Excerpted from Chapter 6 of Genetics and Mental Retardation Syndromes: A New Look at Behavior and Interventions, by Elisabeth M. Dykens, Ph.D., Robert M. Hodapp, Ph.D., & Brenda M. Finucane, M.S.

Copyright © 2000 by Paul H. Brookes Publishing Co. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.

Prader-Willi syndrome, first identified in the mid-1950s, continues to fascinate both researchers and interventionists. Part of the disorder's intrigue arises from its hallmark symptoms of hyperphagia, or overeating, and marked propensity to obesity — unique features of the syndrome. But as Judith Hall (1991) highlighted in The New York Times, Prader-Willi syndrome is also noteworthy for its pivotal role in recent molecular genetic history.

To this day, Prader-Willi syndrome captivates genetic and behavioral researchers alike, and as a result the past decades have witnessed a ground swell of new knowledge about this disorder. As summarized in this chapter, we now know that Prader-Willi syndrome

• Is the first known human disorder to show the effects of genomic imprinting, leading to revolutionary changes in the field of molecular genetics
• Is the leading known genetic cause of obesity
• Shows two distinctive stages in early childhood — difficulty sucking and failure to thrive in infancy followed by hyperphagia, or eating too much and thriving too well
• Includes many individuals who have a fondness for (and, possibly, strengths in) solving jigsaw puzzles
• Involves increased risks of compulsive behaviors, as well as other maladaptive features
• Presents unique challenges related to food management and choice and self-determination

Historical Background

In 1956, Prader, Labhart, and Willi published in a German journal a short paper entitled "A Syndrome of Obesity, Short Stature, Hypogonadism, and Learning Disability, with Hypotonia During the Neonatal Period" (see Clarke, Boer, & Webb, 1995). Similar to Langdon Down's short paper on Down syndrome, the article introducing Prader-Willi syndrome is noteworthy for its brief but careful description of the syndrome. Reporting on nine individuals, Prader et al. described their patients' obesity, short stature, hypotonia, and failure to thrive during infancy. The authors even speculated that Prader-Willi syndrome "appears, therefore, to be a hypothalamic disorder" (1956, p. 39). Although researchers have made many advances in this syndrome, hypothalamic anomalies remain the leading — and still unresolved — culprit of at least some of the disorder's cardinal clinical features (Swaab, 1997).

We now know that the disorder generally results from one of two causes — paternal deletion or maternal uniparental disomy (to be discussed in the next section on genetics) — and that the prevalence rate of Prader-Willi syndrome ranges from 1 in 10,000 to 1 in 15,000 individuals. In recent years, researchers have also come to appreciate the "multisystem" nature of this disorder, or the many physical, diagnostic, and behavioral issues that, along with the food issues, deserve attention.

Genetic, Medical, and Physical Issues

Although the exact hypothalamic impairment has yet to be identified, considerable progress has been made in identifying the genetic basis of Prader-Willi syndrome. From the early 1980s on, it was understood that most individuals with the syndrome have a small deletion at a certain area (q11-13) on the long arm of chromosome 15 (Ledbetter et al., 1981). With a few exceptions, the remainder of individuals with Prader-Willi syndrome have typical-appearing chromosomes under the microscope.

But what causes Prader-Willi syndrome in the remaining individuals? As molecular genetic technology improved in the late 1980s, researchers discovered two things. First, the deletions causing Prader-Will syndrome always occurred solely in the chromosome 15 inherited from the father (Butler, 1990; Nicholls, Knoll, Butler, Karam, & Lalande, 1989). Second, those individuals without a deletion had two chromosome 15s inherited from the mother, and no chromosome 15 from the father — a situation called maternal uniparental disomy, or UPD (Nicholls et al., 1989). In individuals with UPD, the chromosomes themselves are typical in number and structure, but the inheritance pattern is wrong. In effect, all individuals with Prader-Willi syndrome have it because they lack the father's contribution to the specific region of the long arm of chromosome 15 associated with this disorder.

The genetic findings in Prader-Willi syndrome can be explained by a phenomenon called genetic (or genomic) imprinting (see Chapter 2). In imprinting, genes or groups of neighboring genes are expressed differently depending on the sex of the parent from whom they were inherited. The genes themselves are not altered, but instead some genes are inactivated or switched off. In the typical situation, the maternally derived copies of chromosome 15 in the critical region for Prader-Willi syndrome are inactivated, and only the paternally derived region is expressed in cells. But when the paternal copy of this region is missing — by deletion or by complete absence as in maternal disomy — there is no active copy of the genetic information, and an abnormality in development results in Prader-Willi syndrome (Nicholls, 1993). Although several paternally expressed genes have been identified in the Prader-Willi critical region, only the disruption of one of these genes (called SNRPN and perhaps another gene called NDN) is significant to the Prader-Willi phenotype (Khan & Wood, 1999).

Prader-Willi syndrome is caused, then, by the absence of the typically active, paternally inherited genes at a particular location on the long arm of chromosome 15. In about 70% of cases, this absence is due to a deletion on the chromosome 15 inherited from the father; most remaining individuals have UPD, or two copies of chromosome 15 from the mother (Mascari et al., 1992; Nicholls et al., 1989; Robinson et al., 1991). An additional 5% of individuals have a translocation or other structural abnormality involving chromosome 15. Finally, a very small percentage (1%-5%) have neither deletion nor UPD, but rather a micro-deletion in the center controlling the imprinting process within 15q11-q13 (Buiting et al., 1995; Saitoh et al., 1997). Though small, this last group includes virtually all cases in which there has been a recurrence of Prader-Willi syndrome within a family.

More refined understandings of the genetics of Prader-Willi syndrome have led researchers to examine possible phenotypic differences across the various genetic subtypes of this disorder. Physically, those with paternal deletions seem more apt to show the syndrome's typical facial features, as well as hypopigmentation (Butler, 1989; Cassidy et al., 1997; Gillessen-Kaesbach, Robinson, et al., 1995; Mitchell et al., 1996). Hypopigmentation, or fair complexion or coloring, is attributed to the deletion of a gene for tyrosinase positive albinoidism in the Prader-Willi critical region. Relative to those with deletions, people with UPD may have increased birth weight, a shorter course of gavage feeding (feeding through a tube) in infancy, and a later onset of hyperphagia (Gillessen-Kaesbach, Robinson, et al., 1995; Mitchell et al., 1996); some of these features, however, are not observed as being consistent. (Gunay-Aygun, Heeger, Schwartz, & Cassidy, 1997). Advanced maternal age is also seen among mothers who bear children with UPD. More subtle physical features in offspring with maternal UPD may lead to a later age of diagnosis in these individuals (Gunay-Aygun et al., 1997). The relatively few individuals with Prader-Willi syndrome who have microdeletions in the imprinting center seem phenotypically similar to others, except that they do not have hypopigmentation (Saitoh et al., 1997). Observations regarding physical features have provoked a new series of studies on possible behavioral differences across deleted versus UPD cases; preliminary findings are presented later in this chapter.

Diagnosis

Given the recent and fast-paced developments in the genetics of Prader-Willi syndrome, many people were first diagnosed clinically — that is, from their physical and behavioral features. And, as the disorder is relatively rare (making the costs of widespread genetic testing prohibitive), in 1993 professionals working in this syndrome published a list of "consensus clinical criteria" for the disorder (Holm et al., 1993). Although genetic testing has evolved to the point of being both highly accurate and readily available, these clinical criteria, listed in Table 6.1, are still extremely valuable in suggesting the diagnosis and indicating the need for diagnostic testing. No one individual will have all of the manifestations of the disorder listed in Table 6.1, and considerable variability exists in the severity of each of the clinical criteria.

Several genetic tests can now be used to detect Prader-Willi syndrome. Although high resolution cytogenetic analysis can often detect the 15q11-q13 deletion, this technique gives unacceptably high false-negative and false-positive rates. For these reasons, cytogenetic tests are no longer considered sufficient for diagnostic purposes. Instead, the definitive diagnostic test for the common size deletion causing Prader-Willi syndrome is FISH (see Chapter 2). The American Society of Human Genetics/American College of Medical Genetics Test and Technology Transfer Committee has recently published a statement regarding the status of genetic testing for Prader-Willi syndrome (ASHG/ACMG Statement, 1996). Prenatal detection of Prader-Willi syndrome is also now possible.

Although to date there have been no reports of recurrence of Prader-Willi syndrome in families in which one child has Prader-Willi syndrome from either a deletion or from UPD, theoretically the syndrome can recur in a family. Because UPD, in particular, is caused by a chromosomal nondisjunction (which can recur and is related to advanced maternal age), there is some risk of families having a second child with UPD. In both deletion and UPD, a 1% or less recurrence risk has been deemed appropriate for genetic counseling purposes. In contrast, in the small number of families with an imprinting mutation, a recurrence risk of up to 50% pertains, as the imprinting mutation likely involves a dominant mutation in the paternal grandmother's germline.