1. Brun CC, Nicolson R, Lepore N, Chou YY, Vidal CN, Devito TJ, Drost DJ, Williamson PC, Rajakumar N, Toga AW, Thompson PM. {{Mapping brain abnormalities in boys with autism}}. {Hum Brain Mapp};2009 (Jun 24)
Children with autism spectrum disorder (ASD) exhibit characteristic cognitive and behavioral differences, but no systematic pattern of neuroanatomical differences has been consistently found. Recent neurodevelopmental models posit an abnormal early surge in subcortical white matter growth in at least some autistic children, perhaps normalizing by adulthood, but other studies report subcortical white matter deficits. To investigate the profile of these alterations in 3D, we mapped brain volumetric differences using a relatively new method, tensor-based morphometry. 3D T1-weighted brain MRIs of 24 male children with ASD (age: 9.5 years +/- 3.2 SD) and 26 age-matched healthy controls (age: 10.3 +/- 2.4 SD) were fluidly registered to match a common anatomical template. Autistic children had significantly enlarged frontal lobes (by 3.6% on the left and 5.1% on the right), and all other lobes of the brain were enlarged significantly, or at trend level. By analyzing the applied deformations statistically point-by-point, we detected significant gray matter volume deficits in bilateral parietal, left temporal and left occipital lobes (P = 0.038, corrected), trend-level cerebral white matter volume excesses, and volume deficits in the cerebellar vermis, adjacent to volume excesses in other cerebellar regions. This profile of excesses and deficits in adjacent regions may (1) indicate impaired neuronal connectivity, resulting from aberrant myelination and/or an inflammatory process, and (2) help to understand inconsistent findings of regional brain tissue excesses and deficits in autism. Hum Brain Mapp, 2009. (c) 2009 Wiley-Liss, Inc.
2. Bucan M, Abrahams BS, Wang K, Glessner JT, Herman EI, Sonnenblick LI, Alvarez Retuerto AI, Imielinski M, Hadley D, Bradfield JP, Kim C, Gidaya NB, Lindquist I, Hutman T, Sigman M, Kustanovich V, Lajonchere CM, Singleton A, Kim J, Wassink TH, McMahon WM, Owley T, Sweeney JA, Coon H, Nurnberger JI, Li M, Cantor RM, Minshew NJ, Sutcliffe JS, Cook EH, Dawson G, Buxbaum JD, Grant SF, Schellenberg GD, Geschwind DH, Hakonarson H. {{Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes}}. {PLoS Genet};2009 (Jun);5(6):e1000536.
The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3×10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.
3. d’Orsi G, Demaio V, Scarpelli F, Calvario T, Minervini MG. {{Central sleep apnoea in Rett syndrome}}. {Neurol Sci};2009 (Jun 25)
Breathing disturbances in Rett syndrome were reported almost entirely during wakefulness, with normal respiration during sleep. We studied a case of a proven MECP2 mutation in a girl, whose videopolygraphic and polysomnographic monitoring suggested the evidence of central apnoeas not only during awake, but also during sleep. Apart from prevalent awake respiratory dysfunction, central apnoeas in Rett syndrome may be also present during sleep.
4. Li MR, Pan H, Bao XH, Zhu XW, Cao GN, Zhang YZ, Wu XR.{{ [Methyl-CpG-binding protein 2 gene and CDKL5 gene mutation in patients with Rett syndrome: analysis of 177 Chinese pediatric patients]}}. {Zhonghua Yi Xue Za Zhi};2009 (Feb 3);89(4):224-229.
OBJECTIVE: To study the spectrum of mutations in methyl-CpG-binding protein 2 gene (MECP2) and cyclin-dependent kinase-like 5 gene (CDKL5) in Chinese pediatric patients with Rett syndrome (RTT), and establish a simple, quick, and efficient gene test method as well as screen a strategy of genetic diagnosis for RTT. METHODS: Genomic DNA was extracted using standard procedures from the peripheral blood leukocytes of 117 pediatric patients diagnosed from 1987 to 2007. PCR was used to amplify the exons 1 – 4 of MECP2 using published primers. If no mutation was identified after screening exons 2 – 4, exon 1 was screened. If no mutation was identified in MECP2 by sequencing, multiplex ligation dependent probe amplification (MLPA) was employed to screen for large deletions by using P015C kit. If no mutation was identified in the MECP2 by sequencing and MLPA respectively, then the coding region of CDKL5 was screened by denaturing high performance liquid chromatography (DHPLC). RESULTS: The total mutation frequency in MECP2 and CDKL5 genes among all RTT patients was 82%. MECP2 mutations were found in 86% (137/159) of the patients with classical RTT and in 44% (8/18) of those with atypical RTT. Most of the mutations were missense mutations, accounting for 39%, followed in order of frequency by nonsense mutations 28%, frame shift mutations 17% and large deletions 14.5%. The eight most frequent MECP2 mutations were p.T158M (13%), p.R168X (12%), c.806delG (7%), p.R255X (6%), p.R270X (5%), p.R133C (5%), p.R306C (4%), and p.R106W (3%), with p.T158M as the most common of the MECP2 mutations and c.806delG as a hotspot mutation in Chinese patients with RTT. Only one synonymous mutation was identified in CDKL5. CONCLUSION: The spectrum of MECP2 mutations within the mainland Chinese RTT patients is similar to that of those patients reported in the world. p.T158M, p.R168X, c.806delG, p.R255X, p.R270X, p.R133C, p.R306C, and p.R106W are the hotspot mutations of MECP2 and c.806delG is a specific hotspot mutation in Chinese patients with RTT. The most effective method to screen mutations is to screen the exon 4. MLPA is an effective supplement to the routine methods.
5. Pedrini M, Noguera A, Vinent J, Torra M, Jimenez R. {{Acute oxcarbazepine overdose in an autistic boy}}. {Br J Clin Pharmacol};2009 (May);67(5):579-581.
6. Ruta L, Mugno D, D’Arrigo VG, Vitiello B, Mazzone L. {{Obsessive-compulsive traits in children and adolescents with Asperger syndrome}}. {Eur Child Adolesc Psychiatry};2009 (Jun 26)
The objective of this study is to examine the occurrence and characteristic features of obsessive-compulsive behaviours in children and adolescents with Asperger syndrome (AS), with respect to a matched obsessive compulsive disorder group (OCD) and a typically developing control group (CG). For this purpose, 60 subjects (20 OCD; 18 AS; 22 CG), aged 8-15 years, matched for age, gender and IQ were compared. AS and OCD patients were diagnosed according to the DSM-IV-TR criteria. The Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule were used to assist in the AS diagnosis; the WISC-R was administered to assess IQ. Obsessive and compulsive symptoms were evaluated by using the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). None of the AS children received a formal diagnosis of OCD. The AS group presented significantly higher frequencies of Hoarding obsessions and Repeating, Ordering and Hoarding compulsions compared to CG. The OCD group, in turn, reported significantly higher frequencies of Contamination and Aggressive obsessions and Checking compulsions compared to both the AS group and CG. As expected, the OCD group displayed a higher severity of symptoms (Moderate level of severity) than did the AS group (Mild level of severity). Finally, in our sample, neither the OCD group nor the AS group demonstrated a completely full awareness of the intrusive, unreasonable and distressing nature of symptoms, and the level of insight did not differ between the OCD group and CG, although an absence of insight was observed in the AS group. Children with AS showed higher frequencies of obsessive and compulsive symptoms than did typically developing children, and these features seem to cluster around Hoarding behaviours. Additionally, different patterns of symptoms emerged between the OCD and AS groups. Finally, in our sample, the level of insight was poor in both the OCD and the AS children. Further research should be conducted to better understand the characteristics of repetitive thoughts and behaviours in autism spectrum disorders, and to clarify the underlying neurobiological basis of these symptoms.
