Prevalence of the sphingolipid storage diseases M. Gaucher and M. Niemann-Pick type B: results in a nation-wide screening project in 224 patients

Background: M Gaucher (GD) and Niemann-Pick disease type B (NP-B) are monogenic autosomal-recessive storage diseases. They are caused by reduced activities of lysosomal β-glucocerebrosidase (GBA1 in GD) or acidic sphingomyelinase (ASM in NP-B). Gaucher leads to hepatosplenomegaly, osseous complications and a reduced life expectancy. The frequency of hepatocellular carcinoma is high in GD. Niemann-Pick disease type B leads to hepatosplenomegaly, pancytopenia and a prognostically poor emphysema, some of the patients develop liver cirrhosis. In Germany, between the actual number identified in these patients (respectively < 500) and the reference to the heterozygote frequency predicted number (> 2000) there is a discrepancy. Hepatosplenomegaly is almost never missing. For both there is an effective enzyme supplementation therapy, either recombinant glucocerebrosidase (imiglucerase, velaglucerase, taliglucerase) in GD or the recently approved recombinant sphingomyelinase (olipudase-α) for NP-B.

Methods: Between 2008 – 2014 we carried out an activity determination of β-glucocerebrosidase in white blood cells (GBA) and chitotriosidase (CT) from EDTA blood in cooperation with clinical hematooncologists either from practice or hospital settings after exclusion of hepatic, malignant, purely hematological or infectious etiology of idiopathic hepatosplenomegaly. Gaucher-negative patients, CT-positive patients were offered determining the activity of ASM activity in leukocytes from EDTA blood to identify Niemann-Pick disease type B.

Results: Five of the examined 224 patients had a pathological GBA1 activity, consistent with diagnosis of Gaucher disease. Two of a total of 15 patients with increased chitotriosidase activity, which were Gaucher-negative, exhibited a significantly decreased activity of ASM as a sign of Niemann-Pick type B. The age ranged from 0 – 88 years. Splenomegaly (≥5 multiples of normal, MN) was present in 85%, in 35% of patients studied it was severe (≥15 MN). Hepatomegaly (≥1.25 MN) was seen in 47%, only 7% being severely hepatomegalic (≥2.0 MN). In 57% thrombocytopenia was present, in 40% anemia was found as an expression of hypersplenism. Three of the seven sphingolipidoses had shown no typical storage cells (Gaucher or Niemann-Pick cells) in bone marrow smears.

Discussion: The prevalence of Gaucher disease in patients with idiopathic splenomegaly is about 1:45. Patients with increased chitotriosidase activity and negative Gaucher screening should be examined on the sphingolipidosis Niemann-Pick disease type B. Gaucher treatment with enzyme replacement therapy and substrate reduction therapy has been established for decades and the recently introduced ERT at NP-B seems to be effective. In both diseases, there are abortive forms that can be clinically observed without specific therapy. The determination of CT activity is useful as a screening test and GD- and NP-B-negative cases should be analysed for other entities of lysosomal origin (e.g. cholesterol ester storage disease or Niemann-Pick type C). Typical storage cells in KM may be missing, so a primary biochemical diagnosis is recommended in any idiopathic hepatosplenomegaly.

Corresponding author: vom Dahl, Stephan

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