Basal ganglia calcification and psychosis in 22q11.2 deletion syndrome

Intracerebral calcifications are a facultative symptom of hypoparathyreoidism in 22q11.2 deletion syndrome (22qDS). We describe a patient with 22qDS, basal ganglia calcification (BGC) and psychotic symptoms and discuss the etiological connection of BGC with psychiatric symptoms. Future work needs to determine the prevalence of BGC in 22qDS and psychiatric disorders.     

Increased basal ganglia volumes in velo-cardio-facial syndrome (deletion 22q11.2).

BACKGROUND: This study evaluated differences in caudate volumes in subjects with velo-cardio-facial syndrome due to a 22q11.2 (22qDS) deletion. Because psychosis is observed in 30% of adult subjects with 22qDS, this neurogenetic disorder could represent a putative model for a genetically mediated subtype of schizophrenia.METHODS: Caudate volumes were measured on high-resolution magnetic resonance images in 30 children and adolescents with 22qDS and 30 gender- and age-matched normal comparison subjects.RESULTS: Caudate head volumes were increased in the 22qDS group independent of neuroleptic medications. Subjects with 22qDS also displayed an abnormal pattern of asymmetry in the anterior caudate, with left side greater than right.CONCLUSIONS: Alterations in the basal ganglia circuitry have been implicated in learning, cognitive, and behavioral problems in children and therefore could be involved in the expression of the neurobehavioral phenotype expressed by subjects with 22qDS. Abnormal caudate volume is a neurodevelopmental feature shared with schizophrenia, further establishing 22qDS as a potential neurodevelopmental model for this disorder.     

Schizophrenia and 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22qDS) is a genetic syndrome associated with a chromosome 22q11.2 deletion and variable phenotypic expression that commonly includes schizophrenia. Approximately 1% of patients with schizophrenia have 22qDS. The schizophrenia in 22qDS appears broadly similar to that found in the general population with respect to core signs and symptoms, treatment response, neurocognitive profile, and MRI brain anomalies. However, individuals with a 22qDS form of schizophrenia typically have distinguishable physical features, have a lower IQ, and may differ in auxiliary clinical features. IQ, length of 22q11.2 deletions, and COMT functional allele do not appear to be major risk factors for schizophrenia in 22qDS. Ascertainment biases and small sample sizes are limitations of most studies. Larger studies over the lifespan and continuing education about this underrecognized condition are needed. 22qDS-schizophrenia is an important genetic subtype and a valuable model of neurodevelopmental mechanisms involved in the pathogenesis of schizophrenia.     

COMT implication in cognitive and psychiatric symptoms in chromosome 22q11 microdeletion syndrome: a selective review

22q11.2 deletion syndrome (22q11DS) is a genetic syndrome associated with a microdeletion of the chromosome 22 band q11.2 with an estimated prevalence between 1:2,500 and 1:4,000. Studies of school-age children have shown that individuals with 22q11DS have high rates of psychiatric morbidity. In particular, by late adolescence, about 30% of patients with 22q11DS develop psychotic symptoms. One of the genes located in the microdeletion region of 22q11DS is the Catechol-O-Methyl transferase (COMT) which codes for an enzyme critically involved in the catabolic clearance of dopamine. COMT is critically involved in cognitive related disturbances, and it has often been suggested as a sensitive factor in the development of psychiatric disorders. Several studies have been conducted on the impact of COMT functional polymorphism in 22q11DS and its related cognitive/psychiatric correlates. In this review, we summarize mainly current knowledge on the correlation between schizophrenia/cognitive related symptoms and COMT genetic variations in 22q11DS. A selective literature review on this topic was undertaken. COMT might play an important role in modulating cognitive functions in 22q11DS but a clear relationship between COMT polimorphism and schizophrenia in 22q11DS need further investigation. Despite controversial results, 22q11DS represent a powerful model for studying the role of COMT and other genetic variations in schizophrenia. This is due to high risk in 22qDS patients of developing this disorder and their relative genetic homogeneity. Further research is needed to evaluate all of the polymorphic markers in the COMT gene and its nearby regulatory elements for association with schizophrenia. Identification of specific COMT-dependent molecular, cellular and circuit deficits will provide targets for the development of more efficient treatments for the cognitive and psychiatric symptoms in 22q11DS.     

The schizophrenia phenotype in 22q11 deletion syndrome

OBJECTIVE: This study investigated the schizophrenia phenotype in 24 subjects with 22q11 deletion syndrome (22qDS) and schizophrenia (22qDS-schizophrenia), a rare but relatively homogenous genetic subtype of schizophrenia associated with a microdeletion on chromosome 22. Individuals with 22qDS are at genetically high risk for schizophrenia. METHOD: Standard measures of signs, symptoms, and course of schizophrenia were assessed in 16 adults with 22qDS-schizophrenia who did not meet criteria for mental retardation and in 46 adults with schizophrenia without evidence of 22qDS from a community familial sample. RESULTS: There were no significant differences in age at onset, lifetime or cross-sectional core positive and negative schizophrenic symptoms, or global functioning between the two groups of patients with schizophrenia. Patients with 22qDS-schizophrenia had higher excitement subscale scores and less lifetime substance use than the comparison patients with schizophrenia, but no significant differences in anxiety-depression symptom severity were found between the groups. CONCLUSIONS: These findings indicate that the core clinical schizophrenia phenotype would not distinguish individuals with a 22qDS subtype from those with schizophrenia who did not have the 22qDS subtype. The results provide further support for the utility of 22qDS-schizophrenia as a neurodevelopmental model of schizophrenia as well as support for prospective studies of individuals with 22qDS to help identify precursors of schizophrenia.     

Prevalence of ADHD in children with velocardiofacial syndrome: A preliminary report

Velocardiofacial syndrome (VCFS) is a relatively common multi-anomaly disorder associated with a deletion on chromosome 22. Patients with VCFS have cardiac anomalies, cleft palate, learning problems, and speech and developmental delays. Previous studies found that mood and psychotic illnesses were the most common psychiatric disorders in patients with VCFS. The few studies that have focused solely on children with VCFS, however, have found an increased prevalence of attention-de.cit/ hyperactivity disorder (ADHD). This paper reports on a clinical evaluation and a structured interview that were administered to 52 children with VCFS and their parents. The prevalence of ADHD in this sample was approximately 10 times that in the general population. Awareness of the possibility of increased prevalence of ADHD in VCFS, particularly of the inattentive type, is important because it is likely to be overlooked by parents and clinicians. Intervention with these children may halt the progression of psychiatric illness and improve outcome.     

22q11 DS: genomic mechanisms and gene function in DiGeorge/velocardiofacial syndrome

22q11 deletion syndrome (22qDS), also known as DiGeorge or velocardiofacial syndrome (DGS/VCFS), is a relatively common genetic anomaly that results in malformations of the heart, face and limbs. In addition, patients with 22qDS are at significant risk for psychiatric disorders as well, with one in four developing schizophrenia, and one in six developing major depressive disorders. Like several other deletion syndromes associated with psychiatric or cognitive problems, it has been difficult to determine which of the specific genes in this genomic region may mediate the syndrome. For example, patients with different genomic deletions within the 22q11 region have been found that have similar phenotypes, even though their deletions do not compromise the same set of genes. In this review, we discuss the individual genes found in the region of 22q11 that is commonly deleted in 22qDS patients, and the potential roles each of these genes may play in the syndrome. Although many of these genes are interesting candidates by themselves, we hypothesize that the full spectrum of anomalies associated with 22qDS may result from the combined result of disruptions to numerous genes within the region that are involved in similar developmental or cellular processes.     

Psychotic symptoms in children and adolescents with 22q11.2 deletion syndrome: Neuropsychological and behavioral implications

Individuals with 22q11.2 deletion syndrome (22q11DS) are at increased risk for developing schizophrenia: half of affected adolescents report transient psychotic experiences and up to 30% of adults are diagnosed with schizophrenia. Prospective studies have shown that psychotic symptoms in childhood are predictive of later schizophreniform disorders. The current study aimed to define the prevalence and correlates of psychotic symptoms (PS) in young children and adolescents with 22q11DS. Forty-three children and adolescents with 22q11DS (mean age = 10.62+/-11.19) participated in this study. The occurrence of PS and their neuropsychological and behavioral correlates were investigated through semi-structured interviews and standardized measures. Psychotic symptoms were reported in 28% of the total sample and 17% of pre-adolescent children, and associated with decreased verbal IQ scores [F(1) = 4.41, p = 0.042]. Compared to young patients without PS, young patients with PS were perceived by their parents as more anxious-depressed [F(1) = 4.76, p = 0.035] and withdrawn [F(1) = 7.63, p = 0.009], with reduced adaptive socialization skills [F(1) = 6.88, p = 0.012]. Results suggest that psychotic manifestations are present earlier than typically reported in youngsters with 22q11DS and are accompanied by reduced verbal IQ performance and decreased adaptative social skills. The symptomatic, neuropsychological and behavioral characteristics observed in the current study may constitute central markers of increased risk for psychosis in 22q11DS.     

Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome

OBJECTIVE: The 22q11.2 deletion syndrome is the most common known genetic risk factor for the development of schizophrenia. The authors conducted a longitudinal evaluation of adolescents with 22q11.2 deletion syndrome to identify early risk factors for the development of psychotic disorders. METHOD: Sixty children, 31 with 22q11.2 deletion syndrome and 29 comparison subjects with idiopathic developmental disability matched for age and IQ, underwent a baseline evaluation between 1998 and 2000; of these, 51 children (28 and 23 in the two groups, respectively) underwent follow-up evaluation between 2003 and 2005. A standardized comprehensive psychiatric, psychological, and adaptive functioning evaluation was conducted in both waves. Participants with 22q11.2 deletion syndrome were also genotyped for the catechol O-methyltransferase (COMT) Met/Val polymorphism and underwent magnetic resonance imaging scans. RESULTS: The two groups had similar baseline neuropsychiatric profiles. At follow-up, 32.1% of subjects with 22q11.2 deletion syndrome had developed psychotic disorders as compared with 4.3% of comparison subjects. In the 22q11.2 deletion syndrome group, baseline subthreshold psychotic symptoms interacted both with the COMT genotype and with baseline symptoms of anxiety or depression to predict 61% of the variance in severity of psychosis at follow-up evaluation. Lower baseline verbal IQ was also associated with more severe psychotic symptoms at follow-up evaluation. CONCLUSIONS: Genetic, cognitive, and psychiatric risk factors for the evolution of psychotic disorders in 22q11.2 deletion syndrome during adolescence were identified. Early intervention in the subgroup of children with subthreshold signs of psychosis and internalizing symptoms (especially anxiety symptoms) may reduce the risk of developing psychotic disorders during adolescence.     

The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms

OBJECTIVE: To examine psychopathology and influence of intelligence level on psychiatric symptoms in children with the 22q11.2 deletion syndrome (22q11DS). METHOD: Sixty patients, ages 9 through 18 years, were evaluated. Assessments followed standard protocols, including structured and semistructured interviews of parents, videotaped psychiatric interview, and intelligence assessment of the child. Intelligence level, psychiatric symptoms, and classification provided the main outcome. RESULTS: High rates of autism spectrum disorders (30 of 60, 50.0%) and psychotic symptoms (16 of 60, 26.7%) were found in this sample. In 7 of 60 (11.7%), the psychotic symptoms interfered with behavior and caused considerable distress. In these cases, the diagnosis of a psychotic disorder was applied. The average age of the children with psychotic symptoms at time of assessment was 14.2 years. Although it is likely that the high rate of psychopathology in this sample is to some extent associated with the lower level of cognitive function, a major effect of the degree of cognitive impairment on psychiatric morbidity was not found. CONCLUSION: Autism spectrum disorders and subthreshold autistic symptomatology are common in children with 22q11DS. Furthermore, a high rate of psychosis and psychotic symptoms is found in this childhood sample, suggesting an early onset of psychosis in 22q11DS patients. Autistic and psychotic disorders should be considered to be main elements of the behavioral phenotype of 22q11DS children.     

The relationship between Usher's syndrome and psychosis with Capgras syndrome.

Usher's syndrome is a genetic disorder that causes congenital sensorineural hearing loss, visual impairment due to progressive pigmentary retinopathy, and, often, vestibular dysfunction. The aim of this article is to illustrate a case that clearly demonstrates psychotic symptoms in Usher's syndrome Type III and serves to increase clinical awareness of this disorder and its possible link to psychotic symptoms. There is some evidence in the literature of concurrent psychiatric symptoms, particularly psychotic symptoms, associated with Usher's syndrome, and several theories around this association have been proposed. These theories of associations include a genetic link between the genes responsible for schizophrenia and the genes for Usher's syndrome; a neuropathological explanation as radiologic studies have revealed that patients with Usher's syndrome have CNS abnormalities in multiple brain structures; and a sensory deficit model which proposes that the stressors associated with sensory impairment and the brain's adaptation to changes in sensory inputs place an individual at increased risk for psychopathology.     

Memory in intellectually matched groups of young participants with 22q11.2 deletion syndrome and those with schizophrenia

The 22q11.2 deletion syndrome (22qDS) and schizophrenia have genetic and neuropsychological similarities, but are likely to differ in memory profile. Confirming differences in memory function between the two disorders, and identifying their genetic determinants, can help to define genetic subtypes in both syndromes, identify genetic risk factors for the emergence of psychosis, and develop pharmacological interventions for cognitive dysfunction. However, no study has compared memory function between 22qDS and schizophrenia, while indirect comparisons are confounded by marked differences in IQ between the two populations. We compared verbal and visual memory in 29 children and adolescents with 22qDS and 15 intellectually matched youths with schizophrenia using age-appropriate, directly comparable, Wechsler scales. Verbal memory was markedly superior in the 22qDS group by 21 points. There were no group differences in visual memory. The inherently low COMT activity in 22qDS merits investigation as a potential protective factor for verbal memory.     

Psychosis in a pediatric mood and anxiety disorders clinic: phenomenology and correlates

OBJECTIVES: To examine the demographics and phenomenology of psychosis in a sample of children and adolescents referred to a mood and anxiety disorders clinic. METHOD: Patients (N = 2,031) were assessed with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present Episode version and classified as definite, probable, or nonpsychotic. Clinical and demographic characteristics of the groups were compared,and symptoms of psychosis were analyzed using factor analysis. RESULTS: Definite psychotic symptoms were seen in approximately 90 (4.5%) patients: 80% of these reported hallucinations (mainly auditory), 22% delusions, and 3.3% thought disorder. Of the patients with definite psychotic symptoms, 24% had bipolar disorder, 41% had major depression, 21% had subsyndromal depression, and 14% had schizophrenia spectrum disorders (schizophrenia and schizoaffective disorders). Factor analysis of the definite psychotic symptoms yielded 4 factors: hallucinations, thought disorder, delusions, and manic thought disorder. Psychotic patients had a higher frequency of comorbid disorders and suicidal ideation than nonpsychotic patients. CONCLUSIONS: Outpatient youngsters with mood disorders frequently present with psychotic symptoms, in particular auditory hallucinations. These patients commonly have comorbid psychiatric disorders and suicidal ideation.     

Spectrum of neuropsychiatric features associated with velocardiofacial syndrome (Deletion 22q11.2)

Microdeletion 22q11.2 (22q11DS) is the most frequent chromosomal deletion known in man. Velocardiofacial syndrome is one of numerous clinical syndromes that can be attributed to this micro deletion. There is an increasing recognition of associations with neuropsychiatric disorders. Particularly, schizophrenic psychosis, attention-deficit/hyperactivity disorder (ADHD), intellectual impairment and learning disabilities, seizures and motoric abnormalities have been identified in patients with 22q11DS. Recent studies supported the association of schizophrenia and 22q11DS, but the pathogenetic implications for idiopathic schizophrenia are still controversial. We report on two clinical cases in which psychotic symptoms led to the molecularcytogenetic diagnosis of microdeletion 22q11.2. Additionally, this article gives a systematic review of literature regarding psychiatric disorders, neurologic symptoms and partly corresponding morphological brain abnormalities in 22q11 deletion syndromes.     

Psychiatric disorders in people with 22q11.2 Deletion Syndrome: A population‐based prevalence study in Ireland

Background : 22q11.2 Deletion Syndrome (22q11.2 DS) is a common micro‐deletion syndrome associated with intellectual disability, brain abnormalities and a complex spectrum of psychiatric disorders in both adults and children. Many previous studies have shown that adults with 22q11.2 DS have approximately thirty times greater risk for the developing schizophrenia compared to the general population. Furthermore, studies of children and adolescents with 22q11.2 DS have found high rates of psychotic symptoms, ADHD and anxiety disorders. In this study we initially aim to characterize the psychiatric and neuropsychological phenotype of all individuals in Ireland with 22q11.2 DS and then correlate our findings with genetic association studies and brain imaging. We then intend to undertake a longitudinal study to assess for risk factors of future psychotic illness. Methods : Forty‐four individuals with 22q11.2 DS (Mean age = 14 years, SD = 9) were compared to 25 non‐affected sibling controls (Mean age = 12 years, SD = 4). Psychiatric phenotype assessment was performed using a range of standardized clinical assessments including, the Diagnostic Interview Schedule for Children (DISC), Psychotic Supplement of K‐SADS, Comprehensive Assessment of At Risk Mental State (CAARMS), the Schedule for Clinical Assessment in Neuropsychiatry (SCAN), Child Behaviour Checklist (CBCL) and the Social Communication Questionnaire (SCQ). Results : Preliminary data indicates that individuals in the 22q11.2 DS group have a higher prevalence of psychiatric disorders including; ADHD (41%), psychotic symptoms (19%), schizophrenia (2.7%), specific phobias (38%), depressive episodes (11%), and anxiety disorders (32%). Conclusion : This is the first stage in a longitudinal follow‐up study of individuals with 22q11.2DS in Ireland. Our preliminary results are consistent with previous findings of high rates of psychiatric disorders in people with 22q11.2DS. The challenge remains to identify precursor symptoms in childhood that predicts the later development of psychiatric disorders, particularly schizophrenia in this vulnerable group.     

Manic symptoms and behavioral dysregulation in youth with velocardiofacial syndrome (22q11.2 deletion syndrome)

Mania and bipolar disorder have been reported in adolescents and adults with velocardiofacial syndrome (VCFS; also known as 22q11.2 deletion syndrome). Children with VCFS have a high prevalence of attention-deficit/hyperactivity disorder (ADHD), which may constitute a risk factor for the eventual development of bipolar disorder in this population. Therefore, we sought to determine whether children with VCFS exhibit more manic symptoms than community controls that also may have learning disorders and ADHD. The study population consisted of 86 children with VCFS and 36 community controls from ages 9 to 15 years, using measures of Young Mania Rating Scale-Parent Version, Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL), Child Behavior Checklist (CBCL), and Wechsler Intelligence Scale for Children-3rd edition (WISC-III). The results indicate that manic symptoms were not more prevalent in VCFS than in a community sample of children with learning disorders and ADHD. However, after accounting for symptoms of depression and ADHD, we found that manic symptoms in VCFS predicted uniquely to scores on four Child Behavior Checklist (CBCL) subscales, including anxiety, somatization, thought, and conduct problems. In contrast, manic symptoms in controls predicted uniquely to conduct problems only. Accordingly, our findings of severe behavioral impairment in youth with VCFS and manic symptoms suggest that these children may warrant more intensive monitoring and treatment relative to youth with VCFS and ADHD only.     

22q11 deletion syndrome: a genetic subtype of schizophrenia.

Schizophrenia is likely to be caused by several susceptibility genes and may have environmental factors that interact with susceptibility genes and/or nongenetic causes. Recent evidence supports the likelihood that 22q11 Deletion Syndrome (22qDS) represents an identifiable genetic subtype of schizophrenia. 22qDS is an under-recognized genetic syndrome associated with microdeletions on chromosome 22 and a variable expression that often includes mild congenital dysmorphic features, hypernasal speech, and learning difficulties. Initial evidence indicates that a minority of patients with schizophrenia (approximately 2%) may have 22qDS and that prevalence may be somewhat higher in subpopulations with developmental delay. This paper proposes clinical criteria (including facial features, learning disabilities, hypernasal speech, congenital heart defects and other congenital anomalies) to aid in identifying patients with schizophrenia who may have this subtype and outlines features that may increase the index of suspicion for this syndrome. Although no specific causal gene or genes have yet been identified in the deletion region, 22qDS may represent a more homogeneous subtype of schizophrenia. This subtype may serve as a model for neurodevelopmental origins of schizophrenia that could aid in delineating etiologic and pathogenetic mechanisms.     

Smooth pursuit eye-tracking impairment in childhood-onset psychotic disorders

OBJECTIVE: Although childhood-onset schizophrenia is relatively rare, a sizable group of children with severe emotional disturbances have transient psychotic symptoms that fall outside of current syndrome boundaries. The relationship of this group of children to those with childhood-onset schizophrenia and other childhood psychiatric disorders is unclear. In this study, the authors compared smooth pursuit eye tracking, a biological trait marker associated with schizophrenia, of children and adolescents with psychotic disorder not otherwise specified to that of children with childhood-onset schizophrenia and healthy comparison subjects. METHOD: By means of infrared oculography, smooth pursuit eye movements during a 17 degrees /second visual pursuit task were quantitatively and qualitatively compared in 55 young adolescents (29 with childhood-onset schizophrenia and 26 with psychotic disorder not otherwise specified) and their respective independent healthy comparison groups (a total of 38 healthy subjects). RESULTS: Subjects with childhood-onset schizophrenia had qualitatively poorer eye tracking, higher root mean square error, lower gain, and a greater frequency of catch-up saccades than healthy children. Subjects with psychotic disorder not otherwise specified also had qualitatively poorer eye tracking, higher root mean square error, and lower gain than healthy children, but saccade frequency did not differ significantly. CONCLUSIONS: Children with childhood-onset schizophrenia exhibit a pattern of eye-tracking dysfunction similar to that reported for adult patients. Similar abnormalities were seen in the subjects with psychotic disorder not otherwise specified except that they did not exhibit a greater frequency of catch-up saccades. Prospective longitudinal neurobiological and clinical follow-up studies of both groups are currently underway to further validate the distinction between these two disorders. Also, family studies are planned to establish whether eye-tracking dysfunction represents a trait- or state-related phenomenon in subjects with psychotic disorder not otherwise specified.     

Down syndrome and attention-deficit/hyperactivity disorder (ADHD)

Clinicians might minimize the prevalence of behavioral disorders among mentally retarded people. Decreased attention, hyperactivity, and impulsivity are frequently reported in children with Down syndrome, yet the exact prevalence of attention-deficit/hyperactivity disorder (ADHD) has not been clearly estimated in this population. The objective of this study was to estimate the prevalence of ADHD in children with Down syndrome and to emphasize the possible relationship between ADHD symptoms and the level of mental retardation and common medical comorbidity. In this study, the prevalence of ADHD among Down syndrome children was very high, reaching 43.9%. No significant correlation was found between ADHD symptoms and the level of mental retardation, but significant correlation was found with ophthalmologic problems. We conclude that children with Down syndrome are at increased risk for ADHD. When evaluating children with Down syndrome for attention deficits, psychiatric comorbidity as well as medical problems should be carefully taken into consideration.