What are Prader-Willi and Angelman syndromes?

Risk Factors

In most cases, the defects and deletions in paternal genes that are the cause of PWS occur randomly and are not inherited. However, in a few instances a genetic mutation inherited from the father may cause this disorder.

Researchers do not know what causes the genetic deletions that result in most cases of AS. The majority of people with AS do not have a family history of the disease. However, in a small number of cases AS may be inherited from the mother.

Etiology and Genetics

The primary cause of both syndromes appears to be a small deletion on the long arm of chromosome 15 (del 15q11.2–q13). The deleted area is estimated to be about four million base pairs (bp), small by molecular standards but large enough to contain several genes. This area of chromosome 15 is known to contain several genes that are activated or inactivated depending on the chromosome’s parent of origin (that is, a gene may be turned on in the chromosome inherited from the mother but turned off in the chromosome inherited from the father). This parent-specific activation is referred to as genetic imprinting. It is now known that the deletions causing AS appear in the chromosome inherited from the mother, while those causing PWS occur in the chromosome inherited from the father. Since the genes of only one chromosome are active at a time, any disruption (deletion) in the active chromosome will lead to the effects seen in one of these syndromes.

In 1997 a gene within the AS deletion region called UBE3A
was found to be mutated in approximately 5 percent of AS individuals. These mutations can be as small as a single base pair. In 2014, Genetics Home Reference reported that about 70 percent of AS cases were caused by deletions of the maternal chromosome 15 segment containing UBE3A, while in about 11 percent of AS cases the cause is a mutation in the maternal copy of the gene. UBE3A codes for a protein/enzyme called a ubiquitin protein ligase, and UBE3A is believed to be the causative gene in AS. All mechanisms known to cause AS appear to cause inactivation or absence of this gene. UBE3A is an enzymatic component of a complex protein degradation system termed the ubiquitin-proteasome pathway. This pathway is located in the cytoplasm of all cells. The pathway involves a small protein molecule (ubiquitin) that can be attached to proteins, thereby causing them to be degraded. In the normal brain,
UBE3A inherited from the father is almost completely inactive, so the maternal copy performs most of the ubiquitin-producing function. Inheritance of a UBE3A mutation from the mother causes AS; inheritance of the mutation from the father has no apparent effect on the child. In some families, AS caused by a UBE3A mutation can occur in more than one family member.

Another cause of AS (3 percent of cases) is paternal uniparental disomy (UPD). In this case a child inherits both copies of chromosome 15 from the father, with no copy inherited from the mother. Even though there is no deletion or mutation, the child is still missing the active UBE3A gene because the paternally derived chromosomes only have brain-inactivated UBE3A genes.

A fourth class of AS individuals (3–5 percent) have chromosome 15 copies inherited from both parents, but the copy inherited from the mother functions in the same way as a paternally inherited one would. This is referred to as an “imprinting defect.” Some individuals may have a very small deletion of a region known as the imprinting center (IC), which regulates the activity of UBE3A from a distant location. The mechanism for this is not yet known.

While there are several genetic mechanisms for AS, all of them lead to the typical clinical features found in AS individuals, although minor differences in incidence of features may occur between each group.

In 2014 Genetics Home Reference reported that about 70 percent of Prader-Willi cases are caused by the deletion of a segment of the paternal chromosome 15, while in 25 percent of cases the affected individual has two copies of maternal chromosome 15 instead of one from each parent. The primary genes involved in PWS are SNRPN, a gene that encodes the small nuclear ribonucleotide polypeptide SmN that is found in the fetal and adult brain, and MKRN-AS1 (formerly known as ZFN127AS), a gene that encodes a zinc-finger protein of unknown function. SNRPN is involved in messenger RNA (mRNA) processing, an intermediate step between DNA transcription and protein formation. A mouse model of PWS has been developed with a large deletion that includes the SNRPN region and the PWS imprinting center and shows a phenotype similar to that of infants with PWS.

It is probable that the hypothalamic problems (such as overeating) associated with PWS might result from a loss of SNRPN. The production of this protein is found mainly in the hypothalamic regions of the brain and in the olfactory cortex. Thus, disruption of hypothalamic functions such as satiety are a likely result of this defect. Prader-Willi syndrome is the most common genetic cause of obesity. In addition to its role in satiety, the hypothalamus regulates growth, sexual development, metabolism, body temperature, pigmentation, and mood—all functions that are affected in those with PWS.

PWS may also be caused by uniparental disomy, as seen in AS. However, in PWS both copies of chromosome 15 are derived from the mother instead of from the father.

As mentioned above, the imprinting center may be involved in at least some cases of both syndromes. This chromosome 15 IC is about 100 kilobase pairs (kb) long and includes exon 1 of the SNRPN gene. Mutations in this area appear to prevent the paternal-to-maternal imprinting switch in the AS families and prevents the maternal-to-paternal switch in PWS families. Therefore, it is possible that the IC is needed to regulate alternate RNA splicing in the SNRPN gene transcripts.

Few examples of known parental imprinting occur in humans, so AS and PWS provide rare opportunities for geneticists and biologists to study this important phenomenon. Examples of nonhuman parental imprinting are well known, but the genetic and biochemical mechanisms have not been established. Detailing the IC for chromosome 15 will be key to understanding how imprinting occurs and how the effects of AS and PWS are manifested.

The suggestion has been made that PWS (and therefore disruption of the IC) may also, at least in some cases, have an environmental trigger. A high association of PWS with fathers employed in hydrocarbon-related occupations (such as factory workers, lumbermen, machinists, chemists, and mechanics) at the time of conception has been reported by one investigative team. This is an area that needs further exploration.

Symptoms

Angelman syndrome was first described in 1965 by Dr. Harry Angelman, who described three children with a stiff, jerky gait, absent speech, excessive laughter, and seizures. Newer reports include severe intellectual disability and a characteristic face that is small with a large mouth and prominent chin. These characteristics give rise to the alternate name for the syndrome, that being “happy puppet syndrome.” The syndrome is fairly rare, with an prevalence estimated to be between one in twelve thousand to one in twenty thousand in 2011 according to the US National Library of Medicine's Genetics Home Reference in 2014. AS is usually not recognized at birth or in infancy, since the developmental problems are nonspecific during this period.

Prader-Willi syndrome, by comparison, is characterized by intellectual disability, hypotonia (decreased muscle tone), skin picking, short stature, cryptorchidism (small or undescended testes), and hyperphagia (overeating leading to severe obesity). Delayed motor and language development are common, as is intellectual impairment (the average IQ is about 70). The syndrome was first described by Doctors Andrea Prader, Alexis Labhart, and Heinrich Willi in 1956. Like Angelman syndrome, PWS has a fairly low prevalence, estimated at one in ten thousand to thirty thousand people around the world according to Genetics Home Reference in 2014. Neither condition is race-specific, and neither is considered to be a familial disease.

Screening and Diagnosis

The usual chromosome studies carried out during prenatal diagnosis are interpreted as normal in fetuses with AS and PWS syndromes, since the small abnormalities on chromosome 15 are not detected by this type of study. Likewise, fetal ultrasound offers no help in detecting physical abnormalities related to AS or PWS, since the affected fetus is well formed. Amniotic fluid volume and alpha-fetoprotein levels also appear normal.

Fluorescence in situ hybridization (FISH) is an extremely sensitive assay for determining the presence of deletions on chromosomes. It uses a fluorescence-tagged segment of DNA that binds to the DNA region being studied. Specialized chromosome 15 FISH studies are needed to determine the presence of either syndrome resulting from chromosomal deletions. Testing for parent-specific DNA methylation imprints at the 15q11.2–q13 locus detects more than 99 percent of cases (Driscoll et al.) of PWS and 78 percent of cases of AS (Dagli and Williams). Additionally, UBE3A sequence analysis can find evidence of mutations in about another 11 percent of AS cases. For cases caused by uniparental disomy, polymerase chain reaction (PCR) testing can be used.

Treatment and Therapy

Treatment for both PWS and AS focuses on managing the medical and development problems that are caused by these conditions. Most people with PWS will require specialized care throughout their lives. Many infants who have this disorder need a high-calorie formula to help them gain weight. Older children will need to maintain a reduced-calorie diet in order to control their weight and ensure proper nutrition.

Some children with PWS receive human growth hormones to increase growth and reduce body fat. However, the long-term effects of hormone treatment are not known, and parents should discuss this treatment with an endocrinologist—a specialist who treats hormonal disorders—to determine if it is right for their children. The endocrinologist may also recommend that a child receive hormone replacement therapy (testosterone for males or estrogen and progesterone for females) to replenish low levels of sex hormones.

Children with PWS may also receive physical, speech, occupational, and developmental therapies in order to improve movement and language skills, learn to perform everyday tasks, behave appropriately, and acquire social and interpersonal skills. In addition, a psychologist or psychiatrist may be needed to address a child’s psychological problems, including mood or obsessive-compulsive disorders.

Treatment for AS may include antiseizure medication to control the seizures caused by the disorder. Physical therapy can help children walk and improve other mobility problems; behavioral therapy can teach children to overcome their hyperactivity and short attention spans. Because people with AS usually have limited verbal language skills, communication therapy can help them develop nonverbal language skills through sign language and picture communication.

Prevention and Outcomes

There is no cure for PWS or AS, but the proper therapy and medication can help address the developmental and medical difficulties associated with these disorders.

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