Overview
Clinical Pattern and Disease Mechanism
Gaucher disease is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in GBA1 .
Gaucher disease is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in GBA1. The variants reduce activity of acid beta-glucosidase, also called glucocerebrosidase. This enzyme normally breaks down glucosylceramide inside lysosomes. When the enzyme is deficient, glucosylceramide and related substrates accumulate inside macrophages, producing enlarged storage cells known as Gaucher cells. The macrophage is the clinical link between the enzyme defect and the examination findings. Gaucher cells infiltrate the spleen and liver, where they enlarge the organs and contribute to hypersplenism. In bone marrow, they crowd the haematopoietic space and disrupt bone remodelling. The result is a characteristic combination of splenomegaly, thrombocytopenia or anaemia, and skeletal disease. On microscopy, the cytoplasm may have a “crumpled” or “wrinkled tissue paper” appearance, but this appearance supports rather than establishes the diagnosis. Three principal phenotypes are recognised: - Type 1, non-neuronopathic disease: There is no primary central nervous system involvement. Patients may develop hepatosplenomegaly, cytopenias, bone pain, osteopenia, avascular necrosis, pathological fractures, and the Erlenmeyer flask deformity of the distal femur. - Type 2, acute neuronopathic disease: Neurological deterioration begins...