Cholesteryl ester storage disease

The cholesterol ester storage disease, CESD (of English. Cholesterol ester storage disease), is an extremely rare autosomal recessive lysosomal storage disease.

Etiology and Genetics

A defect in the enzyme lysosomal acid lipase (LAL lysosomal acid lipase = ) results in affected patients to an accumulation ( storage) of cholesterol esters and triglycerides. The gene coding for the acid lipase gene locus is located on chromosome 10 q23.2 - 23.3. It consists of ten exons. Nonsense and missense mutations, and frameshifts and skipping exons may lead to a reduction of the activity of the gene product.

Due to the decreased activity of lysosomal acid lipase can get from the lysosome into the cytoplasm barely lipids. Characterized the control circuit for the regulation of the intracellular cholesterol concentration is interrupted. Low intracellular concentration of cholesterol in turn leads to the upregulation of the endogenous synthesis of cholesterol and LDL - receptor activity. The lysosome receives the endocytosed cholesterol. Due to the endogenous cholesterol synthesis, the cells are overloaded with cholesterol, thereby forming lipid vacuoles. These cause a loss of function of the cells, fibrosis, and ultimately cell death.

In contrast to Wolman 's disease, which has the same genetic cause and is always associated with a poor prognosis, the cholesterol ester storage disease much less serious. The CESD is still a residual activity of lysosomal acid lipase present. This residual activity is sufficient for the cholesterol ester degradation - with the exception of the liver - to accomplish. In both diseases the same gene is affected, only different areas in the LAL gene are mutated. In a case ( in Wolman 's disease), this leads to a complete loss of enzyme activity, in other case ( in the cholesterol ester storage disease) only to a reduction in enzyme activity.

The genetic defect is inherited as an autosomal recessive trait.

Symptoms and diagnosis

The cholesterol ester storage disease is often not diagnosed until after the age of 18. Patients have a high accumulation of lipids in various organs and have a pronounced hypercholesterolemia. The HDL -cholesterol concentration, however, is decreased. The risk of atherosclerosis is accordingly greatly increased. Liver and spleen are enlarged ( hepatosplenomegaly ).

A reliable diagnosis can be made after the determination of enzyme activity.

Prevalence

The cholesterol ester storage disease is extremely rare. The prevalence is estimated at 1:700.000.

Therapy

There are currently no causal therapy for cholesterol ester storage disease. Treatment is symptomatic, such as by the administration of HMG-CoA reductase inhibitors, inhibitors of cholesterol and apolipoprotein B synthesis.

Various clinical programs have successfully performed in recent years to the development of enzyme replacement therapies for lysosomal storage diseases different. The affected enzyme is regularly supplied from external and can reverse or reduce the symptoms.

First clinical studies to develop an enzyme replacement therapy for the lysosmale acid lipase (LAL ) are established and recruit patients worldwide.