Prader-Willi Syndrome Treatment Options

Introduction

What is Prader-Willi Syndrome?

Prader-Willi Syndrome (PWS) is a condition that affects the nervous system and behaviour (therefore called a neurobehavioral condition) and has distinct phases of clinical features. Initially described in 1956¹, it is recognised as a genomic imprinting disorder, meaning that the way in which genes are expressed and inherited from a person’s parents can contribute to how the individual experiences the syndrome.

The primary cause of PWS lies in errors during the production of egg and sperm cells (gametogenesis), resulting in the loss of expression of paternal genes located in the chromosome 15q11-q13 region.^2-6 In addition, this disorder is associated with either maternal disomy 15 where both copies of the chromosome (or parts of it) are inherited from the mother only, imprinting defects, or chromosomal abnormalities in the same region. Chromosomal abnormalities can constitute either the loss, addition of copies, reversal or movement (between chromosomes) of genetic material.

PWS is relatively rare, with an estimated prevalence of 1 in 10,000–30,000 individuals⁷, making it the most common syndromal cause of life-threatening obesity associated with genomic imprinting in humans.

Symptoms and characteristics of Prader-Willi Syndrome

Individuals with PWS exhibit a range of symptoms and characteristics throughout their lives. Infants with PWS typically present with significantly decreased muscle tone or tension (described as hypotonia), feeding difficulties, and failure to thrive due to poor suck and swallowing problems.⁸ They may also have little or no activity from their testes or ovaries (hypogonadism) and respiratory issues.^7-9 As they grow, children with PWS develop extreme hunger or appetite (described as hyperphagia), leading to obesity if not controlled.^7-11

Alongside obesity, they may experience short stature, small hands and feet, and intellectual disabilities, with an average IQ of 65.^7-8 Behavioural problems are common, including obsessive-compulsive disorders, emotional disturbances, anxiety, and skin picking. Patients with PWS may also have a high pain threshold, exhibit impulsive behaviours, and struggle with attention deficit hyperactivity. 

Additionally, disrupted REM sleep is a severe clinical feature in PWS, contributing to the complexity of the disorder. These symptoms often persist throughout life, impacting both physical health and quality of life. Early diagnosis is crucial for improved prognosis and the implementation of potential treatment approaches.

Living with Prader-Willi Syndrome challenges and coping strategies 

Diagnosis and screening

The early diagnosis of PWS may be difficult due to the relatively rare occurrence of the disease and the variability in the severity of physical characteristics and other aspects of the disease. Diagnosis of PWS is primarily based on the clinical picture presented by the patient and confirmed by cytogenetic testing for abnormalities within the 11-13 region on the long arm on the long arm of chromosome 15, referred to as 15q11-q13 region.¹¹

An important tool used during the clinical diagnosis of PWS was created by Holm et al.¹² where symptoms are divided into the categories of major (e.g. low muscle tone), minor (e.g.reduced mortality in infancy) or non-scored auxiliary symptoms (e.g. thermoregulation disorders). The molecular methods used to confirm the clinical diagnosis include Fluorescence in situ hybridization (FISH), DNA methylation analysis, and DNA sequencing analysis which provide insight into chromosomal abnormalities, expression patterns and specific genetic mutations respectively. 

It is possible for families, with a positive history or abnormal prenatal test for PWS, to develop a relationship with a genetic counsellor (GC) as a source of psychosocial support through the testing and diagnostic process.¹² Prenatal testing is suitable for individuals with maternal disomy 15 or fathers carrying the imprinting defect due to a microdeletion.⁸

Patients with PWS will experience a range of clinical features that may change over the course of their lives. These could include low muscle tone, feeding difficulties, hypogonadism and various endocrine abnormalities.^11-16

Screening is necessary for related complications including growth hormone deficiency, hypothyroidism, and adrenal insufficiency to achieve comprehensive management of PWS.^13-19 Overall, regular monitoring for growth, development, hormonal imbalances and behavioural changes is essential throughout the patient’s life to make adjustments for these changes as they happen.

Management and treatment options

The management and treatment options for PWS involve a combination of five approaches that are aimed at controlling a patients’ symptoms, preventing complications, and improving their quality of life. These approaches will be briefly discussed and involve

• nutritional treatment
• pharmacological approach
• surgical approach
• hormonal treatment
• and psychological support and therapy

Nutritional treatment relies on providing a low-calorie diet that is tailored to the needs of the individual, consisting of 30% fat, 45% carbohydrates (with at least 20g of fibre per day), and 25% protein.²⁰ It is recommended that meals are small and frequent to control unusual hunger (hyperphagia).²⁰

Studies have suggested possible benefits for PWS patients from ketogenic or Mediterranean diets either by reducing hunger and improving glycemic control or encouraging weight loss and improved cholesterol levels respectively.^20,21

Pharmacological approaches could be used to affect specific changes which may be changed over the long term. Growth hormone (GH) replacement may be an option for children with growth hormone deficiency (GHD) to help decrease body fat and improve motor and mental performance.^{11,14-16,18,20,21} It cannot be used to control excessive hunger or for long-term management of weight. 

Another pharmacological approach is the use of anti-obesity drugs like orlistat, metformin, and topiramate²¹, that can be used to support nutritional therapy. Whilst these anti-obesity drugs may be able to control hunger and behavioural symptoms, they may be limited in their impact on weight loss. Drugs that dampen the GLP-1 pathway, such as exenatide and liraglutide, have shown promise in reducing appetite and improving glycemic control.²¹

As another approach, hormonal therapy may be important to start and maintain puberty with positive effects on bone density, muscle mass, and overall quality of life.^12,17 In addition, it is important to monitor and manage thyroid and adrenal function to ensure hormonal balance and metabolic stability.^{11,12,14-16,19,20}

Currently, the surgical approach consists of bariatric surgery to deal with severe cases of obesity.^11,14,16-18 For each individual patient, the effectiveness and safety of these procedures need to be carefully evaluated in terms of potential complications and long-term outcomes. All of these approaches may be complemented by psychological counselling and therapy in addressing behavioural issues, learning difficulties, and mental health disorders commonly associated with PWS.^11,13,14 

Challenges and coping strategies

Individuals with PWS may experience a range of unique challenges, including abnormal appetite regulation, decreased energy expenditure and sleep disorders, that have an impact on their quality of life and may cause other clinical features to become worse. Several strategies can be tailored to suit the needs of the individual and their stages of development. Approaches focused on dealing with obesity in individuals with PWS will aim to prevent malnutrition and avoid excessive weight gain.

Nutritional management and behavioural modifications should begin from infancy to help to achieve these goals. These approaches will involve regular exercise and physical activity, possibly incorporating recreational activities and hobbies with the benefit of improving muscle tone, increasing energy usage and offering a distraction from food.

It would be essential to address food-seeking behaviours and access to food, including environmental barriers such as locks on pantries and refrigerators, along with long-term dietary recommendations like a Mediterranean-style diet, rich in fruits, vegetables, whole grains, lean proteins and healthy fats that encourage a feeling of fullness and overall health. 

Individuals with PWS should be mindful that they may be susceptible to a range of sleep disturbances including obstructive sleep apnea (OSA), narcolepsy with or without loss of muscle tone, excessive daytime sleepiness (EDS), chronic insomnia and restless sleep. Given that sleep disorders in PWS are complex, support should be obtained from a group of healthcare providers including endocrinologists, sleep specialists, psychiatrists and behavioural therapists for a comprehensive evaluation and management.¹⁹

Summary

PWS is a multi-systemic neurodevelopmental disorder, the treatment of which involves a multidisciplinary approach. Experts including pediatricians, endocrinologists, clinical geneticists and surgeons, cooperate to provide appropriate care for the complex set of symptoms that PWS patients may experience. Whilst no single treatment has proven benefits, an extended lifespan and better quality of life can be achieved with the support of those involved.