Transition to BioMetabol

Development of a new mass spectrometry-based biomarker for the early and sensitive diagnosis of Gaucher Disease from blood (plasma)

Gaucher disease (GD) is an autosomal recessive hereditary lysosomal storage disorder. Occurrence of the disease is due to a hereditary deficiency of the Glucocerebrosidase, a lysosomal enzyme which divides Glucocerebroside into Glucose and Ceramides. The unmetabolised Glucocerebrosides are stored throughout the whole reticulo-endothelial system. Accumulation of Glycolipid-enriched macrophages establishes a pathoanatomical phenomenon, the so-called Gaucher cells, which can be verified by light microscopy of affected tissues. Activation markers of the macrophages, like the enzyme Chitotriosidase or CCL18, are parameters which follow the course of GD.

Gaucher disease is the most frequently inherited Sphingolipidosis in the general population, and in Ashkenazi Jews, in who the prevalence is much higher (1:450). 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.

The clinical appearance is heterogeneous. The classical phenotype is characterised by visceral organ (Hepatosplenomegaly) and skeleton system (Bone marrow infiltrates up to bone infarcts and pathological fractures) affection. Moreover, consecutive blood cell count changes, Anemia and Thrombocytopenia are 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, since 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 so far been detected in connection with only visceral progress forms (type1). At least the outcome of the non-neuronopathic disorder cases could be improved by the introduction and general availability of enzyme therapy. Under this kind of therapy there is a reduction of liver and spleen size as well as a normalization of the haemogram parameters.

New methods, like mass-spectrometry give a good chance to characterize specific metabolic alterations in the blood (plasma) of affected patients that allow to diagnose in the future the disease earlier, with a higher sensitivity and specificity. In a pilot study lyso-glycosylsphingosine has been determined as a sensitive and specific biomarker (see attached manuscript). 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 blood of the affected patients helping to benefit other patients by an early diagnose and there-by with an earlier treatment.

Inclusion Criteria:

• Informed consent will be obtained from the patient or the parents before any study related procedures.

• Patients of both gender from the first day of life

• The patient has a diagnosis of Gaucher disease or high-grade suspicion for Gaucher disease

• High-grade suspicion present, if one or more criteria are valid:

  1. - Positive family anamnesis for Gaucher disease
  2. - Splenomegaly without identifiable cause
  3. - Hepatomegaly without identifiable cause
  4. - Anemia or thrombocytopenia without identifiable cause
  5. - CNS involvement without identifiable cause

Exclusion Criteria:

• No Informed consent from the patient or the parents before any study related pro-cedures
• No diagnosis of Gaucher disease or no valid criteria for high-grade suspicion of Gaucher disease

Patients with Gaucher disease or high-grade suspicion for Gaucher disease