Lysosomal Storage Disorders: A Practical Guide
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Awareness of lysomal storage disorders needs to be raised and there is very substantial pharmaceutical interest to do so. The disorders are often viewed as obscurities but in fact they are treatable. Enzyme replacement therapy is available for four of the disorders and will be available for a further three disorders in the course of the next year. Substrate reduction therapy is licensed for one of them but in the course of the next 12 months it will be licensed for two others and a new form of substrate reduction therapy is being introduced.
These diseases present to a very wide range of physicians and paediatricians. Gaucher disease may present to orthopaedic surgeons or haematologists with splenomegaly and/or skeletal disease. However, paediatricians see the childhood variants of Gaucher disease and therefore may present it to neurologists. Fabry disease typically does not present in childhood but presents to adult physicians with end organ damage (renal failrure, cardiac disease, stroke, neuropathy, gastrointestinal symptoms). A text book would draw these divergent strands together.
There is substantial scientific interest in these diseases. Gaucher is well recognised as a paradigm of a molecular illness, understood at a basic level which is treatable now with specific therapy and is likely to be treatable with gene therapy within the coming five years. New advances in small molecule therapy – e.g. chaperone treatment, modified antibiotics affecting ribosomal function – are likely to be useful for these diseases in the near future. Trials are already underway. These diseases therefore offer a fabulous platform for teaching modern clinical science from basic genetics right the way through to clinical applications.
unfortunate cases, custodial institutions. Lysosomal Storage Disorders: A Practical Guide, First Edition. Edited by Atul Mehta and Bryan Winchester. © 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd. 153 154 Part 3: Therapy and Patient Issues Genetic counselling In the management of all these conditions, their hereditary basis should be considered for at-risk first-degree relatives. Siblings of affected patients should be evaluated either by appropriate assay of
slowly in childhood rather than rapidly in infancy, is a feature; often these are major features of the Sanfilippo diseases (MPS III A–D) and may be accompanied by seizures. Patients with late-onset forms of metachromatic leukodystrophy, Krabbe and the GM2-gangliosidoses (Tay–Sachs and Chapter 20: Current Treatments Sandhoff diseases) often present with florid psychological disorders, including frontal-type dementia with loss of memory, insight and inhibitions. Behavioural manifestations can
national specialist centre to carry out the assessment and management of patients with Gaucher disease. By May 2000, 171 Gaucher patients were attending these four national centres. However, the cost of the enzyme therapy remained under the control of Local Health Authorities (by then termed Primary Care Trusts), which 189 meant that equity of provision throughout the UK was not achieved. The term ‘post code prescribing’ has been used to describe this unsatisfactory state of affairs. A further
extracellular environment. Conversely, during disease/injury activated microglia proliferate, and, along with infiltrating macrophages, can generate cytotoxic components including reactive oxygen species, nitric oxide and pro-inflammatory cytokines. Microglia and macrophages exhibit altered morphological states in many lysosomal diseases, while activated astrocytes are also a prominent feature contributing to the pathological landscape in the CNS. Some NCLs, gangliosidoses, MPSs, MLs and
thrive, the development of ascites, nephrosis, seizures, multiple dysostosis, hepatosplenomegaly, and cardiomegaly are hallmarks of ISSD. Affected infants may have foetal hydrops and hydrocephalus. Children with this severe form of the condition Chapter 17: Lysosomal Membrane Defects 133 Lysosomal acidification Communication with other membrane systems Transport across the membrane H+ Regulation of autophagy and phagocytosis H+ H+ H+ Figure 17.2 Multiple functions of lysosomal membrane