Gaucher disease is a rare inborn lysosomal disorder affecting the metabolism of sphingolipids; it has been the focus of intense – and productive – therapeutic research. With the introduction of macrophage-targeted enzyme therapy much has been learnt about this highly diverse disorder, which occurs all over the world.
Type 1 Gaucher disease, which occurs in 90-95% of recorded cases, is widely regarded as Gaucher disease with no neurological features -although this restriction does not apply for newly recognized late Parkinsonian complications. Hitherto the most familiar presentation is related to disease principally in the macrophage system: there is hepatosplenomegaly, accompanied by growth retardation, hypersplenism and marrow failure with cytopenias.
Skeletal features are frequent, with osteopenia, osteoporosis, episodes of osteonecrosis – as well as osteolytic lesions, and, occasionally, multiple myeloma. Before specific therapy was available, many patients required splenectomy to improve their haematological condition; but while splenectomy induces a risk of infection and can be obviated, many patients with a history of this intervention have severe and crippling skeletal disease which requires intensive multi-disciplinary care.Chronic neuronopathic disease (type 3) is part of the severe spectrum of the condition: while neurological features declare themselves early in this sub-variant, the manifestations in the skeleton are prominent causes of pain and disability – and together with coincident visceral and haematological disease respond to judicious treatment in the early phases before irreversible injury is established.
The clinical features of Gaucher disease are diverse and pathological expression is equally varied. However, even today, as a multisystem disorder involving complex biochemical and immunological changes, much of its pathogenesis remains elusive. As with other rare disorders due to changes at single genetic loci with large effects, Gaucher disease holds continued promise for better understanding of human physiology and several other disorders of universal medical importance.
Here I will review the diversity of Gaucher disease and the fascinating evolution of its therapy.