Short communication: catechol-O-methyltransferase allelic variation in relation to psychological and hormonal indices of stress in children and adolescents with chromosome 22q11.2 deletion syndrome (22q11.2DS).

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a developmental disorder with high rates of anxiety and psychosis. Catechol-O-methyltransferase (COMT) regulates epinephrine (E), norepinephrine (NE), and dopamine (DA) and is implicated in both anxiety and psychotic disorders. The aim of this study was to determine how COMT variation relates to psychological anxiety and associated stress physiology responsiveness to better understand symptom heterogeneity in people with 22q11.2DS. We examined COMT allelic variation in relation to anxiety and hypothalamic-pituitary-adrenocortical (HPA) and sympathetic-adrenomedullary (SAM) hormonal stress indicators in 30 children and adolescents with 22q11.2DS. Contrary to expectation, individuals with the higher activity COMTval allele had higher anxiety levels versus those with the low activity (COMTmet) allele (p = 0.021; Glass' Δ = 0.69). Anxiety was not correlated with salivary cortisol (CORT) or alpha-amylase (sAA) in either group. Groups did not differ in CORT levels (p = 0.58), but the COMTmet group had higher sAA (p = 0.026; Glass' Δ = 0.67, uncorrected) suggesting greater SAM reactivity but not HPA activity. This suggests that COMT allelic variation may contribute to differences in acute SAM but not slower HPA stress reactivity in those with 22q11.2DS.

Beebe JL ，Martin CR ，Sanders AFP ，Guidry J ，Faheem F ，Atallah J ，Beaton EA ... -  《-》

Biological effects of COMT haplotypes and psychosis risk in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is the most common genetic syndrome associated with schizophrenia. The catechol-O-methyltransferase (COMT) gene is located in the obligatory deletion region, and possible associations between COMT variants and neuropsychiatric manifestations in 22q11.2DS have been reported. The purpose of the current study was to evaluate the effect of COMT hemizygosity and molecular haplotypes on gene expression and enzyme activity and its association with psychotic symptoms in 22q11.2DS. Lymphoblast samples were drawn from 53 individuals with 22q11.2DS and 16 typically developing control subjects. We measured COMT messenger (m)RNA and protein expression and enzyme activity using standard procedures. The presence of a psychotic disorder and cognitive deficits were also evaluated using structured testing. There was an approximately 50% reduction in COMT mRNA, protein, and enzyme activity levels in 22q11.2DS samples. Haplotype analysis revealed clear phenotypic differences between various Val-containing haplotypes on COMT-3' untranslated region extended mRNA, soluble COMT and membrane-bound proteins, and enzyme activity. The G variant of rs165599, a 3' untranslated region single nucleotide polymorphism, was associated with low levels of COMT expression and with the presence of psychosis and lower performance IQ scores in our 22q11.2DS sample. Finally, we demonstrate that the COMT rs74745580 "T" mutation is associated with absent soluble COMT expression and very low COMT activity in two 22q11.2DS individuals. Our findings confirm a robust effect of COMT hemizygosity on COMT activity and show complex interactions of variants within the COMT gene that influence COMT biology and confound conclusions based on associations with the Val158Met genotype alone.

Gothelf D ，Law AJ ，Frisch A ，Chen J ，Zarchi O ，Michaelovsky E ，Ren-Patterson R ，Lipska BK ，Carmel M ，Kolachana B ，Weizman A ，Weinberger DR ... -  《-》

Further evidence for high rates of schizophrenia in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is associated with high rates of psychotic disorder, particularly schizophrenia. The deletion is considered to be a biological model for understanding this debilitating psychiatric disorder. It is unclear whether the psychotic manifestations in 22q11.2DS are similar to those in schizophrenia patients without the deletion. Catechol-O-methyltransferase (COMT), a positional candidate gene for schizophrenia, resides within the 22q11.2 region. It remains unknown whether hemizygosity for this gene is associated with risk of psychotic disorder. This study includes 83 adults with 22q11.2DS, 90 non-deleted individuals with schizophrenia, and 316 normal controls. Psychopathology was assessed using the Schedules for Clinical Assessment in Neuropsychiatry, the Schedules for the Assessment of Positive and Negative Symptoms and the Global Assessment Scale. Schizotypy was assessed with the Kings Schizotypy Questionnaire and Oxford Liverpool Inventory of Feelings and Emotions. IQ estimates were also obtained. Adults with 22q11.2DS were genotyped for a number of COMT polymorphisms as well as the Ashkenazi risk haplotype. This study confirms high rates of psychotic disorder (29%) in individuals with 22q11.2DS of which the majority had schizophrenia (22%). There does not appear to be a differential expression of schizophrenic symptom clusters in 22q11.2DS in relation to sporadic schizophrenia, though schizophrenia in 22q11.2DS seems to be less severe in terms of global assessment scores. Psychosis proneness seems to be of genetic origin in 22q11.2DS as individuals with 22q11.2DS without schizophrenia had higher schizotypy scores than normal controls. Finally, COMT was not associated with schizophrenia status or schizotypy.

Monks S ，Niarchou M ，Davies AR ，Walters JT ，Williams N ，Owen MJ ，van den Bree MB ，Murphy KC ... -  《-》

Stimulant treatment effectiveness, safety and risk for psychosis in individuals with 22q11.2 deletion syndrome.

This study aimed to retrospectively evaluate an association between stimulant treatment for attention-deficit/hyperactivity disorder (ADHD) in individuals with 22q11.2DS and the development of psychotic disorders, to evaluate long-term effectiveness and safety of stimulant treatment in individuals with 22q11.2DS compared to individuals with idiopathic ADHD, and to explore effects of catechol-O-methyltransferase (COMT) genotype on 22q11.2DS response to stimulants and risk of side effects. Rates of stimulant use and methylphenidate equivalent exposure were compared among individuals with 22q11.2DS, between 51 with psychotic disorders and a control group of 57 22q11.2DS without psychotic disorders, from Tel Aviv and Geneva. In addition, 44 individuals with 22q11.2DS and ADHD from Tel Aviv who initiated stimulants before age 18 years were compared to a control group of 35 age- and sex-matched controls with idiopathic ADHD, for treatment effectiveness (Clinical Global Impression Scale-Improvement), and rates of side effects. Stimulant use history and methylphenidate equivalent exposure did not differ among individuals with 22q11.2DS, between those with and without psychotic disorders. The long-term retrospective follow-up (5.3 ± 4.1 years) of stimulant-treated individuals with 22q11.2DS showed a higher rate of significant clinical improvement of ADHD symptoms, compared to idiopathic ADHD individuals (p = 0.013), and similar side effect rates. There was no effect of the COMT genotype on response to stimulants or on any side effects. This preliminary long-term retrospective analysis suggests that stimulant treatment in 22q11.2DS is apparently safe in terms of psychosis conversion and rates of side effects, and that it is effective in alleviating ADHD symptoms.

Basel D ，Mosheva M ，Maeder J ，Schneider M ，Shani S ，Weinberger R ，Eliez S ，Gothelf D ... -  《-》

Identifying patterns of anxiety and depression in children with chromosome 22q11.2 deletion syndrome: comorbidity predicts behavioral difficulties and impaired functional communications.

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a complex genetic disorder with a variable clinical presentation that can include cardiac, neural, immunological, and psychological issues. Previous studies have measured elevated anxiety and depression in children with 22q11.2DS. Comorbity of anxiety and depression is well established in the pediatric literature but the nature of comorbidity patterns has not been empirically established in children with 22q11.2DS. Comorbidity of anxiety and depression has important implications for treatment and prognosis, and may be a marker of risk in this population of children at high-risk for developing schizophrenia. Participants were 131 boys and girls ages 8-14 with (n=76) and without (n=55) 22q11.2DS and their mothers. Children and mothers independently completed self- and parent-report measures of anxiety and depression. Mothers also completed measures of behavioral functioning including the Behavioral Assessment for Children, 2nd ed. (BASC-2). Cluster analyses were conducted to test if theoretically based groupings of anxiety and depression could be identified. We hypothesized four psychological profiles based on child- and mother-reports: low/no anxiety and low/no depression, higher depression and low/no anxiety, higher anxiety and no/low depression, and a comorbid profile of higher anxiety and higher depression. BASC-2 subscale scores were then compared across subgroups of children to determine if a comorbid profile would predict greater behavioral difficulties. In the full sample of children both with and without 22q11.2DS, cluster analyses of self and maternal reported anxiety and depression revealed the expected subgroups: (1) a group of children with higher anxiety/lower depression (anxious); (2) a group with primary depression (lower anxiety/higher depression (depressed)); (3) a comorbid group with higher anxiety/higher depression (comorbid); and, (4) a lowest anxiety/lowest depression group (NP). Mothers' reports produced highly similar groupings. Furthermore, the 22q11.2DS youth were more likely to be in anxiety, depressed or comorbid clusters than the typically developing (TD) youth. Children with 22q11.2DS comorbid for anxiety and depression exhibited the worst functional outcomes (e.g., poor poorer functional communication, and reduced daily life activities). Anxiety, comorbid with depression may be of particular concern in children with 22q11.2DS who arguably carry a greater burden on their stress coping resources than children without a complex genetic disorder. Furthermore, the manifestation of negative mood, anxiety and difficult behavior is likely to reverberate between the child and her or his environment. This can lead to negative interactions with family, peers, and teachers, which in turn further taxes coping resources. Comorbidity of anxiety and depression within a vulnerable population highlights the need for the development of tailored interventions.

Stephenson DD ，Beaton EA ，Weems CF ，Angkustsiri K ，Simon TJ ... -  《-》