The first gene found responsible for KS was initially localized to the distal portion of X chromosome () by studying patients with a “contiguous gene syndrome” (. multiple genes lost due to large deletion of a portion of a chromosome resulting in multiple clinical phenotypes). This cluster of phenotypes included: short stature, chondrodysplasia punctata, intellectual disability, icthyosis and KS. By mapping the genes within this large deletion, the KAL1 gene was identified as the cause of KS. KAL1 is an X-linked gene and IGD is inherited in an X-linked recessive manner. KAL1 is comprised by 14 exons and encodes a secreted extracellular matrix protein called anosmin-1. Anosmin-1 plays an important role in the neuronal migration of both the GnRH neurons as well as the olfactory structures. This dual defect results in the characteristic combination of GnRH deficiency and anosmia, respectively. In addition, patients with KAL1 mutations may have additional non-reproductive phenotypes such as unilateral renal agenesis (absence of one kidney) and mirror movements. It is known that anosmin is also involved in kidney development, thus explaining why some patients with KS have renal agenesis. In addition, anosmin is also important for the crossing of the neurons in the developing brain across the midline, and this accounts for the mirror movements. Although KAL1 is a prototypical X-linked recessive gene, it is now known that some female carriers of KAL1 gene may also manifest IGD, suggesting other genetic mechanisms in these female carriers.
During aging, there is a gradual decrease in the ability to maintain skeletal muscle function and mass. This condition is called sarcopenia , and may be distinct from atrophy in its pathophysiology. While the exact cause of sarcopenia is unknown, it may be induced by a combination of a gradual failure in the satellite cells which help to regenerate skeletal muscle fibers, and a decrease in sensitivity to or the availability of critical secreted growth factors which are necessary to maintain muscle mass and satellite cell survival.