Association between a common haplotype in the COMT gene region and psychiatric disorders in individuals with 22q11.2DS.

The 22q11.2 deletion syndrome (22q11.2DS) is the most common hemizygous deletion syndrome in humans. In addition to a wide range of physical abnormalities 22q11.2DS subjects show high prevalence of several psychiatric disorders. In our previous study we showed that the low-activity allele (158Met) of the COMT gene is a risk factor for attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) in 22q11.2DS individuals. In the present study we have genotyped fifty-five 22q11.2DS individuals and 95 of their parents for eight SNPs in and around the COMT gene. A haplotype composed of three SNPs [rs2097603; rs4680 (158Val/Met); rs165599] representing the major linkage disequilibrium blocks in COMT and previously implicated in functional variation, was found to be associated with ADHD and OCD in 22q11.2DS individuals. A common risk haplotype (G-A-A) was significantly associated with both ADHD (OR 3.13, chi2=4.38, p=0.036) and OCD (OR 4.00, chi2=6.41, p=0.011) in 22q11.2DS individuals. Interestingly, the same haplotype was recently found to be associated with efficient prefrontal performance in the general population. The risk haplotype was not found to be associated with IQ scores in our 22q11.2DS sample. Parental origin of the deletion did not affect the susceptibility to ADHD and OCD in the 22q11.2DS subjects. This study demonstrated the association of a particular COMT haplotype with susceptibility to both ADHD and OCD in 22q11.2DS and supports the hypothesis that COMT gene variations contribute to genetic predisposition to psychiatric disorders in the general population.

Association of the low-activity COMT 158Met allele with ADHD and OCD in subjects with velocardiofacial syndrome.

Velocardiofacial syndrome (VCFS) is caused by a microdeletion in chromosome 22 and is a risk factor for the development of schizophrenia and other psychiatric disorders. The catechol-O-methyltransferase (COMT), residing in the 22q11.2 microdeletion region, is a major candidate gene for genetic susceptibility to neuropsychiatric disorders in VCFS. Individuals with VCFS carrying the low-activity allele (COMTL) are expected to have the lowest possible COMT activity since they have only a single copy of the gene. We explored the possibility that COMTL is associated with psychiatric disorders commonly found in VCFS. Fifty-five unrelated individuals with VCFS underwent psychiatric evaluation and were genotyped for the COMT 158Val/Met polymorphism coding for COMT high/low-activity alleles. The COMTL allele was significantly more prevalent in VCFS subjects with attention deficit hyperactivity disorder (ADHD) (73.9% vs. 33.3%, OR 5.67, chi2=7.76, p=0.005) and obsessive-compulsive disorder (OCD) (78.6% vs. 33.3%, OR 7.33, chi2=7.24, p=0.007) than in the control group (VCFS subjects without OCD, ADHD and schizophrenia/schizoaffective (SZ/SZaff) disorder). The results of this study suggest that greatly reduced COMT activity, as expected in VCFS COMTL individuals may be a risk factor for psychiatric sequelae in this population. Future longitudinal studies focusing on additional COMT polymorphic sites and other candidate genes from the deleted region will elucidate the molecular pathways leading to schizophrenia and other psychiatric disorders in VCFS.

Obsessive-compulsive disorder in patients with velocardiofacial (22q11 deletion) syndrome.

The study of neurogenetic microdeletion syndromes provides an insight into the developmental psychopathology of psychiatric disorders. The aim of the study was to evaluate the prevalence of psychiatric disorders, especially obsessive-compulsive disorder (OCD), in patients with velocardiofacial syndrome (VCFS), a 22q11 microdeletion syndrome. Forty-three subjects with VCFS of mean age 18.3 +/- 10.6 years were comprehensively assessed using semi-structured psychiatric interview and the Yale-Brown obsessive compulsive scale (Y-BOCS). Best estimate diagnoses were made on the basis of information gathered from subjects, parents, teachers, and social workers. Fourteen VCFS subjects (32.6%) met the DSM-IV criteria for OCD. OCD had an early age of onset and generally responded to fluoxetine treatment. It was not related to mental retardation. The most common obsessive-compulsive symptoms were contamination, aggression, somatic worries, hoarding, repetitive questions, and cleaning. Sixteen of the 43 patients (37.2%) had attention-deficit/hyperactivity disorder (ADHD), and 7 (16.2%) had psychotic disorder. The results of our study suggest that there is a strong association between VCFS and early-onset OCD. This finding may be significant in the understanding of the underlying genetic basis of OCD.

Genetic, developmental, and physical factors associated with attention deficit hyperactivity disorder in patients with velocardiofacial syndrome.

Velocardiofacial syndrome (VCFS) is a relatively common developmental neuropsychiatric syndrome caused by a 22q11 microdeletion. There is an extensive variability in the phenotypic expression of this disease. The most common psychiatric disorder in VCFS is attention-deficit/hyperactivity disorder (ADHD), affecting 35-55% of patients. This study investigated the association of familial, developmental, and physical factors with the occurrence of ADHD in 51 patients with nonfamilial VCFS. Twenty-one patients (41.2%) were diagnosed with ADHD. There was a significantly greater prevalence of ADHD in the first-degree relatives of the patients with ADHD than in those without (OR = 5.9, 95% CI = 1.6-22.1, P = 0.006). No differences were noted between the ADHD and non-ADHD groups in mean Obstetric Complication Scale Score, gestational age, birth weight, age at first words, walking, and achieving bowel control. The two groups also had similar IQ scores (total, verbal, and performance) and had a similar average degree of severity of facial dysmorphism and cardiac and cleft anomalies. These findings indicate that ADHD in VCFS has a genetic contribution and the patients' VCFS-related developmental factors and physical illnesses play a lesser role.

Methylphenidate treatment for attention-deficit/hyperactivity disorder in children and adolescents with velocardiofacial syndrome: an open-label study.

BACKGROUND: Velocardiofacial syndrome (VCFS) is a common microdeletion syndrome associated with psychiatric morbidity and developmental disabilities. Although attention-deficit/hyperactivity disorder (ADHD) is the most common psychiatric problem associated with VCFS, there are no reports on methylphenidate treatment in this patient population. Indeed, clinicians have commonly avoided the use of methylphenidate in children with VCFS because of concerns about ineffectiveness or psychotic exacerbation. METHOD: Forty subjects of mean +/- SD age 11.0 +/- 5.0 years with VCFS were assessed for DSM-IV diagnoses using the Schedule for Affective Disorders and Schizophrenia for School-Aged Children, Present and Lifetime Version, and its extended ADHD module (K-SADS-P-ADHD). Those found to have comorbid ADHD were treated with methylphenidate, 0.3 mg/kg once daily. Treatment efficacy was evaluated after 4 weeks with the K-SADS-P-ADHD, the Conners' Abbreviated Teacher Questionnaire, and the Conners' Continuous Performance Test. Side effects were evaluated with a modified version of the Barkley Side Effects Rating Scale. RESULTS: Of the 18 subjects (45%) diagnosed with ADHD, 12 agreed to participate in the study. Their ADHD symptoms, both behavioral and cognitive, improved significantly with treatment. None of the patients showed clinical worsening or psychotic symptoms. Side effects were usually mild and did not warrant discontinuation of methylphenidate. The most common side effects were anorexia and depressive-like symptoms. CONCLUSION: This open-label study indicates that methylphenidate is effective and safe in patients with VCFS. Therefore, its current limited use in this population seems to be unjustified. Larger, controlled clinical and pharmacogenetic studies are needed to confirm these findings.