Al-Sannaa N.A.,Saudi Aramco |
Bay L.,Hospital Juan P. Garrahan |
Barbouth D.S.,University of Miami |
Benhayoun Y.,Pediatric Services |
And 11 more authors.
Orphanet Journal of Rare Diseases | Year: 2015
Background: Enzyme replacement therapy (ERT) with laronidase, (recombinant human α-L-iduronidase; Aldurazyme) is the primary treatment option for patients with attenuated mucopolysaccharidosis type I (MPS I). This study examined the effect of early ERT on clinical manifestations. Methods: This multinational, retrospective case series abstracted data from records of 20 patients with Hurler-Scheie syndrome within nine sibships that included older siblings treated with laronidase after the development of significant clinical symptoms, and younger siblings treated before significant symptomatology. Median age at diagnosis was 5.6 and 0.5 years for older and younger siblings, respectively. Median age at ERT initiation was 7.9 and 1.9 years for older and younger siblings, respectively. Results: Improvement or stabilization of somatic signs and symptoms was more notable in younger siblings. Organomegaly present at onset of ERT improved in the majority of both older and younger siblings. Analysis of physician-rated symptom severity demonstrated that cardiac, musculoskeletal, and cognitive symptoms, when absent or mild in younger siblings at ERT initiation, generally did not develop or progress. The majority of older siblings had height/length Z-scores greater than two standard deviations below the mean (less than -2) at both time points. In general, Z-scores for younger siblings were closer to the sex- and age-matched means at follow-up. Conclusions: These findings suggest early initiation of laronidase, prior to the onset of symptoms in patients with attenuated MPS I, can slow or prevent the development of severe clinical manifestations. © 2015 Al-Sannaa et al. Source
Rainger J.,Institute of Genetic and Molecular Medicine |
Bengani H.,Institute of Genetic and Molecular Medicine |
Campbell L.,Metabolic Section |
Anderson E.,Institute of Genetic and Molecular Medicine |
And 20 more authors.
Human Molecular Genetics | Year: 2012
Biallelic mutations in the gene encoding DHOdehase [dihydroorotate dehydrogenase (DHODH)], an enzyme required for de novo pyrimidine biosynthesis, have been identified as the cause of Miller (Genée-Weidemann or postaxial acrofacial dysostosis) syndrome (MIM 263750). We report compound heterozygous DHODH mutations in four additional families with typical Miller syndrome. Complementation in auxotrophic yeast demonstrated reduced pyrimidine synthesis and in vitro enzymatic analysis confirmed reduced DHOdehase activity in 11 disease-associated missense mutations, with 7 alleles showing discrepant activity between the assays. These discrepancies are partly explained by the domain structure of DHODH and suggest both assays are useful for interpretation of individual alleles. However, in all affected individuals, the genotype predicts that there should be significant residual DHOdehase activity. Urine samples obtained from two mutation-positive cases showed elevated levels of orotic acid (OA) but not dihydroorotate (DHO), an unexpected finding since these represent the product and the substrate of DHODH enzymatic activity, respectively. Screening of four unrelated cases with overlapping but atypical clinical features showed no mutations in either DHODH or the other de novo pyrimidine biosynthesis genes (CAD, UMPS), with these cases also showing normal levels of urinary OA and DHO. In situ analysis of mouse embryos showed Dhodh, Cad and Umps to be strongly expressed in the pharyngeal arch and limb bud, supporting a site- and stage-specific requirement for de novo pyrimidine synthesis. The developmental sensitivity to reduced pyrimidine synthesis capacity may reflect the requirement for an exceptional mitogenic response to growth factor signalling in the affected tissues. © The Author 2012. Published by Oxford University Press. All rights reserved. Source
Mirani M.,Metabolic Section |
Berra C.,Metabolic Section |
Finazzi S.,Dialysis Unit |
Calvetta A.,Dialysis Unit |
And 4 more authors.
Diabetes Technology and Therapeutics | Year: 2010
Background: Type 2 diabetes patients on chronic hemodialysis have a high prevalence of cardiovascular complications and often show a poor glycemic control. Single-spot glycemic measurements are not always meaningful, and the hemoglobin A1c (HbA1c) value does not reflect short-term variations in glucose metabolism in this patient category. Therefore, to better understand their metabolic balance, we studied a group of diabetes patients on hemodialysis by a continuous glucose monitoring (CGM) system. Methods: Twelve insulin-treated type 2 diabetes patients on hemodialysis were studied by a microdialysis-based subcutaneous glucose sensor over a period of 2 days, including the dialysis day (HD) and the following inter-dialytic period ("free" day [FD]). Results: The mean 24-h glycemic value, the mean amplitude of glucose excursions, and the SD of mean glucose were significantly higher in the HD than the FD (186 ±50 vs. 154 ± 25 mg/dL, P<0.05; 75 ± 22 vs. 56±15 mg/dL, P<0.05; and 57± 26 vs. 35 ± 11mg/dL, P<0.05, respectively). Considering the 48-h recording, there was a direct correlation between the mean glucose concentration and the HbA1c (r=0.47, P<0.05), whereas no association was observed between the measures of glucose variability and HbA1c. Conclusions: Insulin-treated diabetes patients on hemodialysis showed different glucose profiles between the HD and the FD. In particular, in the HD they have had an increased glycemic variability, which may represent an adjunctive risk factor for cardiovascular complications. Therefore the use of a CGM system, as a means of assessing the measures of glycemic variability, could improve the management of insulin therapy in these patients. © 2010 Mary Ann Liebert, Inc. Source