1. Addington AM, Gauthier J, Piton A, Hamdan FF, Raymond A, Gogtay N, Miller R, Tossell J, Bakalar J, Germain G, Gochman P, Long R, Rapoport JL, Rouleau GA. {{A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders}}. {Mol Psychiatry} (May 18)
2. Blardi P, de Lalla A, Ceccatelli L, Guerri V, Auteri A, Hayek J. {{Variations of Plasma Leptin and Adiponectin Levels in Autistic Patients}}. {Neurosci Lett} (May 14)
Autism is a neurodevelopmental disorder with pathogenesis not completely understood. Although a genetic origin has been recognized, it has been hypothesized a role for environmental factors, immune dysfunctions, and alterations of neurotransmitter systems. In young autistic patients we investigated plasma leptin and adiponectin levels over a year period. Thirty-five patients, mean age at the basal time 14.1+/-5.4 years, were enrolled. Controls were thirty-five healthy subjects, sex and age matched. Blood samples were withdrawn in the morning at the baseline and 12 months after. In patients leptin concentrations significantly increased, while adiponectin did not significantly change. Leptin values in patients were significantly higher than those found in controls at each time; adiponectin values did not differ at each time between patients and controls. Since patients were not obese, we could hypothesize that leptin might partecipate to clinical manifestations other than weight balance. The role of adiponectin in autism is still debatable.
3. Hallett V, Ronald A, Rijsdijk F, Happe F. {{Association of Autistic-Like and Internalizing Traits During Childhood: A Longitudinal Twin Study}}. {Am J Psychiatry} (May 17)
Objective Children with autism spectrum disorders often experience severe anxiety and depression, yet the explanation for this association remains unclear. The authors examined the longitudinal relationship between autistic-like and internalizing traits across middle to late childhood in a population-representative twin sample. Method Participants were approximately 6,000 twin pairs born in England and Wales from 1994 to 1996. Parental reports of autistic-like and internalizing traits were analyzed at ages 7 and 8 (timepoint 1) and again at age 12 (timepoint 2). The direction and etiology of the associations between these traits were examined within a cross-lagged design. Results Findings revealed an asymmetric bidirectional association between autistic-like and internalizing traits over time. Autistic-like traits at age 7 made a modest but significant contribution to the presence of internalizing traits at age 12. Earlier internalizing traits also influenced the development of later autistic-like traits, although this association was approximately one-half the magnitude. While both traits were moderately to highly heritable, they were largely independent with regard to their genetic influences. Stronger associations were found between the modest shared environmental influences on each trait. Of note, it was autistic-like communication difficulties, rather than social deficits, that made a significant contribution to later internalizing traits. Conclusions The association between autistic-like and internalizing traits was attributable to reciprocal processes occurring across childhood, suggesting that these traits may serve to exacerbate each other over time. Autistic-like communication difficulties had the most notable impact. This association must now be explored within samples of children with diagnosed autism spectrum disorders and internalizing disorders, since this may help to inform the best timing and targeting of clinical intervention.
4. Handley MT, Lian LY, Haynes LP, Burgoyne RD. {{Structural and functional deficits in a neuronal calcium sensor-1 mutant identified in a case of autistic spectrum disorder}}. {PLoS One};5(5):e10534.
Neuronal calcium sensor-1 (NCS-1) is a Ca(2+) sensor protein that has been implicated in the regulation of various aspects of neuronal development and neurotransmission. It exerts its effects through interactions with a range of target proteins one of which is interleukin receptor accessory protein like-1 (IL1RAPL1) protein. Mutations in IL1RAPL1 have recently been associated with autism spectrum disorders and a missense mutation (R102Q) on NCS-1 has been found in one individual with autism. We have examined the effect of this mutation on the structure and function of NCS-1. From use of NMR spectroscopy, it appeared that the R102Q affected the structure of the protein particularly with an increase in the extent of conformational exchange in the C-terminus of the protein. Despite this change NCS-1(R102Q) did not show changes in its affinity for Ca(2+) or binding to IL1RAPL1 and its intracellular localisation was unaffected. Assessment of NCS-1 dynamics indicated that it could rapidly cycle between cytosolic and membrane pools and that the cycling onto the plasma membrane was specifically changed in NCS-1(R102Q) with the loss of a Ca(2+) -dependent component. From these data we speculate that impairment of the normal cycling of NCS-1 by the R102Q mutation could have subtle effects on neuronal signalling and physiology in the developing and adult brain.
5. Piton A, Gauthier J, Hamdan FF, Lafreniere RG, Yang Y, Henrion E, Laurent S, Noreau A, Thibodeau P, Karemera L, Spiegelman D, Kuku F, Duguay J, Destroismaisons L, Jolivet P, Cote M, Lachapelle K, Diallo O, Raymond A, Marineau C, Champagne N, Xiong L, Gaspar C, Riviere JB, Tarabeux J, Cossette P, Krebs MO, Rapoport JL, Addington A, Delisi LE, Mottron L, Joober R, Fombonne E, Drapeau P, Rouleau GA. {{Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia}}. {Mol Psychiatry} (May 18)
Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n=142; 122 males and 20 females) or SCZ (n=143; 95 males and 48 females). We identified >200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).Molecular Psychiatry advance online publication, 18 May 2010; doi:10.1038/mp.2010.54.
6. Tylki-Szymanska A, Gradowska W, Sommer A, Heer A, Walter M, Reinhard C, Omran H, Sass JO, Jurecka A. {{Aminoacylase 1 deficiency associated with autistic behavior}}. {J Inherit Metab Dis} (May 18)
Aminoacylase 1 (ACY1) deficiency is a recently described inborn error of metabolism. Most of the patients reported so far have presented with rather heterogeneous neurologic symptoms. At this moment, it is not clear whether ACY1 deficiency represents a true metabolic disease with a causal relationship between the enzyme defect and the clinical phenotype or merely a biochemical abnormality. Here we present a patient identified in the course of selective screening for inborn errors of metabolism (IEM). The patient was diagnosed with autistic syndrome and admitted to the Children’s Memorial Health Institute (CMHI) for metabolic evaluation. Organic acid analysis using gas chromatography-mass spectrometry (GC-MS) revealed increased urinary excretion of several N-acetylated amino acids, including the derivatives of methionine, glutamic acid, alanine, glycine, leucine, isoleucine, and valine. In Epstein-Barr virus (EBV)-transformed lymphoblasts, ACY1 activity was deficient. The mutation analysis showed a homozygous c.1057C>T transition, predicting a p.Arg353Cys substitution. Both parents were heterozygous for the mutation and had normal results in the organic acid analysis using GC-MS. This article reports the findings of an ACY1-deficient patient presenting with autistic features.
