Prader-Willi syndrome 

Finding out anyone has Prader-Willi syndrome (PWS) is not a death sentence. In fact, there are many people living with PWS who have absolutely normal lives. 

It is important to know that PWS is neither the child’s fault nor the parent’s fault. This is because PWS is a rare genetic condition caused by the absence or lack of expression of certain genes. This shows PWS is inherited, and neither child nor parent has control over it.

The usual symptoms of a baby with PWS are feeding difficulties, poor appetite, and decreased muscle tone, known as hypotonia. Over time, as the baby grows, there is an uncontrollable increase in appetite that becomes excessive, which usually leads to obesity. This condition is called hyperphagia.¹

PWS occurs 1 in 10,000 - 30,000 people. Currently, there are about 350,000 - 400,000 people living with PWS worldwide.²

In this article, we will explain what Prader-Willi syndrome is, the symptoms, how it can be diagnosed, how hyperphagia develops in people living with Prader-Willi syndrome, and how it can be managed. 

Let’s get in!

Causes of Prader-Willi syndrome

PWS is inherited from either the father or the mother or is caused by a mutation. 

If inherited from the father, there is a loss of gene function on the long arm of the paternal chromosome passed from the father to the child. These genes are located on chromosome 15 at 15q11-15q13. The child inherits the absence of these genes or the non-functionality of these genes. This is called paternal 15q11-q13 deletions. It is the most common cause of PWS.³

If inherited from the mother, then double of these genes are inherited from only her without obtaining a copy from the father. This is called maternal uniparental disomy.³

If caused by mutation, then the gene is translocated to another region on chromosome 15, thereby causing the non-expression of the genes and leading to PWS.³

Symptoms

The symptoms of PWS can be classified into ‘being present at birth’ and ‘early childhood to adulthood’.

Symptoms present at birth

• Reduced muscle tone: This is one of the major symptoms of PWS. It is called hypotonia.⁴ The baby’s muscles appear to be very floppy. This is because of the reduction of thyroid hormones (T3, T4) needed for proper development of the muscles⁵
• Poor sucking ability: There are certain muscles in the mouth of a baby responsible for sucking. Due to the reduced muscle tone, the sucking ability of a baby is reduced, causing them to have feeding difficulties
• Unusual tiredness: Due to the difficulty in feeding, the baby will usually be tired
• Distinct facial features: Babies can have an elongated head, almond-shaped eyes, a short upturned nose, a thin upper lip, the enamel can have a defect where it is thin or absent³

Symptoms present from early childhood to adulthood

• Increased appetite for food: This is called hyperphagia. There is an unusually extreme appetite for food whereby the individual consumes large portions of food. They develop unusual food-seeking behaviours such as eating from the garbage, eating frozen foods, or hiding foods
• Obesity: Increase in appetite can lead to weight gain. In normal body composition, there is less fat and more muscle mass, but in PWS, there is a high percentage of fat and less muscle mass⁶
• Underdeveloped sexual organs: This is called hypogonadism. This occurs when sex organs are not fully developed, leading to the production of little or no sex hormones. Puberty can be incomplete or delayed. The females tend to have small clitoris and labia, and they start menstruating very late, usually in their 30s. The man’s penis is smaller than usual. Also, they might not develop facial hairs, and their voice may not deepen as it does with normal men
• Extreme behavioural patterns: Extreme behavioural patterns such as obsessive-compulsive disorder, manipulative behaviour, temper tantrums, repetitive behaviour, anger, and stubbornness. These traits can show up when they are denied food
• Mental disorders: This develops eventually from extreme behavioural patterns. Examples are skin picking, anxiety, and depression
• Delayed speech development: They struggle with articulating their words, and this can go on for a very long time
• Sleep disorders: Their sleep cycle is usually disrupted, causing them to sleep more during the day. Sometimes, they can experience breathing problems while sleeping, and this is called sleep apnea⁷

Diagnosis of Prader-Willi syndrome

In babies less than 3 years of age, PWS can be diagnosed by physical examination and genetic testing.

A physical examination will be prompted when the baby struggles with feeding, which can be identified as reduced sucking ability. During the physical examination, if hypotonia is present, then the baby will be sent for genetic testing. 

In babies greater than 3 years of age, symptoms such as facial features, eating habits, excessive weight gain, underdeveloped sex organs, and behaviour patterns are observed. If present, genetic testing will give confirmation.⁸

Hyperphagia

Hyperphagia is a condition where there is an uncontrollable, increased appetite for food. 

It has been discovered as a major indication of certain inherited disorders associated with obesity. The majority of individuals with hyperphagia are obese.⁹ 

Prader-Willi syndrome and hyperphagia

A baby born with PWS struggles to feed as the ability to suck is impaired. This makes them develop unusual tiredness and appetite to eat is drastically reduced. This affects their development. After the age of 4, there is an increased, uncontrollable appetite for food.¹⁰ 

This occurs through different mechanisms. Let’s find out. 

Hypothalamus dysfunction

• In the brain, there is a part called hypothalamus that is responsible for regulating hunger
• The hypothalamus is signalled by both neural and physiological signals
• In responding to these signals, certain hormones and neurotransmitters are released to the limbic region of the brain that help inform the individual of hunger and the cortical inhibitory regions of the brain that inform the individual of satiety¹¹
• In PWS, there is a dysfunction in the signalling to the hypothalamus, thereby interfering with the release of these hormones and neurotransmitters
• This leads to activation of the limbic regions alone, causing the individual to experience an increased appetite for food rather than satiety

Ghrelin pathway

• Ghrelin is a hormone secreted by the stomach
• Its function is to stimulate appetite for food. So when an individual is hungry, ghrelin is secreted
• However, after eating, the production of ghrelin is reduced
• In PWS, the concentration does not reduce after eating, leading to hyperphagia¹

Leptin pathway

• Leptin is a hormone produced by adipose tissue
• Its function is to regulate food intake and energy use
• In adults with PWS, leptin levels are high, and this is associated with low Brain-Derived Neurotrophic Factor (BDNF)
• BDNF is a neurotransmitter that regulates satiety
• Low BDNF causes the secretion of more leptin, and more leptin leads to hyperphagia¹

Peptide YY

• Peptide YY is a hormone produced in the small intestine
• It is responsible for stimulating satiety
• In people with PWS, the small intestines do not produce enough peptide YY
• When peptide YY is low, it causes hyperphagia¹² 

Orexin A

• Orexin A is a neuropeptide produced in the hypothalamus
• Its function is to stimulate appetite for food, causing increased food intake
• Due to dysfunction in the hypothalamus, there is excessive production of orexin A, leading to hyperphagia¹²

Management strategies

• AZP-531, a drug, has been shown to suppress hyperphagia and reduce fat mass in people with PWS by reducing ghrelin concentration¹³
• A study showed that administering topiramate to people with PWS can help stimulate peptide YY that enhances satiety, hence, reducing hyperphagia¹⁴
• A clinical trial revealed that oral administration of diazoxide to individuals PWS within a 12-week period reduced blood glucose levels, thereby reducing obesity caused by hyperphagia¹⁵
• Setmelanotide has also been discovered to help with weight loss in people with hyperphagia caused by PWS¹⁶
• Another clinical trial showed that carbetocin administered intranasally helped to reduce hyperphagia in people with PWS¹⁷

Summary

Prader-Willi syndrome is a rare genetic condition found in 1 in 10,000 - 30,000 people. It can be inherited from either of both parents or as a result of mutation. 

The major symptoms of Prader-Willi syndrome are the presence of floppy muscles called hypotonia, decreased sucking ability, and an excessive appetite for food called hyperphagia. Since the symptoms can be examined physically, the diagnosis is confirmed through genetic testing.

Hyperphagia can be caused by dysfunctionality of the hypothalamus in the brain, the overproduction of certain hormones and neurotransmitters in the body such as Ghrelin, Leptin and Orexin A, and the underproduction of Peptide YY hormone.

Administration of drugs has been shown to manage hyperphagia in Prader-Willi syndrome. However, consulting with a healthcare provider gives people with PWS a better chance of living well.