Background: Fabry disease is a rare X-linked inherited disorder caused by deficiency of α-Galactosidase A. Hundreds of mutations and non-coding haplotypes in the GLA gene have been described; however, many are variants of unknown significance, prompting doubts about the diagnosis and treatment. The α-Galactosidase A enzymatic activity in dried blood spot (DBS) samples are widely used for screening purposes; however, even when values below the normal are found, new tests are required to confirm the diagnosis. Here we describe an analysis of GLA variants and their correlation with DBS α-Galactosidase A enzymatic activity in a large Brazilian population with Fabry disease symptoms. Results: We analyzed GLA variants by DNA sequencing of 803 male patients with suspected Fabry disease or belonging to high-risk populations; in 179 individuals, 58 different exonic variants were detected. From these, 50 are variants described as pathogenic and eight described as variants of unknown significance. The other individuals presented complex non-coding haplotypes or had no variants. Interestingly, the enzymatic activity in DBS was different among pathogenic variants and the other genotypes, including variants of unknown significance; the first presented mean of 12% of residual activity, while the others presented levels above 70% of the activity found in healthy controls. Conclusion: The activity of α-Galactosidase A in DBS was markedly reduced in males with known pathogenic variants when compared with subjects presenting variants of unknown significance, non-coding haplotypes, or without variants, indicating a possible non-pathogenic potential of these latter genotypes. These findings bring a better understanding about the biochemical results of α-Galactosidase A in DBS samples, as well as the possible non-pathogenic potential of non-coding haplotypes and variants of unknown significance in GLA gene. These results certainly will help clinicians to decide about the treatment of patients carrying variants in the gene causing this rare but life-threatening disease.
<b><i>Background:</i></b> Since renal failure is one of the main causes of death in patients with Fabry disease (FD), renal follow-up is an important part of clinical monitoring in these patients. Despite its known limitations, serum creatinine is still the most widely used biomarker. While new renal biomarkers are described, their effectiveness has not yet been fully evaluated in relation to FD. <b><i>Objectives:</i></b> This study aimed to compare renal biomarkers commonly and rarely used in the evaluation of FD patients. <b><i>Method:</i></b> The usual biomarkers for renal monitoring (microalbuminuria, proteinuria, and creatinine) and some more rarely used (cystatin C, beta 2-microglobulin [β2M], neutrophil gelatinase-associated lipocalin/lipocalin-2) were quantified in the blood and/or urine samples of 40 FD patients, 39 controls without chronic kidney disease (CKD) paired by age and sex and 38 controls with CKD undergoing hemodialysis. <b><i>Results:</i></b> Significant statistical differences (<i>p</i> < 0.05) were observed for cystatin C and lipocalin-2 in plasma levels, for β2M and serum creatinine levels and by estimated glomerular filtration rate when compared FD patients and control group with CKD and for proteinuria and microalbuminuria in urine samples and for lipocalin-2 in plasma levels when compared FD patients and control group without CKD. Urine creatinine (UCreat), pH, and urine specific gravity did not present a significant statistical difference between groups. <b><i>Conclusion:</i></b> Considering serum creatinine as gold standard, all renal parameters evaluated, including receiver operating characteristic curve, indicated β2M as the best biomarker, followed by cystatin C, proteinuria and microalbuminuria, while the results for lipocalin-2 and UCreat do not indicate good predictors of renal impairment. It suggests that at least 2 altered biomarkers should be considered to characterize a renal alteration, thereby establishing a better therapeutic course for FD patients. If possible, along with serum creatinine, measurement of β2M or cystatin C for renal evaluation of Fabry’s patients should be considered.
BackgroundHealthcare-associated infections by carbapenem-resistant Klebsiella pneumoniae are difficult to control. Virulence and antibiotic resistance genes contribute to infection, but the mechanisms associated with the transition from colonization to infection remain unclear.ObjectiveWe investigated the transition from carriage to infection by K. pneumoniae isolates carrying the K. pneumoniae carbapenemase–encoding gene blaKPC (KpKPC).MethodsKpKPC isolates detected within a 10-year period in a single tertiary-care hospital were characterized by pulsed-field gel electrophoresis (PFGE), multilocus sequencing typing, capsular lipopolysaccharide and polysaccharide typing, antimicrobial susceptibility profiles, and the presence of virulence genes. The gastrointestinal load of carbapenem-resistant Enterobacteriaceae and of blaKPC-carrying bacteria was estimated by relative quantification in rectal swabs. Results were evaluated as contributors to the progression from carriage to infection.ResultsNo PGFE type; ST-, K-, or O-serotypes; antimicrobial susceptibility profiles; or the presence of virulence markers, such yersiniabactin and colibactin, were associated with carriage or infection, with ST437 and ST11 being the most prevalent clones. Admission to intensive and semi-intensive care units was a risk factor for the development of infections (OR 2.79, 95% CI 1.375 to 5.687, P=0.005), but higher intestinal loads of carbapenem-resistant Enterobacteriaceae or of blaKPC-carrying bacteria were the only factors associated with the transition from colonization to infection in this cohort (OR 8.601, 95% CI 2.44 to 30.352, P<0.001).ConclusionThe presence of resistance and virulence mechanisms were not associated with progression from colonization to infection, while intestinal colonization by carbapenem-resistant Enterobacteriacea and, more specifically, the load of gastrointestinal carriage emerged as an important determinant of infection.
Rationale: Mucopolysaccharidosis type II (Hunter syndrome) is an X-linked multisystem disorder, caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S). The clinical manifestations of this disease are severe skeletal deformities, airway obstruction, cardiomyopathy, and neurologic deterioration. Patient: The patient was 5 years and 6 months boy, with developmental delay, hearing loss, hepatosplenomegaly, and skeletal dysplasia. He was diagnosed with mucopolysaccharidosis type II based on clinical manifestations, biochemical and genetic analysis. Outcomes: The patient carries a new mutation (c.879-1210_1007-218del) in hemizygosis in the IDS gene, which was defined as pathogenic according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines and as responsible for the mucopolysaccharidosis type II phenotype in the patient.
Skin aging involves genetic, environmental and hormonal factors. Facial wrinkles also depend on muscular activity. Gene expression investigation may be useful for new anti-aging products. To evaluate structure and gene expression differences among exposed and unexposed skin in menopausal women. Cross-sectional study, including 15 menopausal women, 55-65yo, phototype III; photo-exposed, periorbital wrinkles (A1), preauricular, not wrinkled (A2), and unexposed gluteal (A3) areas were described and compared by non-invasive measures, histology, immunohistochemistry and gene expression (RNASeq); participants mean age was 61yo, presenting moderate periorbital wrinkles and light facial photodamage. Higher roughness, wrinkles number and echogenicity were observed in A1 and A2 versus A3. Decreased epidermal thickness and dermal collagen IV were demonstrated in A1 versus A2 and A3. Exposed areas impacted different pathways compared to unexposed. Exposed wrinkled skin (A1) showed impact on cell movement with decreased in ammatory activation state. Pathways related to lipid and aminoacids metabolism were modulated in non-wrinkled exposed (A2) compared to unexposed (A3) skin. Expected histological ndings and gene expression differences among areas were observed. Photoaging in menopausal women may modulate lipid and aminoacids metabolism and decrease in ammatory and keratinization pathways, cellular homeostasis, immune response, brogenesis and lament formation.These ndings may help development of new therapies for skin health and aging control.
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