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We present a newborn diagnosed with posterior amorphous corneal dystrophy (PACD). PACD is a rare disorder with partial or complete posterior lamellar corneal opacification. Genetic screening showed a deletion of chromosome 12q21.33-q22 containing the identified four small leucine-rich proteoglycans (SLRP’s) associated with this particular dystrophy. Neither parents were carrier of the deletion. To our knowledge, this is the first report of ade novomutation causing PACD. [ABSTRACT FROM AUTHOR]

Loss-of-function mutations in CCM1/ KRIT1, CCM2/ MGC4607 and CCM3/ PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations ( CCMs). However, genomic DNA sequencing combined to large rearrangement screening fails to detect a mutation in 5% of those cases. We report a family in which CCM lesions were discovered fortuitously because of the investigation of a developmental delay in a boy. Three members of the family on three generations had typical multiple CCM lesions and no clinical signs related to CCM. No mutation was detected using genomic DNA sequencing and quantitative multiplex PCR of short fluorescent fragments ( QMPSF). cDNA sequencing showed a 99-nucleotide insertion between exons 5 and 6 of CCM1, resulting from a mutation located deep into intron 5 (c.262+132_262+133del) that activates a cryptic splice site. This pseudoexon leads to a premature stop codon. These data highly suggest that deep intronic mutations explain part of the incomplete mutation detection rate in CCM patients and underline the importance of analyzing the cDNA to provide comprehensive CCM diagnostic tests. This kind of mutation may be responsible for apparent sporadic presentations due to a reduced penetrance. [ABSTRACT FROM AUTHOR]

Background: With the development of next generation sequencing technologies in France, exome sequencing (ES) has recently emerged as an opportunity to improve the diagnosis rate of patients presenting an intellectual disability (ID). To help French policy makers determine an adequate tariff for ES, we aimed to assess the unit cost per ES diagnostic test for ID from the preparation of the pre-analytical step until the report writing step and to identify its main cost drivers. Methods: A micro-costing bottom-up approach was conducted for the year 2018 in a French setting as part of the DISSEQ study, a cost-effectiveness study funded by the Ministry of Health and performed in collaboration with the GAD (Génétique des Anomalies du Développement), a genetic team from the Dijon University Hospital, and a public sequencing platform, the Centre National de Recherche en Génomique Humaine (CNRGH). The analysis was conducted from the point of view of these two ES stakeholders. All of the resources (labor, equipment, disposables and reagents, reusable material) required to analyze blood samples were identified, collected and valued. Several sensitivity analyses were performed. Results: The unit nominal cost per ES diagnostic test for ID was estimated to be €2,019.39. Labor represented 50.7% of the total cost. The analytical step (from the preparation of libraries to the analysis of sequences) represented 88% of the total cost. Sensitivity analyses suggested that a simultaneous price decrease of 20% for the capture kit and 50% for the sequencing support kit led to an estimation of €1,769 per ES diagnostic test for ID. Conclusion: This is the first estimation of ES cost to be done in the French setting of ID diagnosis. The estimation is especially influenced by the price of equipment kits, but more generally by the organization of the centers involved in the different steps of the analysis and the time period in which the study was conducted. This information can now be used to define an adequate tariff and assess the efficiency of ES. Trial registration: ClinicalTrials.gov identifier NCT03287206 on September 19, 2017. [ABSTRACT FROM AUTHOR]

Novel semi-conductive fibres from multiwalled carbon nanotubes (MWCNT) based-polyethersulfone (PES) have been produced by wet spinning insight of incorporation in composite matrix. N -methyl-2-pyrrolidone (NMP) was chosen as dispersing medium for MWCNT by sonication and as solvent for PES. MWCNT reinforced-PES fibres were spun into water coagulation bath with an observed instantaneous liquid-liquid demixing. After washing and drying steps, fibres are either directly characterized or annealed at 250 °C during 15 min and 24 h prior to characterization. Scanning electron microscope (SEM) micrographs performed in each configuration disclose presence of macrovoids, pores and empty spaces inside fibres before thermal annealing whereas after thermal annealing, fibres display a cohesive and continuous morphology. A significant mechanical properties improvement of the wet-spun fibres is noticed by rising annealing time. Transmission electron microscope (TEM) investigations have also been carried out and reveal a two phases microstructure in unannealed fibres with a separation between a PES-rich continuous phase and NMP-rich nodules containing exclusively MWCNT. TEM images suggest also thermal annealing process allows solvent evaporation, MWCNT aggregation and a conductive nanofillers network formation in PES nanocomposite fibres. Electrical measurement in unannealed fibres indicate a deficiency of conductive character between 0.25 and 2 wt.% MWCNT whereas a lowering electrical percolation threshold is achieved in fibres by increasing annealing time, around 1.5 and 1 wt.% MWCNT for respectively a 15 min and 24 h thermal annealing. Influence of MWCNT sonication duration on electrical conductivity is also examined showing a gradually reduction of fibres' electrical conductivity by dispersion time increasing until losing their semi-conductive state. A dispersion analysis let suppose that a whole MWCNT agglomerates network is split in smaller but denser clusters which are dispersed and taken away from each other during sonication, which causes the conductive path rupture. [ABSTRACT FROM AUTHOR]

A case study of a 10-year-old male patient with who was diagnosed with variation in the SHH gene leading to microcephaly, intellectual disability, and familial coloboma. The article discusses the diagnosis of the disease with the application of DNA sequencing with the use of Sanger sequencing, use of magnetic resonance imaging (MRI), and phenotype of the patient.

Kabuki syndrome ( KS-OMIM 147920) is a rare developmental disease characterized by the association of multiple congenital anomalies and intellectual disability. This study aimed to investigate intellectual performance in children with KS and link the performance to several clinical features and molecular data. We recruited 31 children with KMT2D mutations who were 6 to 16 years old. They all completed the Weschler Intelligence Scale for Children, fourth edition. We calculated all indexes: the Full Scale Intellectual Quotient ( FSIQ), Verbal Comprehension Index ( VCI), Perceptive Reasoning Index ( PRI), Processing Speed Index ( PSI), and Working Memory Index ( WMI). In addition, molecular data and several clinical symptoms were studied. FSIQ and VCI scores were 10 points lower for patients with a truncating mutation than other types of mutations. In addition, scores for FSIQ, VCI and PRI were lower for children with visual impairment than normal vision. We also identified a discrepancy in indexes characterized by high WMI and VCI and low PRI and PSI. We emphasize the importance of early identification and intensive care of visual disorders in patients with KS and recommend individual assessment of intellectual profile. [ABSTRACT FROM AUTHOR]

Differences of sex development (DSDs) are a group of congenital conditions characterized by a discrepancy between chromosomal, gonadal, and genital sex development of an individual, with significant impact on medical, psychological and reproductive life. The genetic heterogeneity of DSDs complicates the diagnosis and almost half of the patients remains undiagnosed. In this context, chromosomal imbalances in syndromic DSD patients may help to identify new genes implicated in DSDs. In this study, we aimed at describing the burden of chromosomal imbalances including submicroscopic ones (copy number variants or CNVs) in a cohort of prenatal syndromic DSD patients, and review their role in DSDs. Our patients carried at least one pathogenic or likely pathogenic chromosomal imbalance/CNV or low-level mosaicism for aneuploidy. Almost half of the cases resulted from an unbalanced chromosomal rearrangement. Chromosome 9p/q, 4p/q, 3q and 11q anomalies were more frequently observed. Review of the literature confirmed the causative role of CNVs in DSDs, either in disruption of known DSD-causing genes (SOX9, NR0B1, NR5A1, AR, ATRX, ...) or as a tool to suspect new genes in DSDs (HOXD cluster, ADCY2, EMX2, CAMK1D, ...). Recurrent CNVs of regulatory elements without coding sequence content (i.e. duplications/deletions upstream of SOX3 or SOX9) confirm detection of CNVs as a mean to explore our non-coding genome. Thus, CNV detection remains a powerful tool to explore undiagnosed DSDs, either through routine techniques or through emerging technologies such as long-read whole genome sequencing or optical genome mapping. [ABSTRACT FROM AUTHOR]

Holoprosencephaly ( HPE) is the most common congenital cerebral malformation, characterized by impaired forebrain cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been associated with HPE and are often inherited from an unaffected parent, underlying complex genetic bases. It is now emerging that HPE may result from a combination of multiple genetic events, rather than from a single heterozygous mutation. To explore this hypothesis, we undertook whole exome sequencing and targeted high-throughput sequencing approaches to identify mutations in HPE subjects. Here, we report two HPE families in which two mutations are implicated in the disease. In the first family presenting two foetuses with alobar and semi-lobar HPE, we found mutations in two genes involved in HPE, SHH and DISP1, inherited respectively from the father and the mother. The second reported case is a family with a 9-year-old girl presenting lobar HPE, harbouring two compound heterozygous mutations in DISP1. Together, these cases of digenic inheritance and autosomal recessive HPE suggest that in some families, several genetic events are necessary to cause HPE. This study highlights the complexity of HPE inheritance and has to be taken into account by clinicians to improve HPE genetic counselling. [ABSTRACT FROM AUTHOR]

Cornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation. Recently, NIPBL somatic mosaicism has been highlighted through buccal cell DNA study in some patients with a negative molecular analysis on leukocyte DNA. Here, we present a series of 38 patients with a Cornelia de Lange syndrome related to a heterozygous NIPBL mutation identified by Sanger sequencing. The diagnosis was based on the following criteria: (i) intrauterine growth retardation and postnatal short stature, (ii) feeding difficulties and/or gastro-oesophageal reflux, (iii) microcephaly, (iv) intellectual disability, and (v) characteristic facial features. We identified 37 novel NIPBL mutations including 34 in leukocytes and 3 in buccal cells only. All mutations shown to have arisen de novo when parent blood samples were available. The present series confirms the difficulty in predicting the phenotype according to the NIPBL mutation. Until now, somatic mosaicism has been observed for 20 cases which do not seem to be consistently associated with a milder phenotype. Besides, several reports support a postzygotic event for those cases. Considering these elements, we recommend a first-line buccal cell DNA analysis in order to improve gene testing sensitivity in Cornelia de Lange syndrome and genetic counselling. [ABSTRACT FROM AUTHOR]

Otopalatodigital spectrum disorders ( OPDSD) include OPD syndromes types 1 and type 2 ( OPD1, OPD2), Melnick-Needles syndrome ( MNS), and frontometaphyseal dysplasia ( FMD). These conditions are clinically characterized by variable skeletal dysplasia associated in males, with extra-skeletal features including brain malformations, cleft palate, cardiac anomalies, omphalocele and obstructive uropathy. Mutations in the FLNA gene have been reported in most FMD and OPD2 cases and in all instances of typical OPD1 and MNS. Here, we report a series of 10 fetuses and a neonatally deceased newborn displaying a multiple congenital anomalies syndrome suggestive of OPDSD and in whom we performed FLNA analysis. We found a global mutation rate of 44%. This series allows expanding the clinical and FLNA mutational spectrum in OPDSD. However, we emphasize difficulties to correctly discriminate OPDSD based on clinical criteria in fetuses due to the major overlap between these conditions. Molecular analyses may help pathologists to refine clinical diagnosis according to the type and the location of FLNA mutations. Discriminating the type of OPDSD is of importance in order to improve the genetic counseling to provide to families. [ABSTRACT FROM AUTHOR]

Les angioedèmes héréditaires par mutation du facteur XII représentent, selon les séries, 20 à 25 % des angiœdèmes héréditaires bradykiniques à C1 inhibiteur normal. Ils surviennent préférentiellement chez les femmes après la puberté, sous contraception contenant des œstrogènes ou pendant la grossesse. Cependant les hormones ne semblent pas être le seul facteur déclenchant ce type d'angiœdème, en effet certaines patientes développent des angiœdèmes en dehors des grossesses et de la prise de contraception oestroprogestative et quelques séries rapportent des cas de sujets de sexe masculin symptomatiques. L'objectif principal de notre étude est d'étudier la prévalence des symptômes d'angioedeme chez les sujets de sexe masculin et de les caractériser en décrivant leur localisation, leur fréquence, leur durée et leur réponse aux traitements éventuellement administrés. Nous avons réalisé une étude observationnelle rétrospective des manifestations d'angiœdème chez les sujets de sexe masculin porteurs de la mutation du FXII au sein du centre de référence des angiœdèmes de l'hôpital Saint Antoine à Paris, et chez ceux dépistés par le laboratoire de génétique de Grenoble entre juin 2006 et mai 2020. 168 sujets de sexe masculin ont été recensés au sein du centre de référence de l'hôpital Saint Antoine, 21 sont porteurs de la mutation du FXII. Nous avons pu obtenir les informations concernant 22 autres sujets masculins porteur de la mutation suivis dans d'autres centres de référence des angiœdèmes bradykiniques. Parmi ces sujets, 19 % (8/43) sont symptomatiques. L'âge moyen des premiers symptômes est de 29,5 ans (6 à 68 ans). Les localisations principales sont des œdèmes de la face (50 %) et des douleurs abdominales (50 %), moins fréquemment les œdèmes siègent au niveau des extrémités (12 %), du larynx (12 %) et de la langue (12 %). La durée des crises est de 48 à 72 heures, avec une fréquence moyenne de 2,25 crises par an. La réponse au traitement n'a pu être évaluée chez tous les patients ; la moitié des patients ont répondu à l'icatibant ou aux concentrés de C1 Inhibiteur Notre travail a permis de recenser les sujets masculins symptomatiques porteurs de la mutation du facteur XII dépistés en France entre 2006 et 2021. Les manifestations cliniques sont rares ; la localisation et la durée des crises sont similaires à celles observées chez les femmes, mais leurs crises semblent moins fréquentes chez ces derniers. Le mécanisme bradykinique n'a cependant pas pu être confirmé chez tous les sujets. Le suivi de ces patients est donc nécessaire ainsi que leur information sur la maladie, le mode de transmission génétique et sa prise en charge. [ABSTRACT FROM AUTHOR]

Résumé Objectifs Très peu d’études se sont intéressées au suivi gynécologique des femmes présentant un spina bifida et ce sujet est rarement évoqué tant dans les associations de patients que dans les milieux médicaux. Pourtant, ces patientes sont demandeuses de conseils et d’une prise en charge adaptée à leur pathologie. Méthodes Nous avons mené, dans le cadre du centre de référence spina bifida du CHU de Rennes, une étude rétrospective, observationnelle, sur 4 ans, afin d’étudier les éventuelles particularités du suivi gynécologique de ces patientes et de pouvoir adapter notre pratique à leurs besoins. Résultats Quarante-huit patientes ont été incluses. Nous avons mis en évidence, de façon significative, un sur-risque de puberté précoce, d’hypertrophie des petites lèvres et de prolapsus pelvien. Conclusion Le suivi gynécologique des patientes ayant un spina bifida présente quelques particularités intéressantes à connaître. Une étude sur une plus grande série de patientes est nécessaire pour analyser plus précisément les problématiques gynéco-obstétricales et sexologiques de ces femmes. Objectives Few studies have focused on reproductive health care for women with spina bifida. This subject is rarely discussed, whether in patient groups or in the medical community. However, these patients need advice and a care that is appropriate to their condition. Methods In association with the spina bifida reference center of the University Hospital of Rennes, we have conducted a four-year retrospective, observational study. Its aim was to analyze the characteristics of the patients’ gynecological care and to adapt our practice to their needs. Results Forty-eight patients were included. We demonstrated an increased risk of precocious puberty, labia minora hypertrophy and genital prolapse. Conclusion Some specific characteristics of the reproductive health care of patients with spina bifida are interesting to know. A study on a larger series of patients is needed to further analyze the obstetric, gynecological and sexological issues of these women. [ABSTRACT FROM AUTHOR]

Objectifs La phénylcétonurie (PCU) nécessite un régime et un équilibre métabolique très stricts, ce qui peut être un frein au maintien de l’allaitement maternel (AM). Nous rapportons la fréquence et les effets sur le contrôle métabolique et la croissance de l’AM dans la PCU. Sujet / matériels et méthodes Tous les nouveau-nés diagnostiqués dans le Grand Ouest pour une PCU entre 2000 et 2012 et ayant bénéficié d’un AM de plus d’un mois ont été appariés rétrospectivement avec un patient PCU contrôle en allaitement artificiel (AA) et suivis jusqu’à 3 ans. Résultats principaux 19 patients PCU sur 67 ont bénéficié d’un AM. La fréquence de l’AM dans la PCU était très inférieure à la moyenne régionale (28% vs 63%, p<0.0001) mais sa durée médiane tendait à être plus prolongée (23,5 vs 15,5 sem, NS). Les taux moyens de phénylalaninémie durant 3 ans étaient identiques (AM 273 ± 59 vs AA 265 ± 63 μM, NS), de même que leur variabilité (AM 133 ± 79 vs AA 143 ± 65 μM, NS). Il n’y avait pas d’impact sur la croissance ou le bilan nutritionnel à 3 ans. Conclusion Le diagnostic de PCU reste un frein à l’utilisation de l’AM alors que ce dernier permet un équilibre métabolique aussi bon qu’avec un AA. L’AM doit être préconisé en raison de ses effets bénéfiques sur le long terme. [ABSTRACT FROM AUTHOR]

Anophthalmia and microphthalmia ( AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and different genes have been demonstrated to be causative of syndromic and non-syndromic forms of AM. We screened seven AM genes [ GDF6 (growth differentiation factor 6), FOXE3 (forkhead box E3), OTX2 (orthodenticle protein homolog 2), PAX6 (paired box 6), RAX (retina and anterior neural fold homeobox), SOX2 (SRY sex determining region Y-box 2), and VSX2 (visual system homeobox 2 gene)] in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21% of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition eight gene deletions (five SOX2, two OTX2 and one RAX ) were identified using a semi-quantitative multiplex polymerase chain reaction ( PCR) [quantitative multiplex PCR amplification of short fluorescent fragments ( QMPSF)]. The causative genetic defect was identified in 21% of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling. [ABSTRACT FROM AUTHOR]

Abstract: Background: Trisomy 18 and Smith–Lemli–Opitz syndrome are two polymalformative conditions in which a cholesterol defect has been noted. When they occur prenatally, they are associated with a decreased maternal unconjugated estriol (uE3) level. Cholesterol plays an essential role in the Sonic Hedgehog pathway, allowing Shh protein maturation leading to its maximal activity. Many malformations in these two syndromes occur in Shh dependent tissues. We thus sought to assess whether a cholesterol defect could affect the Shh pathway and explain some of the observed malformations. Materials and methods: We selected 14 cases of trisomy 18 and 3 cases of SLO in which the maternal uE3 level was decreased and reported malformations were observed after fetopathological examination. We correlated the number of malformations with maternal uE3 level. We then carried out cholesterol concentrations in separate culture media consisting of trisomy 18, SLO and control amniocytes. Finally, we analyzed the Shh pathway by testing the gene expression of several Shh components: GLI transcription factors, BMP2, BMP4, TGFβ1, COL1A1 and COL1A2. Results and discussion: There was an inverse correlation between phenotypic severity and maternal uE3 levels in SLO and trisomy 18. The cholesterol levels in the amniocyte culture media were correlated with maternal uE3 levels and were significantly lower in T18 and SLO amniocytes, reflecting cholesterol defects. There was an alteration in the Shh pathway since expression of several genes was decreased in T18 and SLO amniocytes. However, these cholesterol defects were not solely responsible for the altered Shh pathway and the malformations observed. [Copyright &y& Elsevier]

Objective: To report four foetal cases of the Binder phenotype associated with maternal autoimmune disorders. Patients and Methods: In three mothers with autoimmune diseases, 2D and 3D ultrasonographic measurements were made on four foetuses with the Binder profile, and were compared with postnatal phenotypes. Results: The Binder phenotype can be detected in early pregnancy (14.5 WG). All foetuses had verticalized nasal bones and midfacial hypoplasia. Punctuate calcifications were found in almost all the cases. No specific maternal auto-antibody has been associated with foetal Binder phenotype. Conclusion: Since the Binder phenotype can be diagnosed at ultrasound examination during pregnancy, it is important to establish the underlying cause so as to assess the foetal prognosis. This study stresses the importance of systematic checks for maternal autoimmune disease in cases of prenatally diagnosed Binder phenotypes. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Masurel-Paulet A, Andrieux J, Callier P, Cuisset JM, Le Caignec C, Holder M, Thauvin-Robinet C, Doray B, Flori E, Alex-Cordier MP, Beri M, Boute O, Delobel B, Dieux A, Vallee L, Jaillard S, Odent S, Isidor B, Beneteau C, Vigneron J, Bilan F, Gilbert-Dussardier B, Dubourg C, Labalme A, Gautier A, Pernes P, Bidon C, Pinoit JM, Huet F, Mugneret F, Aral B, Jonveaux P, Sanlaville D, Faivre L. Delineation of 15q13.3 microdeletions. The increasing use of array-comparative genomic hybridization (array-CGH) to identify copy number variations (CNVs) in patients with developmental delay (DD), mental retardation and/or dysmorphic features has allowed the recent recognition of numerous genomic imbalances, including the 15q13.3 microdeletion. Patients with this microdeletion generally present with relatively consistent breakpoints at BP4 and BP5, which include the CHRNA7 gene. About 100 index cases have been reported since the first publication in 2008. This large number of patients ascertained through highly variable samples has been necessary to describe the full phenotypic spectrum of this microdeletion, ranging from mental retardation with dysmorphic features, epilepsy, neuropsychiatric disturbances with or without cognitive impairment to complete absence of anomalies. Here, we describe a collaborative study reporting a new cohort of 12 index patients and 13 relatives carrying a heterozygous BP4–BP5 microdeletion out of a series of 4625 patients screened by array-CGH for DD. We confirm the clinical expressivity of the disease as well as the incomplete penetrance in seven families. We showed through a review of the literature that males are more likely to be symptomatic. Sequence analysis of CHRNA7 yielded no data to support the unmasking of recessive variants as a cause of phenotypic variability. We also report the first patient carrying a 15q13.3 homozygous microdeletion inherited from both parents. He had severe epileptic encephalopathy with retinopathy, autistic features and choreoathetosis. Besides the classical ∼1.5 Mb BP4–BP5 microdeletion, we also describe three index patients and two relatives with a smaller 500 kb microdeletion, including the CHRNA7 gene. [ABSTRACT FROM AUTHOR]

Mutations in ATRX are associated with a wide and clinically heterogeneous spectrum of X-linked mental retardation syndromes. The ATRX protein, involved in chromatin remodelling, belongs to the family of SWI/SNF DNA helicases and contains a plant homeodomain (PHD)-like domain. To date, more than 60 different mutations have been reported in ATRX. One of them is recurrent and accounts for 20% of all the reported mutations, whereas all others are private. Most mutations are clustered in the two major functional domains, the helicase and the PHD-like domain. So far, no clear genotype–phenotype correlation has been established, with exception to the rare truncating mutations located at the C-terminal part of the protein, which are consistently associated with severe urogenital defects. In this study, we report the molecular analysis performed in 16 families positive for ATRX. Our findings indicate that, in addition to the previously described mutation ‘hotspot’ in the PHD-like domain, two other protein sections emerge as minor ‘hotspots’ in the helicase region encoded by exons 18–20 and 26–29, respectively, gathering 33% of all described mutations. Additionally, based on the clinical data collected for 22 patients from the 16 families, we observe that mutations in the PHD-like domain produce severe and permanent psychomotor deficiency, usually preventing patients from walking, as well as constant urogenital abnormalities, while mutations in the helicase domain lead to delayed but correct psychomotor acquisitions together with mild or absent urogenital abnormalities. In summary, mutations in the helicase domain are associated with milder phenotypes than mutations in the PHD-like domain. [ABSTRACT FROM AUTHOR]

Cockayne syndrome is a multi-systemic, autosomal recessive disease characterised by postnatal growth failure and progressive multi-organ dysfunction. The main clinical features are severe dwarfism (<-2 SD), microcephaly (<-3 SD), psychomotor delay, sensorial loss (cataracts, pigmentary retinopathy, and deafness), and cutaneous photosensitivity. Here, 13 new cases of Cockayne syndrome are reported, which have been clinically diagnosed and confirmed using a biochemical transcription assay. The wide clinical variability, ranging from prenatal features to normal psychomotor development, is emphasised. When cardinal features are lacking, the diagnosis of Cockayne syndrome should be considered when presented with growth retardation, microcephaly, and one of the suggesting features such as enophthalmia, limb ataxia, abnormal auditory evoked responses, or increased ventricular size on cerebral imaging. [ABSTRACT FROM AUTHOR]

Cockayne syndrome is a multi-systemic, autosomal recessive disease characterised by postnatal growth failure and progressive multi-organ dysfunction. The main clinical features are severe dwarfism (<-2 SD), microcephaly (<-3 SD), psychomotor delay, sensorial loss (cataracts, pigmentary retinopathy, and deafness), and cutaneous photosensitivity. Here, 13 new cases of Cockayne syndrome are reported, which have been clinically diagnosed and confirmed using a biochemical transcription assay. The wide clinical variability, ranging from prenatal features to normal psychomotor development, is emphasised. When cardinal features are lacking, the diagnosis of Cockayne syndrome should be considered when presented with growth retardation, microcephaly, and one of the suggesting features such as enophthalmia, limb ataxia, abnormal auditory evoked responses, or increased ventricular size on cerebral imaging. [ABSTRACT FROM AUTHOR]

Holoprosencephaly (HPE) is a severe brain malformation which results from incomplete cleavage of the forebrain during early embryogenesis. The aetiology of HPE is very heterogeneous. Among the genetic factors, SIX3, which is considered to be the functional orthologue of Drosophila genes sine oculis (so) and optix, has been found to be mutated in the homeodomain, in some patients with HPE (HPE2 on chromosome 2p21). We report a new HPE family, presenting a wide spectrum of clinical features, ranging from cyclopia to hypotelorism, in which a mutation was found for the first time in the SIX domain of SIX3: a GG insertion creates a frameshift leading to a nonsense mutation downstream in the homeodomain region. [ABSTRACT FROM AUTHOR]

Introduction La phénylcétonurie (PCU) est une maladie métabolique rare qui est dépistée chez tous les nouveau-nés en France. Les enfants atteints sont traités pendant l’enfance par un régime contrôlé en phénylalanine, jusqu’à un âge variable. L’évolution de la maladie à l’âge adulte est partiellement décrite et certains résultats montrent que le pronostic de ces patients n’est pas optimal [1] . L’objectif de notre étude était de décrire l’incidence des complications neuropsychiatriques de ces patients adultes atteints de PCU. Patients et méthodes Le projet ECOPHEN est une étude de cohorte multicentrique prospective de patients adultes atteints de PCU. Tous les patients ont été diagnostiqués suite au dépistage néonatal. Les résultats de la visite d’inclusion sont présentés et exprimés en moyenne ± écart-type. Résultats Cent quatre-vingt-sept patients ont été inclus (127 femmes, 60 hommes, âge 27,6 ± 6,3 ans). Le nombre de patients avec PCU classique, PCU atypique et hyperphénylalaninémie persistante (HMP) était respectivement de 152, 26 et 9. Cinquante-trois pour cent des patients étaient traités par un régime contrôlé en phénylalanine. Au total, 20 patients (10,7 %) ont eu des troubles neurologiques, uniquement dans le groupe PCU classique (céphalées, tremblements, troubles de l’équilibre ou troubles visuels…). Quarante-huit patients (25,7 %) ont développé des troubles psychiatriques variés (dépression anxiété, troubles du comportement alimentaire…), et ce dans les 3 types de PCU : 40 patients (26,3 %) avec PCU classique vs 6 (23,1 %) avec PCU atypique, vs 2 (22,2 %) avec HMP (NS). Discussion Cette étude a permis d’inclure un grand nombre de patients adultes atteints de PCU, majoritairement de type PCU classique. La population féminine est très majoritairement représentée, en raison des enjeux qui concernent la grossesse PCU. Dans cette étude, l’incidence des troubles neurologiques est faible mais non négligeable, avec des manifestations plus ou moins sévères, dont certaines sont réversibles après une reprise de traitement de la PCU. L’incidence des troubles psychologiques/psychiatriques paraît élevée, et ce dans les 3 groupes de patients. L’absence de groupe témoin ne permet pas de savoir si cette incidence est significativement plus élevée par rapport à des sujets sains. Conclusion L’incidence des troubles neuropsychiatriques n’est pas négligeable dans la PCU de l’adulte. Ces résultats suggèrent de maintenir un régime contrôlé en phénylalanine à long terme [2] . Le suivi des patients atteints de PCU doit inclure un dépistage systématique des troubles neuropsychiatriques. [ABSTRACT FROM AUTHOR]

Introduction: L’utilisation actuelle du BH4 (Kuvan®) est restreinte selon l’AMM (1) aux patients atteints d’un déficit en BH4 démontré, et (2) aux patients phénylcétonuriques (PCU, [Phe]> 600μM) répondeurs âgés de plus de 4 ans. Une extension de son utilisation (test de sensibilité systématique en période néonatale et traitement des PCU sensibles avant 4 ans) devrait permettre d’améliorer la pris en charge de ces patients. Cas cliniques: Nous rapportons le cas de 10 patients dépistés à la naissance pour une hyperphénylalaninémie modérée (HPM, [Phe] 180-600μM) ayant bénéficié d’un traitement par BH4 avant l’âge de 4 ans. La réalisation d’un test néonatal chez 2 patients a permis d’identifier précocement un déficit du métabolisme du BH4. Pour 8 autres patients atteints d’une HPM ou d’une PCU atypique, l’introduction d’un traitement par BH4 avant l’âge de 4 ans a permis d’obtenir un meilleur contrôle métabolique, d’élargir le régime et d’améliorer la qualité de vie des patients. Aucun effet indésirable n’a été rapporté chez ces patients. Conclusion: L’utilisation du BH4 dans les HPM avant l’âge de 4 ans permet d’améliorer la prise en charge diagnostique et thérapeutique des patients dépistés à la naissance. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about sporadic optic atrophy and messenger RNA.