No abstract

The original guidelines drawn up for the management of the neuronopathic forms of Gaucher disease were felt to be in need of revision; in particular, the role of high-dose enzyme replacement therapy (120 IU/kg of body weight every 2 weeks) in stabilizing neurological disease. The existing published evidence was analysed; it was concluded that it did not support the role of high-dose ERT, although this might be required to treat severe visceral disease.

Unlike most adenovirus (Ad) serotypes, the species B Ads do not use the coxsackie-adenovirus receptor as an attachment receptor. The species B attachment receptor(s) has not yet been identified and is also poorly characterized. Species B Ads can be further divided into species B1 and B2 Ads, and these display different organ tropisms, suggesting a difference in receptor usage. We have studied the receptor interactions of the species B1 serotypes 3p and 7p and the species B2 serotypes 11p and 35 and characterized the properties of the species B receptor(s). Reciprocal blocking experiments using unlabeled Ad11p or Ad3p virions to block the binding to A549 cells of (35)S-labeled 3p, 7p, 11p, and 35 showed that only Ad11p virions efficiently blocked the binding of all the species B Ads studied (> or =70%). Thus, there is apparently a common species B Ad receptor (sBAR). However, Ad3p virions only partially (< or =30%) blocked the binding of Ad11p and Ad35 to A549 cells. Binding experiments after trypsin treatment of the cells confirmed that the species B2 serotypes address at least two different receptors on A549 and J82 cells, since sBAR is trypsin sensitive but the species B2 Ad receptor (sB2AR) is not. Both receptors are proteins or glycoproteins, since binding of all species B serotypes was abolished after proteinase K or subtilisin treatment of A549 or J82 cells. Furthermore, binding of the species B serotypes to sBAR was abolished with EDTA and restored with Ca(2+), whereas the binding of Ad11p and Ad35 to SB2AR was independent of divalent cations.

N-Butyldeoxynojirimycin (NB-DNJ, miglustat 'Zavesca') is an orally active iminosugar which inhibits the biosynthesis of macromolecular substrates that accumulate pathologically in glycosphingolipidoses. Clinical trials of NB-DNJ in patients with Gaucher's disease demonstrate the therapeutic potential of such substrate inhibitors in the glycolipid storage disorders. However, macrophage-targetted enzyme replacement using intravenous mannose-terminated human glucocerebrosidase (imiglucerase, Cerezyme) is highly effective in ameliorating many of the manifestations of Gaucher's disease and is a treatment in widespread use. Given that imiglucerase and miglustat are now both licensed for the treatment of Gaucher's disease, there is a need to review their therapeutic status. Here the treatment of type 1 (non-neuronopathic) Gaucher disease is evaluated with particular reference to the emerging role of oral N-butyldeoxynojirimycin (miglustat) as a substrate-reducing agent. This position statement represents the consensus viewpoint of an independent international advisory council to the European Working Group on Gaucher Disease.

The Norrbottnian type of Gaucher disease is characterized by infantile or juvenile onset and variable degrees of neurological symptoms, some of which develop only after splenectomy. A full neuropathological description of this type of Gaucher disease has not been reported previously. The brains of five patients were examined morphologically and biochemically. All presented typical accumulations of glucosylceramide storing cells in the adventitia of vessels in the cerebral and cerebellar sub-cortical white matter (s.c.w.m.). There were differences between the five cases with regard to the accumulation of adventitial storage cells and to the fatty acid pattern of the glucosylceramide isolated from the s.c.w.m., which implicate that the accumulation of glucosylceramide in adventitial cells in the brain is dependent on the generalized lipid storage process and enhanced by splenectomy. Loss of neurones and myelin was noted in the vicinity of accumulations of storage cells in two cases. The five cases showed varying degrees of nerve cell loss, satellitosis and neuronophagia. Lipofuscin with simple and complex lipids but no glycolipids could be demonstrated in neurones light-microscopically. Ultrastructural examination revealed inclusion bodies with bilayers in neurones of the cerebral and cerebellar cortex, dentate nucleus and pons. Because of the bilayered structure of Gaucher cell inclusions the bilayers in neurones are assumed to be formed by glucosylceramide. The fatty acid composition of glucosylceramide isolated from cerebral cortex in all cases suggested that cerebral gangliosides were its main precursor. The highest levels of psychosine (glucosylsphingosine) were seen in the cases with the most advanced nerve cell loss. The morphological and biochemical findings indicate that the neuronopathic process is associated with accumulation of glucosylceramide and psychosine in neurones.