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What are the ethical issues in connection with the support of the most vulnerable people in a context of health crisis, forcing them to be confined? Because the concept of vulnerability is broad and complex, the " Espace éthique PACA-Corse " (PACA-Corsica Ethical Structure) has taken a particular interest in the care of children with disabilities, children entrusted to child welfare services and people with psychiatric disorders. Confinement has led to a reorganisation of the access to healthcare services and medico-social support, possibly revealing or aggravating some situations of vulnerability, or even pushing aside certain people. Those most isolated or at risk of abuse may have experienced a double confinement. How to identify and respond to the needs of people already in vulnerable situations before confinement, who, isolated in the epidemic context, have seen their vulnerabilities increase? While new ways of working have been introduced in times of containment, some were interesting, others have shown their limits. The challenge was to find the right measure to address the specificity of each situation, to activate care networks in an effective and supportive manner, despite limited resources and the emergency context. The difficulty was to make protocols and care values coexist, acting in a reactive and creative way. While revealing vulnerabilities, this period has required both humility toward uncertainty and a duty of responsibility to care for those most in need., (© 2020 Elsevier Masson SAS. All rights reserved.)

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., (© 2019 John Wiley & Sons, Ltd.)

The advent of next generation sequencing (NGS) technologies is so scale-changing that it modifies molecular diagnostics indications and induces laboratories to rethink their diagnostic strategies, until now based on the Sanger sequencing routine. Several high-throughput approaches are available from the sequencing of a gene panel, to an exome, or even a genome. In all cases, a tremendous amount of data is generated, which has to be filtered, interpreted and analyzed using powerful bioinformatics tools. In parallel, ethical considerations are raised to avoid the potential drifts of these powerful approaches. In all medical fields, and particularly in pediatrics, this new strategy offers better efficacy and faster mutation identification, allowing better support and care for patients and their families and even improving genetic counseling. In the present paper, we discuss the different NGS-based approaches and strategies as well as the issues involved in these new technologies applied to molecular diagnosis of rare diseases. Altogether, rare diseases affect more than 3 million people in France and are responsible for about one-third of childhood deaths., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Array comparative genomic hybridization (aCGH) has progressively replaced conventional karyotype in the diagnostic strategy of intellectual disability (ID) and congenital malformations. This technique increases not only the diagnostic rate but also the possibility of finding unexpected variants unrelated to the indication of referral, namely incidental findings. The incidental finding of copy number variants (CNVs) located in X-linked genes in girls addresses the crucial question of genetic counseling in the family. We report here five cases of CNVs involving the dystrophin gene detected by aCGH in girls referred for developmental delay, without any family history of dystrophinopathy. The rearrangements included three in-frame deletions; one maternally and two paternally inherited, and two frameshift duplications: one de novo and one from undetermined inheritance. In two cases, the deletion identified in a girl was transmitted by the asymptomatic father. In the case of the maternally inherited deletion, prenatal diagnosis of dystrophinopathy was proposed for an ongoing pregnancy, whereas the cause of developmental delay in the index case remained unknown. Through these cases, we discussed the challenges of genetic counseling in the family, regarding the predictive issues for male individuals at risk for a muscular dystrophy without precise knowledge of the clinical consequences of some CNVs in the DMD gene., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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&#95;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.

Objective: To evaluate the caregivers' opinions regarding decision-making in termination of pregnancy (TOP) for fetal anomaly., Material and Methods: Questionnaire survey using a semi-structured survey based on visual analogue scales, sent to all multidisciplinary centres for prenatal diagnosis in France. Answers were received from 26 centres nation-wide., Results: Response rate was 39% (213 responses received over 550 questionnaires sent). Fifty-five percent of respondents were women, 90% physicians, 7,5% midwives. A vast majority (69.8%) believes that their own convictions play a bigger role in decision in real practice than in their ideal. The major decisional factors in decision-making for TOP are: the long-term prognosis of the anomaly, a specialized opinion on its curability, the quality of the information given to the future parents, their expressed opinion, the existence of a multidisciplinary decision, the ability of the future parents to understand the medical data, the obtention of a medical consensus, the proof level of the medical information. For only 55% of the respondents, the current legal framework is adequate to manage the situations that result from prenatal diagnostic practices today. The question of late third-trimester TOP raises ethical debate: over a third (37%) see no ethical difference between TOP and withdrawal of care during the neonatal period; the majority (48% versus 43%) feel that ethically speaking a neonate and a foetus at 39 weeks gestational age (GA) should not be treated differently; 37% of the respondents feel that current practice is likely to lead to eugenism., Discussion and Conclusion: As far as TOP is concerned, the huge discrepancies in responses from the professionals highlight the ongoing ethical debate, especially concerning the concept of informed choice in TOP, which we believe should be entirely revisited., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

This article focuses on six questions raised by genetic testing in human: (1) the use of genetic tests, (2) information given to relatives of patients affected with genetic disorders, (3) prenatal and preimplantatory diagnosis for late onset genetic diseases and the use of pangenomic tests in prenatal diagnosis, (4) direct-to-consumer genetic testing, (5) population screening in the age of genomic medicine and (6) incidental findings when genetic testing are used., (Copyright © 2009 Elsevier Masson SAS. All rights reserved.)

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., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Balanced complex chromosomal rearrangements are very rare events in the human population. Translocations involving three or more chromosomes frequently lead to a severe reproductive impairment secondary to meiotic disturbance in males and to chromosomal imbalance in gametes of females. We report a new familial case of complex chromosome anomaly involving chromosomes 13, 14 and 22. Cytogenetic investigations showed a complex chromosomal chromosome rearrangement involving: (i) a Robertsonian translocation between chromosomes 13 and 14; and (ii) a reciprocal translocation between the long arms of chromosome 14 and the long arm of chromosome 22. The aetiology of the translocation was characterized by conventional fluorescence in-situ hybridization (FISH) studies and routine R- and G-banding (RTBG and GBTG) combined with alpha and beta satellite centromeric FISH probes. Predicted configuration of the hexavalent at pachytene stage of meiosis was used to consider the modes of segregation; only two configurations resulted in a normal or balanced gamete karyotype. Reproductive management and genetic counselling are discussed.

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 clinico-pathological features of 17 patients displaying a myopathy with lobulated (trabeculated) fibers are reported. All these patients had a limb girdle phenotype and at least 20% of lobulated fibers in their muscle biopsies. There were ten females and seven males. The onset of symptoms ranged from 2 to 55 years (mean 24). The average age at the time of muscle biopsy was 39 (range 3-63). Interestingly, in six patients, high prevalence of lobulated fibers was observed at the second biopsy only, performed on average 11 years after the first or in another muscle. Six patients had a suggestively positive family history. Facial weakness was noted in two patients (genetic study confirmed FSH dystrophy). The course and the severity of weakness varied from one patient to another. Immunohistochemistry and Western blot analyses revealed one Duchenne carrier, one alpha-sarcoglycanopathy, no dysferlinopathy and four calpain deficiencies (including one patient with FSH dystrophy), but SSCP revealed mutation in the calpain gene in only one of the patients. These results show that (1) myopathies with lobulated fibers are clinically and genetically heterogeneous, (2) lack of calpain expression by Western blot analysis is not always associated with null mutation, (3) a molecular diagnosis is made in less than 40% of myopathy with lobulated fibers, (4) when observed, lobulated fibers are most prominent in proximal muscles and require time to appear.

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., (Copyright 2000 Wiley-Liss, Inc.)

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 SacI (proximal CMT1A-REP). This was further reduced to a 1.7kb 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 3.2kb 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.

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., (Copyright 2000 Wiley-Liss, Inc.)

We report on the auxological and endocrine evolution of 28 patients presenting with Prader-Willi syndrome. Half of them received growth hormone (GH) therapy (group 2). The spontaneous auxological evolution was analyzed in the two groups from 2 to 8 years; the mean SDS for height remained stable (-0.6 +/- 0.6) in group 1 and decreased (from -2.0 +/- 0.9 to -2.7 +/- 0.6) in group 2. Magnetic resonance imaging showed marked pituitary hypoplasia in the two groups. In group 2, the mean GH peak after two provocative tests was 3.8 +/- 2.4 microg/l, the mean SDS values for insulin-like growth factor I levels were -2.0 +/- 1.5 (range from -0.5 to -5.0). The mean duration of GH treatment was 3.6 +/- 2.9 (range 1-9.3) years. 14 children completed 1 year of treatment. The two groups had opposite evolutions in Delta SDS for height (-0.8 +/- 0.8 vs. +1.1 +/- 0.8), for growth velocity (-1.9 +/- 2.2 vs. +2.9 +/- 2.7), and for Z score of the body mass index (+0.37 +/- 1.3 vs. -0.14 +/- 0.76; group 1 vs. group 2). This retrospective study shows that, in children with Prader-Willi syndrome and true GH deficiency, long-term GH therapy is effective in increasing growth velocity and in maintaining body mass index., (Copyright 2001 S. Karger AG, Basel)

Angelman syndrome (AS) is a neurological disorder with a heterogeneous genetic aetiology. It most frequently results from a de novo interstitial deletion in the 15q11-q13 region, but in a few cases it is caused by paternal uniparental disomy (UPD) or an imprinting mutation. The remaining 20 to 30% of AS patients exhibit biparental inheritance and a normal pattern of allelic methylation in the 15q11-q13 region. In this latter group, mutations in the UBE3A gene have recently been shown to be a cause of AS. Here we describe the phenotypic expression in 14 AS cases involving eight UBE3A mutations. These comprise 11 familial cases from five families and three sporadic cases. Subtle differences from the typical phenotype of AS were found. Consistent manifestations were psychomotor delay, a happy disposition, a hyperexcitable personality, EEG abnormalities, and mental retardation with severe speech impairment. The other main manifestations of AS, ataxia, epilepsy, and microcephaly, were either milder or absent in various combinations among the patients. In addition, myoclonus of cortical origin was frequently observed with severe fits inducing myoclonic seizures. The majority of the patients were overweight. This study showed that ataxia, myoclonus, EEG abnormalities, speech impairment, characteristic behavioural phenotype, and abnormal head circumference are attributable to a deficiency in the maternally inherited UBE3A allele. Furthermore, analysis of mutation transmission showed an unexpectedly high rate of somatic mosaicism in normal carriers. These data have important consequences for genetic counselling.

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

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 [Piétu 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.

Angelman 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.

Prader-Willi syndrome (PWS) is a neurogenetic disorder that results from the absence of a normal paternal contribution to the 15q11-13 region. The clinical manifestations of PWS are a transient severe hypotonia in the newborn period, with mental retardation, hypogonadism and obesity observed later in development. Five transcripts with exclusive expression from the paternal allele have been isolated, but none of these has been shown to be involved in PWS. 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 protein, 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 fibroblasts 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.

Exercise intolerance associated with myalgias, muscle cramps or myoglobinuria may be associated with a dystrophinopathy. A search for abnormal dystrophin expression (using immunohistochemistry, immunoblot and DNA analysis) was carried out in a series of 15 patients. They were selected because they presented exercise intolerance, negative biochemical tests (lipid, glycogen and mitochondrial metabolism) and abnormal immunohistochemistry with at least one anti-dystrophin antibody (anti-Dys 1, rod domain; anti-Dys 2, C terminus; anti-Dys 3, N terminus). Lack of anti-Dys 1 immunoreactivity was seen in three patients and abnormal immunoreactivity with all three anti-dystrophin antibodies in two. Immunoblot confirmed the dystrophinopathy in these five patients only, and multiplex polymerase chain reaction DNA analysis revealed a deletion in the dystrophin gene in two of these patients, affecting the proximal part of the rod domain in one and the distal part of this domain in the other. The clinical, biological and histopathological features of the five patients reported here, together with the previous cases reported in the literature, are described and reveal that exercise intolerance associated with dystrophinopathy displays characteristic clinical, biological and immunohistochemical features and defines a new dystrophinopathy phenotype. The absence of staining in the rod domain provides a secure diagnosis of this syndrome. Dystrophinopathy is one etiology of idiopathic myoglobinuria, requiring genetic counseling.

Background: The main features of the Smith-Magenis syndrome include broad flat midface, brachycephaly, broad nasal bridge, brachydactyly, hoarse deep voice, speech and developmental delay, and behavioral anomalies. This syndrome is due to interstitial deletion of chromosome 17p11.2., Case Report: A 7-year-old girl was admitted for mental retardation. Clinical examination showed brachycephaly, broad flat midface, broad nasal bridge, malar hypoplasia, brachydactyly, decreased or absent deep tendon reflexes, and hoarse deep voice. She had a mild deafness, behavioral problems, and sleep disturbances. Chromosome analysis on lymphocytes identified a microdeletion of one chromosome subband 17p11.2. Molecular studies indicated loss of maternal allele., Conclusion: The Smith-Magenis syndrome is probably underdiagnosed because of its usually mild clinical features. High-resolution chromosome analysis is needed for diagnosis.

Angelman syndrome (AS) results from lack of genetic contribution from maternal chromosome 15q11-13. This region encompasses three GABAA receptor subunit genes (beta3, alpha5, and gamma3). The characteristic phenotype of AS is severe mental retardation, ataxic gait, tremulousness, and jerky movements. We studied the movement disorder in 11 AS patients, aged 3 to 28 years. Two patients had paternal uniparental disomy for chromosome 15, 8 had a >3 Mb deletion, and 1 had a microdeletion involving loci D15S10, D15S113, and GABRB3. All patients exhibited quasicontinuous rhythmic myoclonus mainly involving hands and face, accompanied by rhythmic 5- to 10-Hz electroencephalographic (EEG) activity. Electromyographic bursts lasted 35 +/- 13 msec and had a frequency of 11 +/- 2.4 Hz. Burst-locked EEG averaging in 5 patients, generated a premyoclonus transient preceding the burst by 19 +/- 5 msec. A cortical spread pattern of myoclonic cortical activity was observed. Seven patients also demonstrated myoclonic seizures. No giant somatosensory evoked potentials or C-reflex were observed. The silent period following motor evoked potentials was shortened by 70%, indicating motor cortex hyperexcitability. Treatment with piracetam in 5 patients significantly improved myoclonus. We conclude that spontaneous, rhythmic, fast-bursting cortical myoclonus is a prominent feature of AS.

Using a rat histidine decarboxylase (HDC) cDNA probe, we have mapped the HDC gene by in situ hybridization to the q15-q21 region of human chromosome 15 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.

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.

The Angelman syndrome is a neurological disorder characterized by constant features: severe mental retardation, easily provoked laughter, ataxia, absent speech, seizures. Most cases are sporadic but familial cases have been reported. About 60 to 70% of cases are due to an interstitial deletion on the maternally inherited chromosome 15 in the region q11-q13. Rare cases result from paternal disomy. In 30% of patients, neither maternal by inherited deletion, nor paternal disomy, can be found. In this category of patients recurrence risk for sibs is high and molecular mechanisms are not completely known. They appear to be more complex than previously suggested. It is clear that this syndrome is a genetically heterogeneous group. The main example of genomic imprinting in human pathology, Angelman syndrome is now a model in research for understanding molecular mechanisms underlying imprinting.

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.

In 61 patients in whom high doses of corticoids had been administered owing to various indications, the hemodynamic modifications caused by this injection were studied. The corticoids administered were : hydrocortisone hemisucccinate (150 mg/kg), methyl prednisolone sulfate (30 mg/kg), prednisone sodium m sulfobenzoate (50 mg/kg), prednisolone sodium m sulfobenzoate (35 mg/kg) and dexamethasone phosphate (2 mg and 6 mg/kg). The results study the modifications caused by each drug on heart rate, arterial blood pressure, cardiac output, systolic stroke volume and peripheral vascular resistance. The expression of the results is given as a percentage of the variation with statistical study. Methyl-prednisolone sulfobenzoate only leads to slightly marked hemodynamic effects : the four other compounds studied have definite hemodynamic effects, of variable intensity and duration. The most important variations are noted with dexametasone phosphate. From these results, the indications and results of the use of corticoids in states of shock are discussed.