Authors: Perminder S. Sachdev

Secondary Schizophrenia (124 page)

Figure 24.3
Fluorescence in-situ hybridization showing the
presence of both 22q11.2 regions (a) and the deletion (b) with the
commercially available probe (Vysis, Gaithersburg, MD. Courtesy:
Mark Pettenati, PhD, Department of Pediatrics, Wake Forest
Figure 24.2
Sixteen year-old girl with VCFS who does not
University School of Medicine.) (See color plate section.)
demonstrate the typical facial appearance, apart from small ears,
illustrating the variability of these features. The practicing
psychiatric health professional thus needs a high index of suspicion
that it became clear that VCFS had an important dis-to make the diagnosis.

tinguishing characteristic: an extraordinarily high risk
(30%–40%) of major psychiatric illnesses in late ado-deletions are sporadic and occur de novo (> 90 %),
lescence and early adulthood, mainly schizophrenia
but a small percentage are inherited from an affected
(25%–30%) but also schizotypy, bipolar illness, and
parent (7%).

major depression
[7, 8, 9, 10, 16].
Recent evidence
indicates that the frequency of psychiatric diagnoses
Relevance of VCFS to schizophrenia

in adults with VCFS may be even higher (
∼
60%)
Although the well-described intellectual disabilities in
[17].
Overall, such an incredible risk of psychiatric ill-VCFS (discussed later) are findings that are common
nesses has not been described in other conditions asso-

311

to many genetic conditions, it was in the early 1990s
ciated with mental retardation
[18].
In addition, in
Organic Syndromes of Schizophrenia – Section 3

individuals with schizophrenia, there is an increased
ing credence to the supposition that detecting deficits
prevalence of the 22q11.2 deletion (1%–5%)
[19, 20,

in these domains in earlier life may have value in dis-

21].
Thus, because schizophrenia risk is undoubt-ease prediction.

edly increased in VCFS and the incidence of VCFS

Several structural brain abnormalities have been
is increased in individuals with schizophrenia in the
described at the onset of illness in patients with
general population and because genes in the 22q11.2

schizophrenia, such as cortical atrophy, ventricular
interval are likely to be involved in the causation of
enlargement, decreased gray matter, a small corpus
schizophrenia, VCFS offers a unique opportunity to
callosum (CC)
[38, 39, 40, 41],
medial temporal and
examine the factors contributing to this catastrophic
superior temporal gyri abnormalities, decreased dor-illness.

solateral prefrontal cortex and parietal lobes, cavum
septum pellucidi, abnormal basal ganglia, small cerebellum
[42, 43],
and a decrease in the hippocampus,
The neurodevelopmental hypothesis

thalami
[44, 45],
and anterior cingulate gyrus volumes
[46].
Family members of individuals with schizophre-

of schizophrenia

nia, whose vulnerability to the illness is believed to
This hypothesis states that schizophrenia is the out-be increased due to genetic factors, manifest similar
come of an aberration of neurodevelopment that
changes, of lesser severity, strengthening the neurode-begins long before the onset of clinical symptoms
velopmental hypothesis
[47].

[22, 23]
. A combination of genetic and environmen-These brain aberrations in schizophrenia are
tal factors, including pre-and perinatal events, postna-thought to be due to an exaggeration of normal corti-tal developmental processes, and environmental stres-cal development, such that normal development going
sors are believed to result in the illness
[1, 24, 25,

awry may result in the illness. Normally, the corti-

26].
Evidence of abnormal neurodevelopment is procal structures continue to develop well into adoles-vided by the presence of neuropsychological and struc-cence
[48, 49].
Gray matter increases in late child-tural brain abnormalities before and at the onset of ill-hood (peaks at 11.5 years in females and 14.5 years in
ness. Minor facial dysmorphisms
[27, 28, 29]
in these
males) and then decreases in adolescence in a “back
patients are also consistent with the abnormal devel-to the front” pattern, believed to be related to early
opment theory.

neuronal overproduction, followed by selective elimi-A number of studies have reported the occurrence
nation and alteration of dendritic synapses – “synap-of a high frequency of neuropsychological abnor-tic pruning”
[50, 51, 52].
The gray-matter reduction
malities, prior to the onset of illness in individu-occurs first in the dorsal parietal cortices (primary
als with schizophrenia. These include motor delays,
sensorimotor areas) and then progresses to the other
speech problems, cognitive difficulties, impaired social
areas, with the dorso-prefrontal cortex being the last to
skills with poor peer relationships, social anxiety, and
mature, toward the end of the adolescent period. Such
poor intellectual functioning in childhood between
cortical thinning in the frontal and parietal lobes in
the ages of 2 and 15 years
[23,
30, 31, 32].
How-adolescence is associated with improved verbal func-ever, the fairly high frequency of such cognitive prob-tioning
[53].
On neuroimaging in childhood-onset
lems in the general population of children (15%–30%)
schizophrenia, striking loss of gray matter is seen, first
[33]
decreases their predictive value for schizophre-in the parietal lobe, progressing to the temporal lobe,
nia. Assessments of specific higher neurocognitive
and the dorsolateral prefrontal cortices, findings con-deficits such as poor executive function, sustained
sistent with the supposition that excess synaptic prun-attention, and working memory show more promise
ing contributes to the illness
[54].
Similar mechanisms
as being more specific in predicting psychosis in indi-involving exaggerated synaptic pruning have been pro-viduals at high risk
[34, 35, 36].
The recent National
posed in schizophrenia with a typical onset in late ado-Institutes of Mental Health-Measurement and Treat-lescence/early adulthood
[55].

ment Research to Improve Cognition in Schizophre-Underlying such abnormal neurodevelopment,
nia (NIMH-MATRICS) initiative has ranked executive
undoubtedly, are aberrations in the genes that con-functions, attention/vigilance, memory processes, and
tribute to the normal process, but the genetic factors
problem-solving ability as being the most valuable in
operative in schizophrenia remain poorly understood.

312

assessing cognitive deficits in schizophrenia
[37],
lend-Linkage analyses have indicated various areas of the
Chapter 24 – Velocardiofacial syndrome

genome as being implicated, including the 22q11.2

learning disabilities
[57, 58,
59, 60, 61].
The mean intel-region
[56].

ligence quotient (IQ) is 75. A complex and distinctive
The central idea of the neurodevelopmental model
pattern of disabilities occurs with deficits in visual-of schizophrenia is strongly supported by the genetic,
spatial processing, arithmetic performance, language,
psychological, and brain morphometric findings in
reading comprehension, attention, working memory,
individuals with VCFS. The advantages of using VCFS

and executive functioning; and relative strengths in
as a model for schizophrenia are that: (i) the inevitable
reading and spelling skills. This results in a nonverbal
genetic heterogeneity that would occur in a high-risk
learning disability
[58,
59, 60, 62, 63].
This type of non-group in the general population is minimized, because
verbal disability is not unique to VCFS, because it is
individuals with VCFS all have a known deletion,
seen in other genetic conditions such as Turner syn-

(ii) it allows for the study of specific etiological genes
drome
[64].

in the 22q11.2 interval that are known to contribute to
Parallels between children with VCFS (prior to the
schizophrenia in the general population, and (iii) the
onset of psychotic illness) and individuals in the pre-study of children and adolescents with VCFS provides
morbid stage of schizophrenia can be drawn, based
the opportunity to study the trajectory of schizophre-on the similarities in early manifestations. Social and
nia spectrum disorders in a population that is rela-attention problems are common in VCFS
[58]
and
tively untainted by the catastrophic consequences of
are similar to those seen in the premorbid stage
psychotic disorders.

of schizophrenia. Additionally, children with VCFS

in comparison to control subjects manifest less effi-

Prevalence of VCFS in schizophrenia

cient sensorimotor gating in the form of reduced
prepulse inhibition
[65],
easy distractibility, disinhi-It has been found that 1%–2% of individuals with
bition, reduced mismatch negativity, and impaired
schizophrenia in the general population have a
sustained attention, executive function, and verbal
22q11.2 deletion
[19, 20],
whereas 5% of patients with
working memory
[66, 67, 68, 69].
Such significantly
childhood-onset schizophrenia will have VCFS upon
impaired sustained attention, executive function, and
testing
[21]
. It is to be noted that the indication for
working memory are thought to be reliable indicators
testing for the deletion in these studies was the occur-of psychosis risk and are suggestive of frontal and tem-rence of schizophrenia alone. However, if genetic test-poral dysfunction
[69].
The fronto-temporal circuit is
ing were to be offered to those with other abnormal-part of the heteromodal cortices, the dysfunction of
ities such as congenital heart disease or palatal prob-which (particularly the prefrontal cortex) is believed
lems, the incidence of the 22q11.2 deletion could be
to be central to the pathogenesis of schizophrenia
[70].

as high as 30%
[15].
For the practicing clinician, Table

Thus, the early neurocognitive manifestations in VCFS

24.1 lists the features in association with schizophre-

are similar to those that would be expected to occur on
nia that should warrant consideration of testing for
the pathway to schizophrenia.

the 22q11.2 deletion. The FISH test, using a commercial probe (Vysis, Gaithersburg, MD) is widely available through most cytogenetic laboratories.

Psychiatric diagnoses in childhood in VCFS

Children with VCFS seldom develop psychosis prior
Premorbid neuropsychological and

to the age of 15 years or so. Instead, a number
brain morphometric findings in VCFS

of less dramatic abnormalities are seen in approxi-mately 40%, such as attention deficit/hyperactivity dis-This section describes the neuropsychological abnor-order (AD/HD), oppositional defiant disorder (ODD),
malities and structural brain abnormalities that pre-obsessive compulsive disorder (OCD) and anxiety dis-date psychosis in individuals with VCFS.

orders
[71, 72, 73, 74].
Upon systematic psychiatric
assessments of children with VCFS, mood disorders
Psychological abnormalities in children

(40%–60%) and impairment in social skills
[9,
75]
are
common, although at least one study found no dif-with VCFS

ferences in psychiatric diagnoses between VCFS chil-Cognitive deficits are common, with at least 80%

dren and control subjects
[76].
It is widely hypothe-

313

of children experiencing developmental delays and
sized that the minor psychiatric disorders in childhood
Organic Syndromes of Schizophrenia – Section 3

9.5

Figure 24.4
Representation of the
corpus callosum area in children with

VCFS, as compared to control subjects

8.5

df = 1,23; F = 10.52; p = .004

6.5

5.5

CC total area (cm

4.5

±Std. Dev.

±Std. Err.

3.5