Prader-Willi Syndrome (PWS)

Prader-Willi syndrome (PWS) is a rare genetic disorder that derives from nonexistent expression of paternally inherited genes in the q11-13 region of chromosome 15. Two major causes of this error in genomic imprinting are de novo deletion and maternal uniparental disomy 15 (UPD15).^1,2 PWS is characterized by a wide range of neurodevelopmental, nutritional, endocrine, metabolic, and behavioral challenges and a variety of symptoms, including hypotonia, short stature, hypogonadism, and hyperphagia.¹ 

Mortality Rate of PWS

The annual mortality rate of PWS is between 1% and 4%.^1,2 The overall mortality rate is increased in patients with PWS compared to that of the general population, with data pointing to increases in mortality of 7% per year in PWS patients over the age of 30 years and 3% per year in patients aged 0 to 47 years.³ Other studies have reported a mortality rate of 3% per year after the age of 5 years and survival probabilities of 87% and 80% at 35 and 40 years of age, respectively.² 

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Data have also shown that survival estimations in patients with PWS have increased since 2020, which may be related to early diagnosis of the disease and the successful prevention of morbid obesity.³ If patients are able to control their diet and weight, life expectancy may not be significantly impacted.⁴

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Causes of Death in PWS

Although improvements have been made regarding the diagnosis, treatment, and management of PWS, there is still scarce information on recorded causes of death among patients with PWS.⁵

In infants and children, respiratory illness/failure and sudden death associated with dysregulation of temperature have been reported.^2,3 Sepsis and choking were also common causes of death identified in children and adolescents.² 

In adult patients, obesity-related complications, such as cardiovascular problems, diabetes, hypertension, and sleep apnea, have been reported to be the most common overall cause of mortality.³ Deaths attributed to cardiac problems typically reflect heart failure.² PWS also represents the most common known cause of morbid obesity in humans. This obesity can develop following hyperphagia, and obesity-related mortality is more likely to occur in female patients than in male patients.² Behaviors related to the ingestion of large quantities of food can also lead to gastrointestinal perforation, and the rapid ingestion of food combined with swallowing difficulties derived from hypotonia and poor oral and motor coordination can result in aspiration/choking. Male patients are more likely to exhibit aggressive and risky behaviors toward food consumption than female patients.² 

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A significantly increased risk of mortality due to cardiopulmonary events has been reported in patients with UPD15 when compared to that of patients with deletion genetic subtypes.²

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Prevention of Early Death in PWS

Early diagnosis of PWS and the prevention of obesity are considered important steps in the prevention of early death. Weight control requires that food access and food quantity are monitored, which may also decrease the risk of choking while eating. The strict control of food intake may also help avoid gastric rupture. It is therefore important that preventive measures and education of care providers are considered when managing PWS.²

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References

1. Höybye C, Tauber M. Approach to the patient with Prader-Willi syndrome. J Clin Endocrinol Metab. 2022;107(6):1698-1705. doi:10.1210/clinem/dgac082
2. Butler MG, Manzardo AM, Heinemann J, Loker C, Loker J. Causes of death in Prader-Willi syndrome: Prader-Willi Syndrome Association (USA) 40-year mortality survey. Genet Med. 2017;19(6):635-642. doi:10.1038/gim.2016.178
3. Proffitt J, Osann K, McManus B, et al. Contributing factors of mortality in Prader-Willi syndrome. Am J Med Genet A. 2019;179(2):196-205. doi:10.1002/ajmg.a.60688
4. Overview: Prader-Willi syndrome. NHS. Accessed July 28, 2023.
5. Pacoricona Alfaro DL, Lemoine P, Ehlinger V, et al. Causes of death in Prader-Willi syndrome: lessons from 11 years’ experience of a national reference center. Orphanet J Rare Dis. 2019;14(1):238. doi:10.1186/s13023-019-1214-2

Reviewed by Hasan Avcu, MD, on 7/30/2023.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.