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The autosomal recessive demyelinating form of Charcot-Marie-Tooth can be due to SH3TC2 gene pathogenic variants (CMT4C, AR-CMTde-SH3TC2). We report on a series of 13 patients with AR-CMTde-SH3TC2 among a French cohort of 350 patients suffering from all type of inheritance peripheral neuropathy. The SH3TC2 gene appeared to be the most frequently mutated gene for demyelinating neuropathy in this series by NGS. Four new pathogenic variants have been identified: two nonsense variants (p.(Tyr970*), p.(Trp1199*)) and two missense variants (p.(Leu1126Pro), p.(Ala1206Asp)). The recurrent variant p.Arg954* was present in 62%, and seems to be a founder mutation. The phenotype is fairly homogeneous, as all these patients, except the youngest ones, presented scoliosis and/or hearing loss., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The most common inherited peripheral neuropathy is Charcot-Marie-Tooth disease (CMT), with a prevalence of 1/2500. Other symptoms can be associated to the condition, such as hearing loss. Currently, no global hearing impairment assessment has been determined, and the physiopathology is not well known., Methods: The aim of the study was to analyze among a French series of 3,412 patients with inherited peripheral neuropathy (IPN), the ones who also suffer from hearing loss, to establish phenotype-genotype correlations. An NGS strategy for IPN one side and nonsyndromic hearing loss (NSHL) on the other side, were performed., Results: Hearing loss (HL) was present in only 44 patients (1.30%). The clinical data of 27 patients were usable. Demyelinating neuropathy was diagnosed in 15 cases and axonal neuropathy in 12 cases. HL varied from mild to profound. Five cases of auditory neuropathy were noticed. Diagnosis was made for 60% of these patients. Seven novel pathogenic variants were discovered in five different genes: PRPS1; MPZ; SH3TC2; NEFL; and ABHD12. Two patients with PMP22 variant, had also an additional variant in COCH and MYH14 respectively. No pathogenic variant was found at the DFNB1 locus. Genotype-phenotype correlations do exist, especially with SH3TC2, PRPS1, ABHD12, NEFL, and TRPV4., Conclusion: Involvement of PMP22 is not enough to explain hearing loss in patients suffering from IPN. HL can be due to cochlear impairment and/or auditory nerve dysfunction. HL is certainly underdiagnosed, and should be evaluated in every patient suffering from IPN., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Objective: To genotypically and phenotypically characterize a large pediatric myotonic dystrophy type 1 (DM1) cohort to provide a solid frame of data for future evidence-based health management., Methods: Among the 2,697 patients with genetically confirmed DM1 included in the French DM-Scope registry, children were enrolled between January 2010 and February 2016 from 24 centers. Comprehensive cross-sectional analysis of most relevant qualitative and quantitative variables was performed., Results: We studied 314 children (52% females, with 55% congenital, 31% infantile, 14% juvenile form). The age at inclusion was inversely correlated with the CTG repeat length. The paternal transmission rate was higher than expected, especially in the congenital form (13%). A continuum of highly prevalent neurodevelopmental alterations was observed, including cognitive slowing (83%), attention deficit (64%), written language (64%), and spoken language (63%) disorders. Five percent exhibited autism spectrum disorders. Overall, musculoskeletal impairment was mild. Despite low prevalence, cardiorespiratory impairment could be life-threatening, and frequently occurred early in the first decade (25.9%). Gastrointestinal symptoms (27%) and cataracts (7%) were more frequent than expected, while endocrine or metabolic disorders were scarce., Conclusions: The pedDM-Scope study details the main genotype and phenotype characteristics of the 3 DM1 pediatric subgroups. It highlights striking profiles that could be useful in health care management (including transition into adulthood) and health policy planning., (© 2019 American Academy of Neurology.)

The Xq28 duplication involving the MECP2 gene ( MECP2 duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial MECP2 duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of MECP2 duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The molecular basis underlying the clinical variability in symptomatic Duchenne muscular dystrophy (DMD) carriers are still to be precised. We report 26 cases of early symptomatic DMD carriers followed in the French neuromuscular network. Clinical presentation, muscular histological analysis and type of gene mutation, as well as X-chromosome inactivation (XCI) patterns using DNA extracted from peripheral blood or muscle are detailed. The initial symptoms were significant weakness (88%) or exercise intolerance (27%). Clinical severity varied from a Duchenne-like progression to a very mild Becker-like phenotype. Cardiac dysfunction was present in 19% of the cases. Cognitive impairment was worthy of notice, as 27% of the carriers are concerned. The muscular analysis was always contributive, revealing muscular dystrophy (83%), mosaic in immunostaining (81%) and dystrophin abnormalities in western blot analysis (84%). In all, 73% had exonic deletions or duplications and 27% had point mutations. XCI pattern was biased in 62% of the cases. In conclusion, we report the largest series of manifesting DMD carriers at pediatric age and show that exercise intolerance and cognitive impairment may reveal symptomatic DMD carriers. The complete histological and immunohistological study of the muscle is the key of the diagnosis leading to the dystrophin gene analysis. Our study shows also that cognitive impairment in symptomatic DMD carriers is associated with mutations in the distal part of the DMD gene. XCI study does not fully explain the mechanisms as well as the wide spectrum of clinical phenotype, though a clear correlation between the severity of the phenotype and inactivation bias was observed.

Purpose: The purpose of this study was to establish the mutation spectrum of an Usher type I cohort of 61 patients from France and to describe a diagnostic strategy, including a strategy for estimating the pathogenicity of sequence changes., Methods: To optimize the identification of Usher (USH)-causative mutations, taking into account the genetic heterogeneity, preliminary haplotyping at the five USH1 loci was performed to prioritize the gene to be sequenced, as previously described. Coding exons and flanking intronic sequences were sequenced and, where necessary, semiquantitative PCR and multiplex ligation-dependent probe amplification (MLPA) were performed to detect large genomic rearrangements., Results: Four years ' experience confirms that the chosen approach provides an efficient diagnostic service. Sixty-one patients showed an abnormal genotype in one of the five USH1 genes. Genetic heterogeneity was confirmed, and, although MYO7A remains the major gene, involvement of other genes is considerable. Distribution of missense, splicing, premature termination codons (PTCs; due to point substitution and small deletions/ or insertions), and large genomic alterations was determined among the USH genes and clearly highlights the need to pay special attention to the diagnostic approach and interpretation, depending on the mutated gene., Conclusions: Over the 4 years of a diagnostic service offering USH1 patient testing, pathogenic genotypes were identified in most cases (>90%). The complexity and heterogeneity of mutations reinforces the need for a comprehensive approach. Because 32% of the mutations are newly described, the results show that a screening strategy based on known mutations would have solved less than 55% of the cases.

Array-CGH has revealed a large number of copy number variations (CNVs) in patients with multiple congenital anomalies and/or mental retardation (MCA/MR). According to criteria recently listed, pathogenicity was clearly suspected for some CNVs but benign CNVs, considered as polymorphisms, have complicated the interpretation of the results. In this study, genomic DNAs from 132 French patients with unexplained mental retardation were analysed by genome wide high-resolution Agilent 44K oligonucleotide arrays. The results were in accordance with those observed in previous studies: the detection rate of pathogenic CNVs was 14.4%. A non-random involvement of several chromosomal regions was observed. Some of the microimbalances recurrently involved regions (1q21.1, 2q23.1, 2q32q33, 7p13, 17p13.3, 17p11.2, 17q21.31) corresponding to known or novel syndromes. For all the pathogenic CNVs, further cases are needed to allow more accurate genotype-phenotype correlations underscoring the importance of databases to group patients with similar molecular data., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

Neural tube defects (NTDs) are severe congenital malformations due to failure of neural tube formation in early pregnancy. The proof that folic acid prevents NTDs raises the question of whether other parts of homocysteine (Hcy) metabolism may affect rates of NTDs. This French case-control study covered: 77 women aged 17-42 years sampled prior to elective abortion for a severe NTDs (cases) and 61 women aged 20-43 years with a normal pregnancy. Plasma and erythrocyte folate, plasma B6, B12 and Hcy were tested as five polymorphisms MTHFR 677 C --> T, MTHFR 1298 A --> C, MTR 2756 A --> G, MTTR 66 A --> G and TCN2 776 C --> G. Cases had significantly lower erythrocyte folate, plasma folate, B12 and B6 concentrations than the controls, and higher Hcy concentration. The odds ratio was 2.15 (95% CI: 1.00-4.59) for women with the MTRR 66 A --> G allele and it was decreased for mothers carrying the MTHFR 1298 A --> C allele. In multivariate analysis, only the erythrocyte folate concentration (P = 0.005) and plasma B6 concentration (P = 0.020) were predictors. Red cell folate is the main determinant of NTDs in France. Folic acid supplement or flour fortification would prevent most cases. Increased consumption of vitamins B12 and B6 could contribute to the prevention of NTDs. Genetic polymorphisms played only a small role. Until folic acid fortification becomes mandatory, all women of reproductive age should consume folic acid in a multivitamin that also contains B12 and B6., ((c) 2008 Wiley-Liss, Inc.)

Background: The French has been insufficiently characterized so far for mitochondrial DNA (mtDNA) diversity., Aims: The study aimed to enhance the information available for the French mtDNA pool and to explore the potential microgeographical differentiation of two French regions selected for their linguistic and historical idiosyncrasies., Subjects and Methods: A total of 868 samples from 12 different locations in France were collected. They were sequenced for the hypervariable segment I (HVS-I) and typed for haplogroup defining markers from the coding region either by restriction fragment length polymorphism (RFLP) or by a new protocol based on the 5' nuclease allelic discrimination. The mtDNA gene pools of French Basques and Bretons were compared in terms of frequency and composition with relevant neighbouring populations., Results: The French Basques' mtDNA pool shares some common features with that of the Spanish Basques, such as the high frequency of haplogroup H. However, the French Basques exhibit a number of distinct features, most notably expressed in the prevalence of haplogroups linked with the Neolithic diffusion in Europe. In Brittany, Finistère shows closer affinities with Britain and Scandinavia than the two other departments of Brittany., Conclusion: The mtDNA haplogroup composition of the French does not differ significantly from the surrounding European genetic landscape. At a finer grain, microgeographical differentiation can be revealed, as shown for the French Basque country and for Brittany.

Background: Neonatal screening for cystic fibrosis has been a subject of debate over the past few years. This study assesses 10 years of neonatal screening in Brittany, France, and examines its impact on prenatal screening of subsequent pregnancies in couples with an affected child., Methods: The study included all the neonates screened for cystic fibrosis in Brittany from Jan 1, 1989, to Dec 31, 1998. The screening consisted of an immunoreactive trypsinogen assay from dried blood spots, plus, from 1993, mutation analysis. Data were collected on incidence of cystic fibrosis, and genotypic and biochemical characteristics. The use of prenatal screening of subsequent pregnancies in affected families was also investigated., Findings: Of the 343,756 neonates screened, 118 children with cystic fibrosis were identified, giving an incidence of one in 2913. All mutated alleles were characterised: 34 different mutations resulting in 36 genotypes were detected. The introduction of DNA analysis into the protocol greatly reduced the recall rate and increased the sensitivity of the test. The mean cost of the screening programme was US$2.32 per screened child. 39 (34%) of the families identified by neonatal screening opted for subsequent prenatal diagnosis at least once. 12 couples would have benefited from this procedure while their first child was still symptom-free. 42 healthy children were born, and 18 pregnancies were terminated (therapeutic abortion rate of 100%)., Interpretation: We have shown the feasibility of neonatal screening for cystic fibrosis in Brittany. Through the detection of a large range of mutations, neonatal screening provides the opportunity for more reliable prenatal diagnosis and cascade screening. The neonatal screening programme described here could provide a good model for other countries intending to initiate such a scheme.

We have evaluated a two-tier neonatal cystic fibrosis (CF) screening of immunoreactive trypsinogen (IRT) followed by CFTR gene mutation analysis using a systematic scanning of exons 7, 10, and 11, and, if necessary, by direct DNA sequencing. Over an 18-month period we screened 32,300 neonates born in the western part of Britanny. The first tier, involving IRT screening at 3 days of age, utilizes a low elevation of the trypsinogen level (600 ng/ml), which is highly sensitive. The second tier, which corresponds to the exhaustive screening for mutations in three exons of the gene, is highly specific for this population (Britanny). The false positive rate is very low, and no false negatives have been reported to date. This strategy has allowed the identification of five novel alleles (V322A, V317A, 1806 del A, R553G, G544S).

The medical files of 532 patients who underwent medically induced abortion over a 10-year period (1982-1991) in the French department of Ille-et-Vilaine were studied in order to evaluate the indications and outcomes. Among the patients, 358 resided in the department (67%). Comparatively with the number of births during the 10-year period, there was a relative increase in the number of medically induced abortions from 3.5/1000 to 5.5/1000. This parameter was taken into consideration for the interpretation of a parallel decrease in the perinatal mortality during the same period, from 5.9/1000 to 5.1/1000. There was a maternal indication in 91 cases which correspond to the former category of therapeutic induced abortions. There was a clear increase in 1991 corresponding to abortions induced because of extremely premature rupture of the membranes which were formerly allowed to continue to dead births. Foetal indications were frequent: 441 cases (83%). Exogenous causes were lower (15.6%), particularly due to the disappearance of indications resulting from maternal irradiation. For indications related to infection, the vaccination against rubella and improved prenatal diagnosis resulted in the disappearance of rubella as an indication during the last three years of the study and a clear decrease in the number of toxoplasmosis indications. There were few indications due to maternal infection by human immunodeficiency virus (4 cases). Chromosomal abnormalities were the main cause of medically induced abortion among the foetal indications (27.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

We performed mutation analysis and RFLP haplotype analysis of chromosomes associated with classical phenylketonuria (PKU) in contemporary French families. We also did genealogical reconstructions for seven obligate carriers in five contemporary French-Canadian families living in eastern Quebec, who carry the M1V mutation causing PKU. The M1V mutation, heretofore considered to be associated exclusively with French-Canadians, was found on 4 of 152 independent French chromosomes. The French and Quebec M1V mutations all occurred on RFLP haplotype 2. The contemporary mutant French chromosomes clustered in southern Brittany (Finistère Sud). Genealogical reconstructions of the Quebec families identified 53 shared ancestors and a center of diffusion in the Perche region in 17th century France. The two clusters in France, one historical and the other contemporary, are not incompatible, if one assumes the possibilities that settlers returned from Nouvelle France or moved from Perche to southern Brittany. The M1V mutation is serving as a useful marker for historical demography.

Among clinical manifestations of the battered child syndrome, ophthalmic manifestations play a prominent role in the recognition of this syndrome. From personal cases, the authors describe different ocular findings, specially intraocular hemorrhages with the important risk of sequelae. They show the role of the ophthalmologist among several situations. As the ophthalmologist may be the first to examine these traumatized infants his prompt recognition is important to take all necessary steps.

Brittany is celtic, like Ireland and Wales where the incidence of neural tube defects is raised. We searched the hospital files in Brittany for all live and still births, and terminations of pregnancy after prenatal diagnosis for the years 1975-1984. 225 cases of spina bifida and 210 cases of anencephaly were identified; giving an incidence of 0.60 per 1000 births for spina bifida and 0.56 per 1000 births for anencephaly. No seasonality was found for both malformations. Analysis of the sex ratio for anencephaly indicated significantly higher proportion of females to males. Maternal age in the affected group was similar to the normal population. Casual heterogeneity among neural tube defects patients was presumed because 14% of our cases had other congenital anomalies.

We report a clinical analysis of 327 cases of Spina Bifida and 102 cases of Anencephaly in Brittany. Maternal age, parity, birth weight are not different from random population. Male rate is 0.40 for Anencephaly and 0.50 for Spina Bifida. The study of pregnancies shows an increased frequency of hydramnios during anencephaly pregnancies (0.34) and high rate of abnormalities during the pregnancy of Spina Bifida (0.34) or Anencephaly (0.86). Four mothers of Spina Bifida were taking valproic acid. Thirty children (0.07) had other malformations.

Hydrocephalus is a frequent complication of spina bifida. We wanted to find out if the risk of isolated hydrocephalus was greater in families with NTD (anencephaly and spina bifida) from 424 families studied between 1975 and 1984 in Brittany. The risk of recurrence of NTD is 1.8% in these families, the risk of hydrocephalus 0.3% which represents a risk three times greater than that of the population at large. This risk seems all the higher if the proband is a spina bifida of the male sex. However, no X-linked heredity can be reasonably assumed in these cases. We conclude that these families present a higher multifactorial risk of having another malformed child.

We have studied neural tube malformations in twins in order to research into the role of genetic and environmental factors. 12 pairs of twins in which one child had a neural tube defect were studied in Brittany, which is a Celtic country. We found no evidential agreement about the role each factor played. On the other hand there was an excess of twins in the siblings of those with neural tube defects, especially in the siblings of the mothers. There were more dizygotic twin mothers. Analysing the literature has made it possible for us to find a level of agreement of 7.5% for monozygotic twins and 4.6% for dizygotic twins. This last figure corresponds to the recurrence rate found after one case. The aetiological theories are reviewed. Among factors bringing about neural tube defects would seem to be the microenvironment of the uterus and the delay between ovulation and fertilization and implantation of the fertilized egg. Nutrition of the embryo and possible vitamin deficiencies could explain this inter-action between the mother and the fetus. If there is a genetic factor, it is more likely to be maternal than fetal.