Cytogenetic abnormalities and fragile-x syndrome in Autism Spectrum Disorder

BACKGROUND: Autism is a behavioral disorder with impaired social interaction, communication, and repetitive and stereotypic behaviors. About 5–10 % of individuals with autism have 'secondary' autism in which an environmental agent, chromosome abnormality, or single gene disorder can be identified. Ninety percent have idiopathic autism and a major gene has not yet been identified. We have assessed the incidence of chromosome abnormalities and Fragile X syndrome in a population of autistic patients referred to our laboratory. METHODS: Data was analyzed from 433 patients with autistic traits tested using chromosome analysis and/or fluorescence in situ hybridization (FISH) and/or molecular testing for fragile X syndrome by Southern and PCR methods. RESULTS: The median age was 4 years. Sex ratio was 4.5 males to 1 female [354:79]. A chromosome (cs) abnormality was found in 14/421 [3.33 %] cases. The aberrations were: 4/14 [28%] supernumerary markers; 4/14 [28%] deletions; 1/14 [7%] duplication; 3/14 [21%] inversions; 2/14 [14%] translocations. FISH was performed on 23 cases for reasons other than to characterize a previously identified cytogenetic abnormality. All 23 cases were negative. Fragile-X testing by Southern blots and PCR analysis found 7/316 [2.2 %] with an abnormal result. The mutations detected were: a full mutation (fM) and abnormal methylation in 3 [43 %], mosaic mutations with partial methylation of variable clinical significance in 3 [43%] and a permutation carrier [14%]. The frequency of chromosome and fragile-X abnormalities appears to be within the range in reported surveys (cs 4.8-1.7%, FRAX 2–4%). Limitations of our retrospective study include paucity of behavioral diagnostic information, and a specific clinical criterion for testing. CONCLUSIONS: Twenty-eight percent of chromosome abnormalities detected in our study were subtle; therefore a high resolution cytogenetic study with a scrutiny of 15q11.2q13, 2q37 and Xp23.3 region should be standard practice when the indication is autism. The higher incidence of mosaic fragile-X mutations with partial methylation compared to FRAXA positive population [50% vs 15–40%] suggests that faint bands and variations in the Southern band pattern may occur in autistic patients

Longitudinal Antiretroviral Adherence in HIV+ Ugandan Parents and Their Children Initiating HAART in the MTCT-Plus Family Treatment Model: Role of Depression in Declining Adherence Over Time

We conducted a study to assess the effect of family-based treatment on adherence amongst HIV-infected parents and their HIV-infected children attending the Mother-To-Child-Transmission Plus program in Kampala, Uganda. Adherence was assessed using home-based pill counts and self-report. Mean adherence was over 94%. Depression was associated with incomplete adherence on multivariable analysis. Adherence declined over time. Qualitative interviews revealed lack of transportation money, stigma, clinical response to therapy, drug packaging, and cost of therapy may impact adherence. Our results indicate that providing ART to all eligible HIV-infected members in a household is associated with excellent adherence in both parents and children. Adherence to ART among new parents declines over time, even when patients receive treatment at no cost. Depression should be addressed as a potential barrier to adherence. Further study is necessary to assess the long-term impact of this family treatment model on adherence to ART in resource-limited settings

Lactobacillus paracasei Comparative Genomics: Towards Species Pan-Genome Definition and Exploitation of Diversity

Contains fulltext : 119129.pdf (publisher's version ) (Open Access)Lactobacillus paracasei is a member of the normal human and animal gut microbiota and is used extensively in the food industry in starter cultures for dairy products or as probiotics. With the development of low-cost, high-throughput sequencing techniques it has become feasible to sequence many different strains of one species and to determine its "pan-genome". We have sequenced the genomes of 34 different L. paracasei strains, and performed a comparative genomics analysis. We analysed genome synteny and content, focussing on the pan-genome, core genome and variable genome. Each genome was shown to contain around 2800-3100 protein-coding genes, and comparative analysis identified over 4200 ortholog groups that comprise the pan-genome of this species, of which about 1800 ortholog groups make up the conserved core. Several factors previously associated with host-microbe interactions such as pili, cell-envelope proteinase, hydrolases p40 and p75 or the capacity to produce short branched-chain fatty acids (bkd operon) are part of the L. paracasei core genome present in all analysed strains. The variome consists mainly of hypothetical proteins, phages, plasmids, transposon/conjugative elements, and known functions such as sugar metabolism, cell-surface proteins, transporters, CRISPR-associated proteins, and EPS biosynthesis proteins. An enormous variety and variability of sugar utilization gene cassettes were identified, with each strain harbouring between 25-53 cassettes, reflecting the high adaptability of L. paracasei to different niches. A phylogenomic tree was constructed based on total genome contents, and together with an analysis of horizontal gene transfer events we conclude that evolution of these L. paracasei strains is complex and not always related to niche adaptation. The results of this genome content comparison was used, together with high-throughput growth experiments on various carbohydrates, to perform gene-trait matching analysis, in order to link the distribution pattern of a specific phenotype to the presence/absence of specific sets of genes

A unique case of reversion to normal size of a maternal premutation FMR1 allele in a normal boy

Fragile X syndrome (FXS) is caused mostly by expansion and subsequent methylation of the CGG repeat in the 5'UTR of the FMR1 gene, resulting in silencing of the gene, absence of FMRP and development of the FXS phenotype. The expansion also predisposes the CGG repeat and the flanking regions to further instability that may lead to mosaics between a full mutation and a premutation or, rarely, a normal or deleted allele. Here, we report on a 10-year-old boy with no FXS phenotype, who has a normal CGG tract, although he inherited the maternal expanded allele that causes FXS in his two brothers. Southern blotting demonstrated that the mother carries a premutation allele ( approximately 190 CGG), whereas the propositus shows a normal 5.2 kb fragment after HindIII digestion and a smaller 2.2 kb fragment after double HindIII-EagI digestion, without any apparent mosaicism in peripheral blood leukocytes. PCR and sequence analysis of the FMR1 5'UTR revealed an allele of 43 repeats, with two interspersed AGG triplets in position 10 and 25 and an exceptional CCG triplet in position 17. This latter creates an abnormal EagI site compatible with the smaller 2.2 kb fragment observed with Southern blotting. Haplotype analysis proved that the rearranged allele originated from the maternal expanded allele. To the best of our knowledge, this is the first non-mosaic case of reduction in the CGG tract of the FMR1 gene, resulting in a normal allele

Respiratory viral infections in children with asthma: do they matter and can we prevent them?

Background: Asthma is a major public health problem with a huge social and economic burden affecting 300 million people worldwide. Viral respiratory infections are the major cause of acute asthma exacerbations and may contribute to asthma inception in high risk young children with susceptible genetic background. Acute exacerbations are associated with decreased lung growth or accelerated loss of lung function and, as such, add substantially to both the cost and morbidity associated with asthma