FRDA). Decreased FXN levels result in a variety of aberrant phenotypes including loss of activity for iron-sulfur containing enzymes, mitochondrial iron accumulation, and susceptibility to oxidative stress. These symptoms are the primary focus of current therapeutic efforts. In contrast our group is pursuing an alternate strategy of first defining FXN function at a molecular level then using this information to identify small molecule functional replacements. Recently, our group has discovered that FXN functions as an allosteric activator for the human Fe-S cluster assembly complex. The work presented here helps to further define molecular details of FXN activation and explain how FRDA missense mutants are functionally compromised. First, the FRDA missense mutants L182H and L182F were investigated. Unlike other characterized FRDA missense mutants, the L182F variant was not compromised in its ability to bind and activate the Fe-S assembly complex. The L182H variant exhibited an altered circular dichroism signature; suggesting a change in secondary structure relative to native FXN, and rapidly degraded. Together these studies suggest that L182 variants are less stable than native FXN and are likely prone to degradation in FRDA patients. Second, as a regulatory role of FXN suggests that its function is likely controlled by environmental stimuli, different maturation forms of FXN as well as post-translational modification mimics were tested as mechanisms to control FXN regulation. Here experiments were designed to test if a larger polypeptide form of FXN represents a functional form of the protein. Kinetic and analytical ultracentrifugation studies revealed a complex heterogeneous mixture of species some of which can activate the Fe-S assembly complex. A previously identified acetylation site was also tested using mutants that mimic acetylation. These mutants had little effect on the ability of FXN to bind and activate the assembly complex. Third, mutagenesis experiments were designed in which the FXN surface residues were replaced with alanine and the resulting variants were tested in binding and activity assays. These experiments revealed a localized “hot-spot” on the surface of FXN that suggests small cyclic peptide mimics might be able to replace FXN and function as FRDA therapeutics. Unexpectedly, one of the FXN variants exhibited significantly tighter binding and could have relevance for therapeutic development.

Friedreich’s ataxia (FRDA) is an autosomal recessive inherited disorder affecting approximately 1 every 40,000 individuals in Western Europe, is characterized by progressive gait and limb ataxia, dysarthria, areflexia, loss of vibratory and position sense, and a progressive weakness of central origin. Additional features particularly include an hypertrophic cardiomyopathy that can cause premature death. A large GAA repeat expansion in the first intron of the FXN gene is the most common mutation underlying FRDA. Patients show severely reduced levels of the FXN-encoded mitochondrial protein frataxin.<p>Frataxin function is not yet completely elucidated. In frataxin deficiency conditions abnormalities of iron metabolism occur: decreased activities of iron-sulfur cluster (ISC) containing proteins, accumulation of iron in mitochondria and depletion in the cytosol, enhanced cellular iron uptake, and, in some models, reduced heme synthesis. <p>Evidence of oxidative stress has also been found in most though not all models of frataxin deficiency. Accordingly, yfh1-deficient yeast and cells from FRDA patients are highly sensitive to oxidants. Respiratory chain dysfunction further aggravate oxidative stress by increasing leakage of electrons and the formation of superoxide. Frataxin deficient cells not only generate more free radicals, but, they also show a reduced ability to mobilize antioxidant defenses, in particular to induce superoxide dismutase 2 (SOD2).<p>Peroxisome proliferator-activated receptor (PPAR) isoform-gamma play a key role in numerous cellular functions and is a key regulator of mitochondrial biogenesis and of the ROS metabolism. Recruitment of the PPAR coactivator-1a (PGC-1a) mediates many effects of the PPAR-γ activation.<p>In a first work we assessed the potential beneficial effects of a potent PPAR-gamma agonist on frataxin expression in primary fibroblasts from healthy controls and FRDA patients, and Neuroblastoma cells. We used the APAF molecule (1-0-hexadecyl-2-azelaoyl-sn-glycero-3-phosphocoline; C33H66NO9P). Our results show that this compound is able to increase frataxin amount both at transcriptional and post-transcriptional level. At a dose of 20µM frataxin mRNA significantly increases in both controls (p=0.03) and FRDA patients (p=0.002) fibroblasts (1). The finding was confirmed in Neuroblastoma cells (p=0.042). According to previous publications APAF, as others PPAR-gamma agonists is able to up-regulate PGC-1a transcription.<p>In a second part of the study we investigate the role of the PPAR-gamma/PGC-1a pathway in the pathogenesis of FRDA. We performed a microarray analysis of heart and skeletal muscle in a mouse model of frataxin deficiency and we found molecular evidence of increased lipogenesis in skeletal muscle and alteration of fiber-type composition in heart, consistent with insulin resistance and cardiomyopathy, respectively. Since the PPAR-gamma pathway is known to regulate both processes, we hypothesized that dysregulation of this pathway could play a key role in frataxin deficiency. We confirmed this by showing a coordinate dysregulation of Pgc1a and the transcription factor Srebp1 in cellular and animal models of frataxin deficiency, and in cells from FRDA patients, who have marked insulin resistance. Particularly, PGC-1a was found significantly reduced (2) in primary fibroblasts and lymphocytes from FRDA patients (p<0.05). Furthermore, PGC-1a mRNA levels strongly correlate with frataxin relative mRNA levels (r2=0.9, p<0.001). According to this observation, in C2C12 myoblasts, PGC-1a and a reporter gene under the control of the PGC-1a promoter are rapidly down-regulated (p<0.05) when frataxin expression is inhibited by an shRNA in vitro. To further investigate this relation, we then generate PGC-1a deficient fibroblasts cells using a specific siRNA; at 72 hours of transfection frataxin was found down-regulate (p<0.05) in control cells. <p>Taken together those data indicate that some mechanism directly links an early effect of frataxin deficiency with reduced PGC-1a transcription in this cell type, and presumably in other cells that also down-regulate PGC-1α when frataxin levels are low.<p>Finally, since PGC-1a has also emerged as a key factor in the induction of many antioxidant programs in response to oxidative stress, both in vivo and in vitro, in particular in neurons, we tested whether the PGC-1a down-regulation occurring in FRDA cells could be in part responsible for the blunted antioxidant response observed in frataxin deficiency.<p>Using primary fibroblasts from FRDA patients we found reduced SOD2 levels (p<0.05), according to PGC1& / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

La dysfonction ventriculaire gauche reste sous-diagnostiquée en pratique clinique actuelle car les paramètres conventionnels d’échographie ne sont pas suffisamment sensibles pour détecter des modifications fines de la fonction cardiaque. L’introduction récente de l’échocardiographie de suivi des marqueurs acoustiques (speckle tracking echocardiography) a permis par ses capacités descriptives de la mécanique cardiaque, de revisiter la contraction cardiaque et, de ce fait, de proposer une nouvelle approche échographique de l’évaluation de la fonction ventriculaire gauche.<p><p>A travers trois études, nous avons montré que l’analyse des indices de déformation permet d’objectiver des modifications de fonction ventriculaire gauche indétectables en échocardiographie conventionnelle dans des situations complexes à fraction d’éjection conservée, en dépit de l’augmentation modérée de la fréquence cardiaque qui leur est associée. Les situations que nous avons étudiées sont les suivantes :l’adaptation physiologique à l’hypoxie au niveau de la mer et en altitude, et les situations pathologiques que sont le syndrome de mal d’altitude chronique, et la cardiomyopathie associée à l’ataxie de Friedreich.<p><p>L’intégration de nos résultats et des informations disponibles dans la littérature permet de suggérer que l’utilisation de toutes les ressources offertes par l’échocardiographie de suivi des marqueurs acoustiques permet d’améliorer l’évaluation de la fonction cardiaque au-delà de la fraction d’éjection, en offrant une meilleure identification de situations pathologiques mais également une meilleure compréhension de situations physiologiques et pathologiques. <p><p>L’utilisation généralisée des indices de déformation pour l’évaluation de la fonction ventriculaire gauche en pratique clinique connaît néanmoins d’importantes limitations que nous abordons dans la discussion de ce travail. Au terme d’investigations complémentaires et de standardisation de la technique, l’incorporation d’un algorithme d’évaluation échographique de la fonction cardiaque à FEVG conservée combinant les paramètres échographiques conventionnels et les indices de déformation pourra être évalué de façon prospective pour sa translation en pratique clinique, avec pour finalité la proposition d’une définition mieux adaptée de l’insuffisance cardiaque à FEVG conservée.<p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Friedreich’s ataxia (FRDA) is an inherited recessive disorder characterized by progressive neurological disability and heart disease. It is caused by a pathological intronic hyperexpansion of a GAA repeat in the FXN gene, encoding the essential mitochondrial protein frataxin. At the homozygous state, the GAA expansion induces a heterochromatin state with decreased histone acetylation and increased methylation, resulting in a partial deficiency of frataxin expression. This was established in cells from FRDA patients. We showed that the same chromatin changes exist in a GAA based mouse model, KIKI, generated in our laboratory. Furthermore, treatment of KIKI mice with a novel Histone Deacetylase Inhibitor (HDACi), 106, a pimelic diphenylamide that increases frataxin levels in FRDA cell culture, restored frataxin levels in the nervous system and heart of KIKI mice and induced histone hyperacetylation near the GAA repeat. As shown by microarrays, most of the differentially expressed genes in KIKI were corrected towards wild type. In an effort to improve the pharmacological profile of compound 106, we synthesized more compounds based on its structure and specificity. We characterized two of these compounds in FRDA patients’ peripheral blood lymphocytes and in the KIKI mouse model. We observed a sustained frataxin upregulation in both systems, and, by following the time course of the events, we concluded that the effects of these compounds last longer than the time of direct exposure to HDACi. Our results support the pre-clinical development of a therapeutic approach based on pimelic diphenylamide HDACis for FRDA. Laboratory tools to follow disease progression and assess drug efficacy are needed in a slowly progressive neurodegenerative disease such as FRDA. We used microarrays to characterize the gene expression profile in peripheral lymphocytes from FRDA patients, carriers and controls. We identified gene expression changes in heterozygous, clinically unaffected GAA expansion carriers, suggesting that they present a biochemical phenotype, consistent with data from animal models of frataxin deficiency. We identified a subset of genes changing in patients as a result of pathological frataxin deficiency establishing robust gene expression changes in peripheral lymphocytes. These changes can be used as a biomarker to monitor disease progression and potentially assess drug efficacy. To this end, we used he same methodology to characterize the gene expression profiles in peripheral lymphocytes after treatment with pimelic diphenylamide HDACi. This treatment had relevant effects on gene expression on peripheral patients’ blood lymphocytes. It increased frataxin levels in a dose-dependent manner, and partially rescued the gene expression phenotype associated with frataxin deficiency in the tested cell model, thus providing the first application of a biomarker gene set in FRDA. / Doctorat en sciences biomédicales / info:eu-repo/semantics/nonPublished

En Europe, une maladie est définie comme rare dès lors qu'elle touche moins d'une personne sur 2000, ce qui représente moins de 30 000 personnes en France. Il existerait plus de 7000 maladies rares dans le monde dont les deux tiers ont un impact important sur la santé et la qualité de vie des patients. Des études récentes révèlent des vécus possiblement spécifiques aux personnes atteintes de maladies rares, parmi lesquels un désir d'information accru sur les avancées de la recherche et sur les mécanismes physiologiques de leurs maladies ; ou encore l'instauration de rapports collaboratifs plutôt que hiérarchiques avec le corps médical. Or, si les essais cliniques en maladie rare représentent bien souvent un espoir pour ces patients, ils constituent aussi une confrontation parfois difficile à leur maladie et aux impératifs scientifiques et médicaux introduits par la situation de recherche. Notre objectif était d'étudier le vécu d'un essai clinique par des patients atteint d'une ataxie de Friedreich (AF), maladie rare neurodégénérative à l'origine d'une perte progressive de l'autonomie dans le quotidien, ainsi que par leurs parents. Nous avons mené trois études respectivement au cours, à la fin et à la suite d'un essai clinique randomisé en double aveugle (ACTFRIE) auprès de 38 patients âgés de 7 à 24 ans et, pour certains, de leurs parents. Nous avons cherché à déterminer l'évolution de la qualité de vie dans l'AF au cours de deux ans d'essai clinique (étude Qualifrie), les caractéristiques du vécu d'un essai clinique chez les patients et leurs parents (étude M24), et les attentes des patients et, pour certains, de leurs parents, quant au rendu des résultats de l'essai clinique auquel ils ont participé (étude Friecom). Les résultats de l'étude Qualifrie nous apprennent que la participation à un essai clinique peut avoir un effet positif transitoire sur la qualité de vie psychique pour les patients, sans pour autant que des progrès soient retrouvés sur le plan physique, ou notés dans le ressenti des patients. L'étude M24 apporte d'importantes pistes de réflexion sur le positionnement psychologique des patients et de leurs parents dans ces essais cliniques, notamment en termes de « demande » de soin, plutôt que de « volontariat » ; et suggèrent des points de vigilance à l'intention des investigateurs de futurs essais pour assurer aux patients un accord de consentement pleinement libre et éclairé. Enfin, les résultats de l'étude Friecom mettent en évidence la nécessité du rendu des résultats, tant globaux qu'individuels, aux patients des essais cliniques et/ou à leurs parents ; et l'intérêt marqué de cette population atteinte d'une maladie rare pour l'information scientifique concernant sa maladie. L'ensemble de ces travaux met en exergue la nécessité de prendre en compte les spécificités du vécu des essais cliniques par les personnes atteintes de maladies rares, leurs besoins, leurs attentes. Il suggère en outre des améliorations en termes de précautions préalables aux essais cliniques à prendre par les investigateurs. Il s'agit notamment de trouver une juste adéquation entre les attentes des participants et les buts assignés de l'étude. A ce titre, ces travaux mènent à souligner la nécessité centrale de la présence du psychologue dans les essais cliniques en maladie rare, interlocuteur privilégié et essentiel, assurant le lien entre les équipes de soin et les patients (ou participants potentiels) et/ou les parents accompagnants. Plusieurs perspectives de recherches futures sont abordées, d'autant que le contexte particulier des maladies rares semble encore trop peu exploré dans la littérature scientifique, notamment en psychologie ; alors qu'il bénéficierait de façon manifeste du regard et des recommandations d'une grande partie des champs des sciences humaines. / In Europe, a disease is defined as rare if it affects less than one person in 2000, which represents less than 30,000 people in France. There are estimated to be more than 7000 rare diseases worldwide, two-thirds of which have a significant impact on patients'health and quality of life. Recent studies reveal experiences that may be specific to people with rare diseases, including a desire for more information on the advances in research and the physiological mechanisms of their diseases, ; or the establishment of collaborative rather than hierarchical relationships with the medical profession. Although clinical trials in rare diseases often represent a hope for these patients, they could also constitute a difficult confrontation with their disease and the scientific and medical imperatives introduced by the research situation. Our objective was to study the experience of a clinical trial by patients with Friedreich's ataxia (FA), a rare neurodegenerative disease that causes a progressive loss of autonomy in daily life, and by their parents. We conducted three studies respectively during, at the end of and following a randomized double-blind clinical trial (ACTFRIE) in 38 patients aged from 7 to 24 years and, for some, their parents. We sought to determine the evolution of quality of life in FA during two years of clinical trials (Qualifrie study), the experience's characteristics of a clinical trial in patients and their parents (M24 study), and the expectations of patients and, for some, their parents, regarding the results of the clinical trial in which they participated (Friecom study). The results of the Qualifrie study show us that participation in a clinical trial can have a positive, transient effect on the psychic quality of life for patients, without any improvement in the physical state of the patients, or any improvement in their impressions about it. M24 study provides important reflections on the psychological positioning of patients and their parents in these clinical trials, particularly in terms of "demand" for care, rather than "voluntarism"; and suggests points of vigilance for investigators of future trials to ensure that patients have a fully free and informed consent agreement. Finally, the results of the Friecom study highlight the need for both global and individual results to be delivered to patients and/or their parents in clinical trials; and the strong interest of this rare disease population in providing scientific information about their disease. Overall, this work highlights the need to take into account the specificities of the clinical trial experience of rare disease patients, their needs and expectations. It also suggests improvements in terms of pre-trial precautions to be taken by investigators. This includes finding the right match between the expectations of the participants and the aims of the study. Therefore, this work underlines the necessity of the psychologist's presence in clinical trials in rare diseases, as a privileged and essential professional, ensuring the link between the care teams and patients (or potential participants) and/or accompanying parents. Several perspectives for future research are discussed, especially because of the particular context of rare diseases, which seems to be insufficiently explored in the scientific literature, particularly in psychology; whereas it would clearly benefit from the viewpoint and recommendations of a large part of the fields of the human and social sciences.