Secondary Schizophrenia (125 page)

A recent report of psychotic symptoms in 17% of chil-with VCFS

dren with VCFS below the age of 13 years, most commonly auditory hallucinations, reiterates the occur-Morphometric MRI analyses in VCFS children prior
rence of a spectrum of psychiatric symptoms before
to the development of psychoses have found a variety
the onset of overt psychosis
[79].
Such psychotic symp-of abnormalities such as reduced total brain volume,
toms increase in frequency with age, with reports of
white-matter reductions in nonfrontal areas, grey-28% by age 19 and up to 48% in the age range of 13–
matter reduction in the parietal and occipital lobes,
25 years
[80]
and are often associated with a decline
relatively large frontal lobes, decreased right cerebel-in verbal abilities
[79]
, a finding seen in the high-lar tissue volume, and reductions in the cingulate
risk schizophrenia population as well
[81, 82].
It is
gyrus, temporal lobe, superior temporal gyrus, and
not yet known if aggressive treatment of such early
hippocampus
[89, 90, 91, 92, 93, 94, 95].
A relative
psychotic symptoms would have an impact upon the
increase in the grey matter within the frontal lobes
progression to overt psychosis or upon the prognosis
and the insula and an increase in the volume of the
thereof.

caudate body and the amygdala have been reported
[96,
97, 98, 99, 100]
. The area of the corpus callosum
(CC) is also increased in children with VCFS, compared to control subjects
(Figure 24.4)
[87,
101].
The
Structural brain abnormalities in VCFS

exact significance of such relative increases in brain
On qualitative (routine) studies of brain anatomy in
volume is unclear, because this is in contradiction with
VCFS, midline anomalies (cavum septum pellucidum
the finding of volumetric reduction of these areas in
and a small cerebellar vermis), white-matter hyper-most studies of individuals at high risk of schizophre-densities, and enlarged Sylvian fissures were reported
nia in the general population
[24,
40, 47,
102, 103].

[83, 84, 85, 86,
87].
A cavum septum pellucidum is
However, it indirectly supports the hypothesis that
thought to be indicative of maldevelopment of struc-neuronal dysmaturation occurs in subjects at high
tures bordering it, such as the corpus callosum and
risk of schizophrenia, such as VCFS, due to an exag-the hippocampus, structures frequently reported to be
geration of the normal cortical developmental pro-abnormal in schizophrenia. It is seen in 45% of individ-cesses in childhood, previously discussed. The regional
uals with schizophrenia
[42]
and in a similar percent-increases in grey matter volume may reflect initial neu-age of individuals with VCFS who have schizophrenia
ronal overgrowth and may be correlated with the early
[88].

314

neurocognitive abnormalities that are seen in children
Chapter 24 – Velocardiofacial syndrome

with VCFS (see next paragraph). Grey-matter reduc-that in VCFS subjects without mental retardation, the
tions seen in adults with VCFS who have schizophre-age of onset, lifetime or cross-sectional positive and
nia (discussed later in this chapter) support the notion
negative symptoms and global functioning are simi-that this initial exaggerated neuronal overgrowth may
lar to that seen in individuals with schizophrenia in
be followed by excessive synaptic pruning in later life.

the general population
[107]
. It is to be noted that this
A few cross-sectional studies have attempted
study needs to be replicated, because ascertainment
to correlate the morphological brain abnormalities
bias may have occurred; the VCFS patients were identi-with neuropsychological findings in VCFS children.

fied after a diagnosis of schizophrenia had been already
Two studies have observed that increases in brain
made and thus their features may not be representative
area/volume are associated with behavioral problems
of the VCFS population as a whole. However, further
and minor psychiatric symptoms. In the first study,
evidence for the similarity in the schizophrenia phe-an increase in fronto-striatal grey-matter volume was
notype between the general population and VCFS is
associated with more severe social problems and an
provided by the findings that in childhood schizophre-increase in grey matter in the temporo-occipital lobe
nia associated with VCFS, the age of onset, premor-with elevated schizotypal traits
[99].
The second study
bid functioning, or severity of psychosis were no dif-found that there was a positive correlation between the
ferent than that in the general population
[21].
It is
volume of the amygdala and the internalizing, exter-important to emphasize that schizophrenia represents
nalizing, anxiety, and aggression scores on the child
the most severe of these manifestations and individu-behavior checklist
[100].
Decreases in grey matter have
als with VCFS may frequently have symptoms that are
also been correlated with behavioral problems in chil-less severe, such as major depression and schizotypy,
dren with VCFS. Decreased temporal grey matter was
and it is conceivable that a given individual may fluc-associated with behavioral problems
[104];
whereas
tuate within these diagnostic entities at different time
children with VCFS had a larger area of the CC as
points, as suggested for schizophrenia in the general
a group, those with ADHD had a smaller CC, sim-population
[108].
Further studies with larger sample
ilar to the finding with ADHD in the general pop-sizes are needed to fully define the clinical phenotype
ulation
[103].
The authors of the CC study postu-of schizophrenia in VCFS.

lated that an overall increase in the size of the CC

The neurocognitive abnormalities (working mem-was suggestive of delayed synaptic pruning in chil-ory and executive function) and motor skills of
dren with VCFS. These studies have provided prelimi-individuals with VCFS who have schizophrenia are
nary data that suggest that relative increases/decreases
similar to those that occur with schizophrenia in the
in grey matter (possibly related to abnormal synap-general population
[11].
Similarly, deficits in spatial
tic pruning) are associated with the minor psychiatric
working memory, strategy formation, visual recogni-diagnoses in children with VCFS. An imbalance in
tion, and attention are worse in VCFS adults with
synapses (too many or too few) has long been believed
psychosis than in those without psychosis
[109].
This
to be related to the symptoms of schizophrenia
[24,

apparent lack of distinguishing features between VCFS

105]
. Future research involving longitudinal studies
related schizophrenia and that seen in the general
throughout childhood and adolescence will be critical
population further bolsters the utility of VCFS as a
in determining the nature of such changes and their
model to study the neurodevelopmental hypothesis of
relevance to schizophrenia.

schizophrenia.

Schizophrenia phenotype in VCFS

Quantitative MRI studies in adults

When the first reports of schizophrenia in VCFS

with VCFS

emerged in the early 1990s, initial reports were con-In adults with VCFS, the first quantitative study
flicting, reporting later age of onset and fewer nega-reported that compared to controls, there was loss
tive symptoms
[10],
as well as younger age of onset
of grey matter in frontal and temporal areas, includ-

[16,
106],
due to small sample sizes and inclusion of
ing the insula and diffuse loss of white matter
[88].

VCFS individuals who were mentally retarded. Since
On diffusion tensor imaging, VCFS adolescents and
then, a report of a series of VCFS patients indicates
adults had evidence of impaired fronto-temporal
315

Organic Syndromes of Schizophrenia – Section 3

connectivity compared to control subjects
[110].
High-

Molecular genetics of schizophrenia as

lighting the differences between VCFS adults with
related to chromosome 22q11.2

schizophrenia and those without, Chow and col-leagues reported a decrease in total grey matter,
Linkage studies in families with schizophrenia, unre-regional differences in grey and white matter in
lated to VCFS, are indicative of this region contain-the frontal, temporal, and parietal lobes, and an
ing a gene(s) that predispose(s) to schizophrenia
[3,

increased volume of cerebrospinal fluid in those with
56,
114].
A few families with bipolar disorder have also
schizophrenia
[111]
. A more recent study found that
been linked to the same interval
[115, 116].
Although
within VCFS adults, those with schizophrenia have
DNA studies thus far have failed to identify a specific
reduced brain volumes affecting both grey and white
gene(s) that is (are) etiologically related
[117, 118],
it is
matter and increased CSF volumes, compared to VCFS

likely that a gene(s) in the 22q11.2 region is (are) con-subjects without schizophrenia and control subjects
tributory to the illness in the general population as well
[112].
Although these studies are few in numbers and
as in individuals with VCFS.

involve small numbers of subjects, the decrease in grey
It is to be noted that because individuals with VCFS

matter in the heteromodal cortices in VCFS individ-have a deletion encompassing
∼
35 genes on one chro-uals with schizophrenia is consistent with the sup-mosome 22 with the corresponding genes on the other
position that during the period of adolescence and
chromosome 22 being present, they are haploinsuffi-early adulthood, the normal process of synaptic prun-cient/hemizygous for these genes.

ing may well be exaggerated in these individuals
[111,

It is believed that decreased expression of this
112]
. Other findings in this group include loss of white
sequential group of genes due to the haploinsuffi-matter, a smaller cerebellum, a cavum septum pelluciency may be the cause of schizophrenia in VCFS

cidum, and large ventricles
[86,
88,
110],
findings sim-

[119,
120, 121].
In addition, it is possible that spe-ilar to schizophrenia in the general population.

cific single nucleotide polymorphisms (SNPs) in the
remaining allele of the genes in the 22q11.2 interval
Treatment of VCFS-associated

may contribute to psychosis risk in these individuals.

The presence or absence of such polymorphisms in
psychiatric illnesses

the hemizygous genes (remaining copy) could partly
There is a paucity of clinical trials that have exam-account for the variability seen in the occurrence
ined the efficacy of specific treatments (both behav-of psychoses, because 60%–75% of VCFS individu-ioral and pharmacological interventions) in children
als do not develop psychiatric illnesses, although the
and adults with VCFS. Although clinicians remain
overwhelming majority of affected individuals have
concerned about the possibility of unmasking psy-the same size deletion. Such polymorphisms in the
chosis by treating ADHD with methylphenidate, at
“normal” allele have been postulated as accounting for
least one study as well the clinical experience of psy-the variability in manifestations in several genetic dis-chiatrists familiar with VCFS seem to indicate that
orders, including VCFS
[122, 123].

this medication is both safe and efficacious in VCFS

The deleted segment in individuals with VCFS

individuals
[78,
113].
The pharmacological treatment
is about 3 Mb in size. However, the region that is
of schizophrenia in VCFS, based on the existing lit-thought to be critical for the etiology of schizophre-erature, appears similar to that in the general pop-nia is about 1.5 Mb
[19]
. SNPs within one or more
ulation, with newer atypical antipsychotic medica-genes in this critical interval
(Figure 24.5)
may alter
tions being effective
[10, 21,
107].
There are no lit-the abundance of the proteins (usually by decreas-erature reports of systematic evaluations of behav-ing transcription), thus contributing to the risk of
ioral interventions in the psychiatric manifestations in
schizophrenia
[5,
124, 125, 126].
Detailed below are
VCFS. In the future, controlled clinical trials exam-some of these genes, the most promising of which are
ining the value of both the psychological and phar-the COMT and PRODH genes that are involved in
macological treatments are essential to formulating
dopaminergic and glutaminergic neurotransmission,
better management strategies and to effectively eval-respectively. Dopamine and glutamate are thought to
uate the benefits of early intervention in this high-risk
be major mediators of schizophrenia in the general
population.