Central monoamine dysfunction in Prader-Willi syndrome: a mechanistic framework for core clinical features

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental and neurobehavioral disorder characterized by hyperphagia and behavioral, endocrine, arousal, and cognitive dysregulation. Although caused by loss of paternally expressed, maternally imprinted genes in 15q11-q13, the mechanisms linking this lesion to the broad clinical phenotype remain incompletely understood. This review synthesizes evidence that central monoaminergic dysfunction, encompassing serotonin, dopamine, and norepinephrine, provides an integrative, though not exclusive, mechanistic framework for core features of PWS. Human studies indicate altered monoamine turnover, increased monoamine catabolism and blunted catecholaminergic stress responses. Neuroimaging implicates monoamine-sensitive networks involving hypothalamus, orbitofrontal and cingulate cortex, striatum, insula and cerebellum during tasks probing hunger, reward, and behavioral control. Clinical experience with monoaminergic agents demonstrates domain-specific benefits, particularly for behavioral, affective, and arousal-related symptoms, alongside marked inter-individual variability, including vulnerability to behavioral activation in some individuals Epigenetic evidence supports altered monoaminergic regulation in PWS, including differential methylation of genes involved in monoamine metabolism and transport, such as monoamine oxidase A and dopamine transporter, which may contribute to clinical heterogeneity. Genetic studies further link the PWS imprinting defect to monoaminergic biology: loss of small nucleolar RNAs (SNORD115 and SNORD116) and protein-coding genes such as MAGEL2 and NDN perturbs multiple, overlapping pathways, including serotonergic receptor processing, hypothalamic neuropeptide regulation, dopamine neuron development, and locus coeruleus function in experimental models. Together, these findings suggest that inter-related disturbances across monoaminergic systems, acting through both direct and indirect mechanisms, contribute to hallmark PWS manifestations and support a monoaminergic framework for rational, mechanism-informed therapeutic development.