Secondary Schizophrenia (127 page)

later in this chapter.

A mother and her two children (both with Asperger
In Dfl/
+
mice with a heterozygous deletion of a
syndrome) with phenotypic features of VCFS, but no
subset of 18 genes corresponding to the 22q11.2 inter-detectable 22q11.2 deletion, had a heterozygous dele-val, reduced PPI and reduced learning and difficulty
tion within the TBX1 gene. This was cited as evidence
in processing complex information were noted, com-that TBX1 is involved in the behavioral abnormali-pared to wild-type mice
[170]
. The authors pointed
ties in VCFS
[165]
. There was no information regard-out the similarities to the neurocognitive abnormal-ing possible psychosis in this family and, although of
ities that have been described in schizophrenia in
interest, further studies are necessary to confirm this
humans. In the Lgdel/
+
mice with a deletion of 27

association.

genes, reduced PPI and an exaggerated startle were
Other genes of interest in the causation of
noticed
[169].
Other studies have attempted to link
schizophrenia in this interval could be identified in
these deficits, especially reduced PPI, to specific genes
the future by expression patterns of these genes within
by creating point mutations/deletions of single genes
the developing fetal and adult brain
[166].
Because
using the mouse model. In the COMT knockout mice,
individuals with VCFS are hemizygous for genes in the
there were no differences in PPI between the heterozy-22q11.2 interval, genotype analysis and correlations
gous and homozygous states
[130].
Cognitive impair-with psychological and neuroanatomical findings
ments in the COMT knockout mice have yet to be
would be more easily feasible than with traditional
studied. In mice homozygous for a missense muta-

319

high-risk families.

tion in the PRODH gene, elevated proline levels and
Organic Syndromes of Schizophrenia – Section 3

reduced PPI were observed, whereas mice heterozy-phenotype, rather than haploinsufficiency of a single
gous for the mutation had near normal proline lev-gene.

els, but no observation was made on their behavior
Gene expression studies in mouse models are use-

[171].
Intriguingly, mice that have a deletion of one
ful in identifying genes that could be involved in the
PRODH gene in conjunction with deletions of con-pathogenesis of schizophrenia in VCFS. Profiling of
tiguous genes in the 22q11.2 interval (including the
gene expression within the hippocampus in mice with
TBX1, COMT, PRODH, and ZDHHC8 genes), show
the heterozygous deletion of a subset of genes cor-more abnormal PPI, despite normal proline levels,
responding to the 22q11.2 interval demonstrated a
as compared to mice homozygous for the missense
33% reduction in expression of 12 genes, including the
mutation discussed previously
[170]
, indicative of the
PRODH and COMT genes. The ZDHHC8 gene expres-possibility that mechanisms other than gene dosage
sion was not reduced
[173].
However, illustrating once
are responsible for the association between PRODH

more the limitations of the mouse model in delineating
and abnormal sensorimotor gating. One such plausi-schizophrenia pathogenesis in VCFS, this gene profile
ble mechanism is the additive effect of the deletion
in the mouse model showed virtually no overlap with
of several genes in the 22q11DS interval. An interac-the profile seen in human hippocampal neurons
[174].

tion between PRODH and COMT has been suggested;
In conclusion, VCFS represents an etiological sub-PRODH deficient mice have increased dopamine lev-type of schizophrenia spectrum disorders. Testing
els in the frontal cortex, as a result of which there is
for VCFS should be considered in individuals with
compensatory upregulation of the COMT gene prod-schizophrenia who have had congenital anomalies
uct normally
[154]
. Because individuals with VCFS

or dysmorphic features. Preliminary studies in VCFS

may be unable to compensate in this manner for the
individuals have shown that premorbid psychologi-PRODH heterozygosity due to the coexisting COMT

cal and structural brain abnormalities are common
deletion, they may be at an added disadvantage in
in these individuals and overlap those seen in indi-combating the effects of decreased PRODH expression,
viduals with and at risk of schizophrenia. These data
thus exponentially increasing their vulnerability to
strongly support the notion that neuronal dysmatura-psychosis.

tion and disrupted synaptic pruning are likely involved
The relationship between the ZDHHC8 gene and
in the pathogenesis of cognitive and behavioral abnor-sensorimotor gating has been addressed in one study
malities in childhood in VCFS, similar to the model
in mice. Although there was a suggestion of a gender-proposed by proponents of the neurodevelopmental
specific effect on PPI, with females showing mod-hypothesis of schizophrenia. Emerging correlations
estly reduced PPI, it appears, based on the avail-between the psychological and morphometric brain
able evidence, that ZDHHC8 heterozygosity in and
findings hold the promise that such changes may be
of itself is unlikely to cause behavioral abnormalities
beneficial in predicting psychosis in the future. Genes
in the mouse model
[125].
A role for the TBX1 and
in the 22q11.2 interval are undoubtedly involved in
GNB1L genes in causing reduced PPI in the mouse
the causation of schizophrenia in VCFS and are very
model has been suggested
[165];
because TBX1 is
likely to contribute to the illness in the general pop-expressed in vascular tissue of the mouse brain, it has
ulation. Thus, prospective studies of the psychologi-been postulated that disruption of the microvascula-cal and brain morphometric changes and the genet-ture may be responsible for the reduced PPI. How-ics of the deleted interval in children and adolescents
ever, other studies have not found behavioral abnor-with VCFS offer the unparalleled opportunity to delin-malities in mice that were haploinsufficient for TBX1

eate the trajectory of events that occur on the pathway
[169,
172].
Thus, the role of TBX1 in the psychi-toward schizophrenia. Such an understanding of the
atric manifestations in the mouse model is yet to
neurodevelopmental basis of schizophrenia promises
be fully defined. In general, the existing evidence in
better understanding of the pathogenesis and poten-the mouse models of VCFS substantiates the suppo-tially early identification and treatment of the most
sition that the concomitant loss of several genes in
vulnerable individuals, thereby improving the chances
the deleted interval is likely to cause the psychiatric
of a better prognosis.

320

Chapter 24 – Velocardiofacial syndrome

References

bipolar affective disorder? Am J

population. Schizophr Res, 2001.

Psychiatry, 1996.
153
:1541–7.

52
:167–70.

1. Weinberger D. R. Implications of

normal brain development for the

10. Murphy K. C., Jones L. A., Owen

21. Sporn A., Addington A., Reiss A.

pathogenesis of schizophrenia.

M. J. High rates of schizophrenia

L.,
et al.
22q11 deletion syndrome
Arch Gen Psychiatry, 1987.

in adults with velocardio-facial

in childhood onset schizophrenia:

44
:660–9.

syndrome. Arch Gen Psychiatry,

an update. Mol Psychiatry, 2004.

1999.
56
:940–5.

9
:225–6.

2. Andreasen N. C., Nopoulos P.,

O’Leary D. S.,
et al.
Defining the
11. Chow E. W., Watson M., Young D.

22. Andreasen N. C. A unitary model

phenotype of schizophrenia:

A.,
et al.
Neurocognitive profile in
of schizophrenia: Bleuler’s

cognitive dysmetria and its neural

22q11 deletion syndrome and

“fragmented phrene” as

mechanisms. Biol Psychiatry,

schizophrenia. Schizophr Res,

schizencephaly. Arch Gen

1999.
46
:908–20.

2006.
87
:270–78.

Psychiatry, 1999.
56
:781–7.

3. Hovatta I., Lichtermann D.,

12. Wilson D. I.Cross I. E., Wren C.

23. Rapoport J. L., Addington A. M.,

Juvonen H.,
et al.
Linkage analysis
Minimum prevalence of

Frangou S.,
et al.
The neuro-

of putative schizophrenia gene

chromosome 22q11 deletions. Am

developmental model of

candidate regions on

J Hum Genet, 1994. 55:A169.

schizophrenia: update 2005. Mol

chromosomes 3p, 5q, 6p, 8p, 20p

Psychiatry, 2005.
10
:434–49.

13. Tezenas Du M. S., Mendizabai H.,

and 22q in a population-based

24. Keshavan M. S., Anderson S.,

Ayme S.,
et al.
(1996) Prevalence
sampled Finnish family set. Mol

Pettegrew J. W. Is schizophrenia

of 22q11 microdeletion. J Med

Psychiatry, 1998.
3
:452–7.

due to excessive synaptic pruning

Genet, 1996.
33
:719.

4. Shaw S. H., Kelly M., Smith A. B.,

in the prefrontal cortex? The

14. Shprintzen R. J. Velocardiofacial

et al.
A genome-wide search for

Feinberg hypothesis revisited.

syndrome. Otolaryngol Clin North

schizophrenia susceptibility

J Psychiatr Res, 1994.
28
:239–65.

Am, 2000.
33
:1217–40, vi.

genes. Am J Med Genet, 1998.

25. Keshavan M. S. Development,

81
:364–76.

15. Bassett A. S., Chow E. W. 22q11

disease and degeneration in

5. Liu H., Abecasis G. R., Heath S.

deletion syndrome: a genetic

schizophrenia: a unitary

C.,
et al.
Genetic variation in the
subtype of schizophrenia. Biol

pathophysiological model.

22q11 locus and susceptibility to

Psychiatry, 1999.
46
:882–91.

J Psychiatr Res, 1999.
33
:513–21.

schizophrenia. Proc Natl Acad Sci

16. Bassett A. S., Hodgkinson K.,

26. O’Callaghan E., Larkin C.,

USA, 2002.
99
:16859–64.

Chow E. W.,
et al.
22q11 deletion
Kinsella A.,
et al.
Familial,

6. Kendler K. S. Hierarchy and

syndrome in adults with

obstetric, and other clinical

heritability: the role of diagnosis

schizophrenia. Am J Med Genet,

correlates of minor physical

and modeling in psychiatric

1998.
81
:328–37.

anomalies in schizophrenia. Am J

genetics. Am J Psychiatry, 2002.

17. Bassett A. S., Chow E. W., Husted

Psychiatry, 1991.
148
:479–83.

159
:515–18.

J.,
et al.
Clinical features of 78

26. Pantelis C., Yucel M., Wood S. J.,

7. Shprintzen R. J., Goldberg R.,

adults with 22q11 Deletion

et al.
Early and late neuro-

Golding-Kushner K. J.,
et al.

Syndrome. Am J Med Genet A,

developmental disturbances in

Late-onset psychosis in the

2005.
138
:307–13.

schizophrenia and their

velocardio-facial syndrome.

18. Fraser W., Nolan M. (1994)

functional consequences. Aust

Am J Med Genet, 1992.
42
:
Psychiatric disorders in mental

NZ J Psychiatry, 2003.
37
:399–406.

141–2.

retardation. In Mental Health in

27. Green M. F., Satz P., Gaier D. J.,

8. Pulver A. E., Nestadt G., Goldberg

Mental Retardation, Bouras N.

et al.
Minor physical anomalies in
R.,
et al.
Psychotic illness in

(Ed.). Cambridge: Cambridge

schizophrenia. Schizophr Bull,

patients diagnosed with

University Press, pp. 79–92.

1989.
15
:91–9.

velocardio-facial syndrome and

19. Karayiorgou M., Morris M. A.,