1. Bajaj N, Soon D, Quinn N. {{Fragile X-Associated tremor ataxia syndrome sine tremor}}. {Mov Disord};2011 (May 31)
2. Carmona-Mora P, Walz K. {{Retinoic Acid Induced 1, RAI1: A Dosage Sensitive Gene Related to Neurobehavioral Alterations Including Autistic Behavior}}. {Curr Genomics};2010 (Dec);11(8):607-617.
Genomic structural changes, such as gene Copy Number Variations (CNVs) are extremely abundant in the human genome. An enormous effort is currently ongoing to recognize and catalogue human CNVs and their associations with abnormal phenotypic outcomes. Recently, several reports related neuropsychiatric diseases (i.e. autism spectrum disorders, schizophrenia, mental retardation, behavioral problems, epilepsy) with specific CNV. Moreover, for some conditions, both the deletion and duplication of the same genomic segment are related to the phenotype. Syndromes associated with CNVs (microdeletion and microduplication) have long been known to display specific neurobehavioral traits. It is important to note that not every gene is susceptible to gene dosage changes and there are only a few dosage sensitive genes. Smith-Magenis (SMS) and Potocki-Lupski (PTLS) syndromes are associated with a reciprocal microdeletion and microduplication within chromosome 17p11.2. in humans. The dosage sensitive gene responsible for most phenotypes in SMS has been identified: the Retinoic Acid Induced 1 (RAI1). Studies on mouse models and humans suggest that RAI1 is likely the dosage sensitive gene responsible for clinical features in PTLS. In addition, the human RAI1 gene has been implicated in several neurobehavioral traits as spinocerebellar ataxia (SCA2), schizophrenia and non syndromic autism. In this review we discuss the evidence of RAI1 as a dosage sensitive gene, its relationship with different neurobehavioral traits, gene structure and mutations, and what is known about its molecular and cellular function, as a first step in the elucidation of the mechanisms that relate dosage sensitive genes with abnormal neurobehavioral outcomes.
3. Geier DA, Kern JK, Davis G, King PG, Adams JB, Young JL, Geier MR. {{A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders}}. {Med Sci Monit};2011 (Jun 1);17(6):PI15-23.
Background: L-carnitine was proposed as a potential treatment for patients diagnosed with an autism spectrum disorder to improve mitochondrial dysfunction, but no prior randomized controlled trials have been conducted.<br /> Material/Methods: Thirty subjects diagnosed with an ASD were randomly assigned to receive a standardized regimen (50 mg L-carnitine/kg bodyweight/day) of liquid L-carnitine (n=19) or placebo (n=11) for 3-months. Measures included changes in professionally completed Childhood Autism Rating Scale (CARS), hand muscle testing, and modified clinical global impression (CGI) forms; parent completed Autism Treatment Evaluation Checklist (ATEC), treatment adherence measurement (TAM), frequency and intensity of side effect rating (FISER)/global rating of side effect burden (GRSEB)/patient report of incidence of side effects (PRISE) forms; and lab testing.<br /> Results: Significant improvements were observed in CARS (-2.03, 95% CI=-3.7 to -0.31), CGI (-0.69, 95% CI=-1.1 to -0.06), and ATEC scores. Significant correlations between changes in serum free-carnitine levels and positive clinical changes were observed for hand muscle strength (R2=0.23, P=0.046), cognitive scores (R2=0.27, P=0.019), and CARS scores (R2=0.20, P=0.047). Study subjects were protocol-compliant (average adherence was >85%) and generally well-tolerated the L-carnitine therapy given.<br /> Conclusions: L-carnitine therapy (50 mg/kilogram-bodyweight/day) administered for 3-months significantly improved several clinical measurements of ASD severity, but subsequent studies are recommended.<br />
4. Lai G, Schneider HD, Schwarzenberger JC, Hirsch J. {{Speech Stimulation during Functional MR Imaging as a Potential Indicator of Autism}}. {Radiology};2011 (May 31)
Purpose: To determine the feasibility of applying functional magnetic resonance (MR) imaging as an objective indicator of language disability in autism by using passive speech stimulation. Materials and Methods: This prospective study was approved by the institutional review board, and informed consent was obtained from the parents or guardians of all subjects. Functional MR imaging was performed during passive presentations of prerecorded speech in 15 control subjects (mean age +/- standard deviation, 12.1 years +/- 4.3) and 12 language-impaired, age-matched autistic subjects (mean age, 12.4 years +/- 4.7). An additional 27 autistic children (mean age, 8.4 years +/- 3.1), who underwent imaging while sedated with propofol as part of routine clinical MR evaluations, were also included. Activation maps for each subject were computed by using univariate general linear model analyses. The spread (quantified as number of voxels) and amplitude of the functional MR imaging activation were then quantified within two anatomically specified regions of interest known to be involved with language: the primary auditory cortex (A1) and the superior temporal gyrus (STG). Group differences were compared by using analysis of variance, two-sample t tests, and Wilcoxon rank sum tests where appropriate. The threshold for autism was defined as 1 standard deviation below the control mean for subjects imaged in the alert state. A similar threshold was estimated for sedated autistic subjects on the basis of differences between nonsedated and sedated autistic subjects. Results: Activity in A1 did not differ between autistic and control subjects. However, mean amplitude and spread of activity in the STG differed between autistic and control subjects (P < .001). Values for 10 of the 12 (83%) nonsedated autistic subjects decreased at least 1 standard deviation below the control distribution. The threshold derived from sedation-adjusted values of the control group enabled identification of 26 of the 27 (96%) sedated autistic subjects. Conclusion: Functional MR imaging activation within the STG in response to passive speech stimulation helped differentiate autistic from control subjects, demonstrating the potential utility of functional MR imaging as an objective indicator of language impairment in autism. Future studies may lead to an early and objective indicator for autism with these methods. (c) RSNA, 2011.
5. Song G, Tin C, Giacometti E, Poon CS. {{Habituation without NMDA Receptor-Dependent Desensitization of Hering-Breuer Apnea Reflex in a Mecp2 Mutant Mouse Model of Rett Syndrome}}. {Front Integr Neurosci};2011;5:6.
Non-associative learning is a basic neuroadaptive behavior exhibited in almost all animal species and sensory modalities but its functions and mechanisms in the mammalian brain are poorly understood. Previous studies have identified two distinct forms of non-associative learning in the classic Hering-Breuer inflation reflex (HBIR) induced apnea in rats: NMDA receptor (NMDAR)-independent habituation in a primary vagal pathway and NMDAR-dependent desensitization in a secondary pontine pathway. Here, we show that abnormal non-associative learning of the HBIR may underlie the endophenotypic tachypnea in an animal model of Rett syndrome (RTT), an autism-spectrum disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2). Mecp2(+/-) symptomatic mice on a mixed-strain background demonstrated significantly increased resting respiratory frequency with shortened expiration and normal inspiratory duration compared with asymptomatic mutants and wild-type controls, a phenotype that is characteristic of girls with RTT. Low-intensity electrical stimulation of the vagus nerve elicited fictive HBIR with time-dependent habituation in both Mecp2(+/-) and wild-type mice. However, time-dependent desensitization of the HBIR was evidenced only in wild-type controls and asymptomatic mutant mice but was absent or suppressed in Mecp2(+/-) symptomatic mice or in wild-type mice after blockade of NMDAR with dizocilpine. Remarkably, approximately 50% of the Mecp2(+/-) mice developed these X-linked phenotypes despite somatic mosaicism. Such RTT-like respiratory endophenotypes in mixed-strain Mecp2(+/-) mice differed from those previously reported in Mecp2(-/y) mice on pure C57BL/6J background. These findings provide the first evidence indicating that impaired NMDAR-dependent desensitization of the HBIR may contribute to the endophenotypic tachypnea in RTT.
6. Young AM, Campbell E, Lynch S, Suckling J, Powis SJ. {{Aberrant NF-KappaB Expression in Autism Spectrum Condition: A Mechanism for Neuroinflammation}}. {Front Psychiatry};2011;2:27.
Autism spectrum condition (ASC) is recognized as having an inflammatory component. Post-mortem brain samples from patients with ASC display neuroglial activation and inflammatory markers in cerebrospinal fluid, although little is known about the underlying molecular mechanisms. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) is a protein found in almost all cell types and mediates regulation of immune response by inducing the expression of inflammatory cytokines and chemokines, establishing a feedback mechanism that can produce chronic or excessive inflammation. This article describes immunodetection and immunofluorescence measurements of NF-kappaB in human post-mortem samples of orbitofrontal cortex tissue donated to two independent centers: London Brain Bank, Kings College London, UK (ASC: n = 3, controls: n = 4) and Autism Tissue Program, Harvard Brain Bank, USA (ASC: n = 6, controls: n = 5). The hypothesis was that concentrations of NF-kappaB would be elevated, especially in activated microglia in ASC, and pH would be concomitantly reduced (i.e., acidification). Neurons, astrocytes, and microglia all demonstrated increased extranuclear and nuclear translocated NF-kappaB p65 expression in brain tissue from ASC donors relative to samples from matched controls. These between-groups differences were increased in astrocytes and microglia relative to neurons, but particularly pronounced for highly mature microglia. Measurement of pH in homogenized samples demonstrated a 0.98-unit difference in means and a strong (F = 98.3; p = 0.00018) linear relationship to the expression of nuclear translocated NF-kappaB in mature microglia. Acridine orange staining localized pH reductions to lysosomal compartments. In summary, NF-kappaB is aberrantly expressed in orbitofrontal cortex in patients with ASC, as part of a putative molecular cascade leading to inflammation, especially of resident immune cells in brain regions associated with the behavioral and clinical symptoms of ASC.
