Hadassah Identifies the Gene Behind a Rare Disease of Fat Metabolism

When HA applied for a permit to come to Hadassah from Gaza, she didn’t know that she would be making a significant contribution to our understanding of the genetics of lipid metabolism.a

HA had not yet been diagnosed with an extremely rare disease: Congenital Generalized Lipodystrophy (CGL.)a

Lipodystrophies are a group of unusual diseases characterized by partial or generalized loss or absence of fat. CGL is an  rare disease, with an estimated worldwide prevalence is  of about  one in 10 million. The most characteristic clinical feature is near total lack of body fat and extreme muscularity present at birth. These patients develop extremely high levels of triglycerides, insulin resistance and associated complications, such as diabetes mellitus, fatty liver, polycystic ovary syndrome, and hypertension.  The genes involved in CGL have a role in differentiation and function of fat cells, and the processing of fat in other tissues. Our patient had a total cholesterol of 1314, triglycerides of over 8000, and LDL of 1260!a

Once Hadassah cardiologist Dr. Ronen Durst with medical  student – Koby Gorin, made the diagnosis in HA, they evaluated her family with the aim of determining the specific mutation.a

They found 6 affected family members, and were able to identify a novel frameshift mutation in the AGPAT2 gene.a

 AGPAT2 is on chromosome 9, encoding an enzyme which is a key intermediate in the biosynthesis of fats in the body. The Hadassah team is continuing to work on understanding the molecular mechanism of this gene, which will broaden our understanding of fat metabolism in this disease and in the general population.a

For now, the most effective treatment for CGL is  the use of recombinant leptin, which can lead to a reduction in triglyceride levels and insulin resistance.  Maybe someday this work will lead to a genetic therapy of this disease, and perhaps other avenues for treatment of abnormalities of fat metabolism.a