Prader-Willi Syndrome (PWS)

Prader-Willi syndrome (PWS) is a rare, genetic neurobehavioral disorder that affects multiple systems, including the metabolic, endocrine, musculoskeletal, gastrointestinal, cardiovascular, respiratory, and nervous systems. PWS is characterized by severe hypotonia, feeding difficulties, and developmental and growth delays during infancy, followed by hyperphagia and morbid obesity in early childhood. ¹  

Many individuals with PWS present with growth hormone deficiency as well as hypothalamic dysfunction, which result in endocrinopathies including hypogonadism, hypothyroidism, central adrenal insufficiency, and osteoporosis/osteopenia. In addition, type II diabetes mellitus often develops in these individuals, particularly those with obesity.^1,2 

Behavioral problems, such as temper tantrums, stubbornness, and obsessive-compulsive behaviors (eg, skin picking), sleep disturbances, and distinctive facial characteristics are common in people with PWS.²

Genetic Pathophysiology of PWS

PWS is the first human disorder recognized to be associated with genomic imprinting, in which genes are differentially expressed depending on whether they were inherited from the mother or the father. Loss of gene function in the imprinting center region (15q11.2-q13) on chromosome 15 causes PWS.³

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No single gene has been identified that accounts for all the various signs and symptoms of PWS.⁴ The MKRN3, MAGEL2, NDN, and SNORD115 genes found in the imprinting region on chromosome 15 do not account for the full spectrum of PWS symptoms.⁴ It is likely that the wide variations in the phenotypic presentations of individuals with PWS result from the loss of function of several different genes on chromosome 15.² 

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One cluster of genes, the SNORD116 gene cluster, encodes small nucleolar ribonucleic acids (snoRNAs), which have essential roles in regulating various RNA molecules that affect protein synthesis and other cellular functions.^2,5,6 Researchers suspect that alterations in SNORD116 are significantly involved in causing the signs and symptoms of PWS, although the exact mechanisms behind this connection are unknown. They have discovered an overlap of 23 genes between SNORD116 overexpression and abnormal expression within the dysfunctional hypothalamus of patients with PWS. ^2,6 This hypothalamic dysfunction accounts for many of the endocrine symptoms of individuals with PWS. Researchers are still working to discover the exact pathogenic mechanisms that contribute to the development of various PWS symptoms.⁶

Certain symptoms occur more or less frequently in specific molecular genetic subtypes of PWS. For example, academic performance and cognitive abilities are better and compulsiveness is greater in patients with type I paternal deletions than in those with type II paternal deletions. In individuals with maternal uniparental disomy subtypes of PWS, post-term delivery, a high verbal IQ, psychosis, and autistic characteristics are relatively common, but the hypopigmentation and distinctive facial characteristics seen in many people with PWS are less common.⁴ 

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Genotype-Phenotype Connections

MKRN3

The Makorin Ring Finger Protein 3 gene (MKRN3, ZNF127) encodes a zinc finger protein within the Makorin family that is paternally expressed in human adult tissues, with the highest level of expression found in the testes. The MKRN3 gene is associated with inhibition of the initiation of puberty, and loss of function mutations in this gene are recognized as the main genetic cause of central precocious puberty. This established connection suggests that MKRN3 affects the hypothalamic-pituitary-gonadal axis, and alterations or loss of function in this gene may explain hypogonadism and infertility in patients with PWS.⁴

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MAGEL2

In murine studies, loss of expression of the MAGE Family Member L2 gene (MAGEL2) has been correlated with certain phenotypic features seen in PWS, including endocrine dysfunction, neonatal growth restriction, excessive weight gain, increased adiposity, impaired hypothalamic regulation, impaired reproductive function, and altered circadian rhythm.^4,7,8 

Loss of MAGEL2 expression disrupts the leptin-mediated depolarization of pro-opiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus in mice, resulting in decreased repression of food intake and uncontrolled storage of fat, which is regulated by leptin. Complex interactions between POMC, leptin, neuropeptide Y (NPY), and agouti-related peptide (AgRP) play a role in insulin pathways, energy metabolism, and glucose homeostasis.⁹ This connection may explain the hyperphagia, lack of satiety, obesity, and onset of type II diabetes seen in many individuals with PWS.^4,9,10

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NDN

The necdin gene (NDN) encodes a DNA-binding protein expressed in mature neurons within the hypothalamus. It has been speculated that this protein regulates gonadotropin hormone-releasing hormone (GnRH) by controlling the intracellular processes required for neuronal and axonal outgrowth in the hypothalamus. Loss of NDN expression correlates directly with a decreased number of GnRH neurons and decreased axonal targeting within the hypothalamus, which may contribute to hypogonadism and infertility in PWS.^4,11-13 

OCA2

Loss of expression of the oculocutaneous albinism gene (OCA2) in chromosome 15 results in hypopigmentation of the hair, eyes, and skin in some people with PWS.²

Research into other genes located in the 15q11.2-q13 region is ongoing to discover and test other connections with the major signs and symptoms of PWS.²

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References

1. Fermin Gutierrez MA, Mendez MD. Prader-Willi syndrome. StatPearls [Internet]. Updated January 31, 2023. Accessed July 22, 2023.
2. Prader-Willi syndrome. MedlinePlus. Accessed July 22, 2023.
3. Scheimann A. Prader-Willi syndrome: pathophysiology. Medscape. Updated August 27, 2021. Accessed July 22, 2023.
4. Costa RA, Ferreira IR, Cintra HA, Gomes LHF, Guida L da C. Genotype-phenotype relationships and endocrine findings in Prader-Willi syndrome. Front Endocrinol (Lausanne). 2019;10:864. doi:10.3389/fendo.2019.00864
5. Bratkovič T, Božič J, Rogelj B. Functional diversity of small nucleolar RNAs. Nucleic Acids Res. 2020;48(4):1627-1651. doi:10.1093/nar/gkz1140
6. Falaleeva M, Surface J, Shen M, de la Grange P, Stamm S. SNORD116 and SNORD115 change expression of multiple genes and modify each other’s activity. Gene. 2015;572(2):266-273. doi:10.1016/j.gene.2015.07.023
7. Bischof JM, Stewart CL, Wevrick R. Inactivation of the mouse Magel2 gene results in growth abnormalities similar to Prader-Willi syndrome. Hum Mol Genet. 2007;16(22):2713-2719. doi:10.1093/hmg/ddm225
8. Devos J, Weselake SV, Wevrick R. Magel2, a Prader-Willi syndrome candidate gene, modulates the activities of circadian rhythm proteins in cultured cells. J Circadian Rhythms. 2011;9(1):12. doi:10.1186/1740-3391-9-12
9. Varela L, Horvath TL. Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis. EMBO Rep. 2012;13(12):1079-1086. doi:10.1038/embor.2012.174
10. Mercer RE, Michaelson SD, Chee MJS, Atallah TA, Wevrick R, Colmers WF. Magel2 is required for leptin-mediated depolarization of POMC neurons in the hypothalamic arcuate nucleus in mice. PLoS Genet. 2013;9(1):e1003207. doi:10.1371/journal.pgen.1003207
11. Jay P, Rougeulle C, Massacrier A, et al. The human necdin gene, NDN, is maternally imprinted and located in the Prader-Willi syndrome chromosomal region. Nat Genet. 1997;17(3):357-361. doi:10.1038/ng1197-357
12. Lee S, Walker CL, Karten B, et al. Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth. Hum Mol Genet. 2005;14(5):627-637. doi:10.1093/hmg/ddi059
13. Watrin F, Roëckel N, Lacroix L, et al. The mouse necdin gene is expressed from the paternal allele only and lies in the 7C region of the mouse chromosome 7, a region of conserved synteny to the human Prader-Willi syndrome region. Eur J Hum Genet. 1997;5(5):324-332. 

Reviewed by Harshi Dhingra, MD, on 7/24/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.