Dr Nicholas Smith is an Australian physician specialising in paediatric neurology. Dr Smith has recently joined the University of Cambridge Lysosomal Storage Disease Research Group led by Prof.Timothy Cox where he plans to study the neuropathology of a variety of lysosomal storage disorders including Gaucher Disease. Dr Smith hopes that a greater understanding of the neurological pathogenesis in these conditions will contribute to the development of improved therapeutic interventions for patients with neurological disease. As part of his work at Addenbrooke’s Dr Smith plans to undertake a collaborative study into the role LIMP – 2, he explains the theory behind the study:
‘With a population frequency variously estimated at 1/200,000 – 1/ 40,000 Gaucher disease represents one of the most common inborn errors of lysosomal function. In the UK this equates to around 200 – 300 individuals, 5-10% of whom manifest neurological involvement; the so called neuronopathic variant. ‘Together with the management of bone disease, effective therapy for neurological manifestations of Gaucher disease continues to represent an unmet clinical need for patients.
‘Neuronopathic disease has traditionally been categorised as one of two subclasses; type 2 (acute neuronopathic) and type 3 (chronic neuronopathic) disease. Type 2 disease is characterised by relentlessly progressive neurodegeneration beginning in infancy, whilst type 3 disease is more variable with onset ranging from infancy to adulthood with a generally slower, at times almost indolent, rate of progression. However, a further subset of patients increasingly recognised and previously thought to be free of central nervous system (brain and spinal cord) involvement are those with late onset neurological features. These patients develop abnormalities of movement resembling Parkinson’s disease. This has led to the now widely accepted view that neuronopathic Gaucher disease most likely represents a continuous spectrum of central nervous system involvement. Nevertheless, the traditional classifications are still widely used and remain helpful to patients, families and clinicians when attempting to predict how a particular person with Gaucher disease may fare.
‘Why then do some Gaucher patients develop nervous system involvement whilst others do not? Despite a global effort to address this question the answers remain frustratingly elusive. Over 95% of all cases arise from genetic variation in the gene encoding the critical enzyme (glucocerebrosidase) that is deficient in Gaucher disease. In a further small group of patients disease results from an abnormality of an associated protein SAP-C (the sphingolipid activator protein C) that is required to assist the critical enzyme in its function. However, numerous studies throughout the international Gaucher population, have failed to identify all but broad correlations between specific genetic variations and the clinical presentation of disease. In fact, individuals with identical genetic changes can have neuronopathic or non-neuronopathic forms of disease.
Various suggestions to explain this phenomenon include the possibility of associated factors, often termed epigenetic factors, which influence a particular gene’s function, individual differences in the number of repeat sequences in a person’s genetic code (termed copy number variation) and the presence of secondary ‘modifier’ gene changes which predispose an individual with the Gaucher disease mutation to manifest a particular clinical pattern.
Limp – 2 Gene
‘Recent, exciting work by Professor Paul Saftig and his team from Christian-Albrechts University Kiel, in collaboration with Dr. Tim Edmunds, a top scientist in the Genzyme corporation, has identified a protein, the Lysosomal Integral Membrane Protein type 2 (LIMP-2) which plays an important functional role in ensuring that the enzyme which is deficient or dysfunctional in Gaucher disease is transported from its site of production to its site of action, the lysosome.
Studies in mice that are genetically engineered to be deficient in LIMP-2 results in animals with prominent neurological abnormalities; including poor balance, deafness, disease of the peripheral nerves and an accumulation of an abnormal, as yet unidentified, storage material in their brains. People without Gaucher disease, who have been found to have abnormalities in both copies of the LIMP-2 gene are extremely rare. These individuals manifest a severe, adult onset disorder called Action Myoclonus Renal Failure Syndrome (AMRF); which surprisingly displays some features in common with neuronopathic Gaucher disease. A few cases of Gaucher disease have also been reported to occur secondary to abnormalities of the LIMP-2 gene.
One such case was highlighted at the recent European Working Group on Gaucher Disease (EWGGD) meeting in Budapest earlier this year. It therefore seems possible that variation in the genetic sequence of the LIMP-2 gene may be an important determinant of neurological manifestations in Gaucher disease. ‘Confirmation of such a relationship would provide a valuable tool helping to predict the course of disease in individual patients. Additionally it would help identify those in whom experimental therapies targeted to the brain may be of benefit.
A study aimed to address the possibility of this association in UK Gaucher patients is planned as a collaborative effort amongst the national Gaucher treatment centres with the support of the UK. Gaucher Association. Voluntary participation in the study would involve the granting of permission to review patient medical files and obtain a blood sample for DNA analysis (in most cases this sample will have already been taken and stored at the time of diagnosis). Strict patient confidentiality will be employed and no identifiable information will be included in the study. Further details can be obtained from the coordinating centre, The Lysosomal Diseases Research Group, University of Cambridge, Addenbrooke’s Hospital [Please contact Dr.
Nicholas Smith; Ph: 01223 336868 or email: firstname.lastname@example.org
The Alan Gordon Memorial Award was established in memory of our first treasurer, Alan Gordon, who died in December 1995. Alan and his wife Gloria were founding members of the Gauchers Association. Find out more
Back by popular demand Sunday 21st May 2017