Cardiomyopathies are diseases of the heart muscle tissue and often lead to heart failure. Most of them are inborn and can be caused by gene defects (mutations) affecting various proteins needed either for the contraction or the energy supply of the heart. The subject of professor Kilimann’s research was a rare but particularly malignant form of cardiomyopathy: “fatal congenital nonlysosomal heart glycogenosis” (FCNHG). Children with this disease have a dramatically enlarged heart (5 times the normal weight) and arrhythmia, and die from heart failure and respiratory complications at a few weeks of age.
— Earlier biochemical research had attributed this disease to a defect in an enzyme of energy metabolism, phosphorylase kinase (Phk), but when we analyzed the Phk genes, we found them to be normal. The earlier molecular explanation of FCNHG was apparently in error. We finally had the idea to look into another gene, of AMP-activated protein kinase (PRKAG2), which is also involved in energy metabolism and was known to cause a related but much milder cardiomyopathy that develops in juvenile or young adult patients. Indeed, in several patients from different countries we found exactly the same mutation. In collaboration with a British laboratory, the mutant protein was produced in the test tube, and found to be much more severely altered in its molecular properties than the mutant proteins from adult patients described previously, says Manfred Kilimann.
These findings have no immediate therapeutic consequences in this severe disease, for which there is no known cure other than a heart transplantation. However, they make diagnosis, prognosis and genetic counseling much more reliable. One important finding of these studies is that the FCNHG mutation always arises newly. Parents of a child with this mutation can therefore be given the reassuring advice that the risk of having another affected child is very low. Moreover, the results have implications far beyond FCNHG. AMP-activated protein kinase is also involved in cardiac infarction and type 2 diabetes, and therefore is an important potential drug target in these widespread diseases. Understanding its molecular structure and functioning, to which these studies have contributed, is expected to aid in drug development.
— Solving the riddle of FCNHG has required much effort and determination. We have worked on it for 12 years, analyzing 11 genes, in collaboration with partners in Germany, Britain and the USA. Having finally cracked the problem is a very rewarding experience for me, being both a scientist and a medical doctor.