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327

Section 3

Organic syndromes of schizophrenia: genetic disorders related to SLP

Stewart L. Einfeld, Sophie Kavanagh, Arabella Smith, and Bruce J. Tonge
Facts box

short stature, small hands and feet, and characteristic
r

facies. Early onset of obesity is associated with hyper-Prader-Willi Syndrome (PWS) is a congenital
phagia and the development of other maladaptive
disorder characterized by infantile

behaviors
[1, 2, 3].
Hypothalamic dysfunction is evi-hypotonia, hypogonadism, mild intellectual
denced by deficiency of growth hormone
[4]
and leu-disability, short stature, small hands and feet,
tinising hormone
[5].
A reduced number of oxytocin-and characteristic facies.

producing cells has been found
[6].
DNA studies have
r
DNA studies have shown that PWS may arise
shown that PWS may arise by three different mecha-by three different mechanisms acting within
nisms acting within the imprinted region of chromo-the imprinted region of chromosome
some 15(q11–13)
[7, 8].
A functional paternal PWS

15(q11–13). The three mechanisms are

gene is essential for normal development. The three
paternal deletion, maternal uniparental
mechanisms are paternal deletion of the PWS locus on
disomy (UPD), and a rare abnormality

chromosome 15(q11–13) in about 74% of cases (most
within the imprinting control mechanism.

clearly seen on FISH), maternal uniparental disomy
r
The true rate of psychotic disorder in this
(UPD) in approximately 24%, and a rare abnormal-population remains to be determined, but all
ity within the imprinting control mechanism in 1%–
reported rates are high, between 10% and
2% of cases
[8].
High resolution cytogenetic testing
30%.

alone is unreliable for the diagnosis of PWS compared
r
Psychotic episodes begin in adolescence or
with DNA studies
[9]
. A DNA methylation test can dif-early adulthood. Most studies describe the
ferentiate the maternal and paternal chromosomes by
psychosis in PWS as having an intermittent
their methylation pattern and is the definitive diagnos-relapsing course, with full recovery between
tic test, although it does not provide the mechanism.

episodes

r
Individuals with PWS because of UPD have
Psychosis in PWS

about five times the risk of developing
psychosis compared with those with a

There have been a number of reports of psychotic ill-deletion. The mechanism of this increased
ness in those with PWS, suggesting that there may be
risk is unknown.

an association between these conditions. Some authors
r
Other types of psychopathology and problem
have attempted to determine the prevalence of psy-behaviors in this population include severe
chotic symptoms in those with PWS. Clarke
[10]
sur-hyperphagia and associated behaviors
veyed the caregivers of 95 people with PWS. There
including stealing food and pica; depression;
was a known genetic diagnosis in 40 cases (42%). They
temper tantrums, impulsivity, stubbornness;
found that 6.3% of 95 subjects had experienced a pos-and skin-picking and obsessive or

sible psychotic disorder in the preceding month. Boer
compulsive-like symptoms.

and colleagues
[11]
found that 6 of 54 adults (11%)
with genetically proven PWS could be given a diagnosis of psychotic illness. Beardsmore and colleagues
What is Prader-Willi Syndrome?

[12]
found that 21.7% of a sample of 23 adults with
PWS is a congenital disorder characterized by infantile
PWS had current psychotic symptoms. However, this
328

hypotonia, hypogonadism, mild intellectual disability,
sample may have been over representative of those
Chapter 25 – Psychosis in Prader-Willi Syndrome

with psychiatric problems because some cases were
Course and treatment of psychosis

recruited from a psychiatric service. Descheemaeker
in PWS

and colleagues
[13]
followed up on 53 people with
confirmed PWS seen at a genetic clinic, for 15 years.

Psychotic episodes begin in adolescence or early adult-They found that 4 (7.5%) of these people devel-hood. Most studies describe the psychosis in PWS

oped psychotic symptoms. Vogels and colleagues
[14]

as having an intermittent relapsing course, with full
also followed up on a group with confirmed PWS

recovery between episodes
[19, 22, 23].
The best
through a genetic clinic; 59 patients were followed for
description of the psychosis in PWS may be an inter-10 years; 6 (10.2%) experienced a psychotic episode.

mittent schizo-affective disorder. There have been
Bray and colleagues
[15],
in describing a series of
no controlled studies of antipsychotic medications
40 patients with PWS, reported that 2 had required
in individuals with PWS. In the authors’ experi-hospitalization for brief psychotic episodes. Whitman
ence, psychotic symptoms have resolved rather quickly
and Accardo [16] assessed a nonclinical sample of
with small doses of antipsychotic medication. There
35 adolescents with PWS. They found that psychotic
are conflicting case reports regarding the efficacy of
symptoms were commonly reported: 11% reported
sodium valproate to manage the affective symptoms in
visual hallucinations as “very true/often,” whereas 11%

PWS.

reported strange ideation and 29% reported paranoid/suspicious as “very true/often.” Bartolucci and
Influence of genetic subtype on

Younger
[17]
reported 4 of 9 people with PWS referred
psychosis in PWS

for psychiatric consultation as having symptoms of
psychosis. The present authors found 16% of their PWS

Does the genetic type of PWS determine the risk of
subjects forming part of the Australian Child to Adult
developing psychosis? We summarized the findings in
Development study
[18]
to have a history of psychosis.

all studies
[10, 11, 12, 13, 14, 23, 24]
that have reported
Soni and colleagues
[19]
found 29% of 119 individ-interpretable data. These studies have tended to show
uals with PWS had a history of psychotic symptoms.

that UPD and imprinting defects are more likely to
The true rate of psychotic disorder in this population
be associated with psychosis, but this finding has been
remains to be determined, but all reported rates are
inconsistent. In all the reported series taken together,
high, between 10 and 30%.

there were 78 adults with PWS due to a deletion, of
whom 11 had suffered a psychosis, 38 subjects with
UPD of whom 26 had suffered psychosis, and 5 with
Other psychopathology in PWS

imprinting defects of whom 4 had suffered psychosis.

PWS has been shown to be associated with a range
This means that the relative risk for psychosis for dele-of symptoms of psychopathology apart from symp-tion: UPD: imprinting defect is approximately 1:5:6.

toms of psychosis. Most prominent is the severe hyper-phagia and associated behaviors including stealing
Why is psychotic illness more

food and pica
[3].
Affective symptoms are also com-

common in the uniparental disomy

monly reported. In the study of Soni and colleagues
[19],
23% had a history of depressive disorder, and
subtype of PWS?

10% bipolar disorder. Verhoeven and colleagues
[20]

What could account for the increased risk of psychosis
described the symptoms in their cohort as “cycloid
when PWS is caused by UPD? The genetic defects
psychosis.” That is, a sudden onset of delusions and/ or
causing PWS all feature loss of the paternal region
hallucinations accompanied by depressive symptoms
by deletion, imprinting center defect, or UPD. The
that resolve without residual dysfunction. Dykens
deletions take out specific defined regions of chromo-and Cassidy
[21]
found that severe temper tantrums,
some 15, the common large deletion (from bands q11–
impulsivity, and stubbornness were reported as sig-13), or the imprinting center microdeletions (exons
nificant problems in a high proportion of individuals
within the SNRPN gene). On the other hand, UPD

with PWS. Ninety-seven percent had persistent skin-is of the whole chromosome 15 (only rarely has par-picking, and 71% had obsessive or compulsive-like
tial UPD been described in PWS
[25]).
Any hypoth-symptoms. These findings were broadly replicated in
esis to explain a preponderance of PWS in patients
329

an independent sample by Einfeld and colleagues
[3].

with UPD must acknowledge that another gene(s) on
Organic Syndromes of Schizophrenia – Section 3

chromosome 15 is maternally imprinted and when no
and bipolar affective disorders
[26].
In PWS, mater-paternal copy is present leads to deleterious effects on
nal UPD may contribute to psychosis in patients pre-brain function.

disposed to these disorders, due either to disomy for
For this purpose, putative genes could be within
a given “deleterious” maternal gene or nullisomy for
the critical 15(q11–13) region or outside this region.

a “necessary” paternal gene
[27].
Our current level of
The genes within the region that encode a protein
understanding of the link between psychosis and PWS

comprise SNRPN (controlling RNA splicing), SNURF

is less advanced than for the velo-cardio-facial syn-

(a ring finger protein that can bind DNA), the P

drome
[28].
However, in that condition the effects are
gene (which codes for tyrosinase positive albinism),
a consequence of a deletion. In PWS, genomic defects
GABRA B3, A5, G3 (GABA receptor subunit genes),
produce their consequences through abnormalities of
E6AP (UBE3A) (the Angelman Syndrome gene),

imprinting, in which abnormalities of gene function
Necdin (encodes a DNA binding protein), and Marko-may be less apparent.

rin 3 (also known as ZNF127, a zinc finger protein
that is able to bind DNA). The role of most of these
genes is to control expression. The GABA genes act in
Conclusion