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International audience; Objectives: Pseudomonas aeruginosa occupies a central position in nosocomial infections and remains a significant cause of morbidity and mortality. The aim of this study was to characterize carbapenem resistance mechanisms in P. aeruginosa isolates from clinical specimens collected at the University Hospital of Oran, western Algeria. Materials and Methods: The identification of 214 nonduplicated P. aeruginosa isolates (collected from January to December 2016) was confirmed using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Thirteen antibiotics were tested using the disc diffusion method. Carbapenemase-encoding genes were detected with the GeneXpert system and multiplex polymerase chain reaction (PCR). Clonal relatedness was determined using multilocus sequence typing (MLST) and the seven housekeeping genes were further used for phylogenetic analysis of imipenem-resistant P. aeruginosa using concatenated gene fragments. The flanking regions of the blaVIM-4 gene were analyzed by whole-genome sequencing. Results: Eleven isolates (5.39%) were resistant to carbapenems. PCR amplification and sequencing showed that six of these isolates (2.94%) harbored the blaVIM-4 gene that was carried on a novel class 1 integron. MLST analysis assigned the tested isolates to seven different sequence types (STs), of which two were new (ST3349 and ST3350) and five were previously described (ST244, ST499, ST709, ST809, and ST1239). Conclusion: In this study, we reported P. aeruginosa isolates producing VIM-4 in an Algerian hospital. The blaVIM-4 is harbored in class 1 integron with a new arrangement of genes cassettes.

International audience; Hereditary distal renal tubular acidosis (dRTA) is a rare disorder characterized by metabolic acidosis due to impaired renal acid excretion. To date, three genes (ATP6V1B1, ATP6V0A4 and SLC4A1) have been reported to be responsible for this genetic disorder. Notably, mutations of ATP6V1B1 gene, which encode B1-subunit of H + -ATPase pump cause distal renal tubular acidosis often, associated with sensorineural hearing loss (SNHL). Furthermore, enlarged vestibular aqueduct (EVA) was also described in some patients with ATP6V1B1 mutations. Four Algerian unrelated patients presented with dRTA and SNHL were recruited. The ATP6V1B1 gene was preferentially analyzed in all these patients by Sanger sequencing. We identified two previously reported variants in ATP6V1B1 gene: a frameshift mutation (c.1155dupC: p.(Ile386Hisfs*56) in exon 12 and a splicing mutation in intron 2 (c.175-1G > C: p?). Both mutations were homozygous in affected members. Interestingly, one patient with p.(Ile386Hisfs*56) mutation presented profound SNHL and bilateral enlarged vestibular aqueduct (EVA). Our study indicates the importance contribution of ATP6V1B1 gene mutations to the pathogenesis of the dRTA in the Algerian population and will contribute to introducing principles to predict the characteristics of the dRTA in patients. Thus, screening for this gene could allow rapid patient management and provide adequate genetic counseling.

International audience; Introduction: DFNB1, caused by mutations of GJB2 or GJB6, is the most prevalent genetic form of nonsyndromic (i.e., isolated) congenital deafness in countries located around the Mediterranean Sea. Because some mutations are restricted to specific ethnic-geographic groups, we studied the prevalence and spectrum of GJB2/GJB6 mutations in deaf patients originating from two different Algerian regions, Kabylie and Sahara.Patients and methods: Among 91 reportedly unrelated Algerian patients affected by prelingual deafness, 80 patients (41 from Kabylie and 39 from Sahara) were diagnosed with isolated deafness. All had profound deafness, except one patient with mild deafness. They were screened for the presence of GJB2 mutations by direct sequencing of the single coding exon of GJB2. Patients without mutations were then screened for the presence of the most frequent two deletions of GJB6: del(GJB6-D13S1854) and del(GJB6-D13S1830).Results: Causative mutations were found in 13 and 8 patients from Kabylie and Sahara, respectively, accounting for more than a quarter of the cohort. The c.35delG, p.Gly12Valfs*2 mutation remains the most important mutation both in Kabylie (10 patients) and Sahara (7 patients). All detected patients were homozygous for this mutation. In addition, two other mutations (c.139G > T, p.Glu47* and c.167delT, p.Leu56Argfs*26) were found homozygous in one family each, and two patients were compound heterozygotes for (c.35delG p.Gly12Valfs*2/c.139G > T, p.Glu47*). No deletion of GJB6 was detected.Conclusion: We confirm that mutations in GJB2, mainly c.35delG, are one of the most prevalent causes of nonsyndromic congenital deafness in Algeria, whereas the del (GJB6-D13S1854) and del (GJB6-D13S1830) deletions of GJB6 contribute little, if any. Further investigation is needed to identify the cause of deafness in other patients without diagnostic.

Resume Objectifs Etudier la prevalence des papillomavirus humains (HPV) dans des cancers de localisation differente chez des patients residant dans la region ouest de l’Algerie durant une periode comprise entre 2010 et 2014. Materiel et methodes L’ADN extrait d’echantillons fixes au formol et inclus en paraffine provenait de 39 cancers de la sphere ano-genitale, 10 cancers des VADS et 36 cancers de la peau. La presence d’ADN d’HPV a ete recherchee en utilisant le test INNO-LiPA HPV Genotyping Extra®. Resultats La prevalence des HPV etait de 100 % dans les cancers du col uterin, 40 % dans les cancers du vagin, 17 % dans l’ensemble des cancers de la vulve, 33 % dans les cancers de l’anus, 0 % dans les cancers de l’amygdale et du larynx et 6,4 % dans les cancers spinocellulaires. Les HPV16 et 18 ont ete detectes seuls dans 52 % et 12 % des cancers du col uterin respectivement et associes a d’autres HPV dans 4 % et 16 % des cas respectivement. Conclusion L’ensemble de nos resultats sont globalement en accord avec ceux de la litterature. Des etudes de plus grande ampleur s’averent necessaires pour promouvoir la vaccination anti-HPV en Algerie.

International audience; Background: Consanguinity rate is high in Algeria, and the population is thus at high risk for genetic diseases transmitted on an autosomal recessive mode. Inherited congenital hearing impairment (HI) is a highly heterogeneous disorder, which affects approximately 1 in 800 Algerian newborns. Several hundreds of genes responsible for deafness have been reported among which more than one hundred are responsible for isolated deafness, of which 19 have already been reported to be involved in the Algerian population. This study focuses on patients from the Ghardaïa province, an ethnically and geographically isolated region of Southern Algeria that has the highest consanguinity rate in the country (56%).Methods: Eleven families, with at least two related members experiencing moderate to profound congenital HI, were recruited and screened for mutations in known HI genes.Results: A preliminary screening for common mutations in GJB2 and GJB6 identified the prevalent GJB2:c.35delG mutation in four families. Targeted exome sequencing further identified the causal mutations in the remaining seven families: CIB2:c.97C > T; p.(Arg33*), MYO7A:c.470+1G > A; p.(?), and SLC26A4:c.410C > T; p.(Ser137Leu) biallelic mutations in two families each, and a TECTA:c.2743 A > G; p.(Ile915Val) monoallelic mutation in the only family with autosomal dominant transmission of the HI. Of note, the missense mutations of SLC26A4 and TECTA had not been previously reported.Conclusion: These results further substantiate the genetic heterogeneity of HI, even in reportedly isolated populations. However, several families may harbor the same mutations as a result of a long history of marriages between relatives. This study has important implications for the HI molecular diagnosis strategy, and to develop genetic counseling for families originating from the Ghardaïa province of Algeria.

We report the genetic analysis of a large series of 76 Algerian patients from 65 unrelated families who presented with early onset severe muscular dystrophy and a clinical phenotype resembling limb-girdle muscular dystrophy type 2C.To define the genetic basis of the diseases in these families, we undertook a series of analyses of the γ-sarcoglycan (SGCG) and DMD genes.Fifteen families were shown to carry SGCG variants. Only 2 kinds of causative mutations were identified in the population, mostly in the homozygous state: the well-known c.525delT and the previously described c.87dupT. In the DMD gene, 12 distinctive patterns of deletion were identified, mostly affecting the dystrophin central region.Our data suggest that a simple molecular screen consisting of 2 allele-specific polymerase chain reactions (PCRs) and a set of 3 multiplex PCRs can diagnose half of the patients who present with progressive muscular dystrophy in the developing nation of Algeria. Muscle Nerve 56: 129-135, 2017.

International audience; X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) gene defect. XLA patients have absent or reduced number of peripheral B cells and a profound deficiency in all immunoglobulin isotypes. This multicenter study reports the clinical, immunological and molecular features of Bruton's disease in 40 North African male patients. Fifty male out of 63 (male and female) patients diagnosed with serum agammaglobulinemia and non detectable to less than 2 % peripheral B cells were enrolled. The search for BTK gene mutations was performed for all of them by genomic DNA amplification and Sanger sequencing. We identified 33 different mutations in the BTK gene in 40 patients including 12 missense mutations, 6 nonsense mutations, 6 splice-site mutations, 5 frameshift, 2 large deletions, one complex mutation and one in-frame deletion. Seventeen of these mutations are novel. This large series shows a lower frequency of XLA among male patients from North Africa with agammaglobulinemia and absent to low B cells compared with other international studies (63.5 % vs 85 %). No strong evidence for genotype-phenotype correlation was observed. This study adds to other reports from highly consanguineous North African populations, showing lower frequency of X-linked forms as compared to AR forms of the same primary immunodeficiency. Furthermore, a large number of novel BTK mutations were identified and could further help identify carriers for genetic counseling.

Parasitological investigations on ruminal paramphistomosis were carried out in 2033 cattle over a 14-month period in three Algerian slaughterhouses to determine the prevalence and intensity of this disease. The prevalence of infection varied from different slaughterhouses (1.2% at El Khroub, 7.5% at Ferdjioua and 12.1% at Jijel). The worm burden was significantly higher in cattle from El Khroub than for those slaughtered in the other two sites (a mean of 984.1 parasites compared with 87.5 and 140.7 at Jijel and Ferdjioua, respectively). No significant correlation between prevalence, intensity of infection and age of cattle was noted. Overall, females were significantly more infected than males, whereas the sex of animals was independent of worm burdens recovered in slaughtered cattle. The climatic conditions of provinces in which the slaughterhouses were located (a more temperate climate for Jijel and semiarid conditions for the other two provinces) may partly explain variations noted in prevalence and intensity of infection. The present results will contribute to our understanding of the epidemiology of Paramphistomum daubneyi infections in north-eastern Algeria.

International audience; Giant axonal neuropathy (GAN), a severe childhood disorder affecting both the peripheral nerves and the central nervous system, is due to mutations in the GAN gene encoding gigaxonin, a protein implicated in the cytoskeletal functions and dynamics. In the majority of the GAN series reported to date, patients had the classical clinical phenotype characterized by a severe axonal neuropathy with kinky hair and early onset CNS involvement including cerebellar and pyramidal signs. We present 12 patients (6 families) with GAN mutations and different clinical phenotypes. Four families were harbouring an identical homozygous nonsense mutation but with different severe clinical phenotypes, one patient had a novel missense homozygous mutation with a peculiar moderate phenotype and prominent skeletal deformations. The last family (4 patients) harbouring a homozygous missense mutation had the mildest form of the disease. In contrast with recent reported series of patients with typical GAN clinical features, the present series demonstrate obvious clinical heterogeneity.

International audience; OBJECTIVES:Several studies have shown lower carotid-femoral pulse wave velocity (cfPWV) levels in women compared to men, a difference that could partially explain the increased longevity in women. However, these studies have been performed in industrial countries while few data are available in emerging populations. We studied arterial stiffness, as evaluated by cfPWV, in elderly Algerian men and women.METHODS:cfPWV was studied in 321 Algerian men (81.2 ± 5.3 years) and women (81.1 ± 4.4 years). An age-matched and sex-matched cohort of European individuals (n = 321) was used as a control group.RESULTS:Comparatively to men, Algerian women exhibited higher BMI and heart rate (HR), higher prevalence of hypertension, and were more frequently treated for hypertension. cfPWV was not different between Algerian men (14.8 ± 3.3 m/s) and women (14.9 ± 3.4 m/s). By contrast, in Europeans, women had lower cfPWV (12.7 ± 2.7 m/s) than men (14.0 ± 3.3 m/s; P

International audience; Inflammatory bowel diseases (IBDs) are chronic inflammatory diseases of the gastrointestinal tract, which are clinically present as 1 of the 2 disorders, Crohn's disease (CD) or ulcerative colitis (UC) (Rogler 2004). The immune dysregulation in the intestine plays a critical role in the pathogenesis of IBD, involving a wide range of molecules, including cytokines. The aim of this work was to study the involvement of T-helper 17 (Th17) subset in the bowel disease pathogenesis by the nitric oxide (NO) pathway in Algerian patients with IBD. We investigated the correlation between the proinflammatory cytokines [(interleukin (IL)-17, IL-23, and IL-6] and NO production in 2 groups of patients. We analyzed the expression of messenger RNAs (mRNAs) encoding Th17 cytokines, cytokine receptors, and NO synthase 2 (NOS2) in plasma of the patients. In the same way, the expression of p-signal transducer and activator of transcription 3 (STAT3) and NOS2 was measured by immunofluorescence and immunohistochemistry. We also studied NO modulation by proinflammatory cytokines (IL-17A, IL-6, tumor necrosis factor α, or IL-1β) in the presence or absence of all-trans retinoic acid (At RA) in peripheral blood mononuclear cells (PBMCs), monocytes, and in colonic mucosa cultures. Analysis of cytokines, cytokine receptors, and NOS2 transcripts revealed that the levels of mRNA transcripts of the indicated genes are elevated in all IBD groups. Our study shows a significant positive correlation between the NO and IL-17A, IL-23, and IL-6 levels in plasma of the patients with IBD. Interestingly, the correlation is significantly higher in patients with active CD. Our study shows that both p-STAT3 and inducible NOS expression was upregulated in PBMCs and colonic mucosa, especially in patients with active CD. At RA downregulates NO production in the presence of proinflammatory cytokines for the 2 groups of patients. Collectively, our study indicates that the IL-23/IL-17A axis plays a pivotal role in IBD pathogenesis through the NO pathway.

BackgroundIn 1962 approximately 1.5 million French people living in Algeria were repatriated to France in very poor and often life-threatening conditions. These people constitute a cohort for the study of the long-term impact of gene–environment interaction on depression.AimsTo examine the interaction between a highly stressful life event and subsequent depression, and its modulation by a length polymorphism of the serotonin transporter gene (5–HTTLPR).MethodA community sample of people aged 65 years and over residing in the Montpellier region of the south of France was randomly recruited from electoral rolls. Genotyping was performed on 248 repatriated persons and 632 controls. Current and lifetime major and minor depressive disorders were assessed according to DSM-IV criteria.ResultsA significant relationship was observed between exposure to repatriation and subsequent depression (PP = 0.62). After controlling for age, gender, education, disability, recent life events and cognitive function, the gene–environment interaction (repatriation×5-HTTLPR) was globally significant (PPPP = 0.067).ConclusionsThe association between depression and war repatriation was significantly modulated by 5-HTTLPR genotype but this appeared to occur only in people who were younger at the time of exposure.

International audience; PURPOSE: Investigate the genotype-phenotype correlations for five TGFBI (transforming growth factor, beta-induced) mutations including one novel pathogenic variant and one complex allele affecting the fourth FAS1 domain of keratoepithelin, and their potential effects on the protein's structure. METHODS: Three unrelated families were clinically diagnosed with lattice corneal dystrophy (CD) and one with an unclassified CD of Bowman's layer. Mutations in the TGFBI gene were detected by direct sequencing, and the functional impact of each variant was predicted using in silico algorithms. Corneal phenotypes, including histological examinations, were compared with the literature data. Furthermore, molecular modeling studies of these mutations were performed. RESULTS: Two distinct missense mutations affecting the same residue at position 509 of keratoepithelin: p.Leu509Pro (c.1526T>C) and p.Leu509Arg (c.1526T>G) were found to be associated with a lattice-type CD. The novel p.Val613Gly (c.1828T>G) TGFBI mutation was found in a sporadic case of an Algerian individual affected by lattice CD. Finally, the Bowman's layer CD was linked to the association in cis of the p.Met502Val and p.Arg555Gln variants, leading to the reclassification of this CD as atypical Thiel-Behnke CD. Structural modeling of these TGFBI mutations argues in favor of these mutations being responsible for instability and/or incorrect folding of keratoepithelin, predictions that are compatible with the clinical diagnoses. CONCLUSIONS: Description of a novel TGFBI mutation and a complex TGFBI allele further extends the mutational spectrum of TGFBI. Moreover, we show convincing evidence that TGFBI mutations affecting Leu509 are linked to the lattice phenotype in two unrelated French families, contrasting with findings previously reported. The p.Leu509Pro was reported to be associated with both amyloid and non-amyloid aggregates, whereas p.Leu509Arg has been described as being responsible for Epithelial Basement Membrane Dystrophy (EBMD).

International audience; Since 2005, an outbreak of human cutaneous leishmaniasis (CL) in Ghardaïa, south Algeria, was studied and one output of these investigations was the identification of two Leishmania species, Leishmania major and Leishmania killicki, as the CL causative agents. In the present study, we were curious to focus on sand fly fauna present in this area and detection of Leishmania-positive sand fly females. Sand flies (3717) were collected during two seasons using sticky papers and CDC light traps in urban, rural and sylvatic sites. Twelve Phlebotomus species were identified. Phlebotomus papatasi was dominant in the urban site while Phlebotomus sergenti and Phlebotomus riouxi/chabaudi were dominant in the sylvatic site. Out of 74 P. sergenti females captured by CDC light traps in the sylvatic site populated by Ghardaïas' Gundi (Massoutiera mzabi), three ones were hosting Leishmania promastigotes. PCR-RFLP and sequencing of seven single-copy coding DNA sequences identified the promastigotes as L. killicki. Furthermore, laboratory experiments revealed that L. killicki isolate sampled from a CL patient inhabiting the studied region develop well in P. sergenti females. Our findings strongly suggest that the human cutaneous leishmaniases caused by L. killicki is a zoonotic disease with P. sergenti sand flies acting as hosts and vectors and gundi rodents as reservoirs.

International audience; Homozygous mutations in the ASPM gene are a major cause of autosomal recessive primary microcephaly (MCPH). Here we report on a consanguineous Algerian family in which three out of five children presented with severe microcephaly, simplified cortical gyration, mild to severe mental retardation and low to low-normal birth weight. Given the parental consanguinity with the unaffected parents being third cousins once removed, the most probable pattern of inheritance was autosomal recessive. Linkage and mutational analyses identified compound heterozygous truncating mutations within the ASPM gene segregating with MCPH (c.2389C>T [p.Arg797X] and c.7781_7782delAG [p.Gln2594fsX6]). These results highlight some of the pitfalls of genetic analysis in consanguineous families. They also suggest that low birth weight may be a feature of MCPH, a finding that needs confirmation, and confirm that ASPM mutations are associated with simplified cortical gyration.

International audience; While TPM2 mutations identified so far in muscular diseases were all associated with a dominant inheritance pattern, we report the identification of a homozygous null allele mutation in the TPM2 gene in a patient who presented with a recessive form of nemaline myopathy associated with a non-lethal multiple pterygium syndrome (Escobar-MPS MIM# 265000). The TPM2 mutation led to a complete absence of the skeletal muscle isoform of beta-tropomyosin not compensated by expression of other beta-tropomyosin isoforms. Escobar syndrome has been recently described as a prenatal form of myasthenia associated with recessive mutations in genes of the neuromuscular junction (CHRNG, CHRNA1, CHRND, RAPSN). This observation expands the cause of Escobar variant-MPS to a component of the contractile apparatus. This first report of the clinical expression of the complete absence of TPM2 in human indicated that TPM2 expression at the early period of prenatal life plays a major role for normal fetal movements.

International audience; The Charcot-Marie-Tooth (CMT) disorders comprise a group of clinically and genetically heterogeneous hereditary motor and sensory neuropathies, which are mainly characterized by muscle weakness and wasting, foot deformities, and electrophysiological, as well as histological, changes. A subtype, CMT2, is defined by a slight or absent reduction of nerve-conduction velocities together with the loss of large myelinated fibers and axonal degeneration. CMT2 phenotypes are also characterized by a large genetic heterogeneity, although only two genes---NF-L and KIF1Bbeta---have been identified to date. Homozygosity mapping in inbred Algerian families with autosomal recessive CMT2 (AR-CMT2) provided evidence of linkage to chromosome 1q21.2-q21.3 in two families (Zmax=4.14). All patients shared a common homozygous ancestral haplotype that was suggestive of a founder mutation as the cause of the phenotype. A unique homozygous mutation in LMNA (which encodes lamin A/C, a component of the nuclear envelope) was identified in all affected members and in additional patients with CMT2 from a third, unrelated family. Ultrastructural exploration of sciatic nerves of LMNA null (i.e., -/-) mice was performed and revealed a strong reduction of axon density, axonal enlargement, and the presence of nonmyelinated axons, all of which were highly similar to the phenotypes of human peripheral axonopathies. The finding of site-specific amino acid substitutions in limb-girdle muscular dystrophy type 1B, autosomal dominant Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy type 1A, autosomal dominant partial lipodystrophy, and, now, AR-CMT2 suggests the existence of distinct functional domains in lamin A/C that are essential for the maintenance and integrity of different cell lineages. To our knowledge, this report constitutes the first evidence of the recessive inheritance of a mutation that causes CMT2; additionally, we suggest that mutations in LMNA may also be the cause of the genetically overlapping disorder CMT2B1.