1. Fehr S, Bebbington A, Nassar N, Downs J, Ronen GM, de Klerk N, Leonard H. {{Trends in the diagnosis of Rett syndrome in Australia}}. {Pediatr Res};2011 (May 16)
Modifications to diagnostic criteria and introduction of genetic testing have likely affected the pattern and timing of Rett syndrome diagnosis. The trends in incidence and prevalence of Rett syndrome in Australia were examined; the cumulative risk of a female being diagnosed determined; and the impact of changes to diagnostic criteria and availability of genetic testing on these frequencies investigated. The population-based Australian Rett Syndrome Database was used to identify a total of 349 verified Rett syndrome females born 1976-2006 and diagnosed 1982-2008. The proportion of female cases born and diagnosed per year and the cumulative risk of a diagnosis were determined. The median age of Rett syndrome diagnosis decreased from 4.5 years if diagnosed before 2000 to 3.5 years if diagnosed after 1999. The cumulative risk of diagnosis had almost doubled by 32 years of age (1/15361 or 6.51 per 100,000 person years (95% CI 5.65-7.39)) in comparison to five years of age (1/8905 or 11.23 per 100,000 person years (95% CI 10.03-12.45)). Earlier age of diagnosis may result in families experiencing less stress and emotional strain compared to those with delayed diagnosis. ABBREVIATIONS::
2. Leekam SR, Prior MR, Uljarevic M. {{Restricted and repetitive behaviors in autism spectrum disorders: A review of research in the last decade}}. {Psychol Bull};2011 (May 16)
Restricted and repetitive behaviors (RRBs) are a core feature of autism spectrum disorders. They constitute a major barrier to learning and social adaptation, but research on their definition, cause, and capacity for change has been relatively neglected. The last decade of research has brought new measurement techniques that have improved the description of RRBs. Research has also identified distinctive subtypes of RRBs in autism spectrum disorders. Research on potential causal origins and immediate triggers for RRBs is still at an early stage. However, promising new ideas and evidence are emerging from neurobiology and developmental psychology that identify neural adaptation, lack of environmental stimulation, arousal, and adaptive functions as key factors for the onset and maintenance of RRBs. Further research is needed to understand how these factors interact with each other to create and sustain atypical levels of RRB. The literature indicates that RRBs have the potential to spontaneously reduce across time, and this is enhanced for those with increased age and cognitive and language ability. Research on interventions is sparse. Pharmacological treatments can be helpful in some children but have adverse side effects. Behavioral intervention methods provide the better intervention option with positive effects, but a more systematic and targeted approach is urgently needed. Evidence suggests that we will learn best from the last decade of research by taking a developmental perspective, by directing future research toward subtypes of RRBs, and by implementing early intervention targeted to improve RRBs before these behaviors become entrenched. (PsycINFO Database Record (c) 2011 APA, all rights reserved).
3. Manning SE, Davin CA, Barfield WD, Kotelchuck M, Clements K, Diop H, Osbahr T, Smith LA. {{Early Diagnoses of Autism Spectrum Disorders in Massachusetts Birth Cohorts, 2001-2005}}. {Pediatrics};2011 (May 16)
Objective: We examined trends in autism spectrum disorder diagnoses by age 36 months (early diagnoses) and identified characteristics associated with early diagnoses. Methods: Massachusetts birth certificate and early-intervention program data were linked to identify infants born between 2001 and 2005 who were enrolled in early intervention and receiving autism-related services before age 36 months (through December 31, 2008). Trends in early autism spectrum disorders were examined using Cochran-Armitage trend tests. chi(2) Statistics were used to compare distributions of selected characteristics for children with and without autism spectrum disorders. Multivariate logistic regression analyses were conducted to identify independent predictors of early diagnoses. Results: A total of 3013 children (77.5 per 10 000 study population births) were enrolled in early intervention for autism spectrum disorder by age 36 months. Autism spectrum disorder incidence increased from 56 per 10 000 infants among the 2001 birth cohort to 93 per 10 000 infants in 2005. Infants of mothers younger than 24 years of age, whose primary language was not English or who were foreign-born had lower odds of an early autism spectrum disorder diagnosis. Maternal age older than 30 years was associated with increased odds of an early autism spectrum disorder diagnosis. Odds of early autism spectrum disorders were 4.5 (95% confidence interval: 4.1-5.0) times higher for boys than girls. Conclusions: Early autism spectrum disorder diagnoses are increasing in Massachusetts, reflecting the national trend observed among older children. Linkage of early-intervention program data with population-based vital statistics is valuable for monitoring autism spectrum disorder trends and planning developmental and educational service needs.
4. Roche-Martinez A, Gerotina E, Armstrong-Moron J, Sans-Capdevila O, Pineda M. {{[FOXG1, a new gene responsible for the congenital form of Rett syndrome.]}}. {Rev Neurol};2011 (May 16);52(10):597-602.
INTRODUCTION. Rett syndrome (RS) is a neurodevelopmental disorder that affects girls almost exclusively. The identification of mutations in the MECP2 and CDKL5 genes offers genetic confirmation of the clinical diagnosis. The FOXG1 gene appears to be a novel cause of the congenital variant of RS. CASE REPORT. We describe the first Spanish patient with the atypical (congenital) variant of RS with mutation of the FOXG1 gene and the case is compared with 12 patients previously reported in the literature; clinical criteria that suggest alterations in FOXG1 are proposed. The patient was referred at the age of 6 months due to overall retardation, axial hypotonia, microcephaly and a peculiar phenotype. Magnetic resonance imaging of the brain revealed hypoplasia of the corpus callosum, frontal atrophy and ventriculomegaly. The appearance of hand-to-mouth stereotypic movements at 12 months pointed the clinical diagnosis towards an atypical variant of RS, the congenital form; there was progressive improvement of visual contact and interest in her surroundings. Frequent respiratory infections and obstructive sleep apnoea syndrome. At the age of 5 years there was partial control over the axial tone, grasping with the hands, good contact and babbling, without epilepsy or behavioural disorders. The MECP2 and subtelomeric deletion study did not reveal any alterations; two polymorphisms were identified in the CDKL5 gene and a pathogenic mutation was found in FOXG1 (c.624C>G p.Tyr203X). CONCLUSIONS. It has been shown that 92% of patients with mutations in the FOXG1 gene present the congenital form of RS with severe generalised hypotonia, early acquired microcephaly (-3 to -6 standard deviations) and peculiar phenotype. When faced with a diagnosis of RS with no alterations in the MECP2 and CDKL5 genes, especially in the case of the congenital variant, the FOXG1 gene must be investigated. The molecular diagnosis confirms the clinical diagnosis and provides the family with genetic counselling.
5. Roende G, Ravn K, Fuglsang K, Andersen H, Nielsen JB, Brondum-Nielsen K, Jensen JE. {{DXA-measurements in Rett syndrome reveal small bones with low bone mass}}. {J Bone Miner Res};2011 (May 16)
Low bone mass is reported in growth retarded patients harbouring mutations in the X-linked Methyl-CpG-binding protein 2 gene (MECP2) causing Rett syndrome (RTT). We present the first study addressing both bone mineral density (BMD) and bone size in RTT. Our object was to determine whether patients with RTT do have low BMD when correcting for smaller bones by examination with dual-energy X-ray absorptiometry (DXA). We compared areal BMD (aBMD(spine) and aBMD(total hip) ) and volumetric bone mineral apparent density (vBMAD(spine) and vBMAD(neck) ) in 61 patients and 122 matched healthy controls. Further, spine and hip aBMD and vBMAD of patients were associated to clinical risk factors of low BMD, low-energy fractures, MECP2 mutation groups and X chromosome inactivation (XCI). Patients with RTT had reduced bone size in the order of 10%, and showed lower values of spine and hip aBMD and vBMAD (p < 0.001), adjusted for age, pubertal status and body mass index (BMI). aBMD(spine) , vBMAD(spine) and aBMD(total hip) were associated to low-energy fractures (p < 0.05). Walking was significantly associated to aBMD(total hip) and vBMAD(neck,) adjusted for age and BMI. Further, vBMAD(neck) was significantly associated to a diagnosis of epilepsy, anti-epileptic treatment and MECP2 mutation group, but none of the associations to vBMAD(neck) remained clinically significant in a multiple adjusted model including age and BMI. Neither aBMD(spine) , vBMAD(spine) and aBMD(total hip) were significantly associated to epilepsy, anti-epileptic treatment, MECP2 mutation group, XCI and vitamin D status. Low bone mass and small bones are evident in RTT indicating an apparent low bone formation phenotype. (c) 2011 American Society for Bone and Mineral Research.
6. Stephenson DT, O’Neill SM, Narayan S, Tiwari A, Arnold E, Samaroo H, Du F, Ring R, Campbell B, Pletcher M, Vaidya VA, Morton D. {{Histopathologic characterization of the BTBR mouse model of autistic-like behavior reveals selective changes in neurodevelopmental proteins and adult hippocampal neurogenesis}}. {Mol Autism};2011 (May 16);2(1):7.
ABSTRACT: BACKGROUND: The inbred mouse strain, BTBR T+ tf/J (BTBR) exhibits behavioral deficits which mimic the core deficits of autism. Neuroanatomically, the BTBR strain is also characterized by a complete absence of the corpus callosum. The goal of this study was to identify novel molecular and cellular changes in the BTBR mouse focusing on, neuronal, synaptic, glial and plasticity markers in the limbic system as a model for identifying putative molecular and cellular substrates associated with autistic behaviors. . METHODS: Forebrains of 8 to 10 week old male BTBR and aged matched C57Bl/6J controls were evaluated by immunohistochemistry using free floating and paraffin embedded sections. Twenty antibodies directed to antigens specific to neurons, synapses and glia were used. Nissl, Timm’s and acetylcholinesterase (AchE) stains were performed to assess cytoarchitecture, mossy fibers and cholinergic fiber density, respectively. In the hippocampus, quantitative stereological estimates for the mitotic marker bromodeoxyuridine were performed to determine hippocampal progenitor proliferation, survival and differentiation and BDNF mRNA was quantified by in situ hybridization. Quantitative image analysis was performed for NG2, doublecortin, NeuroD, GAD67 and PSA-NCAM. RESULTS: In midline structures including the region of the absent corpus callosum of BTBR mice, myelin markers myelin basic protein (MBP) and 2′ , 3′ -cyclic nucleotide 3′ -phosphodiesterase (CNPase) were reduced and oligodendrocyte precursor NG2 was increased. MBP and CNPase were expressed in small ectopic white matter bundles within the cingulate cortex. Microglia and astrocytes showed no evidence of gliosis, yet orientations of glial fibers were altered in specific white matter areas. In the hippocampus, evidence of reduced neurogenesis included significant reductions in the number of doublecortin, PSA-NCAM, and NeuroD immunoreactive cells in the subgranular zone of the dentate gyrus and a marked reduction in the number of BrdU positive progenitors Furthermore, a significant and profound reduction in BDNF mRNA in the BTBR dentate gyrus was observed. No significant differences were observed in the expression of acetylcholinesterase, mossy fiber synapses, and immunoreactivities for MAP2, parvalbumin, GAD65 and GAD67. CONCLUSIONS: We documented modest and selective alterations in glia, neurons and synapses in BTBR forebrain, along with reduced adult hippocampal neurogenesis. Of all markers examined, the most distinctive changes were observed in the neurodevelopmental proteins NG2, PSA-NCAM, NeuroD and doublecortin. Our results are consistent with aberrant development of the nervous system in BTBR mice and may reveal novel substrates to link callosal abnormalities and autistic behaviors. The changes that we observed in the BTBR mice suggest potential novel therapeutic strategies for intervention in autism spectrum disorders.
