Prader-Willi syndrome (PWS) is caused by specific genetic abnormalities involving a particular region on chromosome 15, specifically the paternal copy of chromosome 15. The core cause lies in the loss of function of genes in the 15q11-q13 region that are normally expressed only from the father’s chromosome. This loss can happen in several ways, but all result in the same outcome: the absence or disruption of paternal gene expression in this critical region.
The most common cause is a **deletion** of a segment of the paternal chromosome 15. In this case, a chunk of DNA containing several important genes is missing entirely. Without these genes, the body cannot produce certain proteins necessary for normal development and regulation of hunger, growth, and other functions. This deletion accounts for the majority of PWS cases.
Another cause is **maternal uniparental disomy (UPD)**, where a child inherits two copies of chromosome 15 from the mother and none from the father. Since the genes in the PWS region are only active when inherited from the father, having two maternal copies means these genes are not expressed at all, leading to PWS symptoms.
A less common cause involves an **imprinting defect**, where the paternal chromosome 15 is present but the genes in the PWS region are incorrectly “turned off” due to faulty epigenetic marks. Normally, these genes are “imprinted” so that only the paternal copy is active, but in this defect, the paternal genes behave like maternal ones and remain silent.
These genetic changes disrupt the normal function of the hypothalamus, a part of the brain that controls hunger, growth hormone release, temperature regulation, and other vital processes. Because of this disruption, individuals with PWS experience a range of symptoms including weak muscle tone at birth, poor feeding initially, delayed development, and later an insatiable appetite that often leads to obesity if not carefully managed.
The genetic causes of PWS occur randomly during the formation of reproductive cells or early embryonic development. They are usually not inherited from parents but arise spontaneously. This randomness explains why PWS is rare, occurring in about 1 in 15,000 births.
The absence of paternal gene expression in the 15q11-q13 region affects multiple systems:
– **Muscle tone and development:** Weak muscle tone (hypotonia) is present from birth, causing feeding difficulties and delayed motor milestones.
– **Growth and metabolism:** Growth hormone deficiency is common, leading to short stature and increased body fat.
– **Appetite regulation:** The hypothalamic dysfunction causes hyperphagia, an uncontrollable hunger that begins in early childhood, driving excessive eating and obesity.
– **Cognitive and behavioral effects:** Intellectual disabilities, learning difficulties, and behavioral challenges such as temper outbursts and compulsive behaviors are common.
– **Other features:** Distinct facial characteristics, sleep abnormalities, and reduced sensitivity to pain are also linked to the genetic disruption.
Because the syndrome results from missing or inactive paternal genes, the exact symptoms and severity can vary depending on the type of genetic abnormality. For example, individuals with the deletion subtype often have more severe obesity and related complications compared to those with maternal uniparental disomy.
Understanding the genetic basis of Prader-Willi syndrome has been crucial for diagnosis and management. Genetic testing can identify the specific cause, which helps guide treatment and informs family planning. While there is no cure, early diagnosis allows for interventions such as growth hormone therapy, strict nutritional management, and behavioral support to improve quality of life.
In essence, Prader-Willi syndrome is caused by the loss of function of paternal genes on chromosome 15 due to deletion, maternal uniparental disomy, or imprinting defects. This genetic disruption impairs hypothalamic regulation, leading to the hallmark features of the syndrome including muscle weakness, developmental delays, and an overwhelming drive to eat.
