Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by loss of function of paternally expressed imprinted genes on chromosome 15q11.2-q13, most commonly through a de novo paternal deletion (65-75% of cases), maternal uniparental disomy (UPD, where both chromosome 15 copies are maternally inherited, ~25% of cases), or imprinting center defects (~1-3%). The critical region contains several genes (SNRPN, MAGEL2, NECDIN, and the SNORD116 cluster of small nucleolar RNAs) that are normally expressed only from the paternal allele due to genomic imprinting — when the paternal copies are absent or silenced, these genes produce no functional protein. The SNORD116 cluster is believed to be the primary contributor to the hyperphagia phenotype. The central pathophysiology of PWS involves hypothalamic dysfunction affecting multiple neuroendocrine axes. Hypothalamic appetite regulation is profoundly disrupted: the arcuate nucleus fails to generate appropriate satiety signals, ghrelin levels are paradoxically elevated (3-4 times normal, unlike typical obesity where ghrelin is suppressed), and oxytocin-producing neurons in the paraventricular nucleus are reduced by ~40%. This creates an insatiable drive to eat (hyperphagia) that is neurobiological, not behavioral — patients experience...