1. {{Neurodevelopmental disorders: Metabolic conditions during pregnancy could be a risk factor for autism}}. {Nat Rev Neurol};2012 (May 22)
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2. Celestino-Soper PB, Violante S, Crawford EL, Luo R, Lionel AC, Delaby E, Cai G, Sadikovic B, Lee K, Lo C, Gao K, Person RE, Moss TJ, German JR, Huang N, Shinawi M, Treadwell-Deering D, Szatmari P, Roberts W, Fernandez B, Schroer RJ, Stevenson RE, Buxbaum JD, Betancur C, Scherer SW, Sanders SJ, Geschwind DH, Sutcliffe JS, Hurles ME, Wanders RJ, Shaw CA, Leal SM, Cook EH, Jr., Goin-Kochel RP, Vaz FM, Beaudet AL. {{A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism}}. {Proc Natl Acad Sci U S A};2012 (May 22);109(21):7974-7981.
We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene in a proband with autism. TMLHE maps to the X chromosome and encodes the first enzyme in carnitine biosynthesis, 6-N-trimethyllysine dioxygenase. Deletion of exon 2 of TMLHE causes enzyme deficiency, resulting in increased substrate concentration (6-N-trimethyllysine) and decreased product levels (3-hydroxy-6-N-trimethyllysine and gamma-butyrobetaine) in plasma and urine. TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not significantly increased in frequency in probands from simplex autism families (9 in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 or 1 in 130; P = 0.023). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (metaanalysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism.
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3. Cortesi F, Giannotti F, Sebastiani T, Panunzi S, Valente D. {{Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial}}. {J Sleep Res};2012 (May 22)
Although melatonin and cognitive-behavioural therapy have shown efficacy in treating sleep disorders in children with autism spectrum disorders, little is known about their relative or combined efficacy. One hundred and sixty children with autism spectrum disorders, aged 4-10 years, suffering from sleep onset insomnia and impaired sleep maintenance, were assigned randomly to either (1) combination of controlled-release melatonin and cognitive-behavioural therapy; (2) controlled-release melatonin; (3) four sessions of cognitive-behavioural therapy; or (4) placebo drug treatment condition for 12 weeks in a 1 : 1 : 1 : 1 ratio. Children were studied at baseline and after 12 weeks of treatment. Treatment response was assessed with 1-week actigraphic monitoring, sleep diary and sleep questionnaire. Main outcome measures, derived actigraphically, were sleep latency, total sleep time, wake after sleep onset and number of awakenings. The active treatment groups all resulted in improvements across all outcome measures, with moderate-to-large effect sizes from baseline to a 12-week assessment. Melatonin treatment was mainly effective in reducing insomnia symptoms, while cognitive-behavioural therapy had a light positive impact mainly on sleep latency, suggesting that some behavioural aspects might play a role in determining initial insomnia. The combination treatment group showed a trend to outperform other active treatment groups, with fewer dropouts and a greater proportion of treatment responders achieving clinically significant changes (63.38% normative sleep efficiency criterion of >85% and 84.62%, sleep onset latency <30 min). This study demonstrates that adding behavioural intervention to melatonin treatment seems to result in a better treatment response, at least in the short term.
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4. Griswold AJ, Ma D, Cukier HN, Nations LD, Schmidt MA, Chung RH, Jaworski JM, Salyakina D, Konidari I, Whitehead PL, Wright HH, Abramson RK, Williams SM, Menon R, Martin ER, Haines JL, Gilbert JR, Cuccaro ML, Pericak-Vance MA. {{Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways}}. {Hum Mol Genet};2012 (May 22)
Autism spectrum disorders (ASDs) are highly heritable, yet relatively few associated genetic loci have been replicated. Copy number variations (CNVs) have been implicated in autism; however, the majority of loci contribute to <1% of the disease population. Therefore, independent studies are important to refine associated CNV regions and discover novel susceptibility genes. In this study, a genome-wide SNP array was utilized for CNV detection by two distinct algorithms in a European ancestry case-control data set. We identify a significantly higher burden in the number and size of deletions, and disrupting more genes in ASD cases. Moreover, 18 deletions larger than 1 Mb were detected exclusively in cases, implicating novel regions at 2q22.1, 3p26.3, 4q12 and 14q23. Case-specific CNVs provided further evidence for pathways previously implicated in ASDs, revealing new candidate genes within the GABAergic signaling and neural development pathways. These include DBI, an allosteric binder of GABA receptors, GABARAPL1, the GABA receptor-associated protein, and SLC6A11, a postsynaptic GABA transporter. We also identified CNVs in COBL, deletions of which cause defects in neuronal cytoskeleton morphogenesis in model vertebrates, and DNER, a neuron-specific Notch ligand required for cerebellar development. Moreover, we found evidence of genetic overlap between ASDs and other neurodevelopmental and neuropsychiatric diseases. These genes include glutamate receptors (GRID1, GRIK2 and GRIK4), synaptic regulators (NRXN3, SLC6A8 and SYN3), transcription factor (ZNF804A) and RNA-binding protein FMR1. Taken together, these CNVs may be a few of the missing pieces of ASD heritability and lead to discovering novel etiological mechanisms.
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5. Malpass K. {{Neurodevelopmental disorders: Unlocking the secrets of autism through whole-exome sequencing}}. {Nat Rev Neurol};2012 (May 22)
