Dr. Christian Schaaf and his group, in collaboration with Dr. Jennifer Miller, has published a new study examining clinical similarities and differences between Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS). Dr. Schaaf was the first to describe SYS, which is caused by mutations in one of the genes in the PWS region (MAGEL2). Whereas individuals with PWS have several genes missing/inactivated on chromosome 15, those with SYS have a mutation in the MAGEL2 gene only. You might think that those with SYS would therefore exhibit similar, but fewer, or less severe symptoms, than PWS. In fact, there are differences between the two disorders, but like everything else associated with PWS, it’s complicated.
It was previously shown that some aspects of SYS are unique to this population (e.g., joint contractures), but other clinical problems (hypotonia and poor feeding in the newborn period, intellectual disability, behavioral challenges) are shared in both disorders. Hyperphagia, or excessive appetite, is noted only in a subset of those with SYS, whereas it is almost always present in by late childhood in PWS. Here, with FPWR support, Dr. Schaaf’s group looked more closely at individuals with SYS to better understand the overlap between the two disorders, examining in depth the hormonal, metabolic and bone changes in nine individuals with SYS, and comparing the findings to PWS.
The authors first looked at endocrine/hormone changes in SYS, where some striking similarities were found with PWS. Like PWS, individuals with SYS had growth hormone deficiency accompanied by low IGF-1 (insulin-like growth factor) and IGF-binding protein 3. This suggests a similar basis for reduced growth in SYS and PWS, and that SYS patients might also benefit from growth hormone therapy. The authors suggest that formal studies be undertaken to evaluate the possible risks and benefits of GH therapy in SYS.
Increases in Ghrelin
Another important hormone, ghrelin (a.k.a, the “hunger hormone”) was found to be abnormally high in SYS, even higher than is usually found in PWS, where it also elevated. This was somewhat surprising given that the food drive in SYS is generally not as much of an issue as it is in PWS, where high ghrelin is believed by many to cause the increased appetite. Since ghrelin comes in both an active and an inactive form, which were not distinguished by the lab test used, it may be that the active form of ghrelin is actually not high in SYS. Alternatively, it could be that individuals with SYS aren’t responsive to the increased levels of ghrelin, or that the more severe intellectual disability typical of SYS means that individuals are experiencing hunger but can’t express it well. Another possibility that need to be considered is that high ghrelin may not be the root cause of hunger in PWS or SYS – a suggestion that has been supported by some other studies. Additional research will be needed to sort through these possibilities.
Bone Changes In SYS and PWS
There were also some notable bone changes in SYS that were reminiscent of PWS. These included a high incidence of scoliosis (3 of 9 patients) and very low bone mineral density in all of the individuals who would comply with the DEXA scans. This suggests that the origin of abnormal bone features in both PWS and SYS may be linked to abnormal or absent function of the MAGEL2 protein, and thus MAGEL2 may have a critical role in normal bone formation.
Overall, this paper describes novel findings about SYS with respect to hormone abnormalities, bone density deficiencies and body composition changes. It also suggests that therapies like GH therapy, which have demonstrated strong benefit in the PWS population, should be considered in SYS. However, it also leaves us with some mysteries. In particular, the role of ghrelin in driving appetite in PWS, SYS and in healthy individuals is not fully understood and may be further confounded by the finding of high ghrelin levels in SYS individuals who don’t seem to have a significant drive to eat. Additional studies, including the evaluation drugs targeting ghrelin for the treatment for hyperphagia in PWS, may help resolve some of the current uncertainties.