Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia.

Hypophosphatasia (HPP) is a rare autosomal dominant or recessive metabolic disorder caused by mutations in the tissue nonspecific alkaline phosphatase gene (ALPL). To date, over 300 different mutations in ALPL have been identified. Disease severity is widely variable with severe forms usually manifesting during perinatal and/or infantile periods while mild forms are sometimes only diagnosed in adulthood or remain undiagnosed. Common clinical features of HPP are defects in bone and tooth mineralization along with the biochemical hallmark of decreased serum alkaline phosphatase activity. The incidence of severe HPP is approximately 1 in 300,000 in Europe and 1 in 100,000 in Canada. We present the clinical and molecular findings of 83 probands and 28 family members, referred for genetic analysis due to a clinical and biochemical suspicion of HPP. Patient referrals included those with isolated low alkaline phosphatase levels and without any additional clinical features, to those with a severe skeletal dysplasia. Thirty-six (43.3%) probands were found to have pathogenic ALPL mutations. Eleven previously unreported mutations were identified, thus adding to the ever increasing list of ALPL mutations. Seven of these eleven were inherited in an autosomal dominant manner while the remaining four were observed in the homozygous state. Thus, this study includes a large number of well-characterized patients with hypophosphatasemia which has permitted us to study the genotype:phenotype correlation. Accurate diagnosis of patients with a clinical suspicion of HPP is crucial as not only is the disease life-threatening but the patients may be offered bone targeted enzymatic replacement therapy. © 2017 Wiley Periodicals, Inc.

Pediatric inflammatory bowel disease: increasing incidence, decreasing surgery rate, and compromised nutritional status: A prospective population-based cohort study 2007-2009.

BACKGROUND: The aim was to evaluate the incidence, treatment, surgery rate, and anthropometry at diagnosis of children with inflammatory bowel disease (IBD). METHODS: Patients diagnosed between January 1, 2007 to December 31, 2009 in Eastern Denmark, Funen, and Aarhus were included from a background population of 668,056 children <15 years of age. For evaluation of incidence, treatment, and surgery rate, a subcohort from Eastern Denmark was extracted for comparison with a previously published population-based cohort from the same geographical area (1998-2006). RESULTS: In all, 130 children with IBD: 65 with Crohn's disease (CD), 62 with ulcerative colitis (UC), and three with IBD unclassified (IBDU) were included. The mean incidence rates per 10(6) in 2007-2009 were: IBD: 6.4 (95% confidence interval [CI]: 5.4-7.7), CD: 3.2 (2.5-4.1), UC: 3.1 (2.4-4.0) and IBDU: 0.2 (0.05-0.5). Comparing the two cohorts from Eastern Denmark we found higher incidence rates for IBD (5.0 and 7.2 in 1998-2000 and 2007-2009, respectively, P = 0.02) and CD (2.3 versus 3.3, P = 0.04). Furthermore, we found a significant decrease in surgery rates (15.8/100 person-years versus 4.2, P = 0.02) and an increase in the rate of initiating immunomodulators (IM) within the first year (29.0/100 person-years versus 69.2, P < 0.001). IM use was associated with a trend towards a decreased surgery risk (relative risk [RR] 0.38; 0.15-1.0). Children with CD had poor nutritional status at diagnosis compared with the general pediatric population. CONCLUSIONS: Over the past 12 years we found an increase in the incidence of IBD in children, an increasing use of IM, and decreasing 1-year surgery rates. CD patients had poor nutritional status.

Incidence of ulcerative colitis and Crohn's disease in Danish children: Still rising or levelling out?

AIM: To describe the development in incidence and prevalence of paediatric inflammatory bowel disease (IBD) in Eastern Denmark during a six-year period. METHODS: All patients <15 years with IBD in Eastern Denmark in the two following periods were included: 1) 1.1.1998-31.12.2000 and 2) 1.1.2002-31.12.2004. The mean background population (children <15 years) in Eastern Denmark was 421,898 persons in period 1 and 439,443 persons in period 2. Patients were identified using the ICD-10 classification (DK500-519). The following data were extracted from the files: diagnosis, change in diagnosis, age at diagnosis, localisation, extra-intestinal symptoms, surgery and county of residence. Incidence and prevalence for ulcerative colitis (UC), Crohn's disease (CD) and indeterminate colitis (IC) were calculated per 100,000 children <15 years. RESULTS: 98 patients (50 UC, 44 CD, 4 IC), median age 9.8 years (range 2-14) and 12.8 (range 0.5-14) for UC and CD, respectively, were identified in period 1. In the second period 145 patients (70 UC, 64 CD, 11 IC) were included with a median age of 11 years (range 1-14) and 12.5 (range 0.5-14) for UC and CD, respectively. The prevalence of IBD was 15.8 and 20.3 in 1998-2000 and 2002-2004, respectively. The incidence of IBD was 4.3 (UC: 1.8; CD: 2.3; IC: 0.2) and 6.1 (UC: 2.6; CD: 3.1; IC: 0.3), respectively, for the two periods (p>0.05). CONCLUSIONS: In our study we found an insignificant increase in the incidence of both CD and UC, indicating that the previously reported rising incidence might be levelling out.

Comparison of chlorzoxazone one-sample methods to estimate CYP2E1 activity in humans.

OBJECTIVE: Comparison of a one-sample with a multi-sample method (the metabolic fractional clearance) to estimate CYP2E1 activity in humans. METHODS: Healthy, male Caucasians ( n=19) were included. The multi-sample fractional clearance (Cl(fe)) of chlorzoxazone was compared with one-time-point clearance estimation (Cl(est)) at 3, 4, 5 and 6 h. Furthermore, the metabolite/drug ratios (MRs) estimated from one-time-point samples at 1, 2, 3, 4, 5 and 6 h were compared with Cl(fe). RESULTS: The concordance between Cl(est) and Cl(fe) was highest at 6 h. The minimal mean prediction error (MPE) of Cl(est) as a percentage of actual mean Cl(fe) was -4.2% at 6 h. Furthermore, regarding Cl(fe), there was a negligible difference ( P=0.56) of bias between Cl(est) at 3 h (MPE=-8.9%) and 6 h (MPE=-4.2%). The best concordance between MR and Cl(fe) was found at 3 h (r=0.74; P<0.001). CONCLUSION: All three single-dose-sample estimates, Cl(est) at 3 h or 6 h, and MR at 3 h, can serve as reliable markers of CYP2E1 activity. The one-sample clearance method is an accurate, renal function-independent measure of the intrinsic activity; it is simple to use and easily applicable to humans.