Salient associated features in autism or PWS include co-occurring psychiatric disorders, concerns with food and obesity, difficulties with sleep, and apparent strengths in visual–spatial functioning. Although not exhaustive, these features are relatively well-studied within each disorder and suggest several intriguing avenues for future research that directly compares groups with PWS versus ASD.
Psychiatric disorders
Psychiatric studies in PWS have relied solely on diagnostic labels, leaving specific psychiatric symptoms unclear or poorly described. Examining PWS cases that screened positive for psychopathology, Soni et al. (
2007) report that affective illness was more prevalent in mUPD versus deletion cases (64% as opposed 28%). Further, they note that more severe psychiatric presentations, including bipolar illness and psychosis with or without depression, were only seen in those with mUPD. In contrast, Descheemaeker et al. (
2002) followed 52 adults with PWS; and of the eight with psychiatric diagnoses, “bipolar affective disorders” were only reported in those with paternal deletions.
Examining 33 cases with mUPD, aged 5–36 years (
M = 19 years), we found that they were more than twice as likely as their counterparts with deletions to have been psychiatrically hospitalized (55% versus 20%; Dykens and Roof
2008). Unlike those with deletions, our mUPD sample also manifested significant, age-related increases in thought problems, noncompliant behavior, obsessions, and hoarding. These findings are consistent with previous reports of age-related increases in psychopathologies in this genetic subtype. A case example of a young adult with mUPD and co-occurring psychosis is presented in Table
4.
Table 4
Case example of PWS mUPD and psychosis
JJ, a 21-year-old male with PWS due to mUPD, lives at home with his parents and attends a vocational day program. He is healthy following a weight loss of 103 lb at age 17 that occurred during and after a stay in an in-patient hospital specializing in PWS. At the time of his follow-up research visit, JJ weighed 136 lb, was 5 ft tall, and taking antipsychotic medications. His parents were diligent with his diet and locking food. JJ was quite proud of his weight loss and tended to open conversations with, “I lost 103 lb, are you proud of me?” |
JJ’s parents reported increased agitation and aggressive behavior aimed at both them and his program staff (e.g., hitting, pushing, verbal threats). He was emotionally labile, laughing, for example, over something funny “in my head” and then within seconds being verbally abusive. At age 14 JJ experienced auditory and visual hallucinations, including an episode when his parents found him sitting naked on a couch outside their bedroom door, seeing and talking to make believe cartoon characters. He was subsequently placed on anti-psychotic medications but continued to have looseness of thoughts and magical thinking. |
During his visit to the lab, JJ hit the staff and then demanded that they repeat the phrase “No, I did not hit you”, and he became enraged when they did not exactly comply. JJ’s speech was repetitious, nasal, pressured and perseverative, and sprinkled with demands that the staff repeat phrases verbatim that were unrelated to context, e.g., “Yes, that really looks like blue green.” JJ believed that others could know what he was thinking even if he did not say it aloud and he became angry when the staff would not acknowledge his powers and believed that they were making fun of him. He was not oriented to person or place and insisted on eating lunch at his favorite restaurant some 600 miles away. |
JJ’s cognitive level (FSIQ = 41) had declined dramatically since his first psychotic episode at age 14 when he was functioning in the borderline range (FSIQ = 77). His parents were quite concerned that his escalating and bizarre behavior would not allow him to continue in the vocational day program and they feared that they would need to quit working in order to take care of him. The research team referred JJ to a PWS residential program for evaluation and possible placement as his escalating behaviors and thought disturbances required a more intensive treatment approach. |
Explanations for high rates of psychosis in mUPD generally implicate increased expression of maternally imprinted genes, especially UBE3A. Recently, however, gamma-aminobutyric acid receptor genes located in the PWS 15q11–q13 region have also been implicated; these genes are receptors for the brain’s primary inhibitory neurotransmitter. Sharp et al. (
2010) recently identified a novel differentially methylated regions (DMR) in the PWS critical region that was distal to gamma-aminobutyric acid A receptor-γ3 (GABRG3). Webb et al. (
2008) previously identified this same region as conferring increased risks of psychosis in adults with PWS due to mUPD, but not paternal deletion. While other DMRs in the 15q11–q13 region showed complete maternal or paternal methylation, this GABRG3 region was only partially methylated, suggesting that imprinting at this site is weakly regulated (Sharp et al.
2010). Relatively weaker parent of origin expression may help explain previous conflicting reports about methylation at the GABRG3 site. Sharp et al. (
2010) hypothesize that this DMR represents a promising candidate locus, or genetic or epigenetic variation that confers risks for psychosis in PWS, and future work may suggest ties to autism as well.
If the majority of people with mUPD develop psychosis or severe affective illness by late adolescence or early adulthood (Boer et al.
2002; Vogels et al.
2003), then PWS due to mUPD may provide an extremely useful window into psychosis in the general population. However, the specific symptoms associated with psychosis in PWS have yet to be well-described, leaving it unknown if these episodes are characterized by visual or auditory hallucinations, cognitive distortions, magical thinking, paranoia, severe or unusual obsessions, or by withdrawal, irritability, oppositionality, and changes in sleep, appetite, or activity levels.
Using a retrospective record review of adults with mUPD and psychosis, Vogels et al. (
2003) noted that most had symptoms of autism or autism diagnoses as children. This finding is puzzling, as data on secondary psychiatric conditions in people with ASD consistently find increased rates of depression and anxiety disorders, but substantially less overlap with psychosis or schizophrenia (Joshi et al.
2010; Leyfer et al.
2006; Tasatsanis
2003). Based on a psychopharmacology clinic sample of children and adolescents, Joshi et al. (
2010) found that 61% of 217 patients with ASDs had multiple anxiety disorders, 83% had attention deficit hyperactivity disorder (ADHD), and 20% had psychosis. These rates were significantly higher than non-ASD clinic patients and confirm earlier reports of elevated ADHD, anxiety and affective disorders, but not psychosis, in persons with ASD (Leyfer et al.
2006). The 20% of ASD patients with psychosis in the Joshi et al. (
2010) study were not further described. If psychosis is indeed rare in autism, then comorbidities of both autism and psychosis in PWS is quite discrepant with the general ASD population.
It is not clear how to best reconcile research indicating high rates of both autism and psychosis in PWS. Some suggest an apparent “evolution” from autism in childhood to psychosis in adulthood (Descheemaeker et al.
2002). Others assert that autism diagnoses in neurodevelopmental disorders with strong associations to schizophrenia, such as 22q deletion syndrome or Klineflelter’s syndrome, are actually false positives (e.g., Eliez
2007). In this view, autism diagnoses are an unsuccessful or superficial effort to capture premorbid personality or social dysfunction or what is essentially a prodromal state on the road to psychosis. Still others hypothesize that autism and psychosis are diametric disorders in their clinical phenotypes, and genetic and neural underpinnings (Crespi and Badcock
2008). Crespi (
2008) used disruptions in maternal imprinting and proneness to autism in AS versus disrupted paternal imprinting and proneness to psychosis in PWS to support the conflict theory of imprinting in evolutionary biology.
However, none of these possible explanations can be properly evaluated without detailed data on aberrant social, cognitive, or emotional processes in PWS. Categorical diagnoses of autism or psychosis are inadequate, and more fine-tuned and nuanced phenotypic descriptions in PWS are needed in order to address these hypotheses. An unclear symptom picture in PWS also severely limits treatment. If up to 40% of those with mUPD and 20% with deletions indeed develop autism, then they may benefit from early interventions that help children with autism in general. If the majority of persons with mUPD develop psychosis, then treatment can also move to a prevention mode, perhaps minimizing disease course via pharmacotherapy, behavioral, or other interventions. Preventative measures, however, first require identification of the symptoms being targeted and when they emerge or worsen.
Food and obesity
Although hyperphagia in PWS stands out, the drive for food in affected individuals is actually quite nuanced. Unlike previous views of PWS as a “two-stage” disorder (failure to thrive followed by onset of hyperphagia in early childhood), PWS is comprised of up to seven distinct nutritional stages and transitional periods that reflect different phases of food intake, underlying neuroendocrine status, and degree of obesity (Miller et al.
2011). Full-blown hyperphagia varies in length and also waxes and wanes in severity (Dykens et al.
2007). People with PWS rarely vomit or report gastrointestinal (GI) distress, yet these relatively benign complaints in most people can signal a life-threatening emergency in PWS related to acute gastric dilation, perforation, necrosis, and death (Stevenson et al.
2007). Higher risks of gastric dilation and rupture are seen in individuals with rapid weight loss or who are generally slim but have a binge-eating episode.
In contrast to hyperphagia in PWS, approximately 23% of children and adolescents with ASD have food selectivity, including food refusal, a limited food repertoire, and high frequency of eating single foods (Bandini et al.
2010). Food selectivity in ASD may relate to GI distress, including constipation, encopresis, and diarrhea, seen in approximately 25% of children with this disorder (e.g., Joshi et al.
2010; Nikolov et al.
2009). Recent data implicate associations between the MET C polymorphism and GI symptoms in children with ASD as well as associations between MET C and social and communicative symptoms but only in those with GI difficulties (Campbell et al.
2009).
Relative to the general population, children and adolescents with ASD are more likely to be obese or overweight. Compared to typical 10–17 year olds, Chen et al. (
2010) found much higher rates of obesity in children with autism (12.2% versus 23.4%, respectively). Among adults, Eaves and Ho (
2008) report that 42% were overweight or obese. Risk factors for obesity in ASD are similar to those seen in other disability groups, including a sedentary lifestyle, lack of regular activities or exercise, not being able to readily access gyms or recreational sports, limited knowledge about nutrition or healthy food choices, and appetite-altering side effects of psychotropic medications. Although obesity is increasingly identified in ASD, few evidence-based, weight-reduction programs exist that take into account the unique aspects of ASD.
Complications of obesity are the leading causes of premature death in adults with PWS (e.g., Einfeld et al.
2006); and obesity in this syndrome is related to mental health in complicated ways. In the general population, being overweight or obese is often associated with low self-esteem, and losing weight and being fit and trim with improved esteem (e.g., Simon et al.
2006). People with PWS, however, seem to show the opposite pattern. Specifically, adolescents and adults with lower body mass indices have increased compulsive behaviors, hoarding, and withdrawal, and are also more nervous, tense, tearful, distressed, upset, agitated, and cognitively disorganized (Dykens
2004; Hartley et al.
2005).
Although reasons for these counterintuitive finding are unknown, they may be associated with the effort, and physiological and psychological stress, of maintaining a lower weight. Due to their hypotonia and low-resting metabolic rate, persons with PWS typically require fewer calories than others to lose or maintain weight. Chronic, very low caloric restrictions (800–1,200 k/cal daily) or sudden weight loss may contribute to increased distress, disorganization, or compulsivity, perhaps more so in those already at risk due to mUPD. Simply put, the lifelong experience of being “always hungry, never full” may lead to more distress when access to food is curbed and weight loss or maintenance is achieved. Future studies using biomarkers of stress could shed some light on these hypotheses and inform decisions about balancing dietary restrictions with quality of life in persons with PWS and their families.
Sleep
Sleep disturbances occur in the majority of children with autism, especially sleep-onset insomnia, nocturnal awakening, and shorter overall nighttime sleep duration (Goldman et al.
2009). Examining sleep in a large cohort of children with ASD, Goldman et al. (
2009) found that poor sleepers, as determined by polysomnography, actigraphy, and parent report, had more daytime behavior problems, primarily hyperactivity and repetitive behaviors, than those deemed good sleepers. Further, actigraphic measures of wakefulness after sleep onset and sleep fragmentation were correlated with hyperactivity and restrictive and repetitive behaviors.
Aberrant sleep in PWS is well-described, including high rates of central and obstructive sleep apnea, abnormal arousal, abnormal circadian rhythm in rapid eye movement (REM) sleep, night awakenings, and excessive daytime sleepiness (Maas et al.
2010; Yee et al.
2007). Obesity may worsen some of these sleep parameters, yet does not completely explain abnormal REM or excessive daytime sleepiness, which are likely related to hypothalamic dysfunction (Bruni et al.
2010). Indeed, excessive daytime sleepiness can be quite impairing for individuals, regardless of their weight. Although disrupted sleep is associated with behavior problems in people with autism and intellectual disabilities in general (see Richdale and Schreck
2009 for a review), such relations are not readily apparent in PWS (e.g., Maas et al.
2010).
Beyond behavior problems, compelling evidence from both clinical and typical populations link sleep duration and quality to specific aspects of memory and cognition (see Durmer and Dinges
2005 for a review). Even so, researchers have yet to examine relations between sleep and cognition in PWS, autism, or other disability groups. Persons with PWS are prone to obstructive sleep apnea (e.g., Bruni et al.
2007), a known risk factor for cognitive deficits, which further highlights the need for research on cognition, sleep, behavior, and mood in this syndrome.
Visual–spatial strengths
Relative to their verbal skills, persons with autism appear to have strengths in visual–spatial processing. Earlier work found that people with ASD performed relatively well on standardized tasks assessing visual–spatial and pattern recognition, including block design, object assembly, or the imbedded figures test. More recent studies have fine-tuned these observations, pointing, for example, to intact or enhanced performance on static visual features or patterns, and inferior performance on more complex and dynamic spatial memory tasks (Bertone et al.
2005).
Persons with PWS have a similar profile. Early studies indicated relative strengths in visual–spatial functioning on standardized IQ tasks (e.g., block design), and individuals with PWS were also rumored to excel at jigsaw puzzles (Holm et al.
1993). Compared to others with intellectual disabilities, those with PWS spend more time engaged with puzzles (Dykens and Rosner
1999), and they also far outperform both IQ- and age-matched controls on jigsaw puzzles (Dykens
2002). Interestingly, they have only modest relative strengths in standardized visual spatial tasks. Verdine et al. (
2008) administered puzzles and tasks tapping spatial perception, mental rotation, and spatial visualization to a sample with PWS- and MA-matched controls. Although the PWS group performed relatively poorly on the spatial tasks, they performed very well on interlocking jigsaw puzzles, including achromatic puzzles. The typical control group used a visual approach to puzzle solving, while those with PWS had a pronounced, shape-based approach. Persons with autism are also rumored to excel at jigsaw puzzles, and a competency with puzzles is one of several specialized interests tapped in the ADI-R. Even so, researchers have yet to formally assess puzzle skills in this population and how they relate to broader visual–spatial functioning.
Next steps for research
Although far from exhaustive, this review highlights phenotypic similarities and differences across PWS and ASD, as well as salient knowledge gaps that need to be addressed in future research. These gaps are reflected in Table
5, which summarizes areas of phenotypic overlap and difference addressed in this review. Importantly, as few studies have directly compared participants with PWS or ASD, many features in Table
5 are “best guess” hypotheses based on findings within each disorder.
Table 5
Hypothesized similarities and differences in core symptoms and associated features of ASD and PWS
Repetitive behaviors | + | + |
Symmetry/exactness | + | + |
Narrow interests (not food) | ± | ± |
Skin picking | + | Limited data |
Hoarding | + | Limited data |
Need for sameness | + | + |
Verbal perseveration | + | + |
Stereotypies | − | ± |
Self-injury (not skin picking) | − | ± |
Poor peer relations | + | + |
Impaired theory of mind | Limited data | ± |
Poor emotional recognition | Limited data | ± |
Aberrant face processing | Limited data | + |
Problems reading social cues | Limited data | + |
Psychosis | ± | Limited data |
Positive symptoms | ± | Limited data |
Negative symptoms | + | Limited data |
Anxiety disorders | + | + |
Depressive disorders | ± | ± |
Excessive daytime sleepiness | + | − |
Sleep-onset insomnia | − | ± |
Nocturnal awakening | ± | ± |
Obstructive sleep apnea | ± | − |
Obesity | ± | ± |
Hyperphagia | + | − |
Food preoccupations | ± | − |
Limited food selectivity | − | ± |
Eating/food rituals | ± | ± |
Cognitive deficits | + | ± |
Facility w/jigsaw puzzles | ± | Limited data |
Future comparative studies are needed that take several methodological considerations into account. First, researchers need to use such gold standard tools for assessing autism in PWS as the ADOS-R and the ADI-R. Even so, these brief, interview-based assessments may not necessarily capture features of PWS that could discriminate between PWS and ASD. Consistent with best practices, then, researchers need to carefully review ADOS scores along with other behavioral, developmental, and medical data in making autism diagnoses in PWS and other genetic disorders.
A second issue pertains to comparison groups. Depending on the questions under study, various combinations of groups could be compared including individuals with PWS who do versus do not have autism diagnoses and who are appropriately matched to individuals with autism spectrum disorders or other intellectual disabilities. While these groups help distinguish features seen in PWS versus autism, a more nuanced approach uses comparison groups that selectively target the constructs under study. The type or severity of compulsive behaviors, for example, could be variably compared across people with PWS, PWS plus ASD, ASD, obsessive–compulsive disorder, and subtypes of patients with OCD (e.g., hoarders). Social–cognitive deficits could be compared across individuals with PWS, autism, schizophrenia, and atypical psychosis including the neurobiological underpinnings of these impairments (see Sasson et al.
2011). By studying “endophenotypes”, these approaches emphasize neural, genetic, hormonal, psychophysiological, or developmental processes that are shared or distinctive to these disparate conditions.
Finally, gaps in knowledge need to be filled in with an eye toward clinical relevance. Careful descriptions of aberrant social, cognitive, and neural processes are needed for future research that aims to identify how the expression of susceptibility genes in the PWS/AS region (e.g., UBE3A, snoRNAs, and GABRG3) contributes to autism, psychosis, or other challenges. These behavioral and neural discoveries are needed to make more informed and immediate decisions about intervention. For example, should pharmacotherapy or other treatments begin as soon as adolescents with PWS show even a slight worsening or subtle onset of problems in thinking or mood? What other risk or protective factors derived from the autism, schizophrenia, or intellectual disabilities literature could inform treatment in PWS? Conversely, how does PWS inform genetic and other risks for autism or psychosis in the general population? Although PWS has not been as rigorously studied as other genetic conditions associated with autism or psychosis, it holds considerable promise for shedding new light on mechanisms and treatments for these otherwise debilitating disorders.