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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The 5 cases discussed are representative and reflect the nature and development of psychiatric symptoms in a majority of the 25 VCFS cases that were studied.[34] In our original sample, 68% of cases (17/25) were diagnosed with bipolar spectrum disorders, while 35% (5/20) obtained syndromal diagnoses of ADHD. We did not observe schizophrenic denouement in the juvenile sample. Even when psychotic features were present in children and adolescents, they were mood congruent, and the overall clinical features were consistent with affective psychoses. We attribute the evident disparity in diagnoses between this study and a previous study by Pulver and colleagues[28] to the age difference of the study populations and the predominance of psychotic symptoms in the individuals they examined and diagnosed with schizophrenia. In addition, the characteristic flat or blunted facial expression and the concreteness of thought that are characteristic features of the VCFS phenotype make it easy to understand the potential for diagnostic confusion. Psychotic forms of mood disorders are often diagnosed on initial presentation as schizophrenia.[46,47,48] Increasingly, retrospective diagnostic surveys have found that patients with an earlier age of onset of affective illness are far more likely to receive a diagnosis of schizophrenia, possibly because psychotic symptomatology predominates in those patients whose bipolar disorder presents in adolescence.[49,50,51,52,53,54]

Adolescents diagnosed with bipolar disorder and followed in a community sample[55] exhibited a chronic course, indicating that even relatively mild forms of bipolar disorder in children and adolescents are serious conditions that are associated with substantial impairment and comorbidity. This also appears consistent with our observations in the older VCFS patients, who appear to have more severe and chronic forms of bipolar disorder. Although no definitive conclusions can be reached by a study of such a small sample size, it will be important for clinicians who follow patients with VCFS to be exceedingly cautious in the diagnoses of ADHD because of the potential for the induction and perhaps kindling of bipolar disorder by stimulant drugs used to treat this condition.[56] Additionally, because of the reported chronic course of childhood bipolar spectrum disorders, early intervention with mood-stabilizing agents will need to be seriously considered for this patient population.

In addition to the challenge of differentiating mania and psychotic depression from schizophrenia, there is a close but incompletely defined relationship between ADHD and early-onset bipolar disorder. Many children and adolescents in the general population who are diagnosed with bipolar disorder have symptoms consistent with, preceding, or comorbid with ADHD.[57,58,59,60] Similarly, early-onset bipolar patients are commonly diagnosed as having ADHD in childhood.[56,57,58,59] Noting that distractibility, impulsivity, hyperactivity, and emotional lability are characteristic of both ADHD and bipolar disorder, Carlson[54] concluded that the relationship between these disorders required further clarification. Case reports of manic children comment on the overlap of symptoms between these 2 disorders.[56,59,60] A recent study by Wozniak and colleagues[61] has lent some clarification to this relationship by finding that almost all (94%) children evaluated with current or previous mania in their sample (N=45) also met criteria for ADHD, while only a small minority (19%) with a diagnosis of ADHD also met DSM-III-R criteria for current or previous mania. This comorbidity of ADHD and bipolar disorder is consistent with our observations in VCFS patients.

There are several possible explanations for the high rate of bipolar disorder we have observed in VCFS patients. One is that the deleted region in this subgroup extends to include a critical gene, which when hemizygous increases the susceptibility to develop psychiatric illness or a specific psychiatric illness like bipolar disorder. Another possibility is that there is a modifying gene at this locus that, in combination with other unlinked genes, produces the bipolar-disorder phenotype.

Two studies have provided suggestive evidence of linkage of schizophrenia and of bipolar disorder to loci on chromosome 22q11.[28,43] The departure point for each study was based on differing diagnostic findings in VCFS. Allelic association studies[38,41] (D. Papolos, et al, unpublished data, 1997) point to the possibility that a polymorphism of the COMT gene (commonly deleted in VCFS), which produces a low-activity form of the enzyme, is significantly associated with several behavioral phenotypes, including ultra-rapid-cycling bipolar disorder, OCD in males, and aggressive tendencies in schizophrenics.

Complex disorders like bipolar disorder have been commonly thought to consist of a combination of several disorders, each caused by a single gene, or at least a gene of major effect. It is possible that a common gene polymorphism will be found to predispose to several psychiatric conditions (rapid-cycling bipolar disorder and OCD). Such a possibility does not necessarily presuppose a single gene for complex traits, but rather assumes that complex traits comprise several subtraits, each influenced by a single gene.

The frequent association between bipolar disorder and VCFS makes this an important population to study in more detail. If this unusually strong association is confirmed in a larger sample, deletional mapping with a well-characterized phenotype may enable us to narrow down a relatively small portion of the genome associated with the illness. The determination of a minimally deleted region in VCFS patients with bipolar disorder could lead to the identification of major or modifying genes that are responsible for the illness. Such an effort could provide a less expensive and more rapid alternative to a labor-intensive whole genome search with the attendant necessity for replication in large numbers of affected kindreds. The strong association between early-onset bipolar disorder among an unexpectedly high proportion of patients with VCFS will likely provide a new and fruitful line of investigation into the molecular basis of these conditions.

Further psychiatric assessment of a larger sample of individuals with VCFS, both cross-sectionally and longitudinally, will likely serve to resolve the current diagnostic controversy. It will also define the presentation and clinical course of a particular behavioral phenotype in a complex genetic disorder, from its earliest manifestations, as well as the developmental changes on the expression of the illness. With very few extant studies of early-onset bipolar disorder, such a view would be of immeasurable value to child and adolescent psychiatrists who currently struggle with the problems inherent in the early identification of this illness.


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