|
 Prader-Willi
syndrome (PWS) is a developmental disorder characterized by mental retardation
or learning disability, infantile hypotonia and poor suck reflex, growth
retardation, delayed sexual development, and the childhood onset of pronounced
hyperphagia. Food-related difficulties are the most striking and widely
recognized sequelae of this syndrome. Without appropriate dietary and
behavioral intervention, almost everyone with PWS will become dangerously
obese. However, in addition to these well-known problems with food, those
with PWS also suffer from a range of psychiatric and behavioral difficulties,
including high rates of depression, obsessions, and compulsions.
PWS
is a relatively rare disorder, with an incidence of approximately 1 in
10,000 to 15,000 live births. Nonetheless, it has figured prominently
in the recent history of genetics. This is due in large part to its surprising
relationship with Angelman syndrome (AS) and the resulting identification
of genomic imprinting in humans. Moreover, as research into the various
aspects of this disorder has progressed, it has become increasingly evident
that PWS may provide neuroscientists a valuable window into the complex
interplay of genes, brain, and behavior.
At
first glance, the genetics of PWS appear to be rather straightforward.
For most affected individuals, a sporadic (as opposed to familial) loss
of chromosomal material in the region 15q11-q13 leads to the predictable
clinical phenotype. However, a closer look suggests that there is considerable
subtlety and complexity to the genetic mechanisms involved. At first,
geneticists were baffled by the observation that AS is caused by a deletion
involving the same chromosomal region in which PWS is involved. The relationship
between the two syndromes was particularly unexpected because of the absence
of any significant clinical overlap between the two, with AS leading to
severe mental retardation, seizures, and the absence of language.
By
the mid-1980s, it had become clear that the key to the genetic distinction
between PWS and AS was the parental origin of the chromosome containing
the deletion. In PWS, the deletion is always found on the paternally donated
chromosome. Conversely, in AS, the deletion is always located on the maternally
donated chromosome. This discovery led to the recognition that gene expression
in humans may be dictated by the chromosome on which the particular copy
of that gene resides. This phenomenon, known as genomic imprinting, has
been discussed in greater detail in 2 recent columns.
Over
the past decade, researchers discovered that PWS may result not only from
a chromosomal deletion, but also from maternal uniparental disomy (UPD).
In this situation, 2 copies of the maternal chromosome are inherited with
no paternal contribution. In the normal circumstance, the paternally donated
chromosome expresses multiple genes in the PWS region, while the maternal
chromosome is largely silent. In the case of UPD, without the presence
of a chromosome donated from the father, normal imprinting on the 2 maternally
donated chromosomes leads to the absence of gene expression in this interval.
As a result, despite the presence of 2 intact chromosomes, there is a
functional abnormality that is largely equivalent to the structural
abnormality found in the more common 15q11-q13 deletions. In addition,
in about 5% of affected individuals, abnormalities in the mechanism of
imprinting may lead to the absence of gene expression from the paternally
donated chromosome, resulting in the PWS phenotype. This occurs when the
imprinting control center is itself mutated.
The
specific genes in the 15q11-q13 region that result in the various manifestations
of PWS have not yet been identified. The small nuclear ribonucleoprotein
associated polypeptide N (SNRPN) has been the object of considerable study.
This gene is involved in protein splicing, it is expressed throughout
the brain, and its promoter resides within the smallest chromosomal region
of overlap among all deletions leading to PWS. However, findings from
animal knockouts and rare cases of chromosomal rearrangements in humans
have suggested that the PWS phenotype may not be the direct result of
a loss of SNRPN expression. A number of other candidate genes have
been identified as well, including the neuronal protein, necdin (NDN).
This gene, when knocked out, leads to failure-to-thrive in certain strains
of mice, a phenotype that is clearly analogous to the poor suck reflex
and failure-to-thrive seen in infants with PWS. It is interesting that
knockout mice that survive these initial difficulties go on to develop
normally. Figure 1 illustrates the genes contained within the PWS/AS region.
There
has long been speculation that the genetic abnormalities found in PWS
lead to hypothalamic dysfunction, which in turn is responsible for the
clinical phenotype. There are multiple lines of evidence in support of
this hypothesis. For instance, the frequent occurrence of premature and
postdates delivery of PWS infants suggests that there may be abnormalities
in the fetal hypothalamus because of its known role in the regulation
of labor. Moreover, the combination of abnormal food intake regulation,
delayed sexual development, sleep irregularities, difficulties with thermoregulation,
and growth hormone problems often found in individuals with PWS all point
to this brain region playing a key role in the clinical manifestations
of the syndrome.
Several
controlled studies have provided additional clues about the neuropathology
of PWS. One small but important postmortem study showed relatively few
oxytocin-secreting neurons in certain regions of the hypothalamus. A subsequent
study of 5 subjects with PWS showed that the level of oxytocin in their
CSF was actually increased compared with controls. While the direction
of the difference was surprising in light of the postmortem data, taken
together the results suggest some abnormality in the regulation of this
important hypothalamic peptide. Finally, a structural magnetic resonance
imaging (MRI) study of individuals with PWS hinted at functional abnormalities
in this same brain region based on the absence in several patients of
what is known as the ³posterior pituitary bright spot,² which is thought
to be a marker for hypothalamic function.
Despite
the multiple signs pointing in the direction of the hypothalamus, several
studies have identified other brain regions and neuropeptides as possibly
being involved in PWS. A study that included both MRI and magnetic resonance
spectroscopy showed diffuse minor abnormalities in subjects versus controls,
including slightly enlarged ventricles, cortical atrophy, and a small
brainstem. In addition, there has been a report of abnormalities in plasma
[gamma]-aminobutyric acid (GABA) in PWS subjects. This neurotransmitter
has been the subject of some interest, because loci for GABA receptor
subunits are located in the vicinity of 15q11-q13, just telomeric to the
PWS/AS critical region.
For
those who are not familiar with the syndrome, it may be difficult to grasp
just how profound and far-reaching chronic hyperphagia is for those with
PWS and their loved ones. Hoarding food is common, as is stealing or sneaking
to circumvent dietary restrictions. Without significant intervention,
which often includes locking cabinets and refrigerators, almost everyone
with PWS will become obese. Given the combination of poor muscle tone,
small stature, and a driven appetite, the extent of this obesity may readily
become life-threatening. During childhood and into adolescence, restrictions
on food may lead to constant conflicts, and parents and other caregivers
are often in the difficult position of having to enforce diets that would
leave a person of normal appetite feeling constantly hungry.
If
this difficulty with food were not a sufficient hurdle, persons with PWS
also suffer from a range of behavioral and psychiatric difficulties apart
from food, including obsessions, compulsions, mood lability, and depression,
which may often be quite severe. While children and adolescents with PWS
have, on average, mild levels of cognitive delay, their behavioral and
psychiatric difficulties typically result in highly restrictive levels
of care and are often the source of enormous distress for patients and
their families.
These
types of difficulties have been the subject of a growing body of research
over the past decade. Conventional clinical wisdom as well as descriptive
studies have long held that some personality characteristics and psychiatric
difficulties observed in those with PWS are in fact a distinctive feature
of the syndrome, a so-called ³behavioral phenotype.² As the number of
well-controlled investigations into the adaptive and psychological functioning
of those with PWS has grown, this clinical folklore has been largely substantiated
by experimental data. (Fig.
1).
The
notion that those with PWS have a distinctive behavioral phenotype is
nonetheless still somewhat controversial. There is an understandable reluctance
on the part of clinicians and researchers to paint a group of individuals
with an overly broad brush. However, in the case of PWS, several carefully
done studies have identified both a set of behaviors and personality attributes
that do, on average, distinguish those with the syndrome from other developmentally
delayed individuals with and without clearly identified genetic syndromes.
The concept of a behavioral phenotype may be difficult to accept if it
is taken as a description of every person with a syndrome. A more useful
definition is that a behavioral phenotype is simply a heightened probability
that people with a given syndrome will exhibit behavioral or developmental
characteristics relative to others without the syndrome. For example,
hyperphagia is not unique to persons with PWS, and not everyone with the
syndrome exhibits it. However, the odds are that a 1-year-old with PWS
will develop this difficulty in the succeeding 3 years.
Several
recent studies demonstrate that such a heightened probability clearly
applies to obsessions and compulsions apart from the issues around food.
A study in the mid-1990s showed that more than 60% of PWS subjects had
obsessive-compulsive symptoms with moderate to severe levels of symptom-related
distress and adaptive impairment. More than half of subjects met clinical
criteria for obsessive-compulsive disorder (OCD). Their symptoms were
of similar type and severity to those found in persons with OCD without
mental retardation. Two subsequent studies supported these data and demonstrated
that increased obsessive-compulsive symptomatology could not be easily
accounted for by rater bias, obesity, or even hyperphagia.
Recent
studies have compared those with PWS to other groups with genetic syndromes
as well as those with mental retardation of mixed etiology. Overall, those
with PWS appear to have more behavioral disturbances than controls, including
tantrums, irritability, and agitation. Those with PWS also seem likely
to have skin-picking, repetitive speech, and ³underactivity.² There have
been numerous observations that those with PWS suffer from both depression
and anxiety, although controlled studies regarding depressive and anxious
symptoms (apart from OCD) have yet to be conducted.
The
PWS behavioral phenotype is not limited to psychiatric and behavioral
difficulties. Many individuals with PWS also show a distinctive, although
not necessarily unique, profile of cognitive strengths and weaknesses.
Those with the disorder span a large range of intelligence, from average
ability to severe retardation. The mean IQ is 70, which is high relative
to that found in other genetic mental retardation syndromes. Adaptively,
however, even those with normal IQ rarely function at a level commensurate
with this measure of intelligence, usually because of interference from
the food-related and other behavioral problems. Academically, reading/decoding
and comprehension may exceed arithmetic skills, although academic performance
may not be sufficiently uneven to meet learning disability criteria. Some
people with PWS have relative strengths in spatial-perceptual organization
and visual processing. By contrast, weaknesses have commonly been noted
in sequential processing and short-term memory tasks, including visual,
motoric, and auditory short-term memory.
In
summary, research into PWS over the past decade has begun to establish
some links between genetic abnormalities, brain function, and behavioral
and cognitive attributes. Genes in the region of 15q1113 may be abnormally
expressed as the result of either a structural or functional abnormality
in this chromosomal region. Although the specific genetic culprits have
not yet been identified, the genetic lesion(s) appear to lead to hypothalamic
dysfunction. Finally, the accumulated evidence suggests that whatever
the underlying neuropathology, those with PWS often display some evidence
of a behavioral phenotype that clearly includes obsessive-compulsive symptoms,
skin-picking, hyperphagia, low activity levels, behavioral outbursts,
and a distinctive cognitive profile compared to controls with mental retardation.
This
emerging picture of genebrainbehavior relationships suggests a range
of important research questions. For instance, is the hypothalamus the
key brain region affected by the gene or genes underlying the behavioral
aspects of PWS? What roles do the hypothalamus and hypothalamic peptides
play in the rituals, obsessions and compulsions, and mood lability often
seen in those with PWS? Does this brain region contribute to similar manifestations
in those without PWS? Are all persons with PWS, regardless of the underlying
genetic mechanism, equally likely to display aspects of the behavioral
as well as physical and developmental phenotype?
As
these questions are answered, it is likely that avenues for improved treatment
will reveal themselves. More broadly, this view of how genes, brain, body,
and mind interact will provide some unexpected clues about the roots of
psychopathology in other psychiatric conditions.
top of page
|
