Decreased intellectual functioning was among the four original defining characteristics of PWS [
1]. Subsequent studies document a typical neurobehavioral profile that includes altered intellectual functioning and centrally driven maladaptive behaviors, including the hallmark hyperphagia that exists in the context of a more extensive food related behavioral constellation, an age related emotional and behavioral profile, altered sensory processing, social deficits and for many a predictable psychiatric profile [
47‐
51].
Intellectual Functioning
Following the original description, early studies of intellectual development documented a wide range of intellectual abilities, although most affected individuals tested in the borderline to mildly slow IQ ranges. As more sensitive genetic testing has become available, the population of individuals with PWS has become more clearly defined. Table
3 highlights studies of individuals with PWS who had genetic confirmation of their diagnosis, and who received age appropriate and properly administered cognitive testing, supplemented with measures of adaptive functioning.
Table 3
Intelligence Quotient (IQ)
| 1999 | 46 | 17.7 | 21.6 | 64.9 | 13.5 | 0 |
| 2001 | 18 | 14.3 | 73 | 27 | 0 | 0 |
| 2002 | 55 | 14.1 | 25.4 | 27.3 | 40 | 7.3 |
| 2004 | 55 | 21.0 | 31 | 41.8 | 27.2 | 0 |
| 2010 | 85 | 24.2 | 7 | 54 | 39 | 0 |
| 2000 | 47 | 23.2 | 24 | 38 | 30 | 8 |
The Israeli data are notable for the number of individuals testing in a normal range, and represents a distribution of IQ scores that is quite different from the remaining four studies. The reasons for this are unclear. Setting aside the Israeli data and averaging across the remaining studies, all with approximately the same number of participants, Full Scale IQ ranges are as follows: ≥ 70 in 21%; mild cognitive impairment in 47%; moderate cognitive impairment in 32% and severe to profound cognitive impairment in 2%. An earlier report by Curf and Fryns [
56] reported a greater proportion of subjects both in the > 70 and in the mildly impaired range, however their population included many subjects for whom no genetic testing was available and thus may have included individuals who did not have PWS.
Separate from the overall range of functioning among an affected population is the question of subtype differences in intellectual functioning. Such differences may be relevant in understanding the role of various genes in the overall clinical features and phenotype of this disorder. While most studies have not found significant subtype differences in overall IQ scores, at least 2 studies have reported a greater number of UPD subjects with normal IQ scores when compared to those with deletion [
57‐
59]. Indeed Torrado et al reported that 61.5% of those with UPD had a Full scale IQ > 70, while only 10.5% of the subjects with deletion scored in that range. However, the mean age of Torrado's subject population was 4.09 years (range 12 days-17 years), so that the significance and overall stability of the obtained IQ scores is open to question. Statistically significant subtype differences have been reported for overall Verbal vs. Performance IQ scores with at least 2 studies reporting that those with UPD have higher verbal IQ scores and those with a deletion subtype have higher performance IQ scores [
49,
54], although more recently Copet et al [
54] found that only the greater performance IQ of the deletion group vs a disomy group was statistically significant. Keep in mind that even when subtype scores are statistically significant, in no case have those differences ever reached the level of 1 SD for the test in question. Thus, whether these statistical differences are reflected as clinically relevant functional differences between subtypes is a question that must be raised.
In addition to mild cognitive deficits which are seen in most individuals with PWS, the overall cognitive profile at all ages includes cognitive rigidity, attentional deficits, problems with short term memory, auditory processing, sequential processing, arithmetic and social cognition. Relative strengths include long term memory, visual spatial performance, simultaneous processing, unusual abilities with jigsaw puzzles, particularly in the deletion subtype and for some reading decoding (devoid of comprehension).
Neuro-behavioral Profile
While there are a number of clinical descriptions of a typical behavior profile among those with PWS, from the earliest efforts behavioral studies have primarily focused on describing and quantifying the development of problem behaviors and psychiatric difficulties. Despite calls to include investigations of strength and adaptive behaviors [
60], these remain a rare study focus. Moreover many studies include such a wide age range, often including infants through late adulthood measured at a single point in time. Parceling out developmental aspects of the behavior profile requires a critical combination of clinical and empirical evidence. Nonetheless studies across time, taken together, yield a general behavior picture that is remarkably consistent across affected individuals, despite variation in severity and intensity across individuals and within the same individual across time. Foremost among these behaviors is the hyperphagia and associated food related behavior constellation. In addition, most clinical and empirical studies document the commonality of hoarding; cognitive rigidity along with the need for sameness, temper outbursts and emotional lability, repetitive and perseverative behaviors and skin-picking.
Hyperphagia remains the cardinal defining feature of PWS. Nonetheless, the hyperphagia is only one aspect of a larger food-related behavior constellation that included preoccupations surrounding food; food seeking/foraging; sneaking, hiding and hoarding food; eating unusual food-related items (sticks of butter, used cooking grease, decaying food, garbage), food flavored items, such as shampoos and for many, manipulative and sometimes illegal behaviors designed to acquire food. While hyperphagia is found in other genetic syndromes (e.g. WAGR syndrome, Bardet-Biedel syndrome), the development of the hyperphagia and eating patterns associated with PWS, distinguish the hyperphagia associated with PWS from other disorders. Primary among these is the relatively late age of emergence, the rapid escalation and intensification of the hyperphagia following several years of poor to relatively normal eating, often accompanied early on by failure to thrive. Additional distinguishing characteristics include the duration of eating, amount of food eaten and a delayed to absent deceleration of eating, leading to gorging when both physiologic satiation and volume induced discomfort should preclude additional intake.
In the daily run of life, this is reflected as constant talking about food and unrelenting requests and demands of parents and other caregivers for food, that when denied often precipitate a tantrum. This frequently happens at the grocery or while shopping in other stores that may also have food or candy aisles and at restaurants. The denial-related tantrums can be of such a nature that parents give in as a method of avoiding the behavior, thus creating a pattern that escalates in severity and intensity over time. In addition affected individuals display a constant preoccupation with food leading to extraordinary vigilance for detecting food anywhere in the environment often resulting in stealing other's lunches at school or work, food from teacher's desks or caregiver's purses, stealing food at home or in shopping areas, begging others for food, foraging in garbage cans, entering another's home in search of food and manipulating others to obtain food. It is a rare parent who has not received a call from the school or vocational site indicating that the affected individual has been obtaining extra food by convincing caregivers that parents are ill or haven't had time to feed them, often for an extended period of time.
The etiology of the hyperphagia remains elusive. Long attributed to a hypothalamically mediated failure of satiety control [
61,
62], current studies suggest a far more complex etiology than previously hypothesized, including, for many a theoretical reorientation that views the hyperphagia as reflecting a starvation syndrome rather than an obesity syndrome. From this vantage point, the obesity associated with PWS is seen as resulting from a physiologic signaling defect indicating that the body is in a constant state of starvation similar to that of malnourished infants, thus leading to the constant drive to obtain food.
To date there is no effective pharmacologic intervention. Management is environmental and behavioral, requiring restricted access to food in all environments, locks on cabinets and refrigerators, constant supervision, as well as measures to prevent obesity which include calorie restrictive diets, consistently scheduled meals and snacks and regularly scheduled physical activity. While simple in concept, the number of environments encountered in any given day, along with the cooperation needed from the individuals in those environments presents challenges that may be insurmountable for some families. Accounts from both parents and individuals with PWS support that strict limit setting with regard to foraging and food access is associated with reduced anxiety and a sense of safety [
63].
Behavioral Disturbances
Separate from the food related behavioral issues, multiple studies document that affected individuals are more prone to behavioral disturbances including hoarding; inflexibility of thinking and behavior; repetitive and perseverative behaviors; the need for sameness; tantrums and emotional lability; and skin picking [
62]. Furthermore, the overall rate, severity and chronicity of these disturbances are frequently more intense than those associated with comparable genetic disorders or cognitive impairments or other obese groups [
43,
64,
65]. Like the hyperphagia, the behavioral patterns appear to evolve over time with predictable epochs. Most authors agree that, on the whole, infants and young toddlers with PWS are affectionate, placid and generally cheerful, largely compliant and usually cooperative. However as the hyperphagia emerges, a separate and distinctly negative behavioral shift is also observed including an emergence and escalation of both food and non food related tantrums, a shorter tolerance for frustration combined with an overreaction to frustration; repetitive and ritualistic behavior as well as becoming " stuck " or perseverating on issues both in thought and speech; and other behavior problems including increasing oppositional tendencies, a lessened ability to " go with the flow " along with a drive for sameness and " increasing stubbornness and rigidity ". Comparison studies indicate that typically developing children and other children with mental retardation also exhibit the emergence of such behaviors, but they occur only transiently, that is, the problem appears and then subsides. However the emergence of such behaviors in those with PWS not only is persistent, but appears to escalate with age, increasing in severity and intensity, independent of intellectual, language or motor abilities [
66,
67].
Chronic behavior disturbances, including emotional lability accompanied by unbridled displays of temper; repetitive, ritualistic and compulsive like behaviors and hoarding become particularly prevalent in adolescence and persist well into adulthood, distinguishing these individuals from both younger children and older individuals with PWS, as well as from typical adolescents. In addition there has recently been an increasing recognition of accompanying social cognition and social interaction deficits among affected individuals, including an inability to read facial expressions of emotion and difficulty interpreting visually presented social information, such as those inherent in any social interaction [
68,
69]. Indeed several authors sum up the behavioral profile of those with PWS as " egocentric " and who argue, lie, manipulate and confabulate to change rules, obtain their wishes or justify behavior. Their social judgement is poor, even considering their intellectual ability; and interpretations of visually presented social information is on a level with children who have pervasive developmental disorder [
62]. Although some behavioral modulation is often seen in later ages, nonetheless problematic behaviors still exceed those seen in other comparison groups.
The expression of this behavioral phenotype does appear to depend, at least to some degree, on genetic subtype, with hoarding and overt behavioral expressions of frustration, anger and aggression more common among those with a deletion, as is a greater likelihood of modulation in middle adulthood. Internalizing and autistic spectrum behaviors are more common among those with UPD, and appear to be unremitting with little age related modulation [
70,
71].
Sensory Issues in the form of an altered sensitivity to pain, failure to exhibit fevers when expected and high rates of skin picking and gouging other body areas are extremely problematic among this group of individuals. While little research has been done around the issues of pain and lack of fever when expected, nonetheless blunted pain sensitivity and lack of appropriate fever response and the inherent dangers these present are clinically well documented. In this same spectrum, skin picking and other similar self injurious behavior occurs with increased prevalence in PWS when compared to a general intellectually impaired population [
67,
72]. When looking specifically at a population of those with PWS, skin picking is ubiquitous and when quantified, is as prevalent and problematic and in some studies even more so than hyperphagia [
47]. It is the source of significant behavior and medical concerns and management challenges. Management is directed towards minimizing both the occurrence and impact of the behavior. To this end, a recent survey of 67 affected children and adolescents documented skin picking in 96% of respondents, which were directly associated with measures of anxiety, inattention, oppositional behaviors, function and quality of life [
73]. Thus separate from medical management, behavior management must be focused on decreasing anxiety and boredom while eliminating opportunities for picking.
A number of case series across time have alluded to a small subset of individuals for whom seizures were problematic; however, it was generally thought that these represented incidental findings rather than a risk associated with PWS. A recent report by Fan et al [
74] documented seizure activity in 10 of 56 subjects between the ages of 1-37 years, with suspicion in yet another 6 subjects. Among the ten subjects with documented seizure, one youngster's seizure disorder was attributed to sequelae of a grade II intraventricular hemorrhage associated with an early pre-term birth. Among the other nine cases, eight occurred in those with a deletion subtype and the other in a subject whose etiology was a presumed imprinting center defect; none were found among those with a disomy. After reviewing prior studies in which seizures were reported, the authors conclude that the overall prevalence of seizures in PWS is 16 -17%. Further they suggest that among those with a deletion, the risk for seizure in a PWS population is three to four fold times greater than that expected in a general pediatric population.
Psychiatric Illness
For many, this wide ranging problematic, behavioral profile can become sufficiently impairing that hospitalization is needed, while for others it evolves into frank psychiatric difficulties. In fact, Cassidy found behavioral concerns to be the most frequent cause of hospitalization [
75]. By late adolescence 15-17% will evidence a diagnosable mood disorder [
76]. This appears to be especially true for those with UPD. Separate from a categorical psychiatric diagnosis, studies consistently document that the level of behavioral and thought psychopathology, such as delusions, paranoid ideation, common in adolescents and adults with PWS exceeds that of others with an intellectual disability of other origins or of a typical population [
65,
67], and is the primary source of residential and vocational failure and family stress among affected adolescents and adults. While pharmacologic intervention can be helpful and in the case of psychosis is mandatory, environmental restructuring and positive behavior support programs are even more critical for facilitating recovery and preventing further difficulties.
The proliferation of less invasive and more available brain imaging techniques during the past decade offers the possibility of new insights into the central origin of the behavioral picture associated with PWS. Mantoulan [
77] compared MRI and PET scans in PWS and non-PWS individuals. MRI images did not show evidence of anatomic abnormalities. However the PET scans showed hypoperfused brain regions, particularly in the anterior cingulum and superior temporal regions. The authors went on to correlate regional cerebral blood flow (rCBF) in the hypoperfused regions with results from the Child Behavior Check list (CBCL) and identified significant correlations, which suggested that the functional consequences of these perfusion abnormalities in specific brain regions might help to explain the social and behavioral issues observed in PWS. Similarly, a number of studies looking at brain processing of food related concerns have yielded mixed findings [
78‐
80]. Functional findings must be considered tentative as the technology is sufficiently challenging that few affected individuals can tolerate the technology nor cooperate with the necessary tasks. Nonetheless, as the technology evolves, the possibility for future studies holds great promise.