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Feb
04

A rare disease a day: Gaucher Disease

Continuing the rare disease a day theme started yesterday with Hunter Syndrome, today the focus is on Gaucher disease (also called Gaucher’s disease). This is the most common autosomal recessive  lysosomal storage disease. It is caused by mutations in the beta-glucocerebrosidase gene GBA1 and results in the build up of glucosylceramide in in the spleen, liver, kidneys, lungs, brain and bone marrow.

Common Symptoms include: Painless hepatomegaly and splenomegaly, Hypersplenism and pancytopenia,  severe pain associated with joints and bone, neurological symptoms, osteoporosis, deformity of the distal femur in the shape of an Erlenmeyer flask and Yellowish-brown skin pigmentation.

There are 3 clinical sub types:

Type 1 (or non-neuropathic type) is the most common form of the disease and these patients may live well into adulthood

Type 2 (or acute infantile neuropathic Gaucher’s disease) is usually fatal by age 3.

Type 3 (the chronic neuropathic form) in which patients live into their teens or adulthood.

Treatment for Type 1 and Type 3 forms of the disease includes using recombinant glucocerebrosidase (imiglucerase), Velaglucerase alfa or Taliglucerase alfa.

In type I patients for whom enzyme replacement therapy is unsuitable then miglustat may be used. This molecule acts as a substrate reduction therapy by inhibition of the enzyme glucosylceramide synthase.

There is also considerable research into chaperones for treating Gaucher disease. For example recent published work using iminosugar click clusters. This work showed that prodrugs (acetylation) had higher enzyme activity increases. There seems to be no shortage of chaperones and of course ambroxol and there are several efforts that have found nM compounds but with limited chaperone activity. A herb derivative of celastrol, was recently shown to modulate molecular chaperones and increase the enzyme activity. These compounds are similar to those used as chaperones for Niemann Pick type C1. 

This makes you wonder if there is anything that can be done for the Type II form of the disease in which the enzyme is hardly released into the lysosomes and which is quickly fatal. One study  used iminoxylitol analogs as chaperones and had a significant effect on  the L444P mutation in human fibroblasts. With so many studies on chaperones for this disease this may help other related lysosomal diseases too.

 

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  1. sean says:

    Diltiazem as a chaperone…http://www.ncbi.nlm.nih.gov/pubmed/19167257

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