Muscle weakness (hypotonia) is often the most obvious first symptom in newborns with PWS. While hypotonia in infants is most severe, low muscle tone continues to limit endurance and reduce participation in daily activities in children and adults with PWS.
Infants and children with a genetically related disorder, Schaaf-Yang syndrome, lack the MAGEL2 gene but have normal function of other PWS genes. People with Schaaf-Yang syndrome also suffer from lifelong moderate to severe hypotonia. This suggests that the MAGEL2 gene is vital for normal muscle function, both before birth and on an ongoing basis. Considering that loss of MAGEL2 in Schaaf-Yang syndrome and in PWS may be responsible for muscle weakness, it is important to understand how and why MAGEL2 is critical for normal muscle fuction. My team and I are working on this important question with support through an FPWR research grant on the loss of MAGEL2 and hypotonia in Prader-Willi syndrome.
Muscle weakness in PWS may be partly caused by reduced stimulation from the nerves that normally send signals back and forth from the muscles to the spinal cord and brain. However, we've now discovered that the MAGEL2 protein is indispensible in the muscle cells themselves. The results are described in a recent publication in the Journal of Human Molecular Genetics titled "Muscle dysfunction caused by loss of Magel2 in a mouse model of Prader-Willi and Schaaf-Yang syndromes dysfunction caused by loss of Magel2 in a mouse model of Prader-Willi and Schaaf-Yang syndromes."
We examined mice that are missing MAGEL2, and found that these mutant mice have smaller and weaker muscles than the mice that have a normal MAGEL2 gene. Mice missing MAGEL2 cannot run as fast or as far when tested on a treadmill. When MAGEL2 is missing, the muscle cells are less able to go throught the normal process of breaking down and reusing muscle proteins for energy and to build new muscle proteins.
The next step in our research is to identify therapeutics that are either in use or in development for similar conditions in which muscles become smaller and weaker, such as atrophy of aging or the loss of muscle in patients with cancer. These therapies will be tested in the MAGEL2 mouse model to determine their therapeutic potential to improve muscle mass and muscle tone in children and adults with PWS or Schaaf-Yang syndrome.
FPWR is additionally funding work to further understand the clinical similarities and differences between Prader-Willi and Schaaf-Yang syndromes. This will help define additional roles of MAGEL2 in PWS. The project "The MAGEL2 phenotype in comparison to classic Prader-Willi syndrome" is being conducted by Dr. Christian Schaaf at Baylor College of Medicine.