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Diagnosis and Management of Autism Spectrum Disorder in the Era of Genomics: Rare Disorders Can Pave the Way for Targeted Treatments.

May 30, 2015 - 8:55am

Diagnosis and Management of Autism Spectrum Disorder in the Era of Genomics: Rare Disorders Can Pave the Way for Targeted Treatments.

Pediatr Clin North Am. 2015 Jun;62(3):607-618

Authors: Baker E, Jeste SS

Abstract
Although the diagnosis of autism spectrum disorder (ASD) is based on behavioral signs and symptoms, the evaluation of a child with ASD has become increasingly focused on the identification of the genetic etiology of the disorder. In this review, we begin with a clinical overview of ASD, highlighting the heterogeneity of the disorder. We then discuss the genetics of ASD and present updated guidelines on genetic testing. We then consider the insights gained from the identification of both single gene disorders and rare variants, with regard to clinical phenomenology and potential treatment targets.

PMID: 26022165 [PubMed - as supplied by publisher]

Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome.

May 29, 2015 - 8:10am
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Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome.

Arch Dis Child. 2015 Mar;100(3):259-64

Authors: Laffargue F, Bourthoumieu S, Llanas B, Baudouin V, Lahoche A, Morin D, Bessenay L, De Parscau L, Cloarec S, Delrue MA, Taupiac E, Dizier E, Laroche C, Bahans C, Yardin C, Lacombe D, Guigonis V

Abstract
OBJECTIVE: 17q12 microdeletion syndrome involves 15 genes, including HNF1B, and is considered to confer a high risk of neuropsychiatric disorders. Patients with HNF1B gene deletion diagnosed secondary to renal disorders are only very rarely reported to have neuropsychiatric disorders. Interestingly, however, when tested, patients with HNF1B gene deletion are found to have 17q12 deletion. This brings into question the extent to which 17q12 deletion is genuinely associated with severe neuropsychological disorders and in which patients. In this study, we sought to confirm 17q12 microdeletion in kidney patients initially diagnosed with HNF1B gene deletion and evaluate neuropsychological disorders in these patients compared with those with HNF1B point mutation.
PATIENTS AND DESIGN: Thirty-nine children with HNF1B disorders (26 with deletions) diagnosed secondary to renal abnormalities were included in this prospective study and tested for 17q12 microdeletion and neuropsychological disorders.
RESULTS: The same 17q12 microdeletion found in patients with neuropsychological disorders was identified in all of our patients with HNF1B deletion. Neurological examinations found no severe impairments except for one patient with autism. No significant differences were found between patients with deletions and those with point mutations as concerns learning abilities and schooling. Nevertheless, patients with deletions tended to have lower developmental quotients and more difficulties at school.
CONCLUSIONS: Complete deletion of the HNF1B gene and 17q12 microdeletion syndrome are actually the same genetic disorder. The neuropsychological phenotype of patients appears less severe when 17q12 deletion is diagnosed secondary to kidney rather than neuropsychological abnormalities. These data may influence antenatal counselling.

PMID: 25324567 [PubMed - indexed for MEDLINE]

Social cognition, face processing, and oxytocin receptor single nucleotide polymorphisms in typically developing children.

May 29, 2015 - 8:10am
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Social cognition, face processing, and oxytocin receptor single nucleotide polymorphisms in typically developing children.

Dev Cogn Neurosci. 2014 Jul;9:160-71

Authors: Slane MM, Lusk LG, Boomer KB, Hare AE, King MK, Evans DW

Abstract
Recent research has provided evidence of a link between behavioral measures of social cognition (SC) and neural and genetic correlates. Differences in face processing and variations in the oxytocin receptor (OXTR) gene have been associated with SC deficits and autism spectrum disorder (ASD) traits. Much work has examined the qualitative differences between those with ASD and typically developing (TD) individuals, but very little has been done to quantify the natural variation in ASD-like traits in the typical population. The present study examines this variation in TD children using a multidimensional perspective involving behavior assessment, neural electroencephalogram (EEG) testing, and OXTR genotyping. Children completed a series of neurocognitive assessments, provided saliva samples for sequencing, and completed a face processing task while connected to an EEG. No clear pattern emerged for EEG covariates or genotypes for individual OXTR single nucleotide polymorphisms (SNPs). However, SNPs rs2254298 and rs53576 consistently interacted such that the AG/GG allele combination of these SNPs was associated with poorer performance on neurocognitive measures. These results suggest that neither SNP in isolation is risk-conferring, but rather that the combination of rs2254298(A/G) and rs53576(G/G) confers a deleterious effect on SC across several neurocognitive measures.

PMID: 24814480 [PubMed - indexed for MEDLINE]

Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.

May 29, 2015 - 8:10am
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Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.

Neurogenetics. 2014 May;15(2):117-27

Authors: Egger G, Roetzer KM, Noor A, Lionel AC, Mahmood H, Schwarzbraun T, Boright O, Mikhailov A, Marshall CR, Windpassinger C, Petek E, Scherer SW, Kaschnitz W, Vincent JB

Abstract
Autism or autism spectrum disorder (ASD) is a range of neurodevelopmental disorders starting in early childhood and is characterized by impairments in communication and reciprocal social interaction and presence of restricted and repetitive patterns of behavior. The contribution of genetic factors to autism is clear in twin and family studies. It is apparent that, overall, ASD is a complex non-Mendelian disorder. Recent studies suggest that copy number variations (CNVs) play a significant role in the etiology of ASD. For the current work, we recruited 245 family members from 73 ASD families from Styria, Austria. The DNA from probands was genotyped with Affymetrix single nucleotide polymorphism (SNP) 6.0 microarrays to screen for CNVs in their genomes. Analysis of the microarray data was performed using three different algorithms, and a list of stringent calls was compared to existing CNV data from over 2,357 controls of European ancestry. For stringent calls not present in controls, quantitative real-time PCR (qRT-PCR) was used to validate the CNVs in the probands and in their family members. Twenty-two CNVs were validated from this set (five of which are apparently de novo), many of which appear likely to disrupt genes that may be considered as good candidates for neuropsychiatric disorders, including DLG2, S100B, ARX, DIP2A, HPCAL1, and GPHN. Several others disrupt genes that have previously been implicated in autism, such as BDNF, AUTS2, DPP6, and C18orf22, and our data add to the growing evidence of their involvement in ASD.

PMID: 24643514 [PubMed - indexed for MEDLINE]

Infantile spasms syndrome, West syndrome and related phenotypes: what we know in 2013.

May 29, 2015 - 8:10am
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Infantile spasms syndrome, West syndrome and related phenotypes: what we know in 2013.

Brain Dev. 2014 Oct;36(9):739-51

Authors: Pavone P, Striano P, Falsaperla R, Pavone L, Ruggieri M

Abstract
The current spectrum of disorders associated to clinical spasms with onset in infancy is wider than previously thought; accordingly, its terminology has changed. Nowadays, the term Infantile spasms syndrome (ISs) defines an epileptic syndrome occurring in children younger than 1 year (rarely older than 2 years), with clinical (epileptic: i.e., associated to an epileptiform EEG) spasms usually occurring in clusters whose most characteristic EEG finding is hypsarrhythmia [the spasms are often associated with developmental arrest or regression]. The term West syndrome (WS) refers to a form (a subset) of ISs, characterised by the combination of clustered spasms and hypsarrhythmia on an EEG and delayed brain development or regression [currently, it is no longer required that delayed development occur before the onset of spasms]. Less usually, spasms may occur singly rather than in clusters [infantile spasms single-spasm variant (ISSV)], hypsarrhythmia can be (incidentally) recorded without any evidence of clinical spasms [hypsarrhythmia without infantile spasms (HWIS)] or typical clinical spasms may manifest in absence of hypsarrhythmia [infantile spasms without hypsarrhythmia (ISW)]. There is a growing evidence that ISs and related phenotypes may result, besides from acquired events, from disturbances in key genetic pathways of brain development: specifically, in the gene regulatory network of GABAergic forebrain dorsal-ventral development, and abnormalities in molecules expressed at the synapse. Children with these genetic associations also have phenotypes beyond epilepsy, including dysmorphic features, autism, movement disorders and systemic malformations. The prognosis depends on: (a) the cause, which gives origin to the attacks (the complex malformation forms being more severe); (b) the EEG pattern(s); (c) the appearance of seizures prior to the spasms; and (d) the rapid response to treatment. Currently, the first-line treatment includes the adrenocorticotropic hormone ACTH and vigabatrin. In the near future the gold standard could be the development of new therapies that target specific pathways of pathogenesis. In this article we review the past and growing number of clinical, genetic, molecular and therapeutic discoveries on this expanding topic.

PMID: 24268986 [PubMed - indexed for MEDLINE]

A unique binding mode of the eukaryotic translation initiation factor 4E for guiding the design of novel peptide inhibitors.

May 28, 2015 - 7:10am

A unique binding mode of the eukaryotic translation initiation factor 4E for guiding the design of novel peptide inhibitors.

Protein Sci. 2015 May 26;

Authors: Di Marino D, D'Annessa I, Tancredi H, Bagni C, Gallicchio E

Abstract
The interaction between the eukaryotic translation initiation factor 4E (eIF4E) and eIF4E binding proteins (4E-BP) is a promising template for the inhibition of eIF4E and the treatment of diseases such as cancer and a spectrum of autism disorders, including the Fragile X syndrome. Here we report an atomically detailed model of the complex between eIF4E and a peptide fragment of a 4E-BP, the cytoplasmic Fragile X interacting protein (CYFIP1). This model was generated using computer simulations with enhanced sampling from an alchemical replica exchange approach and validated using long molecular dynamics simulations. 4E-BP proteins act as post-transcriptional regulators by binding to eIF4E and preventing mRNA translation. Dysregulation of eIF4E activity has been linked to cancer, Fragile X syndrome and Autism Spectrum Disorders (ASDs). Therefore, the study of the mechanism of inhibition of eIF4E by 4E-BPs is key to the development of drug therapies targeting this regulatory pathways. The results obtained in this work indicate that CYFIP1 interacts with eIF4E by an unique mode not shared by other 4E-BP proteins and elucidate the mechanism by which CYFIP1 interacts with eIF4E despite having a sequence binding motif significantly different from most 4E-BPs. Our study suggests an alternative strategy for the design of eIF4E inhibitor peptides with superior potency and specificity than currently available. This article is protected by copyright. All rights reserved.

PMID: 26013047 [PubMed - as supplied by publisher]

Full UPF3B function is critical for neuronal differentiation of neural stem cells.

May 28, 2015 - 7:10am

Full UPF3B function is critical for neuronal differentiation of neural stem cells.

Mol Brain. 2015;8(1):33

Authors: Alrahbeni T, Sartor F, Anderson J, Miedzybrodzka Z, McCaig C, Müller B

Abstract
BACKGROUND: Mutation in the UPF3B gene on chromosome X is implicated in neurodevelopmental disorders including X-linked intellectual disability, autism and schizophrenia. The protein UPF3B is involved in the nonsense-mediated mRNA decay pathway (NMD) that controls mRNA stability and functions in the prevention of the synthesis of truncated proteins.
RESULTS: Here we show that NMD pathway components UPF3B and UPF1 are down-regulated during differentiation of neural stem cells into neurons. Using tethered function assays we found that UPF3B missense mutations described in families with neurodevelopmental disorders reduced the activity of UPF3B protein in NMD. In neural stem cells, UPF3B protein was detected in the cytoplasm and in the nucleus. Similarly in neurons, UPF3B protein was detected in neurites, the somatic cytoplasm and in the nucleus. In both cell types nuclear UPF3B protein was enriched in the nucleolus. Using GFP tagged UPF3B proteins we found that the missense mutations did not affect the cellular localisation. Expression of missense mutant UPF3B disturbed neuronal differentiation and reduced the complexity of the branching of neurites. Neuronal differentiation was similarly affected in the presence of the NMD inhibitor Amlexanox. The expression of mutant UPF3B proteins lead to a subtle increase in mRNA levels of selected NMD targets.
CONCLUSIONS: Together our findings indicate that, despite the down-regulation of NMD factors, functional NMD is critical for neuronal differentiation. We propose that the neurodevelopmental phenotype of UPF3B missense mutation is caused by impairment of NMD function altering neuronal differentiation.

PMID: 26012578 [PubMed - in process]

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us.

May 28, 2015 - 7:10am
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Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us.

Learn Mem. 2014 Oct;21(10):543-55

Authors: Santos AR, Kanellopoulos AK, Bagni C

Abstract
The Fragile X syndrome (FXS) is the most frequent form of inherited mental disability and is considered a monogenic cause of autism spectrum disorder. FXS is caused by a triplet expansion that inhibits the expression of the FMR1 gene. The gene product, the Fragile X Mental Retardation Protein (FMRP), regulates mRNA metabolism in brain and nonneuronal cells. During brain development, FMRP controls the expression of key molecules involved in receptor signaling, cytoskeleton remodeling, protein synthesis and, ultimately, spine morphology. Symptoms associated with FXS include neurodevelopmental delay, cognitive impairment, anxiety, hyperactivity, and autistic-like behavior. Twenty years ago the first Fmr1 KO mouse to study FXS was generated, and several years later other key models including the mutant Drosophila melanogaster, dFmr1, have further helped the understanding of the cellular and molecular causes behind this complex syndrome. Here, we review to which extent these biological models are affected by the absence of FMRP, pointing out the similarities with the observed human dysfunction. Additionally, we discuss several potential treatments under study in animal models that are able to partially revert some of the FXS abnormalities.

PMID: 25227249 [PubMed - indexed for MEDLINE]

Interaction of neurodevelopmental pathways and synaptic plasticity in mental retardation, autism spectrum disorder and schizophrenia: implications for psychiatry.

May 28, 2015 - 7:10am
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Interaction of neurodevelopmental pathways and synaptic plasticity in mental retardation, autism spectrum disorder and schizophrenia: implications for psychiatry.

World J Biol Psychiatry. 2014 Sep;15(7):507-16

Authors: Waltereit R, Banaschewski T, Meyer-Lindenberg A, Poustka L

Abstract
OBJECTIVES: Schizophrenia (SCZ), autism spectrum disorder (ASD) and mental retardation (MR) are psychiatric disorders with high heritability. They differ in their clinical presentation and in their time course of major symptoms, which predominantly occurs for MR and ASD during childhood and for SCZ during young adult age. Recent findings with focus on the developmental neurobiology of these disorders emphasize shared mechanisms of common origin. These findings propose a continuum of genetic risk factors impacting on synaptic plasticity with MR causing impairments in global cognitive abilities, ASD in social cognition and SCZ in both global and social cognition.
METHODS: We assess here the historical developments that led to the current disease concepts of the three disorders. We then analyse, based on the functions of genes mutated in two or three of the disorders, selected mechanisms shared in neurodevelopmental pathways and synaptic plasticity.
RESULTS: The analysis of the psychopathological constructs supports the existence of three distinct clinical entities but also elaborates important associations. Similarly, there are common mechanisms especially in global and social cognition.
CONCLUSIONS: We discuss implications from this integrated view on MR, ASD and SCZ for child & adolescent and adult psychiatry in pathophysiology and research perspectives.

PMID: 24079538 [PubMed - indexed for MEDLINE]

Microdeletions of ELP4 are Associated with Language Impairment, Autism Spectrum Disorder and Mental Retardation.

May 27, 2015 - 6:59am

Microdeletions of ELP4 are Associated with Language Impairment, Autism Spectrum Disorder and Mental Retardation.

Hum Mutat. 2015 May 23;

Authors: Addis L, Ahn JW, Dobson R, Dixit A, Ogilvie CM, Pinto D, Vaags AK, Coon H, Chaste P, Wilson S, Parr JR, Andrieux J, Lenne B, Tumer Z, Leuzzi V, Aubell K, Koillinen H, Curran S, Marshall CR, Scherer SW, Strug LJ, Collier DA, Pal DK

Abstract
Copy number variations (CNV) are important in the aetiology of neurodevelopmental disorders and show broad phenotypic manifestations. We compared the presence of small CNVs disrupting the ELP4-PAX6 locus in 4092 U.K. individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH), with WTCCC controls (n = 4783). The phenotypic analysis was then extended using the DECIPHER database. We followed up association using an autism patient cohort (n = 3143) compared with six additional control groups (n = 6469). In the clinical discovery series we identified eight cases with ELP4 deletions, and one with a partial duplication of ELP4 and PAX6. These cases were referred for neurological phenotypes including language impairment, developmental delay, autism and epilepsy. Six further cases with a primary diagnosis of ASD and similar secondary phenotypes were identified with ELP4 deletions, as well as another six (out of 9) with neurodevelopmental phenotypes from DECIPHER. CNVs at ELP4 were only present in 1/11252 controls. We found a significant excess of CNVs in discovery cases compared with controls, p = 7.5×10(-3) ; as well as for autism, p = 2.7×10(-3) . Our results suggest ELP4 deletions are highly likely to be pathogenic, predisposing to a range of neurodevelopmental phenotypes from ASD to language impairment and epilepsy. This article is protected by copyright. All rights reserved.

PMID: 26010655 [PubMed - as supplied by publisher]

[A family with creatine transporter deficiency diagnosed with urinary creatine/creatinine ratio and the family history: the third Japanese familial case].

May 27, 2015 - 6:59am
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[A family with creatine transporter deficiency diagnosed with urinary creatine/creatinine ratio and the family history: the third Japanese familial case].

No To Hattatsu. 2015 Jan;47(1):49-52

Authors: Nozaki F, Kumada T, Shibata M, Fujii T, Wada T, Osaka H

Abstract
Creatine transporter deficiency (CRTR-D) is an X-linked disorder characterized by hypotonia, developmental delay, and seizures. We report the third Japanese family with CRTR-D. The proband was an 8-year-old boy who presented with hypotonia, severe intellectual disability and two episodes of seizures associated with/without fever. Among 7 siblings (4 males, 3 females), the eldest brother had severe intellectual disability, epilepsy, and sudden death at 17 years of age, while 18-year-old third elder brother had severe intellectual disability, autism, and drug-resistant epilepsy. The proband's urinary creatine/creatinine ratio was increased. A reduced creatine peak on brain magnetic resonance spectroscopy and a known pathogenic mutation in the SLC6A8 gene (c.1661 C > T;p.Pro554Leu) confirmed the diagnosis of CRTR-D. The same mutation was found in the third elder brother. Their mother was a heterozygote. Symptoms of CRTR-D are non-specific. Urinary creatine/creatinine ratio should be measured in patients with hypotonia, developmental delay, seizure and autism whose family history indicates an X-linked inheritance.

PMID: 25803912 [PubMed - indexed for MEDLINE]

Genetic risk for attention-deficit/hyperactivity disorder contributes to neurodevelopmental traits in the general population.

May 27, 2015 - 6:59am
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Genetic risk for attention-deficit/hyperactivity disorder contributes to neurodevelopmental traits in the general population.

Biol Psychiatry. 2014 Oct 15;76(8):664-71

Authors: Martin J, Hamshere ML, Stergiakouli E, O'Donovan MC, Thapar A

Abstract
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) can be viewed as the extreme end of traits in the general population. Epidemiological and twin studies suggest that ADHD frequently co-occurs with and shares genetic susceptibility with autism spectrum disorder (ASD) and ASD-related traits. The aims of this study were to determine whether a composite of common molecular genetic variants, previously found to be associated with clinically diagnosed ADHD, predicts ADHD and ASD-related traits in the general population.
METHODS: Polygenic risk scores were calculated in the Avon Longitudinal Study of Parents and Children (ALSPAC) population sample (N = 8229) based on a discovery case-control genome-wide association study of childhood ADHD. Regression analyses were used to assess whether polygenic scores predicted ADHD traits and ASD-related measures (pragmatic language abilities and social cognition) in the ALSPAC sample. Polygenic scores were also compared in boys and girls endorsing any (rating ≥ 1) ADHD item (n = 3623).
RESULTS: Polygenic risk for ADHD showed a positive association with ADHD traits (hyperactive-impulsive, p = .0039; inattentive, p = .037). Polygenic risk for ADHD was also negatively associated with pragmatic language abilities (p = .037) but not with social cognition (p = .43). In children with a rating ≥ 1 for ADHD traits, girls had a higher polygenic score than boys (p = .003).
CONCLUSIONS: These findings provide molecular genetic evidence that risk alleles for the categorical disorder of ADHD influence hyperactive-impulsive and attentional traits in the general population. The results further suggest that common genetic variation that contributes to ADHD diagnosis may also influence ASD-related traits, which at their extreme are a characteristic feature of ASD.

PMID: 24673882 [PubMed - indexed for MEDLINE]

Autism and behavior in adult patients with Dravet syndrome (DS).

May 26, 2015 - 8:44am

Autism and behavior in adult patients with Dravet syndrome (DS).

Epilepsy Behav. 2015 May 22;47:11-16

Authors: Berkvens JJ, Veugen I, Veendrick-Meekes MJ, Snoeijen-Schouwenaars FM, Schelhaas HJ, Willemsen MH, Tan IY, Aldenkamp AP

Abstract
INTRODUCTION: Autism and behavioral characteristics in adults with Dravet syndrome (DS) have rarely been systematically studied.
METHOD: Three scales were used to assess the outcomes of DS in adulthood in terms of autism and behavior. All the adult patients with DS, nine male and four female, aged between 18 and 60years, living at the Epilepsy Center Kempenhaeghe in The Netherlands were included in the study. In addition, the past medical history of each patient was systematically screened for diagnoses like autism, Pervasive Development Disorder-Not Otherwise Specified (PDD-NOS), autism spectrum disorder (ASD), hyperactivity, Attention Deficit Hyperactivity Disorder (ADHD), and self-mutilation. Information concerning past and current use of psychoactive drugs was also evaluated.
RESULTS: Eight patients (61.5%) were classified as having autism spectrum disorder (ASD) according to the AVZ-R or according to the medical record. Self-mutilation was seen in four patients (30.8%), hyperactivity in none. Three patients (23.1%) currently used psychoactive drugs.
CONCLUSION: Autism spectrum disorders persist in adult patients with DS, while certain characteristics associated with behavioral problems, such as hyperactivity or use of psychoactive medication, seem to be less prominent than in childhood.

PMID: 26005841 [PubMed - as supplied by publisher]

The relationship between social communication disorder (SCD) and broad autism phenotype (BAP).

May 23, 2015 - 6:03am
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The relationship between social communication disorder (SCD) and broad autism phenotype (BAP).

J Am Acad Child Adolesc Psychiatry. 2014 Oct;53(10):1130

Authors: Tufan E

PMID: 25245357 [PubMed - indexed for MEDLINE]

Editorial comment: Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.

May 23, 2015 - 6:03am
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Editorial comment: Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.

Semin Pediatr Neurol. 2014 Jun;21(2):172

Authors: Schaefer GB

PMID: 25149957 [PubMed - indexed for MEDLINE]

Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.

May 23, 2015 - 6:03am
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Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.

Semin Pediatr Neurol. 2014 Jun;21(2):167-71

Authors: Imitola J, Walleigh D, Anderson CE, Jethva R, Carvalho KS, Legido A, Khurana DS

Abstract
A 7-year-old child presented with atypical absence epilepsy. He also had autism and severe cognitive deficit. As part of his diagnostic workup, a chromosomal microarray analysis was performed, which showed novel biallelic deletions in the neurexin 1 gene (NRXN1). His fraternal twin sister, who also had autism and cognitive impairment, was subsequently found to have the same biallelic deletions. Deletions included a 272-282kb loss at band 2p16.3 in one allele and a smaller 135-174-kb loss on the second allele. Neurexin 1 (NRXN1) is a cell adhesion protein, forming a synaptic complex with neuroligin. This signals a pathway that is critical for activity-dependent synaptic transmission. Mutations in this gene have been associated with autism and neurodevelopmental delay. Although there are many reports of heterozygous mutations with variable expressivity, only 3 cases with biallelic NRXN1 mutations have been previously reported, all of which have a more severe phenotype. We report 2 siblings with biallelic deletions, both of which affect the promoter region and exons 1-5 in the α-NRXN1 isoform, which has a role in the Ca(2+)-dependent release of neurotransmitters in the central nervous system. Our cases expand the phenotype of biallelic α NRXN 1 mutations and emphasize the important role of NRXN1 in autism and intellectual disability. Chromosomal microarray analysis should be the clinical standard in all specialties for first-tier genetic testing in autistic spectrum disorders.

PMID: 25149956 [PubMed - indexed for MEDLINE]

Conserved and divergent processing of neuroligin and neurexin genes: from the nematode C. elegans to human.

May 21, 2015 - 6:06am
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Conserved and divergent processing of neuroligin and neurexin genes: from the nematode C. elegans to human.

Invert Neurosci. 2014 Sep;14(2):79-90

Authors: Calahorro F

Abstract
Neuroligins are cell-adhesion proteins that interact with neurexins at the synapse. This interaction may contribute to differentiation, plasticity and specificity of synapses. In humans, single mutations in neuroligin-encoding genes are implicated in autism spectrum disorder and/or mental retardation. Moreover, some copy number variations and point mutations in neurexin-encoding genes have been linked to neurodevelopmental disorders including autism. Neurexins are subject to extensive alternative splicing, highly regulated in mammals, with a great physiological importance. In addition, neuroligins and neurexins are subjected to proteolytic processes that regulate synaptic transmission modifying pre- and postsynaptic activities and may also regulate the remodelling of spines at specific synapses. Four neuroligin genes exist in mice and five in human, whilst in the nematode Caenorhabditis elegans, there is only one orthologous gene. In a similar manner, in mammals, there are three neurexin genes, each of them encoding two major isoforms named α and β, respectively. In contrast, there is one neurexin gene in C. elegans that also generates two isoforms like mammals. The complexity of the genetic organization of neurexins is due to extensive processing resulting in hundreds of isoforms. In this review, a wide comparison is made between the genes in the nematode and human with a view to better understanding the conservation of processing in these synaptic proteins in C. elegans, which may serve as a genetic model to decipher the synaptopathies underpinning neurodevelopmental disorders such as autism.

PMID: 25148907 [PubMed - indexed for MEDLINE]

Clinical, biochemical and molecular analysis of 13 Japanese patients with β-ureidopropionase deficiency demonstrates high prevalence of the c.977G > A (p.R326Q) mutation.

May 16, 2015 - 7:13am
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Clinical, biochemical and molecular analysis of 13 Japanese patients with β-ureidopropionase deficiency demonstrates high prevalence of the c.977G > A (p.R326Q) mutation.

J Inherit Metab Dis. 2014 Sep;37(5):801-12

Authors: Nakajima Y, Meijer J, Dobritzsch D, Ito T, Meinsma R, Abeling NG, Roelofsen J, Zoetekouw L, Watanabe Y, Tashiro K, Lee T, Takeshima Y, Mitsubuchi H, Yoneyama A, Ohta K, Eto K, Saito K, Kuhara T, van Kuilenburg AB

Abstract
β-ureidopropionase (βUP) deficiency is an autosomal recessive disease characterized by N-carbamyl-β-amino aciduria. To date, only 16 genetically confirmed patients with βUP deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 13 Japanese βUP deficient patients. In this group of patients, three novel missense mutations (p.G31S, p.E271K, and p.I286T) and a recently described mutation (p.R326Q) were identified. The p.R326Q mutation was detected in all 13 patients with eight patients being homozygous for this mutation. Screening for the p.R326Q mutation in 110 Japanese individuals showed an allele frequency of 0.9 %. Transient expression of mutant βUP enzymes in HEK293 cells showed that the p.E271K and p.R326Q mutations cause profound decreases in activity (≤ 1.3 %). Conversely, βUP enzymes containing the p.G31S and p.I286T mutations possess residual activities of 50 and 70 %, respectively, suggesting we cannot exclude the presence of additional mutations in the non-coding region of the UPB1 gene. Analysis of a human βUP homology model revealed that the effects of the mutations (p.G31S, p.E271K, and p.R326Q) on enzyme activity are most likely linked to improper oligomer assembly. Highly variable phenotypes ranging from neurological involvement (including convulsions and autism) to asymptomatic, were observed in diagnosed patients. High prevalence of p.R326Q in the normal Japanese population indicates that βUP deficiency is not as rare as generally considered and screening for βUP deficiency should be included in diagnosis of patients with unexplained neurological abnormalities.

PMID: 24526388 [PubMed - indexed for MEDLINE]

Recurrence rates provide evidence for sex-differential, familial genetic liability for autism spectrum disorders in multiplex families and twins.

May 15, 2015 - 6:41am

Recurrence rates provide evidence for sex-differential, familial genetic liability for autism spectrum disorders in multiplex families and twins.

Mol Autism. 2015;6:27

Authors: Werling DM, Geschwind DH

Abstract
BACKGROUND: Autism spectrum disorders (ASDs) are more prevalent in males, suggesting a multiple threshold liability model in which females are, on average, protected by sex-differential mechanisms. Under this model, autistic females are predicted to carry a more penetrant risk variant load than males and to share this greater genetic liability with their siblings. However, reported ASD recurrence rates have not demonstrated significantly increased risk to siblings of affected girls. Here, we characterize recurrence patterns in multiplex families from the Autism Genetics Resource Exchange (AGRE) to determine if risk in these families follows a female protective model.
METHODS: We assess recurrence rates and quantitative traits in full siblings from 1,120 multiplex nuclear families and concordance rates in 305 twin pairs from AGRE. We consider the first two affected children per family, and one randomly selected autistic twin per pair, as probands. We then compare recurrence rates and phenotypes between males and females and between twin pairs or families with at least one female proband (female-containing (FC)) versus those with only male probands (male-only (MO)).
RESULTS: Among children born after two probands, we observe significantly higher recurrence in males (47.5%) than in females (21.1%; relative risk, RR = 2.25; adjusted P = 6.22e-08) and in siblings of female (44.3%) versus siblings of male probands (30.4%; RR = 1.46; adj. P = 0.036). This sex-differential recurrence is also robust in dizygotic twin pairs (males = 61.5%, females = 19.1%; RR = 3.23; adj. P = 7.66e-09). Additionally, we find a significant negative relationship between interbirth interval and ASD recurrence that is driven by children in MO families.
CONCLUSIONS: By classifying families as MO or FC using two probands instead of one, we observe significant recurrence rate differences between families harboring sex-differential familial liability. However, a significant sex difference in risk to children within FC families suggests that female protective mechanisms are still operative in families carrying high genetic risk loads. Furthermore, the male-specific relationship between shorter interbirth intervals and increased ASD risk is consistent with a potentially greater contribution from environmental factors in males versus higher genetic risk in affected females and their families. Understanding the mechanisms driving these sex-differential risk profiles will be useful for treatment development and prevention.

PMID: 25973164 [PubMed]

The female protective effect in autism spectrum disorder is not mediated by a single genetic locus.

May 15, 2015 - 6:41am

The female protective effect in autism spectrum disorder is not mediated by a single genetic locus.

Mol Autism. 2015;6:25

Authors: Gockley J, Willsey AJ, Dong S, Dougherty JD, Constantino JN, Sanders SJ

Abstract
BACKGROUND: A 4:1 male to female sex bias has consistently been observed in autism spectrum disorder (ASD). Epidemiological and genetic studies suggest a female protective effect (FPE) may account for part of this bias; however, the mechanism of such protection is unknown. Quantitative assessment of ASD symptoms using the Social Responsiveness Scale (SRS) shows a bimodal distribution unique to females in multiplex families. This leads to the hypothesis that a single, common genetic locus on chromosome X might mediate the FPE and produce the ASD sex bias. Such a locus would represent a major therapeutic target and is likely to have been missed by conventional genome-wide association study (GWAS) analysis.
METHODS: To explore this possibility, we performed an association study in affected versus unaffected females, considering three tiers of single nucleotide polymorphisms (SNPs) as follows: 1) regions of chromosome X that escape X-inactivation, 2) all of chromosome X, and 3) genome-wide.
RESULTS: No evidence of a SNP meeting the criteria for a single FPE locus was observed, despite the analysis being well powered to detect this effect.
CONCLUSIONS: The results do not support the hypothesis that the FPE is mediated by a single genetic locus; however, this does not exclude the possibility of multiple genetic loci playing a role in the FPE.

PMID: 25973162 [PubMed]

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