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.     

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.     

A novel sporadic 614-Kb duplication of the 22q11.2 chromosome in a child with amyoplasia

Arthrogryposis is a rare congenital disorder characterized by multiple fixed joint contractures. Decreased fetal movement, regardless of etiology, causes an immobilization of the affected joints and subsequent contractures. Amyoplasia refers to the most common variant of arthrogryposis in which patients develop symmetrical limb contractures because of muscle underdevelopment. It is a sporadic condition with no known genetic abnormality being linked to this syndrome. The authors report a 4-month-old boy with amyoplasia carrying a novel de novo 614-Kb duplication of the 22q11.2 region. Amyoplasia has not been reported in patients with 22q11.2 microduplication syndrome. This particular 614-Kb duplicated segment contains 7 genes located within the typical 22q11.2 duplication region and 2 genes, TUBA8 and USP18, mapping outside of the typical region. This patient broadens the phenotypic spectrum of the 22q11.2 microduplication syndrome and raises the possibility that TUBA8 and USP18 may play an important role in the pathogenesis of amyoplasia.     

Screening for 22q11 deletions in a schizophrenia population.

Since the recognition that adults with velocardiofacial syndrome (VCFS), which is associated with hemizygous interstitial deletions of chromosome 22q11, frequently show psychotic symptoms, deletion of the 22q11.2 region has been proposed as a common genetic abnormality associated with schizophrenia. In studies of schizophrenia patients, such deletions have been detected in more than 1% of schizophrenics, indicating the likely presence of this deletion in a significant number of patients. In this study, we screened for 22q11.2 deletions by genotyping microsatellite markers in 300 schizophrenics and 300 normal controls. The 22q11.2 deletion was confirmed by fluorescent in situ hybridization (FISH). One patient with schizophrenia was found to have a 22q11.2 deletion. The patient was mildly retarded but did not have craniofacial, palatal, or cardiac malformations characteristic of VCFS. Our results indicate that 22q11.2 deletion does not contribute substantially to the development of schizophrenia in general. However, our findings establish the existence of physically near-normal individuals with 22q11.2 deletion among learning disabled or mildly retarded persons with schizophrenia.     

22q11.2 Microduplication syndrome and epilepsy with continuous spikes and waves during sleep (CSWS). A case report and review of the literature

Chromosome 22q11.2 microduplication syndrome is characterized by a variable and usually mild phenotype and by incomplete penetrance. Neurological features of the syndrome may entail intellectual or learning disability, motor delay, and other neurodevelopmental disorders. However, seizures or abnormal EEG are reported in a few cases.We describe a 6-year-old girl with microduplication of chromosome 22q11.2 and epilepsy with continuous spikes and waves during sleep (CSWS). Her behavioral disorder, characterized by hyperactivity, impulsiveness, attention deficit, and aggressiveness, became progressively evident a few months after epilepsy onset, suggesting a link with the interictal epileptic activity characterizing CSWS.We hypothesize that, at least in some cases, the neurodevelopmental deficit seen in the 22q11.2 microduplication syndrome could be the consequence of a disorder of cerebral electrogenesis, suggesting the need for an EEG recording in affected individuals. Moreover, an array-CGH analysis should be performed in all individuals with cryptogenic epilepsy and CSWS.     

22q11.2 deletion and schizophrenia in childhood and adolescence

22q11.2 deletion is the most common microdeletion in humans and one of the most important risk factors for schizophrenia. Nevertheless, case reports of children or adolescents with 22q11.2 deletion and schizophrenia are very rare. After a review of the current knowledge about physical, developmental, behavioural and psychiatric problems in 22q11.2 deletion, the case of a 12;10-year-old boy with schizophrenia and the microdeletion is reported. About three years after the first symptoms, and only after medication with several neuroleptics, the patient reached his pre-morbid functioning level under treatment with risperidone. Under medication with clozapine he had experienced a single event of seizures which were due to hypocalcemia. This case report illustrates the importance of serum calcium controls at regular intervals for patients with 22q11.2 deletion and schizophrenia who are on neuroleptic medication. Ideally, children and adolescents with the deletion and co-morbid psychiatric problems should be treated in child and adolescent psychiatry units specialized in problems associated with the deletion. A good cooperation with other medical services is absolutely necessary.     

Identification and characterization of three inherited genomic copy number variations associated with familial schizophrenia

Schizophrenia is a complex mental disorder with high degree of genetic influence in its etiology. Several recent studies revealed that copy number variations (CNVs) of genomic DNA contributed significantly to the genetic architecture of sporadic schizophrenia. This study aimed to investigate whether CNVs also contribute to the familial forms of schizophrenia. Using array-based comparative genomic hybridization technology, we searched for pathogenic CNV associated with schizophrenia in a sample of 60 index cases from multiplex schizophrenia families. We detected three inherited CNVs that were associated with schizophrenia in three families, including a microdeletion of ~4.4Mb at chromosome 6q12-q13, a microduplication of ~1Mb at chromosome 18q12.3, and an interstitial duplication of ~5Mb at chromosome 15q11.2-q13.1. Our data indicate that CNVs contribute to the genetic underpinnings of the familial forms of schizophrenia as well as of the sporadic form. As 15q11-13 duplication is a well-known recurrent CNV associated with autism in the literature, the detection of the 15q11.2-q13.1 duplication in our schizophrenia patients provides additional support to other studies reporting that schizophrenia is part of the clinical spectrum of 15q11-q13 duplication syndrome.     

Parental origin of the deletion 22q11.2 and brain development in velocardiofacial syndrome: a preliminary study

BACKGROUND: As children with velocardiofacial syndrome (VCFS) develop, they are at increased risk for psychopathology; one third will eventually develop schizophrenia. Because VCFS and the concomitant symptomatology result from a known genetic origin, the biological and behavioral characteristics of the syndrome provide an optimal framework for conceptualizing the associations among genes, brain development, and behavior. The purpose of this study was to investigate the effect of the parental origin of the 22q11.2 microdeletion on the brain development of children and adolescents with VCFS. METHODS: Eighteen persons with VCFS and 18 normal control subjects were matched individually for age and sex. Results of DNA polymorphism analyses determined the parental origin of the deletion. Nine persons with VCFS had a deletion on the maternally derived chromosome 22; 9 persons, on the paternally derived chromosome 22. High-resolution magnetic resonance imaging scans were analyzed to provide quantitative measures of gray and white matter brain tissue. RESULTS: Total brain volume was approximately 11% smaller in the VCFS group than in controls. Comparisons between VCFS subgroups (maternal vs paternal microdeletion 22q11.2) indicated a significant 9% volumetric difference in total volume of cerebral gray matter (volume was greater in patients with paternal microdeletion) but not cerebral white matter. Significant age-related changes in gray matter were detected for subjects whose 22q11.2 deletion was on the maternal chromosome. CONCLUSIONS: Children and adolescents with VCFS experience major alterations in brain volumes. Significant reduction in gray matter development is attributable to presence of 22q11.2 microdeletion on the maternal chromosome.     

Microduplication 22q11.2 in a child with autism spectrum disorder: clinical and genetic study

Microduplication of the 22q11.2 chromosomal region has been recognized since 1999 and has been associated with a highly variable phenotype. Neurodevelopmental impairment and behavioural problems are very common in patients with 22q11.2 duplication. Autism spectrum disorders (ASDs) have previously been reported in only two patients with 22q11.2 duplication and striking dysmorphic features. We report here on a 4‐year‐old male of healthy consanguineous parents presenting with ASD according to DSMIV, revised, criteria as a primary manifestation. The child walked at 16 months and started to say one word and some sounds. Parents noticed a subsequent developmental arrest. At 4 years his functional development age, evaluated by the Psychoeducational Profile, was roughly 6 months. Mild non‐specific facial dysmorphism was noted. Genetic analyses of the child demonstrated a de novo microduplication of the 22q11.2 chromosomal region. This genetic anomaly was best seen in interphases of blood lymphocytes and in buccal smear nuclei. Our case illustrates once again the clinical heterogeneity of the 22q11.2 duplication as well as the wide genetic complexity of ASD. We suggest that genetic evaluation of ASD should include fluorescence in‐situ hybridization analysis of the 22q11.2 chromosomal region.     

Multimodal investigation of triple network connectivity in patients with 22q11DS and association with executive functions

Large‐scale brain networks play a prominent role in cognitive abilities and their activity is impaired in psychiatric disorders, such as schizophrenia. Patients with 22q11.2 deletion syndrome (22q11DS) are at high risk of developing schizophrenia and present similar cognitive impairments, including executive functions deficits. Thus, 22q11DS represents a model for the study of neural biomarkers associated with schizophrenia. In this study, we investigated structural and functional connectivity within and between the Default Mode (DMN), the Central Executive (CEN), and the Saliency network (SN) in 22q11DS using resting‐state fMRI and DTI. Furthermore, we investigated if triple network impairments were related to executive dysfunctions or the presence of psychotic symptoms. Sixty‐three patients with 22q11DS and sixty‐eighty controls (age 6–33 years) were included in the study. Structural connectivity between main nodes of DMN, CEN, and SN was computed using probabilistic tractography. Functional connectivity was computed as the partial correlation between the time courses extracted from each node. Structural and functional connectivity measures were then correlated to executive functions and psychotic symptom scores. Our results showed mainly reduced structural connectivity within the CEN, DMN, and SN, in patients with 22q11DS compared with controls as well as reduced between‐network connectivity. Functional connectivity appeared to be more preserved, with impairments being evident only within the DMN. Structural connectivity impairments were also related to executive dysfunctions. These findings show an association between triple network structural alterations and executive deficits in patients with the microdeletion, suggesting that 22q11DS and schizophrenia share common psychopathological mechanisms. Hum Brain Mapp 38:2177–2189, 2017. © 2017 Wiley Periodicals, Inc.     

Association of ZNF74 gene genotypes with age-at-onset of schizophrenia.

Because of the manifestation of schizophrenic symptoms in individuals with interstitial deletions of chromosome 22q11.2, genes located in 22q11.2 are positional candidates for schizophrenia susceptibility. We genotyped five polymorphisms at D22S941, D22S944, D22S264, and D22S311, and the COMT gene in the common 3Mbp deletion region associated with 22q11 deletion syndrome in 300 Japanese schizophrenics and 300 controls and identified one patient with 22q11 deletion (Arinami et al., 2001). The results showed a trend of different genotypic distributions in D22S264 between patients with schizophrenia and controls (non-corrected p=0.04). Given this finding, we searched for mutations in the ZNF74 gene, which is located 11.2Kbp centromeric to D22S264. The ZNF74 gene is a member of the KRAB-zinc finger gene family and is expressed in the developing brain. Four polymorphisms, 1150T/C, IVS2a-40G/A, E/K46, and [K/N551;L/F552], were detected. The first three polymorphisms were in almost complete linkage disequilibrium. Case-control comparisons for these polymorphisms resulted in similar genotypic and allelic frequencies in patients and controls. The polymorphisms, however, were significantly associated with age-at-onset of schizophrenia (n<0.0001). Subsequent analyses in another Japanese schizophrenic population (n=169) confirmed an age-at-onset association (p<0.0001). These findings suggest that the ZNF74 gene plays a role as one of the modifying factors for schizophrenia.     

How might stress contribute to increased risk for schizophrenia in children with chromosome 22q11.2 deletion syndrome?

The most common human microdeletion occurs at chromosome 22q11.2. The associated syndrome (22q11.2DS) has a complex and variable phenotype with a high risk of schizophrenia. While the role of stress in the etiopathology of schizophrenia has been under investigation for over 30 years (Walker et al. 2008), the stress–diathesis model has yet to be investigated in children with 22q11.2DS. Children with 22q11.2DS face serious medical, behavioral, and socioemotional challenges from infancy into adulthood. Chronic stress elevates glucocorticoids, decreases immunocompetence, negatively impacts brain development and function, and is associated with psychiatric illness in adulthood. Drawing knowledge from the extant and well-developed anxiety and stress literature will provide invaluable insight into the complex etiopathology of schizophrenia in people with 22q11.2DS while suggesting possible early interventions. Childhood anxiety is treatable and stress coping skills can be developed thereby improving quality of life in the short-term and potentially mitigating the risk of developing psychosis.     

Prevalence of 22q11.2 deletions in 311 Dutch patients with schizophrenia

The objectives of this study were 1) to examine whether the prevalence of 22q11.2 deletion syndrome (22q11DS) in schizophrenia patients with the Deficit syndrome is higher than the reported approximately 2% for the population of schizophrenia patients as a whole, and 2) to estimate the overall prevalence of 22q11DS among schizophrenia patients by combining all available studies. Our sample, enriched for patients with the Deficit syndrome, had 88% power to detect an estimated prevalence of 5% of 22q11.2 deletions. No 22q11.2 deletions were detected in 311 schizophrenia patients, 146 of whom met criteria for the Deficit syndrome. Our literature research revealed that in eight studies sixteen deletions were identified in 2133 patients with schizophrenia. This corresponds to a prevalence of 0.75% (95%CI: 0.5%-1.2%). In conclusion: The prevalence of 22q11.2DS in schizophrenia patients with the Deficit syndrome is not higher than in the population of schizophrenia patients as a whole. The prevalence of 22q11.2DS in schizophrenia patients is lower than the frequently reported prevalence of 2% or more.     

The social brain network in 22q11.2 deletion syndrome: a diffusion tensor imaging study

Background

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic disorder that is associated with a 25-fold increase in schizophrenia. Both individuals with 22q11.2DS and those with schizophrenia present with social cognitive deficits, which are putatively subserved by a network of brain regions that are involved in the processing of social cognitive information. This study used two-tensor tractography to examine the white matter tracts believed to underlie the social brain network in a group of 57 young adults with 22q11.2DS compared to 30 unaffected controls.

Results

Results indicated that relative to controls, participants with 22q11.2DS showed significant differences in several DTI metrics within the inferior fronto-occipital fasciculus, cingulum bundle, thalamo-frontal tract, and inferior longitudinal fasciculus. In addition, participants with 22q11.2DS showed significant differences in scores on measures of social cognition, including the Social Responsiveness Scale and Trait Emotional Intelligence Questionnaire. Further analyses among individuals with 22q11.2DS demonstrated an association between DTI metrics and positive and negative symptoms of psychosis, as well as differentiation between individuals with 22q11.2DS and overt psychosis, relative to those with positive prodromal symptoms or no psychosis.

Conclusions

Findings suggest that white matter disruption, specifically disrupted axonal coherence in the right inferior fronto-occipital fasciculus, may be a biomarker for social cognitive difficulties and psychosis in individuals with 22q11.2DS.

     

Psychotic Features as the First Manifestation of 22q11.2 Deletion Syndrome

The 22q11.2 deletion is a genetic disorder which is characterized by abnormalities in cardiac functioning, facial structure, neurobehavioral development, T cell functioning, and velopharyngeal insufficiencies. In the presented case study, 22q11.2 deletion was found in a patient who has psychotic symptoms only. A 25-year-old woman with a history of hypoparathyroidism and hypothyroidism presented with auditory hallucinations and persecutory delusions. After three months of treatment with antipsychotic medications, the patient was readmitted with generalized tonic-clonic seizures. The following week, the patient went into sepsis. A fluorescent in situ hybridization (FISH) analysis revealed the presence of a 22q11.2 microdeletion. This case study suggests that psychotic symptoms can develop prior to the typical symptoms of a 22q11.2 deletion. As such, psychiatrists should test for genetic abnormalities in patients with schizophrenia when these patients present with seizures and immunodeficiencies.     

Psychiatric inpatients and chromosome deletions within 22q11.2

Velocardiofacial syndrome (VCFS) is a congenital disorder characterised by multiple dysmorphisms, cleft palate, cardiac anomalies, and learning disabilities due to a microdeletion of chromosome 22q11.2. Although VCFS is often associated with psychiatric symptoms, its prevalence among psychiatric patients is unknown. A total of 326 patients admitted in September and October 1997 to a Japanese psychiatric hospital were screened for the clinical features of VCFS. Twelve patients with minor facial dysmorphia were identified; chromosomal analysis with fluorescent in situ hybridisation (FISH) was performed in six patients who, further assessment suggested, were most likely to have VCFS. Chromosome 22q11.2 deletion was identified in a 41 year old woman who had symptoms of schizophrenia but no major dysmorphia, such as cardiovascular anomalies and cleft palate. Her behavioural and neuropsychological profiles were similar to those previously reported in VCFS. She was hemizygous for the FISH probe N25 (GDB locus D22S75) and also for probes N72H9 (D22S181), sc11.1a, C443 (D22S941), sc4.1 (D22S134), sc11.1b, N19B3 (D22S264), N122B5 (D22S934), and N77F7 (D22S939). The size of the deletion was about 3 Mb. Our patient had only some features of VCFS including a square nasal root, hypernasal speech, and hypoparathyroidism. She did, however, have the common larger deletion of type A. This finding suggests that psychiatric symptoms in VCFS can occur without major developmental symptoms such as cardiovascular anomalies and cleft palate. Additional patients with schizophrenia may have subtle features of VCFS which are unrecognised on routine medical examinations.     

White matter abnormalities in 22q11.2 deletion syndrome: Preliminary associations with the Nogo-66 receptor gene and symptoms of psychosis

BackgroundThis study utilized diffusion tensor imaging (DTI) to analyze white matter tractography in the anterior limb of the internal capsule (ALIC), fornix, and uncinate fasciculus (UF) of individuals with 22q11.2 deletion syndrome and controls. Aberrations in these tracts have been previously associated with schizophrenia. With up to 25% of individuals with 22q11.2DS developing schizophrenia in adulthood, we hypothesized reduction in structural integrity of these tracts, including an association with prodromal symptoms of psychosis. We further predicted an association between allelic variation in a functional polymorphism of the Nogo-66 receptor gene and 22q11.2DS white matter integrity.MethodsTractography was conducted using fiber assignment by streamline tracking algorithm in DTI Studio. Subjects were genotyped for the rs701428 SNP of the Nogo-66 receptor gene, and assessed for presence of prodromal symptoms.ResultsWe found significant group differences between 22q11.2DS and controls in DTI metrics for all three tracts. DTI metrics of ALIC and UF were associated with prodromal symptoms in 22q11.2DS. Further, ALIC DTI metrics were associated with allelic variation of the rs701428 SNP of the Nogo-66 receptor gene in 22q11.2DS.ConclusionsAlterations in DTI metrics suggest white matter microstructural anomalies of the ALIC, fornix, and UF in 22q11.2DS. Structural differences in ALIC appear to be associated with the Nogo-66 receptor gene, which has been linked to myelin-mediated axonal growth inhibition. Moreover, the association between psychosis symptoms and ALIC and UF metrics suggests that the Nogo-66 receptor gene may represent a susceptibility gene for psychosis through its disruption of white matter microstructure and myelin-associated axonal growth.     

Mikrodeletion 22q11.2Eine zu selten diagnostizierte genetische Veränderung bei psychiatrischen Erkrankungen

Microdeletion 22q11.2 with an estimated incidence of 1:4000 is known to cause the DiGeorge syndrome (DGS) or the velocardiofacial syndrome (VCFS), both usually being diagnosed in the newborn period or childhood. Recent studies have shown that children suffering from VCFS frequently develop psychiatric disorders in late adolescence or adulthood. Here we report the case of a 30-year-old man presenting with slight facial dysmorphisms, hypoparathyreoidism, minor cardiac anomalies, and slight cognitive impairments who had developed a severe personality disorder which eventually led to the diagnosis of microdeletion 22q11.2 with maternal inheritance. Psychiatric patients should be thoroughly examined for typical signs associated with this chromosomal anomaly. Genetic diagnosis is necessary because of the 50% probability of inheritance with possibly severe congenital anomalies. In view of a prevalence of 2% in an unselected group of patients with schizophrenic psychosis, microdeletion 22q11.2 is likely to be underdiagnosed.     

Increased incidence and size of cavum septum pellucidum in children with chromosome 22q11.2 deletion syndrome

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a result of a hemizygotic microdeletion that results in a variety of impairments in children including greater risk for psychiatric ailments in adulthood. We used high-resolution magnetic resonance imaging to accurately quantify the length and, for the first time, volume, of the cavum septum pellucidum (CSP) in children aged 7 to 14 years with 22q11.2DS and typically developing (TD) controls. Significantly greater anteroposterior length and greater CSP volumes were found in children with 22q11.2DS compared with controls. Furthermore, the largest CSP were found only in the 22q11.2DS group and with a much higher incidence than previously reported in the literature. Given the significant midline anomalies in the brains of those affected by 22q11.2DS, large CSP may be a biomarker of atypical brain development. The implication of these larger CSP for cognitive and behavioral development is a topic in need of further investigation.     

Visuospatial working memory in children and adolescents with 22q11.2 deletion syndrome; an fMRI study

22q11.2 deletion syndrome (22q11DS) is a genetic disorder associated with a microdeletion of chromosome 22q11. In addition to high rates of neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder, children with 22q11DS have a specific neuropsychological profile with particular deficits in visuospatial and working memory. However, the neurobiological substrate underlying these deficits is poorly understood. We investigated brain function during a visuospatial working memory (SWM) task in eight children with 22q11DS and 13 healthy controls, using fMRI. Both groups showed task-related activation in dorsolateral prefrontal cortex (DLPFC) and bilateral parietal association cortices. Controls activated parietal and occipital regions significantly more than those with 22q11DS but there was no significant between-group difference in DLPFC. In addition, while controls had a significant age-related increase in the activation of posterior brain regions and an age-related decrease in anterior regions, the 22q11DS children showed the opposite pattern. Genetically determined differences in the development of specific brain systems may underpin the cognitive deficits in 22q11DS, and may contribute to the later development of neuropsychiatric disorders.