Gaucher disease (Gaucher; MIM 230800, 230900, 231000) is an autosomal recessive hereditary lysosomal storage disorder. Occurrence of the disease is due to a hereditary deficiency of the Glucocerebrosidase (EC.126.96.36.199), a lysosomal enzyme which divides Glucocerebroside into Glucose and Ceramides. The unmetabolised Glucocerebrosides are stored throughout the entire reticulo-endothelial system. Accumulation of Glycolipid-enriched Macrophages establishes a pathoanatomical phenomenon, the so-called Gaucher cells, which can be verified by light microscopy. Activation markers of the Macrophages, such as the enzyme Chitotriosidase or CCL18, are parameters which follow the course of Gaucher disease. Gaucher disease is the most frequently inherited Sphingolipidosis in the general population, and in Ashkenazi Jews, in whom the prevalence is much higher (1:450).
New methods, such as mass-spectrometry, provide a good chance of characterizing specific metabolic alterations in the blood (plasma) of affected patients that in the future will allow us to diagnose the disease earlier, with higher sensitivity and specificity. In a pilot study, lyso-glycosylsphingosine was determined as a sensitive and specific biomarker. This is a metabolic product likely to be involved in the pathophysiology of the disease.
Therefore it is the goal of the study to validate this new biochemical marker from the plasma of the affected patients helping to benefit other patients by an early diagnose and thereby with an earlier treatment.
Examining saliva samples will allow us to determine whether measurement of the identified marker lyso-Glucosylsphingosine is feasible in saliva samples and will further promote early detection of Gaucher disease.
What is Gaucher Disease?
The gene which codes the Glucocerebrosidase is on the long arm of chromosome 1 and covers 11 exons. So far, more than 200 different mutations in Gaucher patients have been described, mostly missense mutations. In addition frame-shift- and splice-site-mutations have been detected, as well as insertions and deletions. More frequent mutations are N370S, L444P, IVS2+1G>A, c.84insG, R463C and R496H [Sidransky E. 2004]. The clinical appearance is heterogeneous. The classical phenotype is characterised by visceral organs (Hepatosplenomegaly) and the skeletal system (Bone marrow infiltrates up to bone infarcts and pathological fractures) affection. Moreover, consecutive blood cell count changes, Anemia and Thrombocytopenia, have been reported.
A serious distinction lies in the appearance of neurological manifestations (myoclonus epilepsy, hydrocephalus, ocular movement disturbances). There is discussion on whether the classification into the typical three disease types (type1: non-neuronopathic progress form, type2: acute neuronopathic progress form, type3: chronic neuronopathic progress form) is still up-to-date, as it does not sufficiently reflect the reality of the clinical presentation. A clear genotype-phenotype relationship does not exist. The same DNA mutations are detected in patients with pronounced differences in disease progression. The exception is the mutation N370S, which has been detected so far only in connection with visceral progress forms (type1) [Koprivica et al. 2000]. At least the outcome of the non-neuronopathic disorder cases could be improved by the introduction and general availability of enzyme therapy. With this kind of therapy, there is a reduction of liver and spleen size as well as a normalization of the haemogram parameters.
Although Gaucher disease is a pan-ethnic disorder, the prevalence of this autosomal-recessive disorder is elevated in countries with a higher frequency of consanguinity. Therefore, we estimate that every 400th newborn in Arabian countries may be eligible for inclusion due to high-grade suspicion of Gaucher disease, while approximately every 2000th newborn in a non-Arabian country may be eligible.