Gaucher disease is an autosomal recessive disorder of glycosphingolipid catabolism caused by reduced or absent activity of the lysosomal enzyme β-glucocerebrosidase (GBA). Pathogenic variants in the GBA gene are causative. The enzyme defect leads to progressive systemic accumulation of glucocerebroside (glucosylceramide) or glucosylsphingosine predominantly in the lysosomes of macrophages. With increasing storage, the macrophages increase in size and become so-called Gaucher cells, which can be detected predominantly in the spleen, liver, and bone marrow and are characteristic of the clinical appearance.
In Gaucher disease, a differentiation is made between the non-neuronopathic and neuronopathic forms of the disease. The non-neuronopathic form (classic type I) shows a chronic course with hepatosplenomegaly, hematological changes, and bone involvement without neurological symptoms. This type is the most common, accounting for 95% of cases, although disease onset and clinical expression are variable. The neuronopathic form can be acute or chronic. The acute neuronopathic form (classic type II) is characterized by severe neurologic complications that usually lead to death within the first two years of life. The chronic neuronopathic type (classic type III) differentiates from the acute form by a later onset of the disease and less progression, and is usually associated with marked hepatosplenomegaly and severe bone involvement.
Two treatment strategies are available for the management of Gaucher disease. Enzyme replacement therapy involves intravenous administration of the recombinant enzyme, which degrades glucocerebrosides stored in Gaucher cells. Alternatively, substrate reduction therapy is available, which reduces the rate of synthesis of glucocerebroside, thereby preventing its accumulation. Substrate reduction therapy with the active ingredient eliglustat is designed for the long-term treatment of adult patients with Gaucher disease type I. The efficacy of eliglustat depends on the CYP2D6 metabolizer status of the patient. Therefore, determination of CYP2D6 metabolizer type should be performed prior to initiation of therapy (Cerdelga summary of product characteristics).
Direct measurement of β-glucocerebrosidase activity in leukocytes should be performed prior to molecular genetic testing of the GBA gene (ACMG Practice Guideline, 2011).
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