Chromosomal Abnormalities and Bipolar Affective Disorder: Velo-Cardio-Facial Syndrome

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Medscape Psychiatry & Mental Health eJournal. 1997;2(4) 

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In 1995, Papolos and colleagues reported a very strong association between VCFS and bipolar spectrum disorders.[27] However, this diagnostic finding was in conflict with a previous study that had associated VCFS with schizophrenia.[28]

VCFS, a relatively common congenital disorder, is estimated to affect 1/2000 to 1/3000 individuals.[29,30] The original presenting symptoms, which call attention to its pattern, include hypernasal speech (usually with cleft palate), cardiac anomalies, learning disabilities, and a characteristic facial appearance (Fig. 1) marked by a vertically long face, large nose with large tip and high nasal root, small ears with overfolded helices, narrow "squinting" eyes, and a flaccid expression.[31] Approximately 85% of patients with VCFS have a microdeletion on the long arm of chromosome 22 (a 1-2 megabase interstitial deletion on chromosome 22q11; Fig. 2). It is likely that hemizygosity of 1 or more genes at this locus is responsible for a variety of clinical diagnoses (Fig. 3), including DiGeorge syndrome (DGS) and less severe but related dysmorphologies that encompass familial congenital heart disease and psychiatric or "behavioral" syndromes such as bipolar spectrum disorders.[30,32,33,34] Therefore, a concerted effort to map this chromosomal region is being made by several groups[30,33] (Fig. 4).

Characteristic facial appearance of VCFS includes vertically long face, large nose with large tip and high nasal root, small ears with overfolded helices, narrow "squinting" eyes, and flaccid expression. Adapted with permission from the American Cleft Palate-Craniofacial Association. Originally published in Shprintzen RJ, Goldberg RB, Lewin ML, et al: A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: Velo-cardiofacial syndrome. The Cleft Palate Journal (1978; 15:56-62), Copyright © 1978, the American Cleft Palate-Craniofacial Association, 1978.[31]

A map of chromosome 22 with lines demarcating the most commonly deleted region in VCFS.

Defining most commonly deleted area of 22q11. Short tandem repeat polymorphisms (STRPs) are ideally suited for establishing whether individual is heterozygous or hemizygous at particular region. Eighty-two percent of VCFS patients have deletions that can be defined by STRP markers, and all patients who have deletion share common proximal breakpoint, whereas there are 2 distinct distal breakpoints. Markers D22S941 and D22S944 appear to be consistently hemizygous in patients with deletions. Adapted from Am J Med Genet (1995;56:1391-1403), Copyright © 1995, John Wiley & Sons.

Fluorescence in situ hybridization of interphase nuclei with different probes derived from 22q11 have confirmed that hemizygosity of 1 or more loci at 22q11 is associated with VCFS. One particular cosmid FISH probe, sc11.1, produces 2 hybridization signals within 22q11 referred to as 11.1A and B. Most VCFS patients are deleted for both signals, 11.1A and B, on 1 of the 2 copies of chromosome 22. Although this kind of cytogenetic analysis has been useful for diagnostic purposes, it is inadequate to establish differences in the size of the deletions between different groups of patients (psychiatrically affected and unaffected). For this purpose, higher-resolution methods are required. Courtesy of Dr. Linda Canizzaro.

VCFS is a complex disorder affecting a number of tissues and organ systems, many of which are derived from the neural crest cells of the developing embryo.[30] There seems to be a common underlying embryologic basis, specifically an abnormality in neural crest cell migration, which is critical to the development of structures derived from the third branchial arch and fourth pharyngeal pouch system.[30] Genes residing in the VCFS commonly deleted region, which are considered candidate genes for psychiatric disorders, are being screened for the presence of mutations in patients with psychiatric illness. One candidate, the gene coding for the enzyme catechol O-methyltransferase (COMT), which has already been localized to this region,[35] metabolizes catecholamines, including the neurotransmitters dopamine, norepinephrine, and epinephrine.

Approximately 23% to 25% of the Caucasian population has low COMT activity, as measured in erythrocytes and in the liver, and this variation is genetically determined.[36] A common polymorphism is associated with the 3- to 4-fold variation in COMT activity.[37] We and others have reported that the molecular basis for this variation in COMT enzyme activity is due to a G-to-A transition at codon 158 of the COMT gene, which results in a valine-to-methionine substitution.[38] The 3 resulting genotypes--AA, AG, and GG--can be identified with PCR-based screening techniques. One potential area of inquiry will be to determine whether homozygosity for this functional polymorphism is associated in the general population with a specific behavioral syndrome already identified in the group of VCFS patients, who are lacking the gene (deletion) on 1 chromosome and carrying the low-activity COMT allele on the other.

Variable expression has been found for the somatic anomalies associated with VCFS. Variability of expression of psychiatric disorders has not yet been studied in detail for a large population of individuals with VCFS. Within a few years after the identification of the syndrome in 1978, clinicians at the Center for Cranio-Facial Disorders (CCFD) at Montefiore Medical Center of the Albert Einstein College of Medicine, began to observe several common tempermental features in children with VCFS, such as behavioral inhibition to novel stimuli and enduring fearfulness of painful situations. In addition, a number of psychiatric disorders, including attention-deficit hyperactivity disorder (ADHD), separation anxiety disorder, cyclothymia, and obsessive-compulsive behaviors, were reported.[39]

The first follow-up study of adolescent VCFS patients, who were identified when they were children and remained in contact with the CCFD, revealed that 12 of 32 patients, who were then 16 years of age or older, had severe psychiatric disorders. As this cohort of VCFS children (N=44) reached adolescence, Scambler and associates[30] reported that an unexpectedly high proportion (approximately 30%) developed psychotic disorders. In the first standardized diagnostic study, Pulver and coworkers[28] reported on psychiatric evaluations of 20 late-adolescent to adult cases Shprintzen had diagnosed with VCFS. Of the 20 VCFS patients, who ranged in age from 14 to 36 years, 2 were diagnosed with schizophrenia by DSM-III-R criteria and 2 with schizoaffective disorder, while 3 were diagnosed with adjustment disorder accompanied by depressed mood.

In a separate investigation[27] of children and early adolescents with VCFS, designed to determine the natural history of the behavioral phenotype, the findings were not consistent with the reported association between VCFS and schizophrenia, and the analysis was expanded to include older adolescents and adults. One of the previously reported cases diagnosed by Pulver and colleagues[28] as having schizophrenia and 1 case with schizoaffective disorder were reexamined. One patient (AP1012), previously diagnosed with schizophrenia, was rediagnosed as being schizoaffective-manic. A review of the recent history with the treating psychiatrist revealed that the patient had experienced a manic episode following his first assessment by Pulver.[28] During the diagnostic interview, he was noted to have grandiose delusions without any evidence of being in an affective episode. These delusions had been present for at least 2 months. A second case (AP1018), initially diagnosed as schizoaffective, was rediagnosed as bipolar I (see Case 1), since discrete manic and depressive episodes were present and psychotic symptoms reported by the family were found to be mood-congruent without continuation beyond the resolution of the affective episode.

In a series of VCFS patients (ages 5-34), 68% (17/25) met DSM-III-R criteria (now verified by DSM-IV criteria) for a spectrum of bipolar disorder with full syndromal onset in late childhood or early adolescence (Table I).[34] In addition, 20% (5/20) met DSM-III-R criteria for attention deficit disorder with hyperactivity (ADHD), while 16% (4/20) met criteria for attention deficit without hyperactivity. The average age of onset for syndromal bipolar disorder was 12 years, while evidence of cyclothymia or dysthymia was retrospectively reported as early as age 9 in 4 patients. In general, for those individuals diagnosed with childhood bipolar disorders, symptoms of sleep fragmentation and night-terrors often preceded the appearance of rapid mood swings. Clinical interviews with parents confirmed the presence of frequent spontaneous or reactive oscillations in mood and psychomotor activity. This cyclic pattern typically preceded mania or hypomania and persisted beyond the first manifestation of frank episodes that met DSM-III-R criteria for mania or hypomania. At onset, 6 patients had ultra-rapid cycling with continuous 1- to 2-week episodes and no free interval. In addition to ADHD, other common diagnoses endorsed by the Diagnostic Interview for Children and Adolescents (DICA-R) symptom profiles were oppositional defiant disorder and anxiety disorders (including separation anxiety disorder, avoidant disorder, and obsessive-compulsive disorder). None of the patients in this sample of 25 VCFS cases was diagnosed with schizophrenia, and only 3 had psychotic symptoms during a phase of their illness, all in their twenties or thirties. These findings, observed in a wider age range of VCFS patients, call into question previous associations of VCFS with schizophrenia.


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