Subclinical ochronosis features in alkaptonuria: a cross-sectional study

BackgroundAlkaptonuria (AKU) is present from birth, yet clinical effects are considered to appear later in life. Morbidity of AKU, considered irreversible, is secondary to ochronosis. Age of ochronosis onset is not clearly known. Nitisinone profoundly lowers homogentisic acid (HGA), the metabolic defect in AKU. Nitisinone also arrests ochronosis and slows progression of AKU. However, tyrosinaemia post-nitisinone has been associated with corneal keratopathy, rash and cognitive impairment in HT 1. The optimal time to start nitisinone in AKU is unknown.MethodsIn an open, cross-sectional, single-site study, 32 patients with AKU were to be recruited. The primary outcome was presence of ochronosis in an ear biopsy. Secondary outcomes included analysis of photographs of eyes/ears, serum/urine HGA, markers of tissue damage/inflammation/oxidation, MRI imaging, gait, quality of life and Alkaptonuria Severity Score Index (qAKUSSI).ResultsThirty patients, with mean age (SD) 38 (14) years, were recruited. Percentage pigmentation within ear biopsies increased with age. Ear pigmentation was detected in a 20-year-old woman implying ochronosis can start in patients before the age of 20. Gait and qAKUSSI were outside the normal range in all the patients with AKU.ConclusionsOchronosis can be present before age 20 years.

External Validation of Velazquez-Gomez Severity Score Index and ATLAS Scores and the Identification of Risk Factors Associated with Mortality in Clostridium difficile Infections

Treatment guidelines for Clostridium difficile infection (CDI) are limited by a lack of widely accepted clinical prediction tools (CPTs). Two published CPTs, the Velazquez-Gomez Severity Score Index (VGSSI) and ATLAS scores, were evaluated, and variables showing the greatest correlation with mortality in patients with CDI were identified to further develop an objective, mortality-based CPT. A retrospective review of the charts of 271 hospitalized patients with CDI was performed. VGSSI and ATLAS scores were assigned. Means and correlations of these scores with mortality were evaluated. Multivariate logistic regression analysis was performed on 32 known potential mortality predictor variables. Mortality was overall strongly associated with VGSSI and ATLAS scores with poor correlation within the intermediate ranges. Mean scores for nonsurvivors indicated poor calibration. The variables most associated with mortality were Age, vasopressors, steroids, creatinine level, and albumin. Although both CPTs revealed the ability to discriminate patients at greater risk for mortality, precision and overall calibration were lacking. Five variables were identified which had the greatest correlation with mortality. Utilization of these variables to enhance or modify the existing CPTs is suggested as the next step in the development of a useful and accurate mortality-based CPT for the treatment of CDI.

Correlation Between Glucosylceramide Synthase Gene Polymorphism and Severity Score Index in Type 1 Gaucher Disease

Background: Gaucher disease (GD), caused by a deficiency of the glucocerebrosidase (GC) enzyme, is characterized by the accumulation of glucosylceramide (GlcCer) within lysosomes, resulting in cellular dysfunction and damage. GlcCer is catalyzed by the glucosylceramide synthase (GCS), also known as UDP-glucose ceramide glucosyltransferase, (UGCG), EC 2.4.1.80, first enzyme in glycosphingolipids biosynthesis. Mutations in the glucocerebrosidase (GBA) gene are required to cause GD, but other factors play an important role. Aims: GCS gene is a logical candidate to hypothesize that its variability could be involved in clinical severity. Patients and methods: We have analyzed GCS variants (g.(−295)C>T, g.(−222)ins10, g.148A>G, g.166A>T, g.25510C>G, g.29312A>G and g.34991A>G) in a group of 80 [N370S]+[L444P] heterozygous and 23 N370S homozygous patients. Results: were related with severity score index (SSI). g.(−295)C>T and g.166A>T SNPs were in complete linkage disequilibrium. In the N370S homozygous, carriers of g.(−222)ins10 have higher SSI than non carriers (6.6 vs 2.4, p<0.004). Patient carriers of the A-allele for SNP g.148A>G had higher SSI than the G-allele carriers (6.7 vs 1.5, p<0.001, for [N370S]+[L444P] heterozygous and 4.3 vs 1.7, p<0.001, for [N370S] homozygous). “In silico” studies and electrophoretic mobility shift assay (EMSA) indicate that 10bp insertion at the promoter region generates a new ETF binding site and the g.148a>g variant at intron 1 changes the affinity for the transcription factor AP-2. GlcCer were elevated in patient carriers of one mutated allele of these two variants. Conclusion: our results suggest that the genetic GCS variants could influence in the development and progression of GD severity.