Prader-Willi Syndrome (PWS)

Prader-Willi syndrome (PWS) is a rare, complex, genetic condition characterized in infancy by severe hypotonia, feeding difficulties, poor growth due to growth hormone deficiency, and developmental delays. During early childhood, individuals with PWS develop an insatiable hunger, resulting in hyperphagia that leads to morbid obesity.¹ 

Other common features of PWS include behavioral problems (such as skin picking, obsessive-compulsive behaviors, stubbornness, and temper tantrums), learning difficulties associated with mild to moderate cognitive impairment, distinctive facial features, hypopigmentation, hypogonadism, delayed or incomplete puberty, infertility, short stature, and sleep disturbances.¹

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Genetic Etiology of PWS

Prader-Willi syndrome originates from nonfunctioning genes on a particular region of chromosome 15 at 15q11.2-q13 called the Prader-Willi critical region.^1,2 

Typically, a person inherits 2 copies of chromosome 15: 1 from their father and 1 from their mother. In people unaffected by PWS, only the father’s genes in the Prader-Willi critical region are active. In individuals with PWS, a genetic defect results in inactivity of the paternal genes on chromosome 15.³

Inactivation of the paternal genes on chromosome 15 typically occurs in 1 of 3 ways: deletion of a segment of the paternal genes on chromosome 15 (70% of PWS cases), maternal uniparental disomy (UPD; 25% of PWS cases), or a genetic mutation in the Prader-Willi critical region that inactivates the genes on the paternal copy of chromosome 15 due to an imprinting center defect or chromosome 15 translocations (1% to 3% of PWS cases).^1,3 These different underlying etiologies categorize the main PWS molecular genetic subtypes.

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Paternal Deletion of Chromosome 15q11.2-q13

In this PWS subtype, the paternal copy of chromosome 15q11.2-q13 is missing or has been deleted, while the genes on the maternal copy of chromosome 15 are inactivated as normal.¹

Maternal Uniparental Disomy

In this PWS subtype, an individual with PWS inherits 2 maternal copies of chromosome 15.¹

Imprinting Center Defects

In this PWS subtype, a person with PWS demonstrates biparental inheritance; however, genetic alterations or changes, such as microdeletions or epimutations of the imprinting center, inactivate the genes on the paternal copy of chromosome 15.^1,4

Chromosome 15 Translocations

A very small percentage of individuals develop PWS due to chromosome 15 translocations. In PWS, translocations involve certain portions of chromosome 15 breaking off and rearranging with other chromosomes. These translocations may be classified as either balanced or unbalanced — both of which have been reported in rare cases of PWS.^5-8

This chromosomal rearrangement causes a shift in genetic material within the imprinting center on chromosome 15 and results in an altered set of chromosomes. Balanced chromosomal translocations occur when the rearranged chromosomes do not have any genetic material missing or added, whereas unbalanced chromosomal translocations have genetic material that is missing or added.⁵ 

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Pathogenesis of PWS

This malfunction of several genes on chromosome 15 results in the characteristic features of PWS. Some of these genes encode small nucleolar RNAs (snoRNAs).¹ 

SnoRNAs comprise the most abundant group of short, nonprotein-coding RNAs and perform a variety of functions.^9,10 These functions include^9,10:

• Nucleolytic processing of ribosomal RNAs (rRNAs)
• Guidance of RNAs in post-transcriptional synthesis of 2′-O-methylated nucleotides and pseudouridines in rRNAs, small nuclear RNAs (snRNAs), and potentially other cellular RNAs, including messenger RNAs (mRNAs)
• Regulation of post-transcriptional processes, such as rRNA acetylation, modulation of splicing patterns, and regulation of mRNA abundance and translational efficiency

In particular, the loss of 2 gene clusters located on the imprinted region of chromosome 15 that encode for snoRNAs are implicated in the development of PWS. These orphan brain-specific snoRNAs are SNORD115 and SNORD116. Researchers discovered that overexpression of SNORD116 resulted in 274 alterations in gene expression, while coexpression of SNORD115 and SNORD116 caused 415 changes in gene expression, typically resulting in upregulation of these genes. SNORD116 usually altered mRNA expression levels, while SNORD115 modified SNORD116’s influence on gene expression.^10,11

The researchers then compared overall gene expression in the posterior hypothalamus of individuals with PWS and age-matched unaffected human controls. They selected the hypothalamus since dysfunction in this region of the brain accounts for the majority of PWS-related symptoms. They discovered 5113 alterations in gene expression that occurred in the hypothalamic brain tissues of individuals with PWS compared to normal controls.¹¹ 

Next, they compared these 5113 gene expression alterations with the gene expression alterations found in their SNORD115/SNORD116 analysis, observing an overlap in 23 genes whose expression levels were influenced by SNORD115/SNORD116 in HEK 293T cells (P =.00735).¹¹

Although the deletion or alteration of the SNORD116 gene cluster is believed to play a major role in the pathogenesis of PWS, it is unknown exactly how it contributes to the characteristic behavioral, cognitive, and physical features of PWS.¹ 

Read more about PWS pathophysiology

References 

1. Prader-Willi syndrome. MedlinePlus. Updated May 13, 2022. Accessed July 22, 2023.
2. Driscoll DJ, Miller JL, Cassidy SB. Prader-Willi syndrome. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. GeneReviews^® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2023. October 6, 1998. Updated March 9, 2023. Accessed July 22, 2023. 
3. Strong TV. What is Prader-Willi syndrome? A clear explanation of PWS symptoms, causes, diagnosis, genetics, treatments & research. Foundation for Prader-Willi Research. Accessed July 22, 2023.
4. Butler MG, Miller JL, Forster JL. Prader-Willi syndrome – clinical genetics, diagnosis and treatment approaches: an update. Curr Pediatr Rev. 2019;15(4):207-244. doi:10.2174/1573396315666190716120925
5. Prader-Willi syndrome. National Organization for Rare Disorders (NORD). Updated July 12, 2023. Accessed July 22, 2023.
6. Dang V, Surampalli A, Manzardo AM, et al. Prader-Willi syndrome due to an unbalanced de novo translocation t(15;19)(q12;p13.3). Cytogenet Genome Res. 2016;150(1):29-34. doi:10.1159/000452611
7. Klein OD, Cotter PD, Albertson DG, et al. Prader–Willi syndrome resulting from an unbalanced translocation: characterization by array comparative genomic hybridization. Clin Genet. 2004;65(6):477-482. doi:10.1111/j.0009-9163.2004.00261.x
8. Flori E, Biancalana V, Girard-Lemaire F, et al. Difficulties of genetic counseling and prenatal diagnosis in a consanguineous couple segregating for the same translocation (14;15) (q11;q13) and at risk for Prader-Willi and Angelman syndromes. Eur J Hum Genet. 2004;12(3):181-186. doi:10.1038/sj.ejhg.5201134
9. Kiss T. Small nucleolar RNAs: an abundant group of noncoding RNAs with diverse cellular functions. Cell. 2002;109(2):145-148. doi:10.1016/S0092-8674(02)00718-3
10. 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
11. 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

Reviewed by Hasan Avcu, MD, on 7/25/2023.

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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.