Tamar Steinberg

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

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

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

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

Tic-related cognition, sensory phenomena, and anxiety in children and adolescents with Tourette syndrome

BACKGROUND Tourette syndrome is a protoypical example of developmental psychopathology, with the varying expressions of the disorder and its consequences appearing over time. Sensory urges typically appear after age 10 and are often followed by anxiety and depression. OBJECTIVE To study the associations among tic-related cognitions, premonitory urges, and tic severity in children with Tourette syndrome at different stages of the illness. SUBJECTS Fifty-seven consecutive patients referred to a tic disorders clinic. INSTRUMENTS A battery of instruments was completed: Yale Global Tic Severity Scale, Premonitory Urge for Tics Scale, Screen for Child Anxiety Related Emotional Disorders, and Child Depression Inventory. To examine cognitions, a new measure was developed: the Beliefs About Tics Scale. RESULTS Strong correlations were found between tic-related beliefs and both premonitory urges and tic-related impairments (as measured by the Yale Global Scale). Tic-related beliefs were also strongly correlated with depression in children older than 13 years but not in younger children. CONCLUSIONS The significant correlations between tic-related cognitions, premonitory urges, and tic-related impairments in children emphasize the important role of psychological and sensory factors in the understanding of Tourette syndrome and in its treatment.

Subjective versus objective measures of tic severity in Tourette syndrome – The influence of environment

The objective of this study was to examine the influence of environmental challenges on tic expression by subjective and objective measures. The study group consisted of 41 children aged 6-18 years (M=10.15, SD=2.73) with a primary diagnosis of Tourette syndrome. Subjective measures included the Functional Assessment Interview developed for this study and three standard validated instruments. The objective measure was a video-recording of the patients in five daily-life situations: watching television, doing homework, being alone, receiving attention when ticcing, and talking to a stranger. In addition, the effect of premonitory urges on assessment of tic expression was evaluated. The associations between the subjective and objective measures of tic expression were moderate to low. A significantly higher number of tics were observed in the television situation, and a significantly lower number in the alone situation, compared to the other situations. Higher levels of premonitory urge were associated with greater awareness of objectively measured tic expression. In conclusion, tic expression is significantly influenced by the environment. Subjective measures of tic expression may be misleading. These results have implications for refining the clinical assessment of tics, improving research methodology, and developing new therapeutic strategies.

Microcephaly-Thin Corpus Callosum Syndrome Maps to 8q23.2-q24.12

Postnatal microcephaly is defined as normal head circumference at birth, which progressively declines to more than 2 standard deviations below the average for the patients age and sex. We describe four patients from three consanguineous families of Arab Bedouin origin who presented with autosomal recessive inheritance of progressive microcephaly, spasticity, thin corpus callosum, pyramidal signs, and intellectual disability. Homozygosity mapping (Human Mapping NspI 250K arrays, Affymetrix, Santa Clara, CA) placed the disease locus at 8q23.2-q24.12. The candidate region includes 22 known or predicted genes, including RAD21, which is related to the cohesion complex EIF3H, which is involved in translation initiation, and TAF2, which may be involved in intellectual disability. Identification of the causative gene in our reported family will shed light on the pathogenesis of this severe condition.

Lesions of the corpus callosum in children with neurofibromatosis 1.

Our aim was to determine the rate of focal lesions of the corpus callosum in children with neurofibromatosis type 1, and to characterize their natural history. Magnetic resonance imaging scans of the brain in 79 children with neurofibromatosis type 1 who were followed at the Neurology Clinic of Schneider Childrens Medical Center (Petah Tiqwa, Israel) from 1990-2005 were reviewed. Focal lesions of the corpus callosum were identified in 11 (14%). These included unidentified bright objects in 7 patients (9%), and a neoplastic process in 4 (5%). Follow-up ranged from 1-16 years. Two of 4 tumors had enlarged during follow-up, and one was excised. Neurofibromatosis type 1 may be associated with a 14% prevalence of corpus callosum lesions. Owing to the apparently high frequency of callosal neoplasms in this population (5% in our series), and their tendency to enlarge, careful evaluation and prolonged follow-up are warranted.

Abnormal brain magnetic resonance imaging in two patients with Smith–Magenis syndrome

Smith–Magenis syndrome (SMS) is a clinically recognizable contiguous gene syndrome ascribed to an interstitial deletion in chromosome 17p11.2. Seventy percent of SMS patients have a common deletion interval spanning 3.5 megabases (Mb). Clinical features of SMS include characteristic mild dysmorphic features, ocular anomalies, short stature, brachydactyly, and hypotonia. SMS patients have a unique neurobehavioral phenotype that includes intellectual disability, self‐injurious behavior and severe sleep disturbance. Little has been reported in the medical literature about anatomical brain anomalies in patients with SMS. Here we describe two patients with SMS caused by the common deletion in 17p11.2 diagnosed using chromosomal microarray (CMA). Both patients had a typical clinical presentation and abnormal brain magnetic resonance imaging (MRI) findings. One patient had subependymal periventricular gray matter heterotopia, and the second had a thin corpus callosum, a thin brain stem and hypoplasia of the cerebellar vermis. This report discusses the possible abnormal MRI images in SMS and reviews the literature on brain malformations in SMS. Finally, although structural brain malformations in SMS patients are not a common feature, we suggest baseline routine brain imaging in patients with SMS in particular, and in patients with chromosomal microdeletion/microduplication syndromes in general. Structural brain malformations in these patients may affect the decision‐making process regarding their management.

Specific executive control impairments in Tourette syndrome: The role of response inhibition

BACKGROUND Tourette syndrome (TS) is a childhood-onset disorder characterized by motor and vocal tics. While cognitive features of common comorbid conditions such as attention deficit hyperactive disorder and obsessive compulsive disorder have been widely investigated, the cognitive profile of TS patients remains to be precisely defined. In this regard, the executive functions system (EF) is of especial interest. AIMS The aim of the study was to delineate the various components of executive processes in adult TS patients. METHODS A sample of 19 adults diagnosed with TS and 19 age-matched control subjects underwent computerized battery of executive tasks, as well as block design and memory tests. All patients received a thorough clinical assessment with an emphasis on illness severity. RESULTS There was a marked impairment in response inhibition ability regardless of comorbid conditions, In addition, there was decreased accuracy in set shifting, but not in response time. These results imply that impaired response inhibition in the EF system is the primary cognitive impairment in TS and that many of the previously reported impaired executive functions in TS are secondary to this impairment. CONCLUSIONS This finding of impaired response inhibition in TS may imply that rehabilitation of this inhibition component could prove to be an important therapeutic strategy in adults with TS.

Executive control development in Tourette syndrome and its role in tic reduction

Tourette syndrome (TS) is a childhood-onset disorder characterized by motor and vocal tics. Recent findings point to a possible role of executive functions system development in the tic reduction observed with age. The goal of the present work was to track the development of executive functions system measured by well-established cognitive tasks and its correlation with diminished tic severity over time in order to understand the role of executive functions in the remission process observed in most adults. The first study followed 25 young TS patients, measuring their executive functions and clinical condition at three time- points. In the second study we compared executive functions performance of 19 adult TS patients with 19 healthy controls and 12 remitted TS patients. The first study showed that tic reduction is related to the development of the executive functions components associated with response inhibition. The second study similarly showed impaired inhibition ability in TS patients but not in controls or the remitted TS patients. The remitted group performed at normal or even higher levels on certain measures. We conclude that inhibition, an important executive function, is impaired in subjects suffering from TS and that intact executive function development is related to remission processes.

Non-Motor Aspects of Tic Disorders—New Developments

The cardinal characteristics of tic-related disorders are stereotyped motor movements and vocalizations. However, they may be accompanied by non-motor features that appear sequentially during the course of the disorder and can sometimes be more disabling than the tics themselves. This review presents our perspectives on several non-motor aspects of Tourette syndrome based on the long experience of the Neuropsychiatric Tourette Clinic of a tertiary pediatric medical center. The effect of premonitory urges, sensory modulation disorder, tic-related cognitions, and environmental conditions on the expression and intensity of tics is elaborated, with suggestions for treatment approaches to each. We also describe the mediatory effect of parental attachment style on the link between maternal stress and ticcing intensity and the need to adjust psychotherapy interventions to account for the importance of this factor in emotion regulation. This review is intended to direct attention to the non-motor aspects of Tourette syndrome. An in-depth understanding of this complex and debilitating disorder will facilitate the formulation of innovative therapeutic protocols.