Prader-Willi Syndrome Causes

11 Jan 2022

Explore the genetic underpinnings and causes of Prader-Willi syndrome, including its symptoms, diagnosis, and available treatment options.

Understanding Prader-Willi Syndrome

Prader-Willi Syndrome (PWS) is a complex genetic condition that affects multiple parts of the body. In this section, we'll provide a general overview of the syndrome and discuss its prevalence.

General Overview of Prader-Willi Syndrome

Prader-Willi Syndrome is a rare neurodevelopmental disorder that impacts numerous aspects of an individual's health and development. It is caused by the loss of function of paternally expressed genes on chromosome 15, which can occur due to a number of genetic mechanisms, including paternal deletion of the 15q11–q13 region of the chromosome, maternal uniparental disomy for chromosome 15, or an imprinting mutation [1].

PWS is recognized as the most common genetic cause of life-threatening obesity in humans, arising from errors of genomic imprinting that disrupt the expression of paternally inherited imprinted genes in the chromosome 15q11-q13 region. It leads to severe infantile hypotonia, hyperphagia, developmental delay, short stature, small hands and feet, hypogonadism/hypogenitalism, and craniofacial dysmorphism.

Prevalence of Prader-Willi Syndrome

According to MedlinePlus, Prader-Willi syndrome affects an estimated 1 in 10,000 to 30,000 people worldwide, making it a rare condition. However, the NCBI suggests that it might affect about 1 in 15,000 individuals. These figures underline the fact that Prader-Willi syndrome, though rare, is a significant health concern that merits attention and understanding.

In conclusion, the causes of Prader-Willi syndrome are complex and involve nuanced genetic processes. The syndrome's prevalence underscores the importance of continued research and awareness to improve diagnosis and treatment options.

Genetic Causes of Prader-Willi Syndrome

Prader-Willi syndrome is a complex genetic condition that affects many parts of the body. In order to fully understand the causes of Prader-Willi syndrome, it's important to delve into the genetic mechanisms behind it.

Role of Chromosome 15

Prader-Willi syndrome is primarily caused by abnormalities in the paternal copy of chromosome 15. According to Rare Disease Advisor, approximately 70% of Prader-Willi syndrome cases result from the deletion of the paternal copy of chromosome 15 in the region 15q11.2-q13.

Additionally, the loss of function of genes on chromosome 15, particularly the SNORD116 cluster, is thought to play a major role in causing the signs and symptoms of Prader-Willi syndrome, even though the exact mechanism is unknown [2].

Importance of Paternal Genes

Prader-Willi syndrome is caused by the lack of expression of paternally inherited imprinted genes at the 15q11.2-q13 region. This is due to a lack of expression of the paternal chromosome 15q11-q13, which leads to the loss of imprinted genes on the paternal chromosome.

In simpler terms, the condition is associated with the absence or inactivity of certain genes inherited from the father. It's important to note that this is not a condition that parents can control or prevent. The chromosomal changes that cause Prader-Willi syndrome occur as random events during the formation of reproductive cells in a parent.

Different Genetic Mechanisms

There are different genetic mechanisms that lead to Prader-Willi syndrome. As mentioned earlier, the most common cause (70% of cases) is a deletion in the paternal chromosome 15. However, in about 25% of cases, individuals have two copies of chromosome 15 inherited from their mother (maternal uniparental disomy).

Additionally, Prader-Willi syndrome can rarely be caused by a chromosomal rearrangement called a translocation, or by a genetic alteration that inactivates genes on the paternal chromosome 15. A small number of cases (5%) are due to imprinting center defects or chromosome 15 translocations.

In conclusion, understanding the genetic causes of Prader-Willi syndrome is crucial in the diagnosis and management of the condition. It also provides a basis for genetic counseling for families affected by the syndrome.

Symptoms of Prader-Willi Syndrome

Prader-Willi Syndrome (PWS) presents a range of symptoms that can strongly impact an individual's quality of life. These symptoms typically develop in stages, beginning in infancy and continuing through childhood and into adulthood.

Early Symptoms of the Syndrome

In the earliest stage of life, infants with PWS often exhibit poor muscle tone (hypotonia) which can lead to difficulties with feeding and failure to thrive. Neonatal hypotonia is often accompanied by poor suck reflex, a characteristic that can contribute to feeding difficulties.

Decreased fetal movements, small hands and feet, and a characteristic facial appearance are other common clinical features observed in infants diagnosed with PWS. Strabismus or misalignment of the eyes, and thick, viscous saliva are also noted in some cases.

Symptoms during Childhood and Adulthood

As infants with PWS grow into children, the syndrome presents new challenges. The most noticeable shift is the onset of extreme hyperphagia, an excessive desire to eat, that often leads to rapid weight gain and obesity if not managed carefully.

Motor milestones and language development are typically delayed in children with PWS and some degree of cognitive impairment is present in all cases. This cognitive impairment often persists into adulthood, causing difficulties with learning, problem-solving, and social interaction.

In addition to these challenges, individuals with PWS frequently exhibit obsessive-compulsive behaviors, skin picking, and hoarding behaviors. Hormonal issues are also common, with hypogonadism leading to genital hypoplasia, incomplete pubertal development, and infertility. Short stature is also common if not treated with growth hormone [5].

Sleep abnormalities are another key feature of PWS, which can exacerbate other symptoms and contribute to behavioral difficulties.

Understanding the progression of symptoms in PWS can help parents and caregivers provide effective support and intervention, improving the overall quality of life for individuals with this syndrome.

Diagnosis of Prader-Willi Syndrome

Diagnosing Prader-Willi Syndrome (PWS) entails a series of tests and analyses to confirm the presence of the associated genetic abnormalities. Early diagnosis is crucial to managing the syndrome and mitigating its effects.

Diagnostic Methods

The diagnosis of PWS involves a two-tier approach. Initially, a DNA methylation-based PCR assay is employed to identify the genetic causes of PWS, including paternal deletion, maternal uniparental disomy (UPD), and imprinting mutation. This assay allows for a straightforward and rapid diagnosis during infancy, enabling early interventions such as nutritional management, physical therapy, or growth hormone treatment.

In addition to DNA methylation analysis, an oligo-small nucleotide polymorphism (SNP) combination array (OSA) is recommended. This can identify the molecular cause in most individuals. For individuals with abnormal DNA methylation at 15q11.2-q13, indicating PWS, second-tier testing involves DNA polymorphism testing to identify UPD 15 due to heterodisomy or an epigenetic imprinting defect.

For those with maternal-only imprinting identified on DNA methylation analysis and a normal oligo-SNP combination array (OSA), DNA polymorphism analysis can be used to distinguish uniparental heterodisomy from an imprinting defect by epimutation.

Importance of Early Diagnosis

Early diagnosis of Prader-Willi syndrome is crucial for several reasons. Firstly, it can help parents and caregivers understand the reason behind the unique symptoms of their child, such as delayed growth and persistent hunger, which are thought to be due to malfunctioning of the hypothalamus.

Secondly, early diagnosis allows for timely intervention and management strategies. This can include nutritional management to control the persistent hunger and physical therapy to improve muscle tone. In some cases, growth hormone treatment may also be recommended.

Finally, an early diagnosis can help parents and caregivers connect with support groups and resources, aiding in navigating the challenges associated with PWS. Therefore, if Prader-Willi syndrome is suspected, it is crucial to seek medical advice promptly for a comprehensive diagnostic evaluation.

Treatment and Management of Prader-Willi Syndrome

Treatment for Prader-Willi syndrome is multifaceted, encompassing nutritional management, hormonal and surgical treatments, along with a range of other interventions. The aim is to address the physical, cognitive, and behavioral aspects of the condition and optimize the individual's overall well-being and quality of life [8].

Nutritional Management

Nutritional management forms a critical part of the treatment process for Prader-Willi syndrome. Given that hyperphagia and obesity are major causes of morbidity and mortality in individuals with Prader-Willi Syndrome (PWS), strict supervision of food intake, based on height and weight, is necessary to prevent excessive weight gain [9].

In infancy, special feeding methods may be required to address poor muscle tone and feeding difficulties. As the child grows, the focus of nutritional management shifts towards monitoring caloric intake, promoting healthy eating habits, and maintaining a balanced diet to aid in weight control.

Hormonal and Surgical Treatments

Hormonal treatments, such as growth hormone therapy, are often recommended for individuals with Prader-Willi syndrome. These treatments can help to improve physical strength, increase height, decrease body fat, and enhance motor skills.

Surgical treatments may be considered to address specific issues such as hypogonadism, genital hypoplasia, and pubertal insufficiency. These treatments are tailored to the individual's needs and may involve hormone replacement therapy or surgical interventions.

In addition to these treatments, individuals with Prader-Willi syndrome may require various other interventions such as physical therapy, behavioral interventions, and regular health check-ups. It's crucial to have accurate diagnosis, determination of specific genetic subtypes, and appropriate medical management to address these issues effectively.

Overall, the management of Prader-Willi syndrome requires a comprehensive and multidisciplinary approach. A team of healthcare professionals will work together to create a personalized treatment plan that meets the individual's unique needs and promotes their overall health and well-being.

Role of Genetic Imprinting

Genetic imprinting plays a crucial role in the development of Prader-Willi syndrome. It's a complex process that involves the selective expression of genes based on their parental origin and can significantly influence an individual’s health.

Genetic Imprinting in Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is primarily caused by the lack of expression of paternally inherited imprinted genes at the 15q11.2-q13 region. This absence is due to a lack of expression of the paternal chromosome 15q11-q13, which leads to the loss of imprinted genes on the paternal chromosome.

The loss of the imprinted genes in the 15q11.2-q13 region, due to a deletion on the paternal chromosome, is the main identifiable cause of Prader-Willi syndrome, accounting for around 65-75% of the cases.

In some cases, Prader-Willi syndrome can also result from maternal uniparental disomy for chromosome 15, involving the inheritance of both copies of chromosome 15 from the mother and none from the father.

Additionally, in rare instances, imprinting center defects on chromosome 15 can also lead to Prader-Willi syndrome, where defects disrupt the typical imprinting process and result in the syndrome [3].

Even rarer translocations or mutations on chromosome 15 can also cause Prader-Willi syndrome, highlighting the genetic complexity and variability in the causes of this syndrome.

Comparisons with Other Syndromes

The genetic causes of Prader-Willi syndrome bear certain similarities to another genetic disorder, Angelman syndrome. Both disorders are associated with genetic changes on the same region of chromosome 15.

In the case of Angelman syndrome, the deletion or genetic abnormalities in a specific area of chromosome 15, which accounts for about 70% of cases, leads to the loss of the maternal contribution of the UBE3A gene, causing the symptoms observed in Angelman syndrome [10].

Interestingly, Prader-Willi syndrome is caused by the loss of certain genes in the same region of chromosome 15 that are involved in Angelman syndrome. However, in Prader-Willi syndrome, the loss is linked to the paternal contribution.

In essence, the imprinting on the same region of chromosome 15 is implicated in both Angelman and Prader-Willi syndromes. The loss of the maternal contribution is linked to Angelman syndrome, while the loss of the paternal contribution is linked to Prader-Willi syndrome.

Understanding the role of genetic imprinting in Prader-Willi syndrome not only helps us understand the prader-willi syndrome causes but also provides valuable insights into the genetic mechanisms underlying other similar syndromes.

References

[1]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5456307/

‍[2]: https://medlineplus.gov/genetics/condition/prader-willi-syndrome/

‍[3]: https://www.nature.com/articles/jhg201159

‍[4]: https://www.rarediseaseadvisor.com/hcp-resource/prader-willi-syndrome-risk-factors/

‍[5]: https://www.ncbi.nlm.nih.gov/books/NBK1330/

‍[6]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917289/

‍[7]: https://www.nhs.uk/conditions/prader-willi-syndrome/causes/

‍[8]: https://www.rarediseaseadvisor.com/hcp-resource/prader-willi-syndrome-management/

‍[9]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040524/

‍[10]: https://www.nature.com/scitable/topicpage/imprinting-and-genetic-disease-angelman-prader-willi-923/

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