Epilepsy,neuropsychiatric phenotypes,neuroimaging findings,and genotype-neurophenotype correlation in 22q11.2 deletion syndrome

Objectives:To describe the epilepsy, neuropsychiatric manifestations, and neuroimaging findings in a group of patients with 22q11.2 DS, and to correlate the size of the deleted genetic material with the severity of the phenotype.Methods:We retrospectively analyzed the medical records of 28 patients (21 pediatric patients and 7 adults) with a genetically confirmed diagnosis of 22q11.2 DS. Clinical data (epilepsy, neurological exam, neuropsychological and developmental assessment, and psychiatric disorders), neuroimaging, and cytogenetic tests were analyzed.Results:Of the 28 patients with 22q11.2 DS, 6 (21.4%) had epileptic seizures, 2 had symptomatic hypocalcemic seizures, 4 (14.2%) had a psychiatric disorder, which comprised of attention deficit hyperactivity disorder, autism spectrum disorder, psychosis, and mood disorder, and 17 (60.7%) had developmental delay. All patients with epilepsy had a developmental delay. Twelve patients underwent a neuropsychology assessment. Intellectual levels ranged from moderate intellectual disability (7/12, 58%) to average (5/12, 41.6%). Of the 16 patients, 6 (37.5%) had a normal brain, while 10 (62.5%) had abnormal neuroimaging findings. No significant correlation was found between the size of the deleted genetic material and the severity of the phenotype.Conclusion:22q11.2DS patients are at high risk to develop epilepsy, neuropsychiatric manifestations, and structural brain abnormalities. This indicates that this defined genetic locus is crucial for the development of the nervous system, and patients with 22q11.2 DS have genetic susceptibility to develop epilepsy.

22q11.2 deletion syndrome (22q11.2DS) has to many names such as velocardiofacial syndrome and DiGeorge syndrome, which is the most common microdeletion syndrome.1 It is due to hemizygous microdeletions on chromosome 22q11.2, it occurs 1 in 4000 live births, and 90% occur de novo. Most individuals with 22q11.2 DS lost about 3 Megabases (Mb) of DNA on chromosome 22 at position 22q11.2 in each cell.2 Some affected individuals have smaller deleted genetic material in this region. The clinical picture has a markedly different expression and incomplete penetrance. Therefore, 22q11.2DS has symptoms affecting several systems in the body, including congenital heart anomalies, palatal anomalies, hypocalcemia due to hypoplasia of parathyroid glands, immunodeficiency due to hypoplastic thymus, facial dysmorphism, disorders of cognition and behavior, and psychiatric disorders.3 However, few studies have been conducted on the epilepsy, neurological, neuroimaging, and neuropsychiatric features of 22q11.2 DS.This study aimed to examine the epilepsy, neurological, neuropsychiatric phenotypes, and neuroimaging findings in a series of individuals with 22q11.2 DS and to correlate the genotype with the neurophenotype.     

Failure to detect the 22q11.2 duplication syndrome rearrangement among patients with schizophrenia

Chromosome aberrations have long been studied in an effort to identify susceptibility genes for schizophrenia. Chromosome 22q11.2 microdeletion is associated with DiGeorge and Velocardiofacial syndromes (DG/VCF) and provides the most convincing evidence of an association between molecular cytogenetic abnormality and schizophrenia. In addition, this region is one of the best replicated linkage findings for schizophrenia. Recently, the reciprocal microduplication on 22q11.2 has been reported as a new syndrome. Preliminary data indicates that individuals with these duplications also suffer from neuropsychiatric disorders. In this study we have investigated the appropriateness of testing schizophrenia patients for the 22q11.2 microduplication. We used multiplex ligation-dependent probe amplification (MLPA) to measure copy number changes on the 22q11.2 region in a sample of 190 patients with schizophrenia. Our results corroborate the prevalence of the 22q11.2 microdeletion in patients with schizophrenia and clinical features of DG/VCFS and do not suggest an association between 22q11.2 microduplication and schizophrenia.     

A patient with 22q13 deletion syndrome accompanied by epilepsy with continuous spike-waves during slow wave sleep (CSWS) and cerebral infarction

We describe a patient with 22q13 deletion syndrome accompanied by epilepsy with continuous spike-waves during slow wave sleep (CSWS). This patient showed central hypotonia, mental retardation, disappearance of language, multiple facial anomalies, and intractable epilepsy. Overnight EEG showed CSWS (spike & wave index = 99.2%) at seven years of age. Chromosomal analysis using G-banding revealed a deletion at the end of chromosome 22, indicative of 22q13 syndrome. In addition, subsequent magnetic resonance imaging (MRI) demonstrated cerebral infarction in the left posterior temporal area, which was probably caused by recurrent status epilepticus. Unlike previous case reports, a striking feature in this patient was the development of motor deterioration after 15 years of age. The severe EEG abnormalities and frequent status epilepticus might induce this deterioration and brain infarction.     

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.     

Typical and atypical brain development: a review of neuroimaging studies

In the course of development, the brain undergoes a remarkable process of restructuring as it adapts to the environment and becomes more efficient in processing information. A variety of brain imaging methods can be used to probe how anatomy, connectivity, and function change in the developing brain. Here we review recent discoveries regarding these brain changes in both typically developing individuals and individuals with neurodevelopmental disorders. We begin with typical development, summarizing research on changes in regional brain volume and tissue density, cortical thickness, white matter integrity, and functional connectivity. Space limits preclude the coverage of all neurodevelopmental disorders; instead, we cover a representative selection of studies examining neural correlates of autism, attention deficit/hyperactivity disorder, Fragile X, 22q11.2 deletion syndrome, Williams syndrome, Down syndrome, and Turner syndrome. Where possible, we focus on studies that identify an age by diagnosis interaction, suggesting an altered developmental trajectory. The studies we review generally cover the developmental period from infancy to early adulthood. Great progress has been made over the last 20 years in mapping how the brain matures with MR technology. With ever-improving technology, we expect this progress to accelerate, offering a deeper understanding of brain development, and more effective interventions for neurodevelopmental disorders.     

The feasibility and safety of S-adenosyl-l-methionine (SAMe) for the treatment of neuropsychiatric symptoms in 22q11.2 deletion syndrome: a double-blind placebo-controlled trial

The goal of this trial was to assess the feasibility and safety of using S-adenosyl-l-methionine (SAMe) to treat depressive disorder, attention deficit/hyperactivity disorder (ADHD) and cognitive deficits in individuals with the 22q11.2 deletion syndrome (22q11.2DS). SAMe supposedly enhances the activity of the COMT enzyme. Because individuals with 22q11.2DS have only one copy of the gene responsible for the enzyme, COMT haploinsufficiency may be associated with their psychiatric morbidity and cognitive deficits. We assessed twelve 22q11.2DS individuals with depressive disorder or ADHD in a randomized double-blind cross-over placebo-controlled trial, using SAMe 800?mg bid. Individuals were evaluated for treatment safety and effectiveness during the trial and upon completion at sixth week. Compared to placebo, there were no significant differences in the rate of reported side effects between SAMe and placebo. Despite a general concern that SAMe might induce mania in vulnerable individuals, no manic or psychotic symptoms were exhibited during the SAMe treatment. Individuals with 22q11.2DS with comorbid depressive disorder with or without psychotic symptoms (n?=?5) had a larger numerical improvement on relevant clinical scales compared to placebo. No treatment effect was found on ADHD symptoms in subjects who suffered from 22q11.2DS with comorbid ADHD (n?=?7). Cognitive performance did not improve or deteriorate following treatment with SAMe compared to placebo. In conclusion SAMe treatment up to 1,600?mg/day for 6?weeks in 22q11.2DS individuals appears to be safe, well tolerated and with no serious side effects. No significant benefit in depressive or ADHD symptoms was detected.     

Continuous Spike-and-Wave Activity During Slow-Wave Sleep: Syndrome or EEG Pattern?

PURPOSE: We reviewed the electroclinical pictures and clinical characteristics of 32 patients with continuous spike-and-wave activity during slow sleep (CSWS) to ascertain to what extent this electroencephalogram (EEG) pattern is associated with the age-related CSWS syndrome as defined by the International League Against Epilepsy (ILAE) International Classification or with different clinical settings. METHODS: We reviewed clinical and EEG characteristics of 32 CSWS patients. RESULTS: In all patients, detection of CSWS coincided with a worsening of neurologic status. Ten (34%) patients had the typical features of CSWS syndrome, four were classified as having Landau-Kleffner syndrome, and three had acquired opercular syndromes. The remaining 15 patients, all with symptomatic epilepsy, had CSWS, which lasted for variable periods and might be related to inappropriate drug choice. Three patients of this group had unilateral CSWS and exhibited worsening of spontaneous movements in the hemibody contralateral to CSWS activity lasting for a few hours after awakening. CONCLUSIONS: Our data show that a number of factors can intervene in the genesis of CSWS, which may explain the variability of the associated clinical conditions. In view of this etiologic heterogeneity, it is not possible to classify all the patients with CSWS as having the CSWS syndrome. Therefore, the CSWS syndrome should be considered a category embracing a limited group of patients, whereas the EEG pattern of CSWS is seen commonly in various clinical conditions.     

Neuroradiological and neurofunctional examinations for patients with 22q11.2 deletion

Since the neuroradiological features of patients with 22q11.2 deletion syndrome are not well-understood, examinations using functional imaging were performed in this study. Brain magnetic resonance imaging (MRI) and 1H-magnetic resonance spectroscopy (MRS) were performed using a clinical 3-Tesla MR imager in 4 patients with 22q11.2 deletion syndrome (2 boys and 2 girls; aged 2-6 years.) and 20 age- and sex-matched healthy control subjects. Furthermore, interictal 123I-iomazenil (IMZ) single photon emission computed tomography (SPECT) was examined in 2 of the 4 patients. Among the 4 patients with 22q11.2 deletion syndrome, 2 patients showed polymicrogyria and 1 patient showed agyria. Those patients with brain malformations also showed abnormal brain artery patterns and decreased accumulation of IMZ in 123I-IMZ SPECT. Although all 4 patients showed epileptic discharges in their electroencephalograms (EEG), one patient with polymicrogyria had no seizure episodes. Decreases in γ-aminobutyric acid (GABA) corresponding to the areas of polymicrogyria and/or epileptic discharges in EEG were shown in all patients except for the patient with agyria. Although consistent evidence was not seen in patients with 22q11.2 deletion syndrome in this study, brain malformations and disturbances of the GABAergic nervous system would be underlying mechanisms of the neurodevelopmental abnormalities in this syndrome.     

Neurodevelopmental phenotype associated with CHD8-SUPT16H duplication

Microdeletions encompassing 14q11.2 locus, involving SUPT16H and CHD8, were shown to cause developmental delay, intellectual disability, autism spectrum disorders and macrocephaly. Variations leading to CHD8 haploinsufficiency or loss of function were also shown to lead to a similar phenotype. Recently, a 14q11.2 microduplication syndrome, encompassing CHD8 and SUPT16H, has been described, highlighting the importance of a tight control of at least CHD8 gene-dosage for a normal development. There have been only a few reports of 14q11.2 microduplications. Patients showed variable neurodevelopmental issues of variable severity. Breakpoints of the microduplications were non-recurrent, making interpretation of the CNV and determination of their clinical relevance difficult. Here, we report on two patients with 14q11.2 microduplication encompassing CHD8 and SUPT16H, one of whom had normal intelligence. Review of previous reports describing patients with comparable microduplications allowed for a more precise delineation of the condition and widening of the phenotypic spectrum.

     

SPECT and epilepsy with continuous spike waves during slow-wave sleep

Ten cases of epilepsy with continuous spike waves in slow-wave sleep (CSWS) were evaluated using single photon emission computed tomography (SPECT); in eight patients the EEG paroxysmal abnormalities showed a predominant localization. SPECT carried out using^99mTc-HMPAO allows study of cerebral blood flow (CBF); the examination was performed during phases of drowsiness and the results compared to the EEG data. In four cases SPECT revealed areas of low CBF in sites corresponding to those of the prevalent EEG discharges; in two cases the areas of hypoperfusion did not correspond to those indicated by the EEG; lastly, in four cases SPECT results were negative. The areas of hypoperfusion were predominantly located in the frontal, temporal, and parietal regions. Furthermore, the percentage of positive SPECT results was significantly higher (five cases out of six) in the group in which the CSWS phase was prolonged for at least 1 year, compared to the group in which this phase lasted less than 1 year. Thus, in this type of epilepsy, SPECT reveals focal cortical areas of decreased CBF which correlated generally to the predominant sites of EEG abnormalities. A longer duration of the CSWS phase seems to be associated with a more significant cortical disorder, documented by the presence of areas of hypoperfusion.     

Autism,ADHD, mental retardation and behavior problems in 100 individuals with 22q11 deletion syndrome

This study assessed the prevalence and type of associated neuropsychiatric problems in children and adults with 22q11 deletion syndrome. One-hundred consecutively referred individuals with 22q11 deletion syndrome were given in-depth neuropsychiatric assessments and questionnaires screens.Autism spectrum disorders (ASDs) and/or attention deficit/hyperactivity disorder (ADHD) were diagnosed in 44 cases. ASD was diagnosed in 23 cases of whom only 5 had autistic disorder. ADHD was diagnosed in 30 individuals. In nine of these cases with ASD or ADHD there was a combination of these diagnoses. Mental retardation (MR) with or without ASD/ADHD was diagnosed in 51 individuals. ASD, ADHD, and/or MR were present in 67 cases. Females had higher IQ than males.The results of this study showed that the vast majority of all individuals with 22q11 deletion syndrome have behavior and/or learning problems and more than 40% meet criteria for either ASD, ADHD or both. Neuropsychiatric and neuropsychological evaluations are indicated as parts of the routine clinical assessment of individuals with 22q11 deletion syndrome.     

Investigating the genetic basis of fever‐associated syndromic epilepsies using copy number variation analysis

Fever‐associated syndromic epilepsies ranging from febrile seizures plus (FS+) to Dravet syndrome have a significant genetic component. However, apart from SCN1A mutations in >80% of patients with Dravet syndrome, the genetic underpinnings of these epilepsies remain largely unknown. Therefore, we performed a genome‐wide screening for copy number variations (CNVs) in 36 patients with SCN1A‐negative fever‐associated syndromic epilepsies. Phenotypes included Dravet syndrome (n = 23; 64%), genetic epilepsy with febrile seizures plus (GEFS+) and febrile seizures plus (FS+) (n = 11; 31%) and unclassified fever‐associated epilepsies (n = 2; 6%). Array comparative genomic hybridization (CGH) was performed using Agilent 4 × 180K arrays. We identified 13 rare CNVs in 8 (22%) of 36 individuals. These included known pathogenic CNVs in 4 (11%) of 36 patients: a 1q21.1 duplication in a proband with Dravet syndrome, a 14q23.3 deletion in a proband with FS+, and two deletions at 16p11.2 and 1q44 in two individuals with fever‐associated epilepsy with concomitant autism and/or intellectual disability. In addition, a 3q13.11 duplication in a patient with FS+ and two de novo duplications at 7p14.2 and 18q12.2 in a patient with atypical Dravet syndrome were classified as likely pathogenic. Six CNVs were of unknown significance. The identified genomic aberrations overlap with known neurodevelopmental disorders, suggesting that fever‐associated epilepsy syndromes may be a recurrent clinical presentation of known microdeletion syndromes.     

Is sleep-related consolidation impaired in focal idiopathic epilepsies of childhood? A pilot study

We investigated sleep-related declarative memory consolidation in four children with focal idiopathic epilepsy. In a population of healthy control children, recall of learned pairs of words was increased after a night of sleep, but not after a daytime wakefulness period. In children with epilepsy (1 case of benign epilepsy with centro-temporal spikes, 1 case of benign childhood epilepsy with occipital paroxysms, and 2 cases of epileptic encephalopathy (EE) with continuous spike and waves during slow-wave sleep, CSWS), recall performance significantly decreased overnight, suggesting impairment in sleep-related declarative memory consolidation. Hydrocortisone treatment in one patient with EE with CSWS resulted in normalization of the sleep EEG together with normalization of overnight memory performance, which was not the case in the other EE/CSWS patient whose sleep EEG was only partially improved. These preliminary results suggest that interictal epileptiform discharges in idiopathic focal epilepsies may disrupt the brain processes underlying sleep-related memory consolidation.     

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.     

Two cases of generalized seizures and the Velocardiofacial syndrome – a clinically significant association?

Background Velocardiofacial syndrome (VCFS) is caused by a micro deletion of chromosome 22q11 and associated with multiple system abnormalities. There is an increasing recognition of associations with psychiatric disorders. Neurological and brain abnormalities have been reported but to date no association with generalized epilepsy has been reported in literature. Methods We report two cases of adults with VCFS and primary generalized epilepsy. The details on their background, psychiatric history and history of epilepsy including results of investigations will be discussed. Results Case 1 is an adult male with mild learning disability (LD), VCFS, paranoid schizophrenia and primary generalized epilepsy. Case 2 is an adult female with mild LD, VCFS, schizoaffective disorder and primary generalized epilepsy. The diagnosis of epilepsy in both cases was based on clinical and EEG findings of primary generalized abnormalities. Conclusion As there is an evidence of association between VCFS and psychiatric disorders, this raises the possibility of an association with generalized epilepsy.     

Epileptic encephalopathy of late childhood: Landau-Kleffner syndrome and the syndrome of continuous spikes and waves during slow-wave sleep.

Landau-Kleffner syndrome (LKS) and the syndrome of continuous spikes and waves during slow wave sleep (CSWS) are two points on the spectrum of functional childhood epileptic encephalopathies. They are characterized by a severe paroxysmal EEG disturbance that may permanently alter the critical synaptogenesis by strengthening synaptic contacts that should have been naturally "pruned." The much more common benign epilepsy with centrotemporal spikes is also related to LKS and CSWS by a common pathophysiology. Although prognosis in LKS and CSWS for seizure control is good, cognitive function declines and permanent neuropsychologic dysfunction is seen in many cases. This permanent damage is most evident in those patients who had early-onset EEG abnormality and a prolonged active phase of continuous spike-and-wave discharges during sleep. If the active phase of paroxysmal activity persists for over 2 to 3 years, even successful treatment does not resolve neuropsychologic sequelae. In LKS, the paroxysmal activity permanently affects the posterior temporal area and results in auditory agnosia and language deficits; in CSWS, the frontal lobes are more involved and other cognitive disturbances predominate. Aggressive treatment should include high-dose antiepileptic drugs, corticosteroids, and surgery in specific cases.     

Juvenile myoclonic epilepsy with photosensitivity in a female with Velocardiofacial syndrome (del(22)(q11.2))—Causal relationship or coincidence?

We report on an adolescent female with Velocardiofacial syndrome (del(22)(q11.2)) and an epilepsy phenotype resembling juvenile myoclonic epilepsy (JME). Clinically, the patient has characteristic signs of both disorders. JME has been linked to several chromosomes, but has not been related to 22q11.2 and is rarely observed in other genetic syndromes. We discuss possible explanations for a relationship between the chromosomal aberration and epilepsy as well as the importance of precise delineation of both epilepsy phenotypes and genetic defects in chromosomal disorders.     

Familial partial epilepsy with variable foci: A new family with suggestion of linkage to chromosome 22q12

Familial partial epilepsy with variable foci (FPEVF) is an autosomal dominant form of partial epilepsy characterized by the presence of epileptic seizures originating from different cerebral lobes in different members of the same family. Linkage to chromosomes 22q12 and 2q36 has been reported, although only six families have been published. We studied a new FPEVF family including nine affected individuals. The phenotype in this family was similar to that previously described and consisted of nocturnal and daytime seizures with semiology suggesting a frontal lobe origin. A video‐EEG (electroencephalography) recording of the proband’s seizures is presented and revealed hyperkinetic seizures of frontal lobe origin preceded by left frontal spikes. We excluded linkage to chromosome 2q36 and found a suggestion of linkage to chromosome 22q12 with a lod score of 2.64 (θ = 0) for marker D22S689.     

A comparative study of the neuropsychiatric and neurocognitive phenotype in two microdeletion syndromes: Velocardiofacial (22q11.2 deletion) and Williams (7q11.23 deletion) syndromes

Purpose22q11.2 deletion syndrome (22q11.2DS) and Williams syndrome (WS) are common neurogenetic microdeletion syndromes. The aim of the present study was to compare the neuropsychiatric and neurocognitive phenotypes of 22q11.2DS and WS.MethodsForty-five individuals with 22q11.2DS, 24 with WS, 22 with idiopathic developmental disability (DD) and 22 typically developing (TD) controls were compared for the rates of psychiatric disorders as well as cognitive executive and visuospatial functions.ResultsWe found that while anxiety, mood and disruptive disorders had an equally high prevalence among individuals with 22q11.2DS, WS and DDs, the 22q11.2DS group had the highest rates of psychotic disorders and the WS group had the highest rates of specific phobia. We also found that the WS group demonstrated more severe impairments in both executive and visuospatial functions than the other groups. WS and 22q11.2DS subjects had worse Performance-IQ than Verbal-IQ, a feature typical of non-verbal learning disorders.ConclusionThese findings offer a wide perspective on unique versus common phenotypes in 22q11.2DS and WS.