22q11 Deletion syndrome (22q11DS) is a common microdeletion syndrome with variable expression, including congenital and later onset conditions such as schizophrenia. Most studies indicate that expression does not appear to be related to length of the deletion but there is limited information on the endpoints of even the common deletion breakpoint regions in adults. We used a real-time quantitative PCR (qPCR) approach to fine map 22q11.2 deletions in 44 adults with 22q11DS, 22 with schizophrenia (SZ; 12 M, 10 F; mean age 35.7 SD 8.0 years) and 22 with no history of psychosis (NP; 8 M, 14 F; mean age 27.1 SD 8.6 years). QPCR data were consistent with clinical FISH results using the TUPLE1 or N25 probes. Two subjects (one SZ, one NP) negative for clinical FISH had atypical 22q11.2 deletions confirmed by FISH using the RP11-138C22 probe. Most (n = 34; 18 SZ, 16 NP) subjects shared a common 3 Mb hemizygous 22q11.2 deletion. However, eight subjects showed breakpoint variability: a more telomeric proximal breakpoint (n = 2), or more centromeric (n = 3) or more telomeric distal breakpoint (n = 3). One NP subject had a proximal nested 1.4 Mb deletion. COMT and TBX1 were deleted in all 44 subjects, and PRODH in 40 subjects (19 SZ, 21 NP). The results delineate proximal and distal breakpoint variants in 22q11DS. Neither deletion extent nor PRODH haploinsufficiency appeared to explain the clinical expression of schizophrenia in the present study. Further studies are needed to elucidate the molecular basis of schizophrenia and clinical heterogeneity in 22q11DS.

Cytoplasmic FMRP interacting protein 1 (CYFIP1) is a candidate gene for intellectual disability (ID), autism, schizophrenia and epilepsy. It is a member of a family of proteins that is highly conserved during evolution, sharing high homology with its Drosophila homolog, dCYFIP. CYFIP1 interacts with the Fragile X mental retardation protein (FMRP, encoded by the FMR1 gene), whose absence causes Fragile X syndrome, and with the translation initiation factor eIF4E. It is a member of the WAVE regulatory complex (WRC), thus representing a link between translational regulation and the actin cytoskeleton. Here, we present data showing a correlation between mRNA levels of CYFIP1 and other members of the WRC. This suggests a tight regulation of the levels of the WRC members, not only by post-translational mechanisms, as previously hypothesized. Moreover, we studied the impact of loss of function of both CYFIP1 and FMRP on neuronal growth and differentiation in two animal models – fly and mouse. We show that these two proteins antagonize each other's function not only during neuromuscular junction growth in the fly but also during new neuronal differentiation in the olfactory bulb of adult mice. Mechanistically, FMRP and CYFIP1 modulate mTor signaling in an antagonistic manner, likely via independent pathways, supporting the results obtained in mouse as well as in fly at the morphological level. Collectively, our results illustrate a new model to explain the cellular roles of FMRP and CYFIP1 and the molecular significance of their interaction.

22q11 Deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans, occurring with an incidence of 1 in 4,000. In most cases the submicroscopic deletion spans 3 Mb, but there are a number of other overlapping and non-overlapping deletions that generate a similar phenotype. The majority of the 22q11.2 microdeletions can be ascertained using a standard fluorescence in situ hybridization (FISH) assay probing for TUPLE1 or N25 on 22q11.2. However, this test fails to detect deletions that are either proximal or distal to the FISH probes, and does not provide any information about the length of the deletion. In order to increase the detection rate of 22q11.2 deletion and to better characterize the size and position of such deletions we undertook a study of 22q11.2 cases using multiplex ligation dependent probe amplification (MLPA). We used MLPA to estimate the size of the 22q11.2 deletions in 51 patients positive for TUPLE1 or N25 (FISH) testing, and to investigate 12 patients with clinical features suggestive of 22q11DS and negative FISH results. MLPA analysis confirmed a microdeletion in all 51 FISH-positive samples as well as microduplications in three samples. Further, it allowed us to delineate deletions not previously detected using standard clinical FISH probes in 2 of 12 subjects with clinical features suggestive of 22q11DS. We conclude that MLPA is a cost-effective and accurate diagnostic tool for 22q11DS with a higher sensitivity than FISH alone. Additional advantages of MLPA testing in our study included determination of deletion length and detection of 22q11.2 duplications. (c) 2007 Wiley-Liss, Inc.

-Background: Rett syndrome (RS) is recognized as a pan-ethnic condition. Since the identification of mutations in the MECP2 gene, more patients have been diagnosed, and a broad spectrum of phenotypes has been reported. There is a lack of phenotype-genotype studies. Objective: To describe two cases of Brazilian patients with identified MECP2 mutations. Method: We present two female Brazilian patients with RS. Results: Both patients presented with regression at 2-3 years of age, when stereotypic hand movements, social withdrawal and postnatal deceleration of head growth rate were observed. Both patients presented verbal communication impairment. Case 1 had loss of purposeful hand movements, and severe seizure episodes. Case 2 had milder impairment of purposeful hand movements, and no seizures. They had different mutations, D97Y and R294X, found in exons 3 and 4 of MECP2 gene, respectively. Conclusion: Testing for MECP2 mutations is important to confirm diagnosis and to establish genotype/phenotype correlations, and improve genetic counseling.KEY WORDS: Rett syndrome, MECP2 mutations, Brazilian cases. Síndrome de Rett: caracterização clínica e molecular de dois casos brasileirosRESUMO -Contexto: Síndrome de Rett (RS) é doença pan-étnica de fenótipo bastante variado desde que foram identificadas mutações no gene MECP2 e um número maior de pacientes tem sido diagnosticadas. Existe uma demanda por estudos que investiguem a relação genótipo-fenotipo. Objetivo: Descrever dois casos brasileiros de RS com mutações identificadas. Método: Duas pacientes brasileiras com diagnóstico clínico-molecular de RS foram descritas buscando-se correlacionar genótipo-fenótipo. Resultados: Ambas pacientes apresentaram regressão aos 2-3 anos de idade, movimentos esteriotipados de mãos, retraimento social e desaceleração do crescimento encefálico. Ambas apresentaram déficit de comunicação verbal. Caso 1 também apresentou perda dos movimentos manuais intencionados e crises convulsivas graves. Caso 2 apresentou-se com comprometimento parcial dos movimentos manuais e sem história de crise convulsiva. As mutações distintas, D97Y e R294X, foram encontradas respectivamente em exons 3 e 4 do gene MECP2. Conclusão: A investigacao de mutações no gene MECP2 é importante na confirmação diagnós-tica, investigação genótipo-fenótipo, e aconselhamento genético em síndrome de Rett.

Paediatric obsessive-compulsive disorder (OCD) is a common, yet under-recognized, neuropsychiatric illness in both clinical and community settings. Symptoms tend to be hidden or misunderstood by affected youth, and parents may inadvertently accommodate OCD, thus worsening its severity. These symptoms may include compulsive reassurance seeking, confessing and 'just right' rituals, in addition to more classic OCD behaviours. Fortunately, numerous psychometric measures are available to assist in clinical assessment of this disorder and its sequelae. Once properly diagnosed, paediatric OCD is highly treatable with empirically proven approaches including cognitive-behaviour therapy (CBT) and serotonin reuptake inhibitor (SRI) medications. Clinically meaningful symptom improvement is the norm following these strategies, although full remission is not, as symptoms tend to wax and wane over time. Paediatric OCD is highly co-morbid with other anxiety disorders, tic disorders, depression and attention-deficit hyperactivity disorder, which also require specific attention. For moderate to severe OCD, an interdisciplinary approach combining individual and family CBT with SRI trials is recommended. For severe treatment-refractory illness, early evidence supports the benefit of augmenting agents, such as atypical antipsychotics and potentially those with glutamatergic activity. Clinical outcome assessment in paediatric OCD should always include broad domains of individual and family functioning, in addition to symptom improvement.

obsessive-compulsive disorder (ocD) is a common neuropsychiatric illness; its onset is often in childhood (Busatto et al., 2001). This disorder has been listed among the 10 most disabling illnesses by the World health organization (murray & lopez, 1997) and as the most frequently serious anxiety disorder (Kessler, chiu, Demler, merikangas, & Walters, 2005). Yet many children and adolescents with ocD wait years before an appropriate diagnosis is made. lifetime prevalence rates in youth range between 1% and 3%, and the gross majority of those identified from community studies report being previously undiagnosed and untreated. obsessive-compulsive spectrum disorders (ocSDs) in the differential diagnosis of ocD include tic disorders, trichotillomania (TTm), hypochondriasis, body dysmorphic disorder (BDD), and body-focused repetitive behaviors (BFrB). The failure of prompt identification for these disorders may be attributable to insufficient specialized ocD-related training among clinicians. This is unfortunate because a more chronic and debilitating course is characteristic of cases that are left untreated PharmacoTheraPY For oBSeSSIve-comPulSIve anD relaTeD DISorDerS among chIlDren anD aDoleScenTS S. evelYn STeWarT anD anDrea c. STachon

Pediatric obsessive-compulsive disorder (OCD) is a prevalent condition that responds well to specialized treatment including cognitive behavioral therapy (CBT) or serotonin reuptake inhibitors or their combination. In Brazil, the dissemination of evidence-based treatment for pediatric OCD is hindered because of the peculiarities of the health system. The presence of a multitiered health system (public, insured, and private) with insufficient investment in public mental health and relative inaccessibility of insured/private care for most of the Brazilian population make the implementation of specialized OCD treatment centers largely unavailable in Brazil. Furthermore, lack of appropriate training in child mental health, CBT, and evidence-based approaches to OCD in current psychiatry and psychology training programs further impede improvement in diagnosis and treatment. The challenges faced in the current system in Brazil will be discussed and also strategies and programs that are currently being implemented in the south of Brazil to help address the gaps in treatment for pediatric patients with OCD.