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22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan-McDermid syndrome.

December 15, 2014 - 3:19pm
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22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan-McDermid syndrome.

Genet Med. 2014 Apr;16(4):318-28

Authors: Sarasua SM, Dwivedi A, Boccuto L, Chen CF, Sharp JL, Rollins JD, Collins JS, Rogers RC, Phelan K, DuPont BR

Abstract
PURPOSE: Phelan-McDermid syndrome is a developmental disability syndrome with varying deletions of 22q13 and varying clinical severity. We tested the hypothesis that, in addition to loss of the telomeric gene SHANK3, specific genomic regions within 22q13 are associated with important clinical features.
METHODS: We used a customized oligo array comparative genomic hybridization of 22q12.3-terminus to obtain deletion breakpoints in a cohort of 70 patients with terminal 22q13 deletions. We used association and receiver operating characteristic statistical methods in a novel manner and also incorporated protein interaction networks to identify 22q13 genomic locations and genes associated with clinical features.
RESULTS: Specific genomic regions and candidate genes within 22q13.2q13.32 were associated with severity of speech/language delay, neonatal hypotonia, delayed age at walking, hair-pulling behaviors, male genital anomalies, dysplastic toenails, large/fleshy hands, macrocephaly, short and tall stature, facial asymmetry, and atypical reflexes. We also found regions suggestive of a negative association with autism spectrum disorders.
CONCLUSION: This work advances the field of research beyond the observation of a correlation between deletion size and phenotype and identifies candidate 22q13 loci, and in some cases specific genes, associated with singular clinical features observed in Phelan-McDermid syndrome. Our statistical approach may be useful in genotype-phenotype analyses for other microdeletion or microduplication syndromes.

PMID: 24136618 [PubMed - indexed for MEDLINE]

Autoantibodies against neuronal progenitors in sera from children with autism.

December 15, 2014 - 3:19pm
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Autoantibodies against neuronal progenitors in sera from children with autism.

Brain Dev. 2014 Apr;36(4):322-9

Authors: Mazur-Kolecka B, Cohen IL, Gonzalez M, Jenkins EC, Kaczmarski W, Brown WT, Flory M, Frackowiak J

Abstract
The pathological role of autoantibodies in development of CNS disorders is a new idea with growing interest among neuroscientists. The involvement of autoimmune response in the pathogenesis of autism spectrum disorders (ASD) has been suggested by the presence of multiple brain-specific autoantibodies in children with ASD and in their mothers. The possibility of the effect of autoimmunity on neurogenesis and postnatal brain plasticity has not been determined. The presence of autoantibodies against human neuronal progenitor cells (NPCs) stimulated for neuronal differentiation in culture was tested in sera from children with autism (n=20) and age-matched controls (n=18) by immunoblotting and immunocytochemistry. Immunoreactivity against multiple NPCs proteins of molecular sizes of approximately 55 kDa, 105 kDa, 150 kDa, and 210 kDa in sera from individuals with autism had a higher incidence and was stronger than in control sera which immunoreacted mainly with a 150 kDa protein. The sera from children with autism immunoreacted the strongest with NPCs expressing neuronal markers Tuj1 and doublecortin, but not astrocyte marker GFAP. The epitopes recognized by antibodies from sera were not human-specific because they detected also NPCs in situ in murine hippocampus. The autoimmune reactions against NPCs suggest an impaired tolerance to neural antigens in autism. These autoantibodies may be symptomatic for autism and furthermore, their presence suggests that autoimmunity may affect postnatal neuronal plasticity particularly after impairment of blood-brain barrier. Future studies will determine the diagnostic value of the presence of autoantibodies in autism and the therapeutic value of prevention of autoimmunity in autism.

PMID: 23838310 [PubMed - indexed for MEDLINE]

Co-morbidity of autism and SLI: kinds, kin and complexity.

December 15, 2014 - 3:19pm
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Co-morbidity of autism and SLI: kinds, kin and complexity.

Int J Lang Commun Disord. 2011 Mar-Apr;46(2):127-37

Authors: Tomblin B

Abstract
There has been a long-standing interest in the relationship between specific language impairment (SLI) and autism spectrum disorder (ASD). In the last decade Tager-Flusberg and colleagues have proposed that this relationship consists of a partial overlap between the two. Therefore, among children with ASD there exists a subgroup who have SLI and ASD which has been called 'ALI'. Tager-Flusberg's laboratory has presented several papers showing similar language profiles and brain structure abnormalities in both SLI and ALI. Others (Bishop, Whitehouse, Botting, Williams) have been less convinced that these ALI children have both ASD and SLI. Although they generally agree that the two groups are grossly similar, careful inspection of the data shows that there are differences. I will argue that many of the problems in this debate stem from a view of SLI that represents a particular kind of language learner and therefore a particular and unique profile can be assumed. I argue for recognizing that SLI is not likely to be a unique kind of language learner. Many of the features reported to be characteristic of SLI are also found in other forms of neurodevelopmental disorders. Other features are the outgrowth of studying clinically identified children with SLI and thus the profile appears to reflect biases and practices in the clinical service system. As a result it may be more reasonable to conclude that there is a large group of children with ASD who have poor language skills. The question then remains why are there so many children with ASD who also have poor language? There are several factors that collectively are strong candidates for answers to this question.

PMID: 21401812 [PubMed - indexed for MEDLINE]

A Novel Non-Developmental Role of the SAX-7/L1CAM Cell Adhesion Molecule in Synaptic Regulation in Caenorhabditis elegans.

December 10, 2014 - 7:18am
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A Novel Non-Developmental Role of the SAX-7/L1CAM Cell Adhesion Molecule in Synaptic Regulation in Caenorhabditis elegans.

Genetics. 2014 Dec 8;

Authors: Opperman K, Moseley-Alldredge M, Yochem J, Bell L, Kanayinkal T, Chen L

Abstract
The L1CAM family of cell adhesion molecules is a conserved set of single-pass transmembrane proteins that play diverse roles required for proper nervous system development and function. Mutations in L1CAMs can cause the neurological L1 syndrome and are associated with autism and neuropsychiatric disorders. L1CAM expression in the mature nervous system suggests additional functions besides the well-characterized developmental roles. In this study, we demonstrate that the gene encoding the Caenorhabditis elegans L1CAM, sax-7, genetically interacts with gtl-2, as well as with unc-13 and rab-3, genes that function in neurotransmission. These sax-7 genetic interactions result in synthetic phenotypes that are consistent with abnormal synaptic function. Using an inducible sax-7 expression system and pharmacological reagents that interfere with cholinergic transmission, we uncovered a previously uncharacterized non-developmental role for sax-7 that impinges on synaptic function.

PMID: 25488979 [PubMed - as supplied by publisher]

Preeclampsia, Placental Insufficiency, and Autism Spectrum Disorder or Developmental Delay.

December 9, 2014 - 6:59am

Preeclampsia, Placental Insufficiency, and Autism Spectrum Disorder or Developmental Delay.

JAMA Pediatr. 2014 Dec 8;

Authors: Walker CK, Krakowiak P, Baker A, Hansen RL, Ozonoff S, Hertz-Picciotto I

Abstract
Importance: Increasing evidence suggests that autism spectrum disorder (ASD) and many forms of developmental delay (DD) originate during fetal development. Preeclampsia may trigger aberrant neurodevelopment through placental, maternal, and fetal physiologic mechanisms.
Objective: To determine whether preeclampsia is associated with ASD and/or DD.
Design, Setting, and Participants: The Childhood Autism Risks from Genetics and the Environment (CHARGE) study is a population-based, case-control investigation of ASD and/or DD origins. Children from 20 California counties aged 24 to 60 months at the time of recruitment and living in catchment areas with a biological parent fluent in English or Spanish were enrolled from January 29, 2003, through April 7, 2011. Children with ASD (n = 517) and DD (n = 194) were recruited through the California Department of Developmental Services, the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, and referrals. Controls with typical development (TD) (n = 350) were randomly selected from birth records and frequency matched on age, sex, and broad geographic region. Physicians diagnosing preeclampsia were masked to neurodevelopmental outcome, and those assessing neurodevelopmental function were masked to preeclampsia status.
Exposures: Preeclampsia and placental insufficiency were self-reported and abstracted from medical records.
Main Outcomes and Measures: The Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised were used to confirm ASD, whereas children with DD and TD were confirmed by Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales and were free of autistic symptoms. Hypotheses were formulated before data collection.
Results: Children with ASD were twice as likely to have been exposed in utero to preeclampsia as controls with TD after adjustment for maternal educational level, parity, and prepregnancy obesity (adjusted odds ratio, 2.36; 95% CI, 1.18-4.68); risk increased with greater preeclampsia severity (test for trend, P = .02). Placental insufficiency appeared responsible for the increase in DD risk associated with severe preeclampsia (adjusted odds ratio, 5.49; 95% CI, 2.06-14.64).
Conclusions and Relevance: Preeclampsia, particularly severe disease, is associated with ASD and DD. Faulty placentation manifests in the mother as preeclampsia with vascular damage, enhanced systemic inflammation, and insulin resistance; in the placenta as oxygen and nutrient transfer restriction and oxidative stress; and in the fetus as growth restriction and progressive hypoxemia. All are potential mechanisms for neurodevelopmental compromise.

PMID: 25485869 [PubMed - as supplied by publisher]

Leveraging genetics and genomics to define the causes of mental illness.

December 9, 2014 - 6:59am
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Leveraging genetics and genomics to define the causes of mental illness.

Biol Psychiatry. 2015 Jan 1;77(1):3-5

Authors: State MW, Geschwind DH

PMID: 25483342 [PubMed - in process]

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