Prader Willi and Angelman Syndromes

Prader-Willi syndrome (PWS), with a prevalence of 1 in 10,000, is a rare condition. Children become symptomatic soon after birth. Infants are initially hypotonic and sometimes then fail to thrive. Subsequently, within the first 2 years of life, they become hyperphagic and, eventually, obese. Often they are mildly to moderately mentally retarded. They may be of short stature, with small hands, feet, and gonads. Behavioral problems are common and include obsessive-compulsive symptoms, compulsive food-related behaviors, temper tantrums, and aggression.

Angelman syndrome (AS), also rare, has a prevalence similar to that of PWS. Infants with AS are often hypotonic. They then develop motor delays, ataxia, and moderate to severe mental retardation. Only rarely do they develop speech. They often have characteristic facial features, including a wide mouth, large mandible, pointed chin, prominent tongue, wide spaced teeth, and blue eyes. Some develop the remarkable symptoms of excessive laughter or of puppetlike limb movements. Seizures usually develop soon after birth, and all with AS have abnormal EEGs.

Genetics. Both PWS and AS were known by the mid-1980s to be caused by deletions in the same span of chromosome 15 (15q11-13). How the same deletion could cause two syndromes with such differing phenotypes was at first perplexing. Subsequent investigation then demonstrated that the resulting phenotype depended on which parent donated the chromosome with this particular deletion. PWS resulted in most instances when the deleted chromosome originated from the father, and AS resulted when it originated from the mother.

Although all people had long been known to inherit half their genes from their mother and half from their father, maternally and paternally derived genes were also erroneously thought to be expressed equally in offspring. We now know, however, that the expression of genes in a child is influenced by their passage through the mother's egg and father's sperm. This epigenetic phenomenon, called genetic imprinting, occurs when certain genes become methylated within a gamete of one of the parent's gonads (Davies et al., 2001). Genetic imprinting influences the expression of more than 40 genes, including the genes on chromosome 15 that cause AS and PWS.

The PWS region on chromosome 15 resides immediately upstream from the AS region. Under normal circumstances, the PWS region on the chromosome from the father is active and the AS region is inactive. In the chromosome from the mother, in contrast, the PWS region is inactive and the AS region is active. All of the known genetic defects that produce PWS or AS have in common the abnormal inactivation of one of these normally active regions (Fig. 14.1).

Three different genetic defects can produce PWS (Cassidy et al., 2000; Nicholls and Knepper, 2001). The first, a deletion of both the PWS and AS regions within 15q11-13 on the paternally derived chromosome, occurs in 70 percent of individuals with PWS. This deletion leaves the AS region of the maternally derived chromosome normally functioning, whereas maternal imprinting renders the PWS region on this chromosome inactive. Production of the PWS protein product is therefore deficient. The second genetic defect occurs in 28 percent of children with PWS. In this instance, the child receives two copies of chromosome 15 from the mother, referred to as uniparental disomy (UPD). UPD occurs when two chromosomes from one parent and a single copy of the same chromosome from the other parent are inappropriately passed to the offspring, resulting in a total of three chromosomes instead of the usual two. One of

Maternal Paternal Gamete Gamete

Paternal Deletion 70%

Maternal UPD

Imprinting Defect 2%

ANGELMAN SYNDROME

Maternal Deletion 70%

Imprinting Defect 2-5%

Paternal UPD

UBE3A Mutation

(+) (+) Active PWS-Related Genes PP~| | + | Active AS-Related Genes

^^ ^^ Inactive PWS-Related Genes Inactive AS-Related Genes

X UBE3A Mutation

Figure 14.1. Genetic mechanisms in Prader-Willi and Angelman syndromes. Upper left. Under normal circumstances on the maternally derived chromosome, the Prader-Willi-related genes are inactive and the Angelman syndrome genes are active. On the paternally derived chromosome, the reverse is true—the Prader-Willi-related genes are active and the Angelman syndrome genes are inactive. Upper right: Paternal deletion, maternal uniparental disomy (UPD), and imprinting defects that cause Prader-Willi syndrome are represented in each of the chromosomes derived from the mother and the father. Bottom: Maternal deletion, paternal UPD, imprinting defects, and the UBE3A deletions that cause Angelman syndrome are shown. The percentages represent the approximate percentage of individuals affected by each of these syndromes who have the specified genetic defect.

the three chromosomes is then lost during fertilization. An extra chromosome from the mother and the loss of the chromosome from the father results in maternal UPD. Maternal UPD provides the child with two active AS regions and two inactive PWS regions, because of maternal imprinting of both chromosomes, and thus no production of the PWS protein product is possible. The third genetic defect, in 2 percent of individuals with PWS, results from a mutation in the imprinting center. This is a region of DNA that controls imprinting by regulating the extent of methylation and compaction of adjacent chromatin. A mutation in the imprinting center of the paternal chromosome causes an imprinting defect that inactivates the PWS region of the paternally derived chromosome, leaving no active PWS genes.

Similar genetic mechanisms produce AS. The first defect, occurring in approximately 70 percent of individuals with AS, is a deletion of 15q11-13 on the maternally derived chromosome. This deletion leaves only an active PWS region and inactive AS region (due to paternal imprinting) on the paternally derived chromosome, and thus no AS protein product. The second defect, affecting 2 percent of individuals with AS, is paternal UPD (both copies of chromosome 15 derive from the father). Paternal imprinting of both chromosomes leaves the child with two active PWS and two inactive AS regions, and no AS protein product. The third defect occurs in another 5 percent of individuals with AS. It is a mutation of the imprinting center of the maternally derived chromosome, thus inactivating the AS region of that chromosome. Because the AS region of the paternally derived chromosome is normal and inactive, the AS regions of both chromosomes are inactive and no AS protein product is possible.

Finally, a fourth genetic mechanism causes AS in another 25 percent of children. It is a mutation of a single gene, called UBE3A, that lies within the AS region. It encodes a protein that helps to regulate the action of ubiquitin in degrading recycled or damaged cellular proteins. UBE3A and other proteins attach to ubiquitin, which then is able to target proteins for degradation by cellular proteases. The deletion of UBE3A is therefore thought to lead to the accumulation of inappropriate cellular proteins that disrupt cellular functions. Incidentally, one of the genes within the AS region encodes for a subunit of the GABA-A receptor. Loss of this subunit and the subsequent disturbances in GABAergic transmission causes the seizures seen in children who have AS. Those children with the single gene deletion of UBE3A do not lose the GABA-A receptor subunit and therefore do not have a seizure disorder.

All of the mutations described above, except the single-gene mutation of AS, can be detected with methylation-sensitive DNA probes, because DNA methylation of the imprinting center is the mechanism by which the genes for these disorders are imprinted. The induction of imprinting by methylation in specific areas of DNA offers hope for the development of new genetic treatments of these disorders. Methylation possibly could be removed or reversed on the imprinting center that resides on the normal copy of chromosome 15 in these individuals, for example, thus activating the PWS or AS regions that imprinting otherwise normally inactivates.

Neurobiological Substrate. Although knockout mouse models for PWS and AS now exist, the regions of altered gene expression have not yet been identified. Isolated imaging case studies have not helped to identify anatomical or functional abnormalities in the brains of individuals affected with PWS or AS. Thus, the neurobiological substrate for these disorders is unknown.

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