Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.

BackgroundMucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.MethodsThis 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.ResultsThe two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.ConclusionsLaronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made

Considering Fabry, but Diagnosing MPS I: Difficulties in the Diagnostic Process

Introduction: Recent studies have indicated that a proportion of patients with renal failure, left ventricular hypertrophy, or cryptogenic stroke have sequence variants in their aGal A gene (Fabry disease), which has resulted in an increase in diagnostic activities for this disorder. The diagnostic process for lysosomal storage disorders may result in findings of unknown clinical significance. Here we report such an unexpected outcome. Case: A 32-year-old male presented at the emergency department because of a transient ischemic attack. Extensive investigations revealed no cause and an initial diagnosis of cryptogenic stroke was made. Subsequently, aGal A activity was measured in a bloodspot and was shown to be normal, but the activity of alpha-L-iduronidase (IDUA), used as reference enzyme, was unexpectedly low: 0.5 umol/L (ref = 1.7-14.3). A diagnosis of IDUA deficiency, mucopolysaccharidosis type 1S or Scheie disease was considered. IDUA gene analysis revealed two homozygous sequence alterations: a silent sequence change (979C > T) in exon 7 (N297N) and an unknown missense mutation 875A > T (R263W). Physical examination was completely normal, without clinical signs of mucopolysaccharidosis type I (MPS I). Leukocyte IDUA activity was also low: 2.1 nmol/mg prot/h (ref = 14-40 nmol prot/h), but higher than the patient range of <0.1 nmol/mg prot/h. Urinary glycosaminoglycan levels were normal both quantitatively and qualitatively. It was concluded that there was low IDUA activity without clinical symptoms and the diagnosis of mucopolysaccharidosis I was discarded. Conclusion: The diagnostic process for lysosomal storage disorders may result in biochemical abnormalities of unknown clinical significance. Early evaluation by a specialist in inborn errors of metabolism may help to avoid anxiety in patients and unnecessary additional analyse

10^{10}Be evidence for the Matuyama-Brunhes geomagnetic reversal in the EPICA Dome C ice core

An ice core drilled at Dome C, Antarctica, is the oldest ice core so far retrieved 1. On the basis of ice flow modelling and a comparison between the deuterium signal in the ice with climate records from marine sediment cores, the ice at a depth of 3,190 m in the Dome C core is believed to have been deposited around 800,000 years ago 2, offering a rare opportunity to study climatic and environmental conditions over this time period. However, an independent determination of this age is important because the deuterium profile below a depth of 3,190 m depth does not show the expected correlation with the marine record 2. Here we present evidence for enhanced 10Be deposition in the ice at 3,160-3,170 m, which we interpret as a result of the low dipole field strength during the Matuyama-Brunhes geomagnetic reversal, which occurred about 780,000 years ago. If correct, this provides a crucial tie point between ice cores, marine cores and a radiometric timescale