Inflammatory and Cardiovascular Biomarkers to Monitor Fabry Disease Progression.

Fabry disease is an invalidating multisystemic disorder affecting α-Galactosidase, a rate-limiting hydrolase dedicated to lipid catabolism. Non-metabolized substrates, such as Globotriaosylceramide and its derivatives trigger the direct or indirect activation of inflammatory events and endothelial dysfunction. In spite of the efficacy demonstrated by enzyme replacement therapy or pharmacological chaperones in delaying disease progression, few studies have analyzed whether these treatments can improve the pro-inflammatory state of FD patients. Therefore, the aim of this work was to assess cytokines and cardiovascular risk-related proteins detectable in plasma from FD patients, whether treated or not with ERT, to evaluate the reliability of these markers in monitoring disease stage and treatment effects. We identified inflammatory and endothelial dysfunction markers (ADAMTS-13, TNF-α, GDF-15, MIP-1ß, VEGFA, MPO, and MIC-1) that cooperate in a common pathway and are increased in FD patients' plasma samples. As shown by the assessment of these proteins over time, they can help to evaluate the risk of higher severity in FD, as well as ERT effects. Even though the analyzed proteins cannot be considered as proper biomarkers due to their non-specificity to FD, taken together they can provide a signature of reference molecules with prognostic value for early diagnosis, and evaluation of disease progression and treatment efficacy, using blood samples.

A novel partial deletion of the TBL1XR1 gene detected using SNP array in a patient with motor delay, growth failure and Klinefelter syndrome.

INTRODUCTION: Co-existence pathogenic copy number variation with aneuploidy is a rare phenomenon. Whole TBL1XR1 gene deletions are described and associated with autosomal dominant intellectual development disorder-41 (#616944). However, the phenotypical expression of the TBL1XR1 partial deletion is poorly described. CASE PRESENTATION: We describe the case of a male, aged 18 months, who presented delayed motor development, gait disturbance, mild generalized hypotonia, minor dysmorphic features and growth failure, in addition to Klinefelter syndrome (KS). The single nucleotide polymorphism array revealed the de novo pathogenic interstitial deletion of chromosome 3q26.32 of 202 kb size that encompassed the first two exons of one relevant coding gene: TBL1XR1 (*608628). CONCLUSION: We report a male without clinical signs of KS and overlapped phenotypical features with another TBL1XR1 related disease: Pierpont syndrome (#602342). This patient extends the phenotypic spectrum of TBL1XR1 gene pathogenic variants.

Maternally inherited deletion encompassing the RTL1as and MEG8 genes of the human 14q32 imprinted region in a patient with a mild Kagami-Ogata syndrome phenotype.

Kagami-Ogata syndrome and Temple syndrome are imprinting disorders caused by the abnormal expression of genes in an imprinted cluster on chromosome 14q32. Here, we report a female with mild features of the Kagami-Ogata syndrome phenotype with polyhydramnios, neonatal hypotonia, feeding difficulties, abnormal foot morphology, patent foramen ovale, distal arthrogryposis, normal facial profile, and a bell-shaped thorax without coat hanger ribs. The single nucleotide polymorphism array revealed the interstitial deletion of chromosome 14q32.2-q32.31 (117 kb in size), involving the RTL1as and MEG8 genes, and other small nucleolar RNAs and microRNAs. The differentially methylated regions (DMRs) appeared unaltered. The RTL1as gene deletion and the normal methylation pattern of the MEG3 gene loci were confirmed by methylation-specific multiplex ligation-dependent probe amplification. Deletions of the 14q32 region without involving DMRs, and encompassing only the RTL1as and MEG8 genes, are poorly described in the literature. The mother's chromosomal microarray also confirmed the identical 14q32.2 deletion, although she presented a normal phenotype. The maternally inherited 14q32 deletion was responsible for Kagami-Ogata syndrome in our patient. It was not sufficient, however, to produce Temple syndrome or any other pathogenic phenotype in the patient's mother.

An 88.8-kb Novel Deletion of 19q13.2 Encompassing the ATP1A3 Gene Detected by Array CGH in a Patient with Delayed Psychomotor Development, Generalized Hypotonia and Macrocephaly.

Many neurodevelopmental disorders are caused by the presence of CNVs. Chromosome microarray technology is widely used to accurately detect CNVs. We report the case of a male, aged 3 years, presenting with delayed psychomotor development, generalized hypotonia, encephalopathy, delayed myelination in the central nervous system, and poor motor coordination. The array CGH revealed an interstitial deletion of chromosome 19q13.2 with a size of 88.8 kb involving 3 OMIM genes: RABAC1, ARHGEF1, and ATP1A3. Heterozygous mutations in the ATP1A3 gene are associated with delayed psychomotor development, alternating hemiplegia of childhood type 2 (AHC2), dystonia type 12, and cerebellarataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, also called CAPOS syndrome. The phenotypic expression of partial ATP1A3 deletion is, however, poorly described in the literature. The deletion was confirmed by MLPA, and we identified a hitherto undescribed novel deletion of exons 3b-21 of the ATP1A3 gene. Our data suggest that the deletion of the ATP1A3 gene is a causative factor of the AHC2 phenotype in the patient.

Infection With Chlamydia trachomatis Increases the Risk of High-grade Anal Intraepithelial Neoplasia in People Living With Human Immunodeficiency Virus.

BACKGROUND: We aimed to assess the relationship between sexually transmitted infections (STIs)-including a large panel of human papillomavirus (HPV) genotypes-and high-grade anal intraepithelial neoplasia (HGAIN) in men who have sex with men (MSM) who were living with human immunodeficiency virus (HIV). METHODS: In a prospective study in an HIV cohort, participants underwent high-resolution anoscopy (HRA) for anorectal swabs collection to investigate STIs and for anal biopsy. Multiplex real-time polymerase chain reactions were performed, detecting several STIs and 28 HPV genotypes. Univariate and multivariate generalized linear models were used to analyze the relationships of variables of interest with HGAIN. RESULTS: There were 145 participants included; in 49, 2 HRAs were performed. Ureaplasma urealyticum (UU) was detected in 25 (17.2%) participants, Chlamydia trachomatis (CT) in 13 (9.0%), Mycoplasma genitalium (MG) in 4 (2.8%), HPV16 in 38 (26.2%), HPV52 in 29 (20%), and HPV53 and HPV42 in 28 (19.3%) participants each. There were 35 (24.1%) subjects diagnosed with HGAIN. In the univariate analysis, HGAIN was associated with CT, UU, MG, HPV16, HPV53, HPV68, and HPV70, and significant interactions were found between CT and HPV16 (odds ratio [OR] 31.0 95% confidence interval [CI] 4.3-221.7) and between UU and HPV16 (OR 8.8, 95% CI 2.1-37.5). In the adjusted model, CT, HPV16, HPV53, HPV70, the CD4+/CD8+ ratio, and the interaction between CT and HPV16 remained independent predictors of HGAIN. HPV16, HPV53, and HPV70 persisted in the second HRA in all the participants with recurrent HGAIN. CONCLUSIONS: Coinfection with CT may potentiate the oncogenic capability of HPV16 and increase the risk of HGAIN in people with HIV. HPV53 and HPV70 should be considered among the genotypes associated with HGAIN.

High-grade anal intraepithelial neoplasia is associated with HIV-1 RNA rectal shedding in virologically suppressed MSM.

OBJECTIVE: The protective effect of ART has not yet been definitively established in MSM. We aimed to characterize the factors associated with persistent HIV-1 RNA rectal shedding. METHODS: Prospective study including virologically suppressed MSM from an HIV cohort. High-resolution anoscopy (HRA) was performed for screening of anal dysplasia, and rectal sampling for HIV-1 RNA quantification and sexually transmitted infections (STIs) investigation through multiplex PCR. Both generalized linear mixed (GLM) and zero-altered negative binomial (ZANB) models were performed. RESULTS: One hundred and fifty-five rectal swab samples from 132 virologically suppressed MSM were included. HIV-1 RNA was detectable in 61 (39.3%) samples, with median (IQR) rectal viral load (rVL) of 295.8 (158.8-522) copies/swab. Multivariable GLM showed that the presence of high-grade anal intraepithelial neoplasia (HG-AIN; OR 2.85 [95% CI 1.10-7.38]) and a protease inhibitor-based regimen (OR 2.49 [0.98-6.34]) resulted in increased risk for rectal HIV-1 shedding, whereas higher nadir CD4+/CD8+ T-cell ratio (OR 0.18 [0.04-0.93]) was negatively associated with rectal shedding. ZANB analyses showed that the best predictors of having detectable rVL were lower nadir CD4+/CD8+ T-cell ratio (OR 0.98 [0.96-0.99]) and PI-based regimens (OR 4.85 [1.29-18.24]); the presence of HG-AIN (RR 2.50 [1.41-4.45]), and a higher burden of STIs (RR 1.39 [1.03-1.85]) were predictors of rectal HIV-1 shedding intensity. CONCLUSION: The prevalence of HIV-1 RNA rectal shedding is high in virologically suppressed MSM. In addition to ART and the immune system integrity, local factors, including the co-existence of HG-AIN and the burden of STIs, may account for the persistence of HIV-1 RNA shedding in rectal mucosa.

Evaluation of the Virclia® automated chemiluminescent immunoassay system for diagnosing pneumonia caused by Mycoplasma pneumoniae.

BACKGROUND: Mycoplasma pneumoniae is considered an important etiologic agent of community-acquired pneumonia (CAP) in outpatients. We aimed to evaluate the diagnostic accuracy of a quick automated chemiluminescent immunoassay (CLIA) for M. pneumoniae in a population-based prospective study of CAP. METHODS: A total of 137 outpatients diagnosed with CAP were included in the study. Acute- and convalescent phase sera were analyzed for IgG and IgM to M. pneumoniae with both CLIA (VirClia® ) and ELISA immunoassays. Conventional serological criteria by quantitative ELISA were considered as reference standard. Sensitivity and specificity of the assay were assessed with the construction of receiver operating characteristic (ROC) curves, and the kappa index was used to evaluate the accuracy of the IgG and IgM determinations in the acute phase. RESULTS: Thirty-eight patients were diagnosed with pneumonia by M. pneumoniae. ROC curves for IgG and IgM of convalescent and acute phase (C/A) quotients by the CLIA and ELISA assays were comparable. Specifically, for the CLIA, the best C/A quotient for IgG was 2.617 (sensitivity, 94.9%; specificity, 99.9%), and for IgM 1.400 (sensitivity, 65.8%; specificity, 100%). Regarding the acute phase, the best diagnostic accuracy for the CLIA was obtained with an IgG index of 1.120 (sensitivity, 89.5%; specificity, 73.7%). The CLIA was very simple to execute and required a minimum sample handling. CONCLUSION: The accuracy of the Virclia® assay for the diagnosis of M. pneumoniae infection in outpatients with CAP was equivalent to the quantitative ELISA. The CLIA was quicker to perform and displayed better analytic workability than conventional ELISA.