|
 Velocardiofacial
syndrome (VCFS) is a genetic syndrome with a range of psychiatric symptoms.
Identification of the gene(s) involved in its expression should lead to
an improved understanding of both normal CNS development and how specific
mutations contribute to psychiatric disorders. VCFS was first defined
by Robert Shprintzen more than 20 years ago. Only in recent years, with
the increased interest in molecular biology in psychiatry, has it received
wider recognition.
VCFS
has an estimated prevalence of 1 in 4,000, making it the second most common
genetic syndrome after Down syndrome. It is caused by a microdeletion
in the long arm of chromosome 22. Several disorders, such as DiGeorge
syndrome, some cases of Pierre-Rubin syndrome, and other rarer syndromes,
are caused by a seemingly identical microdeletion. Identification of the
gene(s) that are affected by the deletion will be required before it is
known whether the same or different genes contribute to the expression
of these disorders. Together with VCFS, they are collectively referred
to as the 22q11 deletion syndromes (22qDS).
Ninety
percent of patients with 22qDS have a deletion of approximately 3 million
base pairs, while 7% have smaller deletions of 1.5 million bases. Similar
to other syndromes caused by a microdeletion, the molecular diagnosis
of 22qDS is usually made by fluorescence in situ hybridization (FISH)
(Ward et al., 1999). In FISH, a fluorescently labeled sequence of a few
thousand nucleotides is constructed in the laboratory. This sequence is
used as a probe that will bind to the complementary sequence of bases
on chromosome 22. As there are two copies of each chromosome, two hybridization
signals will appear on the FISH examination in the normal individual.
In those cases in which a deletion is present, fluorescence will be detected
on only one chromosome (Fig.
1). Ninety-five percent of 22qDS can be detected with this technique.
The rest fail to be detected because they are caused by unique deletions
or unbalanced translocations.
There
are several major clinical characteristics of 22qDS. Congenital heart
disease is present in 74% of patients with 22qDS. The most common
are tetralogy of Fallot, interrupted aortic arch, and ventricular septal
defect. Screening of patients with cardiac anomalies ascertained at cardiac
clinics determined that the deletion is present in 3% to 15% of them.
The prevalence of the deletion among cardiac patients is highest for those
with interrupted aortic arch and tetralogy of Fallot. An abnormal facies
is also characteristic of patients with 22qDS. Typically, alae nasae is
hypoplastic, leading to a bulbous nasal tip and prominent nasal root.
The narrow face is long and narrow with flat cheeks, narrow palpebral
fissures, a small mouth, receding chin, and small cupped ears. Palatal
abnormalities are present in 83% of patients. They range from velopharyngeal
incompetence to cleft lip and palate. Hypocalcemia and T-cell immunodeficiency
are typical of the DiGeorge syndrome phenotype and are caused by hypoplastic
parathyroid and thymus glands, respectively. Other features of
22qDS include tortuous retinal vessels, growth retardation, increased
rate of juvenile rheumatoid arthritis, and urinary system anomalies.
The
earliest reports on VCFS patients involved young children. As the patients
grew to school age, it became apparent that they suffered from continuing
behavioral problems. They were often shy and socially withdrawn, with
blunted affect, but also impulsive, disinhibited, and prone to temper
tantrums. Psychotic and affective symptoms often emerged in adolescence
or early adulthood.
About
one forth of VCFS patients develop psychotic symptoms, and a diagnosis
of schizophrenia is often made in adolescence. Indeed, the prevalence
of schizophrenia in VCFS patients is 25 times that of the general population.
In addition, both schizophrenic and nonschizophrenic VCFS patients scored
higher on a scale measuring schizotypal personality. The schizophrenia
associated with VCFS has a chronic and disabling course and is associated
with poor response to classical neuroleptics. Although treatment with
atypical neuroleptics has not been systematically studied, few VCFS patients
have responded well to clozapine for the treatment of their psychotic
symptoms.
Most
studies have found a significant increased prevalence of schizophrenia
in VCFS. Similar increases in the rate of schizophrenia have been described
with other genetic syndromes, such as homocystinuria, acute intermittent
porphyria, and the sphingolipidoses and leukodystrophies. Several studies
have looked at groups of schizophrenic patients and found an increased
rate of VCFS. One team detected 22qD in 2 of 100 adult schizophrenic patients,
a rate about 200 times greater than in the general population. Our group
has reported a 22qD prevalence of 20% in a sample of schizophrenic patients
with at least one prominent physical manifestation of VCFS, such as cardiac
anomaly, cleft palate, or the typical facies. A study by Bassett’s
group found a prevalence of 60% in schizophrenic patients who had at least
two physical manifestations of VCFS. Recently, the Child Psychiatry Branch
of the NIMH reported a 6% rate of 22qD in a cohort of 47 patients with
very-early-onset schizophrenia.
Half
of VCFS children are hypotonic. In addition, most have delays in gross
motor development, such as crawling and walking independently, as well
as fine motor development. Though the psychotic and affective symptoms
of VCFS are largely nonspecific, the cognitive deficits can be more specifically
delineated. Intelligence has been intensively studied in affected preschool
children, adolescents, and adults. The average total IQ score in these
studies falls in the borderline intelligence range of 71 to 78. From 25%
to 40% of patients were mildly retarded. Moderate to severe mental retardation
was rarely found.
The
Performance IQ score was consistently and significantly lower (by approximately
10 points) than the Verbal IQ. Information, comprehension, and coding
subsets were relatively strong, whereas visual-spatial perception and
problem-solving were weak. The language skills were both delayed and impaired
in all VCFS patients, with the impairment being more pronounced in the
expressive than the receptive domain. Although developmental language
disorders are regarded as harbingers of later disabilities in reading,
the latter remained intact in VCFS. Most subjects with VCFS have a history
of special education needs. Taken together, the Verbal–Performance
IQ split and the reading–mathematics splits are compatible with a
nonverbal learning disability.
The
disruption to some cognitive skills and not others indicates that VCFS
may serve as a model for developmental psychopathology. Similar to what
has been found in schizophrenia, patients with VCFS show aberrant early
development marked by psychomotor delays; coordination deficits; specific
deficits in cognition, language, learning and attention; and social withdrawal.
These features strongly suggest a disruption in normal CNS development.
Additional support for this model derives from imaging studies. The brain
imaging findings in schizophrenics, such as enlarged lateral ventricles
and decreased gray matter volume, have also been found in the few magnetic
resonance imaging studies of VCFS patients, with and without schizophrenia.
What
do we know about the developmental pathogenesis of VCFS or 22qDS? The
embryonic neural crest cells are highly migratory cells that give rise
to the mesenchyme of the third and fourth pharyngeal arches which later
differentiate into specific organs and structures of the head, neck, and
aortic arch. The cardiac anomalies, cleft palate, facial dysmorphism,
and maldevelopment of the thymus and parathyroid gland found in 22qDS
indicate that the syndrome is probably the result of an embryonic defect
in the migration of neural crest cells.
The
gene or genes that cause 22qDS are not yet known, although extensive efforts
are under way to detect them. The disorder does not appear to be a contiguous
gene deletion syndrome. One example of a contiguous gene deletion syndrome
is Williams syndrome, which is caused by a microdeletion on chromosome
7. At least 16 genes lie in the large region deleted in Williams, and
the mutations of several of these are thought to explain the varied symptoms
seen with the disorder. Thus the deletion of a gene termed elastin
is believed to be responsible for the connective tissue abnormalities,
while the deletions of several other genes in the same region are thought
to be responsible for the cognitive symptoms.
The
phenotype of 22qDS is highly variable, and there is no correlation between
the pattern or severity of the phenotype and the extent of the deletion.
It is also unclear whether a mutation within a single gene could cause
similar symptoms, although to date only deletions have been found in patients
with the VCFS/DiGeorge phenotype. It is possible that the deletion causes
a disruption to the expression of a transcription factor or other protein
that is required for the expression of genes outside the 22qD region.
The absence of these downstream proteins would be responsible for the
pathophysiology of the disorder.
Several
interesting genes are located within the 22qD region. One is the gene
encoding for catechol-O-methyltransferase (COMT), an enzyme that
degrades dopamine. Several polymorphisms exist within the gene, and at
least one of these is associated with lower biochemical activity of COMT.
A study reported that all VCFS patients with rapid-cycling bipolar affective
disorder had the low-activity COMT allele in the nondeleted chromosome.
However, subsequent studies found no association between the COMT alleles
and schizophrenia with or without VCFS.
Because
VCFS and schizophrenia share common neurodevelopmental abnormalities,
it is possible that the VCFS deleted gene(s) play a role in the pathophysiology
of these abnormalities in schizophrenia as well. Genes encoding for migratory
factors that are expressed in the brain are strong candidates that could
also explain the cytoarchitectural abnormalities in the brains of schizophrenic
patients. There are several such genes in the 22qD region. These include
the goosecoid-like (GSCL) gene which encodes for a homeobox protein;
ARVCF, which is involved in the formation of adherens junctions
between cells; the clathrin heavy chain-like gene that recycles the presynaptic
membrane of vesicles after release of neurotransmitters; and UFD1L,
which is involved in the degradation of proteins. No point mutations,
however, have yet been detected in any of these candidate genes.
Association
studies are a popular technique for identifying genes that contribute
to the expression of a number of psychiatric disorders. Most association
studies have focused on genes involved in the dopaminergic and serotonergic
systems. Although these systems are probably involved at some point in
the pathophysiology of these disorders, it is not certain whether they
play a role in their etiology. Candidate genes in VCFS also include ones
involved in the early growth and development of the brain, such as genes
that regulate the migration of neurons. This line of investigation may
help us to understand the underlying molecular basis of VCFS and perhaps
other developmental disorders.
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