Prader-Willi Syndrome

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Aetiology

Prader-Willi syndrome is caused by genetic changes on an "unstable" region of chromosome 15 that affects the regulation of gene expression, or how genes turn on and off. This part of the chromosome is called unstable because it is prone to being shuffled around by the cell's genetic machinery before the chromosome is passed on from parent to child.

The genetic changes that cause Prader-Willi syndrome occur in a portion of the chromosome, referred to as the Prader-Willi critical region (PWCR), around the time of conception or during early fetal development.1 This region was identified in 1990 using genetic DNA probes. Although Prader-Willi syndrome is genetic, it usually is not inherited and generally develops due to deletions or partial deletions on chromosome 15.

Specific changes to the chromosome can include the following:

- Deletions. A section of a chromosome may be lost or deleted, along with the functions that this section supported. About 65% to 75% of Prader-Willi syndrome cases result from the loss of function of several genes in one region of the father's chromosome 15, due to deletion. The corresponding mother's genes on chromosome 15 are always inactive and thus cannot make up for the deletion on the father's chromosome 15. The missing paternal genes normally play a fundamental role in regulating hunger and fullness.

- Maternal uniparental disomy (pronounced yoo-nuh-puh-REN-tl DAHY-soh-mee). A cell usually contains one set of chromosomes from the father and another set from the mother. In ordinary cases, a child has two chromosome 15s, one from each parent. In 20% to 30% of Prader-Willi syndrome cases, the child has two chromosome 15s from the mother and none from the father. Because genes located in the PWCR are normally inactive in the chromosome that comes from the mother, the child's lack of active genes in this region leads to Prader-Willi syndrome.

- An imprinting center defect. Genes in the PWCR on the chromosome that came from the mother are normally inactivated, due to a process known as "imprinting" that affects whether the cell is able to "read" a gene or not. In less than 5% of Prader-Willi syndrome cases, the chromosome 15 inherited from the father is imprinted in the same way as the mother's. This can be caused by a small deletion in a region of the father's chromosome that controls the imprinting process, called the imprinting center. In these cases, both of the child's copies of chromosome 15 have inactive PWCRs, leading to Prader-Willi syndrome.2

- Although the exact genes responsible for Prader-Willi syndrome haven't been identified, the problem is known to lie in a particular region of chromosome 15.

- With the exceptions of genes related to sex characteristics, all genes come in pairs, one copy inherited from the father (paternal gene) and one copy inherited from the mother (maternal gene). For most types of genes, if one copy is "active," or expressed, then the other copy is also expressed.

- However, some types of genes act alone. In other words, it's normal with certain genes for the paternal gene to be expressed and the maternal gene to be "silent." Therefore, if there's an error with the paternal gene, that piece of genetic information is essentially missing.

- What happens in Prader-Willi syndromePrader-Willi syndrome occurs because certain paternal genes that should be expressed aren't for one of the following reasons:

- Paternal genes on chromosome 15 are missing.

- The person has inherited two copies of chromosome 15 from the mother and no chromosome 15 from the father.

- There's some error or defect in paternal genes on chromosome 15.

- The genetic defect of Prader-Willi syndrome disrupts the normal functions of a portion of the brain called the hypothalamus. Among its many functions, the hypothalamus controls hunger and thirst and releases hormones that prompt the release of other substances responsible for growth and sexual development. A malfunctioning hypothalamus — caused by the defect on chromosome 15 — interferes with each of these processes, resulting in uncontrollable hunger, stunted growth, sexual underdevelopment and other characteristics of Prader-Willi syndrome.

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- COMPLICATIONS

- Obesity-related complicationsMany of the possible complications of Prader-Willi syndrome result from obesity. In addition to having constant hunger, people with the disorder have low muscle mass, which requires lower than average calorie needs. This combination of factors makes a person prone to obesity and the medical problems related to obesity. These possible complications include:

- Type 2 diabetes. Type 2 diabetes is high blood sugar level due to the body's inability to use insulin efficiently. Insulin plays a vital role in making blood sugar (glucose) — the body's fuel — available to the cells. Obesity significantly increases the risk of diabetes.

- Heart disease and stroke. People who are obese are more likely to have high blood pressure, hardened arteries, high cholesterol and other factors that can lead to heart disease and stroke.

- Arthritis. Excess weight can cause the bone and cartilage of joints to wear down, resulting in osteoarthritis.

- Sleep apnea. This sleep disorder is characterized by pauses in breathing during sleep. The disorder can cause daytime fatigue, high blood pressure and, rarely, sudden death. People with Prader-Willi syndrome may have sleep apnea or other sleep disorders even if they aren't obese, but obesity can worsen sleep problems.

- Complications of hypogonadismOther complications arise from hypogonadism, a condition in which the sex organs don't secrete sufficient amounts of the sex hormones testosterone (males) and estrogen and progesterone (females). These may include:

- Sterility. Although there have been a few reports of women with Prader-Willi syndrome becoming pregnant, most people with this disorder are unable to have children (sterile).

- Osteoporosis. Osteoporosis is a condition characterized by weak and brittle bones, which can break easily. People with Prader-Willi syndrome are at an increased risk of developing osteoporosis because they have low levels of sex hormones, which help maintain strong bones.

- Other complicationsEating