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Resume L’ethique du soin permet un questionnement sur les valeurs dans la pratique clinique et sur le sens de la demarche de soin face au sujet malade. La psychiatrie est une discipline medicale dans laquelle la complexite des decisions est frequemment liee a des enjeux ethiques. L’objectif principal de notre etude est d’evaluer l’efficacite de l’organisation de seances d’ethique appliquee, sur le modele des « Moral Case Deliberation », dans un service de psychiatrie generale en France. Des seances mensuelles ont ete organisees durant six mois au sein d’une equipe de soins constituee. Nous avons elabore un questionnaire a partir des donnees de la litterature internationale afin d’evaluer, a posteriori, les effets de ces seances sur la pratique des participants. L’analyse de notre questionnaire a permis de confirmer les effets benefiques attendus par la realisation de seances d’ethique appliquee. Elle a particulierement mis en lumiere l’interet de disposer d’outils differents de la pratique courante dans le but d’augmenter la qualite des soins. Les seances d’ethique appliquee sont les temoins d’une evolution dans la conception de l’ethique avec le passage d’une ethique theorique a une ethique pratique, traitant des situations sensibles du quotidien. Elles pourraient, comme dans d’autres pays, trouver leur place dans l’evaluation et l’amelioration des pratiques professionnelles.

International audience; Objective: Uniparental disomy (UPD) testing is currently recommended during pregnancy in fetuses carrying a balanced Robertsonian translocation (ROB) involving chromosome 14 or 15, both chromosomes containing imprinted genes. The overall risk that such a fetus presents a UPD has been previously estimated to be around ~0.6‐0.8%. However, because UPD are rare events and this estimate has been calculated from a number of studies of limited size, we have reevaluated the risk of UPD in fetuses for whom one of the parents was known to carry a nonhomologous ROB (NHROB).Method: We focused our multicentric study on NHROB involving chromosome 14 and/or 15. A total of 1747 UPD testing were performed in fetuses during pregnancy for the presence of UPD(14) and/or UPD(15).Result: All fetuses were negative except one with a UPD(14) associated with a maternally inherited rob(13;14).Conclusion: Considering these data, the risk of UPD following prenatal diagnosis of an inherited ROB involving chromosome 14 and/or 15 could be estimated to be around 0.06%, far less than the previous estimation. Importantly, the risk of miscarriage following an invasive prenatal sampling is higher than the risk of UPD. Therefore, we do not recommend prenatal testing for UPD for these pregnancies and parents should be reassured.

International audience; Le cancer et la vie, au plus près de soi : une ou un patient nous parle de la vie malgré la maladie, de la vie avec la maladie.

Resume Objectif Evaluer le point de vue des soignants sur les prises de decision d’interruption medicale de grossesse. Materiel et methodes Enquete par questionnaire semi-structure et echelles visuelles analogiques, aupres des personnels de 26 des 40 centres pluridisciplinaires de diagnostic prenatal (CPDPN) francais. Resultats Le taux de reponse etait de 39 %, soit 213 sur 550 personnels interroges. Cinquante-cinq pour cent des repondants etaient des femmes, 90 % des medecins, 7,5 % des sages-femmes. Une large majorite (69,8 %) des repondants estime que leurs convictions personnelles jouent de fait dans la decision d’IMG un role plus grand qu’ils ne le souhaiteraient en principe. Les determinants mis en avant dans la decision d’IMG sont prioritairement le pronostic a long terme de l’anomalie fœtale, l’avis d’un specialiste sur sa curabilite, la clarte de l’information du couple, la position exprimee par le couple, la discussion collegiale, la qualite de la comprehension du couple, le consensus d’equipe, le niveau de preuve de l’information donnee. Pour seulement 55 % des repondants, le cadre legal existant suffit pour gerer les situations generees par la pratique du diagnostic prenatal. La question de l’interruption de grossesse au troisieme trimestre est l’objet d’un debat ethique : 52 % des repondants considerent qu’on ne peut avoir de position ethique differente vis-a vis d’un fœtus au troisieme trimestre et vis-a-vis d’un nouveau-ne, 80 % n’estiment pas que « meme avec une deficience mentale severe la vie vaut mieux que pas de vie du tout », mais 37 % des repondants pensent que cette pratique peut mener vers l’eugenisme . Discussion et conclusion Dans le domaine de l’interruption medicale de grossesse, les reponses contrastees des professionnels soulignent que le debat ethique n’est pas clos, notamment en ce qui concerne la mise en pratique du consentement eclaire.

Resume Dans les hemoglobinopathies considerees comme severes (β-thalassemie majeure, drepanocytose, hydrops fetalis dans l'α-thalassemie), le conseil genetique vise a depister les couples a risque afin de les informer. Ils peuvent ainsi envisager une grossesse en connaissance de cause. Un diagnostic neonatal precoce peut aider a une meilleure prise en charge de leurs enfants atteints. Pour ceux qui le souhaitent, un diagnostic prenatal est envisageable grâce aux techniques de la biologie moleculaire. Il sera suivi d'une interruption de la grossesse si le fœtus est atteint. Les pathologies de la membrane erythrocytaire et celles avec deficit des enzymes erythrocytaires ont une symptomatologie plus benigne. Nous evoquerons la spherocytose et le deficit en G6PD. Le conseil genetique aura pour vocation d'informer sur le risque et d'organiser les conditions d'un diagnostic precoce des enfants atteints.

We have collated the results of cystic fibrosis (CF) mutation analysis conducted in 19 laboratories in France. We have analyzed 7, 420 CF alleles, demonstrating a total of 310 different mutations including 24 not reported previously, accounting for 93.56% of CF genes. The most common were F508del (67.18%; range 61-80), G542X (2.86%; range 1-6.7%), N1303K (2.10%; range 0.75-4.6%), and 1717-1G>A (1.31%; range 0-2.8%). Only 11 mutations had relative frequencies >0. 4%, 140 mutations were found on a small number of CF alleles (from 29 to two), and 154 were unique. These data show a clear geographical and/or ethnic variation in the distribution of the most common CF mutations. This spectrum of CF mutations, the largest ever reported in one country, has generated 481 different genotypes. We also investigated a cohort of 800 French men with congenital bilateral absence of the vas deferens (CBAVD) and identified a total of 137 different CFTR mutations. Screening for the most common CF defects in addition to assessment for IVS8-5T allowed us to detect two mutations in 47.63% and one in 24.63% of CBAVD patients. In a subset of 327 CBAVD men who were more extensively investigated through the scanning of coding/flanking sequences, 516 of 654 (78. 90%) alleles were identified, with 15.90% and 70.95% of patients carrying one or two mutations, respectively, and only 13.15% without any detectable CFTR abnormality. The distribution of genotypes, classified according to the expected effect of their mutations on CFTR protein, clearly differed between both populations. CF patients had two severe mutations (87.77%) or one severe and one mild/variable mutation (11.33%), whereas CBAVD men had either a severe and a mild/variable (87.89%) or two mild/variable (11.57%) mutations.

SummaryAngelman syndrome (AS) is caused by chromosome 15q11-q13 deletions of maternal origin, by paternal uniparental disomy (UPD) 15, by imprinting defects, and by mutations in the UBE3A gene. UBE3A encodes a ubiquitin-protein ligase and shows brain-specific imprinting. Here we describe UBE3A coding-region mutations detected by SSCP analysis in 13 AS individuals or families. Two identical de novo 5-bp duplications in exon 16 were found. Among the other 11 unique mutations, 8 were small deletions or insertions predicted to cause frameshifts, 1 was a mutation to a stop codon, 1 was a missense mutation, and 1 was predicted to cause insertion of an isoleucine in the hect domain of the UBE3A protein, which functions in E2 binding and ubiquitin transfer. Eight of the cases were familial, and five were sporadic. In two familial cases and one sporadic case, mosaicism for UBE3A mutations was detected: in the mother of three AS sons, in the maternal grandfather of two AS first cousins, and in the mother of an AS daughter. The frequencies with which we detected mutations were 5 (14%) of 35 in sporadic cases and 8 (80%) of 10 in familial cases.

Resume Les principales caracteristiques du syndrome de Smith-Magenis sont des criteres mineurs faciaux, une brachydactylie, un retard psychomoteur avec retard de langage et des troubles comportementaux. Ce syndrome est du a une microdeletion du chromosome 17p11.2. Observation. — Une enfant a consulte a l'âge de 7 ans pour un retard psychomoteur. L'examen notait une dysmorphie faciale discrete (brachycephalie, hypoplasie de l'etage moyen de la face, elargissement de la racine du nez, hypoplasie malaire), une brachydactylie, une hyporeflexie osteotendineuse et une voix rauque. Une surdite moderee, des troubles du comportement et des anomalies du sommeil etaient notes. L'etude chromosomique sur lymphocytes a montre une deletion de la sous-bande 17p11.2. L'analyse moleculaire a confirme la deletion par perte de l'allele maternel. Conclusion. — Le syndrome de Smith-Magenis associe des signes cliniques discrets et reste probablement volontiers meconnu. Son diagnostic repose sur l'etude chromosomique.

Les techniques de sequencage de nouvelle generation permettent des explorations globales du genome humain. Apres avoir montre la complexite de l’information a donner et du consentement a recueillir s’agissant de tests genetiques, l’auteur examine les multiples difficultes que souleverait, au regard de l’ethique, un usage insuffisamment pense de ce nouveau champ technologique.

Background DYRK1A plays different functions during development, with an important role in controlling brain growth through neuronal proliferation and neurogenesis. It is expressed in a gene dosage dependent manner since dyrk1a haploinsufficiency induces a reduced brain size in mice, and DYRK1A overexpression is the candidate gene for intellectual disability (ID) and microcephaly in Down syndrome. We have identified a 69 kb deletion including the 5′ region of the DYRK1A gene in a patient with growth retardation, primary microcephaly, facial dysmorphism, seizures, ataxic gait, absent speech and ID. Because four patients previously reported with intragenic DYRK1A rearrangements or 21q22 microdeletions including only DYRK1A presented with overlapping phenotypes, we hypothesised that DYRK1A mutations could be responsible for syndromic ID with severe microcephaly and epilepsy. Methods The DYRK1A gene was studied by direct sequencing and quantitative PCR in a cohort of 105 patients with ID and at least two symptoms from the Angelman syndrome spectrum (microcephaly < −2.5 SD, ataxic gait, seizures and speech delay). Results We identified a de novo frameshift mutation (c.290_291delCT; p.Ser97Cysfs*98) in a patient with growth retardation, primary severe microcephaly, delayed language, ID, and seizures. Conclusion The identification of a truncating mutation in a patient with ID, severe microcephaly, epilepsy, and growth retardation, combined with its dual function in regulating the neural proliferation/neuronal differentiation, adds DYRK1A to the list of genes responsible for such a phenotype. ID, microcephaly, epilepsy, and language delay are the more specific features associated with DYRK1A abnormalities. DYRK1A studies should be discussed in patients presenting such a phenotype.

AZFc deletions of the Y chromosome are the major known genetic cause of spermatogenetic failure. Meiotic studies have shown a prevalence of synaptonemal complex fragmentation and an excess of early-stage sperm cells, suggesting that the maturation block could involve apoptosis. We present a prospective and observational study of apoptotic markers in the sperm of four AZFc-deleted patients and two non-obstructive azoospermic controls without an AZFc deletion. Polycaspases assays and terminal deoxynucleotidyl transferase dUDP nick-end labelling (TUNEL) assays were combined to evaluate the incidence of apoptosis in pre-meiotic, meiotic and post-meiotic germs cells identified, respectively, using anti-melanoma-associated antigen A4 (MAGE-A4), anti-synaptonemal complex protein 3 (SCP3) and anti-sperm acrosome membrane-associated protein 1 (SPACA1) antibodies. We detected apoptosis at all stages of AZFc-deletion spermatogenesis. Using the caspase assay, the incidence of positive cells was found to be heterogeneous for pre-meiotic (from 4.8 to 84.5%) and meiotic stages (from 7.9 to 57.6%), while for post-meiotic cells, the mean incidence was 6% in AZFc-deleted patients compared with 26.5% in controls (P < 0.05). Using the TUNEL assay, the mean percentage with DNA fragmentation for meiotic cells was 54.0% in AZFc-deleted patients compared with 20.3% in controls (P < 0.05), while the percentage of TUNEL-positive post-meiotic cells ranged from 5.3 to 44.7%. Spermatocyte loss in AZFc-deleted patients occurs via the apoptotic pathway. In post-meiotic cells, the lower incidence of apoptosis in testis from three of the four AZFc-deleted patients, compared with controls, is consistent with AZFc deletions having little negative impact on sperm quality.

Objectives This study was performed to understand the parental attitudes, needs and ethical issues associated with perinatal death, to assist in the development of interventions for bereaved families. Study design We conducted a qualitative descriptive survey of parental experiences with perinatal death. We developed a questionnaire based on the Delphi method, conducted semi-directed interviews or asked subjects to return the questionnaire by post. As a secondary analysis, we examined whether certain ethical principles (i.e., the concepts of beneficence, nonmaleficence, autonomy, and justice) were encountered by the study participants. The study population consisted of families who had experienced perinatal death in the maternity department of a French university hospital, as well as members of bereaved parent support groups. Results Six of the 12 parents who participated in the survey were members of a support group. Responses were analyzed according to precise objectives and grouped according to key themes. In particular, we studied deaths that occurred during neonatal palliative care and deaths relating to multiple pregnancies. Parents expressed opinions about the caregivers’ practices (e.g., which practices were beneficial and detrimental). Half of the parents did not feel that their feelings and decisions were respected according to ethical principles. Understanding the experience of parents allows staff to reconsider and change their practices. Conclusions By understanding parents’ feelings toward neonatal death, caregivers can better assist with the grieving process. Our study reveals parents’ attitudes toward the ethical decision-making process and shows that it is difficult for perinatal medicine caregivers to respect parents’ autonomy.

Charcot-Marie-Tooth (CMT) disease is a typical example of a clinically and genetically heterogeneous disorder and, in most cases, is dominantly inherited and caused by a 1.5 megabase duplication on chromosome 17p11.2 containing the PMP22 gene. This is a non-lethal disease with a wide spectrum of severity, from asymptomatism to severe motor and sensory disability. Unpredictable degree of disability is usually the reason why prenatal diagnosis is required and must be addressed. Molecular procedures such as the use of polymorphic non microsatellite STRs, allowing very fast and reliable results even when requiring a gene dosage interpretation are now available and have been recently validated in post-natal diagnosis. Our results indicate that this approach is also the best-adapted method in case of prenatal diagnosis. Nevertheless, ethical considerations raised by prenatal diagnosis in CMT and more generally in non-lethal disorders remain to be actively considered. Here, we present our experience in genetic counselling, and address the psychological issues for 7 CMT at risk pregnancies. In five cases, a CMT1A duplication was evidenced; pregnancy was terminated in four of these cases and the parents from one affected foetus decided to pursue the pregnancy.

The urofacial syndrome (UFS) or Ochoa syndrome has been reported as a rare autosomal recessive disorder comprising a uropathy and facial abnormalities. The gene was mapped on chromosome region 10q23-q24. We report the first European cases of UFS. Haplotype analyses in our French family were compared with those previously described in patients from Columbia and America (literature data). The results are compatible with the same localization of the critical region and favor the hypothesis of genetic homogeneity.

Charcot-Marie-Tooth disease, type 1A (CMT1A) is caused in most cases by a 1.5 Mb duplication on chromosome 17p 11.2 arising after unequal crossing-over between repeated sequences called CMT1A-REPs, flanking the 1.5 Mb unit. A 3.2 kb recombination hot spot has been defined, resulting in a junction fragment between EcoRI (distal CMT1A-REP) and SacI (proximal CMT1A-REP). This was further reduced to a 1.7 kb EcoRI-NsiI fragment, and recently to a 731 bp hot spot region within this fragment. We describe the CMT1A-REPs-based PCR method used to identify CMT1A duplications and report on a family case in which a 29-year-old pregnant woman requested prenatal diagnosis for two successive pregnancies because her husband was affected with CMT1A. Our method enabled us to characterise the duplication in both foetuses and demonstrate that it arose from a rare recombination event taking place outside the 1.7 kb region. Since our approach is simple and enables the entire set of duplications occurring after recombination in the enlarged 3.2 kb region including the hot spot to be detected, we suggest it might be considered for use in primary screening for pre- and postnatal diagnosis of CMT1A.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the absence of amaternal contribution to chromosome 15q11–q13. There are four classes of AS according tomolecular or cytogenetic status: maternal microdeletion of 15q11–q13 (approximately 70% ofAS patients); uniparental disomy (UPD); defects in a putative imprinting centre (IM); thefourth includes 20–30% of AS individuals with biparental inheritance and a normal pattern ofallelic methylation in 15q11–q13. Mutations of UBE3A have recently been identified ascausing AS in the latter group. Few studies have investigated the phenotypic differencesbetween these classes. We compared 20 non-deletion to 20 age-matched deletion patients andfound significant phenotypic differences between the two groups. The more severe phenotypein the deletion group may suggest a contiguous gene syndrome.Keywords: Angelman syndrome; deletion 15q11–q13; uniparental disomy; imprintingmutation; UBE3A mutation; GABRB3 gene

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder for which no candidate gene has yet been identified. The gene corresponding to one of the novel human cDNAs that we cloned on the basis of a muscle restricted expression pattern [Pietu G, Alibert O, Guichard B, et al. Genome Res 1996;6:492-503] was mapped in the region of the FSHD1A genetic locus, i.e. one of the loci involved in this muscular dystrophy. The corresponding encoded protein contains a PDZ and a LIM domain, two protein-protein interaction domains, and was very recently shown to bind alpha-actinin-2 and was named ALP (actinin-associated LIM protein) [Xia H, Winokur S, Kuo W, Altherr M, Bredt D. J Cell Biol 1997;139:507-515]. We raised a specific polyclonal anti-ALP serum against an ALP recombinant polypeptide to evaluate the size, level of expression and subcellular localization of ALP in three patients, clearly diagnosed with FSHD disease. Quantitative or qualitative alterations of ALP expression have not been detected in any of them, thus prompting us to exclude ALP as a FSHD gene candidate.

Prader-Willi syndrome (PWS) is a neurogenetic disorder that results from the absence of a normal paternal contribution to the 15q11–13 region1–3. The clinical manifestations of PWS are a transient severe hypotonia in the newborn period, with mental retardation, hypogonadism and obesity observed later in development4. Five transcripts with exclusive expression from the paternal allele have been isolated, but none of these has been shown to be involved in PWS5,6. In this study, we report the isolation and characterization of NDN, a new human imprinted gene. NDN is exclusively expressed from the paternal allele in the tissues analysed and is located in the PWS region. It encodes a putative protein homologous to the mouse brain-specific NECDIN protein7, NDN; as in mouse, expression in brain is restricted to post-mitotic neurons. NDN displays several characteristics of an imprinted locus, including allelic DNA methylation and asynchronous DNA replication. A complete lack of NDN expression in PWS brain and f ibroblasts indicates that the gene is expressed exclusively from the paternal allele in these tissues and suggests a possible role of this new gene in PWS.

The fragile X syndrome is the most frequent cause of inherited mental retardation. CGG repeat alleles are usually classified as normal, premutation, or full mutation based on the length of this triplet in the 5' untranslated region of the FMR1 gene. The pattern of inheritance follows a two-stage intergenerational process in which the premutation evolves into the full mutation. Some reverse mutations have been described, but they appear to be very rare. We describe a family in which a mother of two affected males herself carried a full mutation. Surprisingly, her clinically normal daughter, initially considered to be a carrier by linkage analysis, carried a very short premutation. Findings from our family study corroborate the hypothesis that the expansion during female transmission could be a postzygotic event and raise the problem of mosaicism.

Using a rat histidine decarboxylase (HDC) cDNA probe, we have mapped the HDC gene by in situ hybridization to the ql5–q2l region of human chromosom e15 and to the E5-G region of murine chromosome 2. These localizations strengthen a syntenic group conserved between human chromosome 15 and mouse chromosome 2. The localization of the HDC gene on the human chromosome 15 map shows that it is not included within the Prader-Willi Syndrome region (PWCR).

We report on clinical, cytogenetic and molecular analyses of 16 patients with inv dup (15) chromosome. We define the content of the inv dup (15) markers, their meiotic origin and the methylation status of the chromosome region involved. Precise phenotype-karyotype-genotype correlations allowed the identification of five different types of marker and demonstrated that even when the molecular content of the inv dup (15) chromosome clearly contributes to the severity of the phenotype, it does not appear to be the only relevant factor. All the markers were of maternal origin with an identical methylation profile, and neither imprinting nor methylation can explain the phenotypic variability. We suggest that the degree of phenotypic severity may be correlated with the severity of epilepsy.

Prader-Willi syndrome (PWS) is a disorder characterized by neonatal hypotonia with poor suck, mild to moderate mental retardation, obesity beginning after 3 yr of age, hypogonadism and characteristic facial features. High resolution cytogenetic studies showed a deletion of the proximal chromosome 15q(q11–q13) region in approximately 50%. Interestingly, the same deletion was described in another distinct mental disorder: the Angelman syndrome (AS). This deletion was confirmed by molecular analyses, and a new mechanism was reported: uniparental disomy (maternal in PWS and paternal in AS) strongly implicate genomic imprinting in this chromosomal region. The principal aim of our group is to apply cytogenetic and molecular biology techniques to perform diagnosis and genetic counselling. Patient studies were usually based on high resolution cytogenetic analysis, quantitative Southern blotting (with D15S9, D15S11, D15S10, D15S12 loci) and dinucleotide repeat polymorphism assay by polymerase chain reaction (PCR) (IR4. 3R and GABARB3). The combination of these different methods allowed us to propose a diagnostic strategy for PWS.

Charcot-Marie-Tooth disease, type 1A (CMT1A) is caused in most cases by a 1.5 Mb duplication on chromosome 17p11.2 arising after unequal crossing-over between repeated sequences called CMT1A-REPs, flanking the 1.5 Mb unit. A 3.2 kb recombination hot spot has been defined, resulting in a junction fragment between EcoRI (distal CMT1A-REP) and Sad (proximal CMT1A-REP). This was further reduced to a 1.7kb EcoRI-Nsil fragment, and recently to a 731 bp hot spot region within this fragment. We describe the CMT1A-REPs-based PCR method used to identify CMT1A duplications and report on a family case in which a 29-year-old pregnant woman requested prenatal diagnosis for two successive pregnancies because her husband was affected with CMT1A. Our method enabled us to characterise the duplication in both foetuses and demonstrate that it arose from a rare recombination event taking place outside the 1.7 kb region. Since our approach is simple and enables the entire set of duplications occurring after recombination in the enlarged 3.2 kb region including the hot spot to be detected, we suggest it might be considered for use in primary screening for pre- and postnatal diagnosis of CMT1A.

International audience; À partir d’un cas concret, l’article présente les enjeux soulevés par l’introduction des objets connectés dans les pratiques de santé. Les contextes normatif, économique et socio-culturel éclairent l’extension de leurs usages et les limites possibles à leur développement dans le secteur de la santé. Puis, les enjeux éthiques révélés par les conflits entre les principes et les valeurs sont identifiés et des pistes de réflexion proposées pour favoriser l’autonomie et l’accompagnement du patient, en tenant compte des vulnérabilités ontologiques, économiques et sociales.