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Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders.

May 12, 2015 - 8:45am
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Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders.

Hum Mol Genet. 2014 Sep 15;23(R1):R1-8

Authors: Burrage LC, Nagamani SC, Campeau PM, Lee BH

Abstract
Branched-chain amino acid (BCAA) metabolism plays a central role in the pathophysiology of both rare inborn errors of metabolism and the more common multifactorial diseases. Although deficiency of the branched-chain ketoacid dehydrogenase (BCKDC) and associated elevations in the BCAAs and their ketoacids have been recognized as the cause of maple syrup urine disease (MSUD) for decades, treatment options for this disorder have been limited to dietary interventions. In recent years, the discovery of improved leucine tolerance after liver transplantation has resulted in a new therapeutic strategy for this disorder. Likewise, targeting the regulation of the BCKDC activity may be an alternative potential treatment strategy for MSUD. The regulation of the BCKDC by the branched-chain ketoacid dehydrogenase kinase has also been implicated in a new inborn error of metabolism characterized by autism, intellectual disability and seizures. Finally, there is a growing body of literature implicating BCAA metabolism in more common disorders such as the metabolic syndrome, cancer and hepatic disease. This review surveys the knowledge acquired on the topic over the past 50 years and focuses on recent developments in the field of BCAA metabolism.

PMID: 24651065 [PubMed - indexed for MEDLINE]

Neural bases of Theory of Mind in children with autism spectrum disorders and children with conduct problems and callous-unemotional traits.

May 12, 2015 - 8:45am
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Neural bases of Theory of Mind in children with autism spectrum disorders and children with conduct problems and callous-unemotional traits.

Dev Sci. 2014 Sep;17(5):786-96

Authors: O'Nions E, Sebastian CL, McCrory E, Chantiluke K, Happé F, Viding E

Abstract
Individuals with autism spectrum disorders (ASD) have difficulty understanding other minds (Theory of Mind; ToM), with atypical processing evident at both behavioural and neural levels. Individuals with conduct problems and high levels of callous-unemotional (CU) traits (CP/HCU) exhibit reduced responsiveness to others' emotions and difficulties interacting with others, but nonetheless perform normally in experimental tests of ToM. The present study aimed to examine the neural underpinnings of ToM in children (aged 10-16) with ASD (N = 16), CP/HCU (N = 16) and typically developing (TD) controls (N = 16) using a non-verbal cartoon vignette task. Whilst individuals with ASD were predicted to show reduced fMRI responses across regions involved in ToM processing, CP/HCU individuals were predicted to show no differences compared with TD controls. The analyses indicated that neural responses did not differ between TD and CP/HCU groups during ToM. TD and CP/HCU children exhibited significantly greater medial prefrontal cortex responses during ToM than did the ASD group. Within the ASD group, responses in medial prefrontal cortex and right temporoparietal junction (TPJ) correlated with symptom severity as measured by the Autism Diagnostic Observation Schedule (ADOS). Findings suggest that although both ASD and CP/HCU are characterized by social difficulties, only children with ASD display atypical neural processing associated with ToM.

PMID: 24636205 [PubMed - indexed for MEDLINE]

Disrupted in schizophrenia 1 modulates medial prefrontal cortex pyramidal neuron activity through cAMP regulation of transient receptor potential C and small-conductance K+ channels.

May 12, 2015 - 8:45am
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Disrupted in schizophrenia 1 modulates medial prefrontal cortex pyramidal neuron activity through cAMP regulation of transient receptor potential C and small-conductance K+ channels.

Biol Psychiatry. 2014 Sep 15;76(6):476-85

Authors: El-Hassar L, Simen AA, Duque A, Patel KD, Kaczmarek LK, Arnsten AF, Yeckel MF

Abstract
BACKGROUND: Disrupted in schizophrenia 1 (DISC1) is a protein implicated in schizophrenia, bipolar disorder, major depressive disorder, and autism. To date, most of research examining DISC1 function has focused on its role in neurodevelopment, despite its presence throughout life. DISC1 also regulates cyclic adenosine monophosphate (cAMP) signaling by increasing type 4 phosphodiesterase catabolism of cAMP when cAMP concentrations are high. In this study, we tested the hypothesis that DISC1, through its regulation of cAMP, modulates I-SK and I-TRPC channel-mediated ionic currents that we have shown previously to regulate the activity of mature prefrontal cortical pyramidal neurons.
METHODS: We used patch-clamp recordings in prefrontal cortical slices from adult rats in which DISC1 function was reduced in vivo by short hairpin RNA viral knockdown or in vitro by dialysis of DISC1 antibodies.
RESULTS: We found that DISC1 disruption resulted in an increase of metabotropic glutamate receptor-induced intracellular calcium (Ca2+) waves, small-conductance K+ (SK)-mediated hyperpolarization and a decrease of transient receptor potential C (TRPC)-mediated sustained depolarization. Consistent with a role for DISC1 in regulation of cAMP signaling, forskolin-induced cAMP production also increased intracellular Ca2+ waves, I-SK and decreased I-TRPC. Lastly, inhibiting cAMP generation with guanfacine, an α2A-noradrenergic agonist, normalized the function of SK and TRPC channels.
CONCLUSIONS: Based on our findings, we propose that diminished DISC1 function, such as occurs in some mental disorders, can lead to the disruption of normal patterns of prefrontal cortex activity through the loss of cAMP regulation of metabotropic glutamate receptor-mediated intracellular Ca2+ waves, SK and TRPC channel activity.

PMID: 24560582 [PubMed - indexed for MEDLINE]

Cognitive deficit and autism spectrum disorders: prospective diagnosis by array CGH.

May 12, 2015 - 8:45am
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Cognitive deficit and autism spectrum disorders: prospective diagnosis by array CGH.

Pathology. 2014 Jan;46(1):41-5

Authors: Nicholl J, Waters W, Mulley JC, Suwalski S, Brown S, Hull Y, Barnett C, Haan E, Thompson EM, Liebelt J, Mcgregor L, Harbord MG, Entwistle J, Munt C, White D, Chitti A, Baulderstone D, Ketteridge D, Array Referral Consortium, Friend K, Bain SM, Yu S

Abstract
The aim of this study was to determine prospectively the frequency of pathogenic chromosomal microdeletions and microduplications in a large group of referred patients with developmental delay (DD), intellectual disability (ID) or autism spectrum disorders (ASD) within a genetic diagnostic service. First tier testing was applied using a standardised oligo-array comparative genomic hybridization (CGH) platform, replacing conventional cytogenetic testing that would have been used in the past. Copy number variants (CNVs) found to be responsible for the clinical condition on the request form could all be subdivided into three groups: well established pathogenic microdeletion/microduplication/aneuploidy syndromes, predicted pathogenic CNVs as interpreted by the laboratory, and recently established pathogenic disease susceptibility CNVs. Totalled from these three groups, with CNVs of uncertain significance excluded, detection rates were: DD (13.0%), ID (15.6%), ASD (2.3%), ASD with DD (8.2%), ASD with ID (12.7%) and unexplained epilepsy with DD, ID and ASD (10.9%). The greater diagnostic sensitivity arising from routine application of array CGH, compared with previously used conventional cytogenetics, outweighs the interpretative issues for the reporting laboratory and referring clinician arising from detection of CNVs of uncertain significance. Precise determination of any previously hidden molecular defect responsible for the patient's condition is translated to improved genetic counselling.

PMID: 24300712 [PubMed - indexed for MEDLINE]

Response to 'Predicting the diagnosis of autism spectrum disorder using gene pathway analysis'.

May 12, 2015 - 8:45am
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Response to 'Predicting the diagnosis of autism spectrum disorder using gene pathway analysis'.

Mol Psychiatry. 2014 Aug;19(8):859-61

Authors: Robinson EB, Howrigan D, Yang J, Ripke S, Anttila V, Duncan LE, Jostins L, Barrett JC, Medland SE, MacArthur DG, Breen G, O'Donovan MC, Wray NR, Devlin B, Daly MJ, Visscher PM, Sullivan PF, Neale BM

PMID: 24145379 [PubMed - indexed for MEDLINE]

Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders.

May 12, 2015 - 8:45am
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Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders.

Mol Psychiatry. 2014 Aug;19(8):872-9

Authors: Kenny EM, Cormican P, Furlong S, Heron E, Kenny G, Fahey C, Kelleher E, Ennis S, Tropea D, Anney R, Corvin AP, Donohoe G, Gallagher L, Gill M, Morris DW

Abstract
Schizophrenia (SZ) and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders that may share an underlying pathology suggested by shared genetic risk variants. We sequenced the exonic regions of 215 genes in 147 ASD cases, 273 SZ cases and 287 controls, to identify rare risk mutations. Genes were primarily selected for their function in the synapse and were categorized as: (1) Neurexin and Neuroligin Interacting Proteins, (2) Post-synaptic Glutamate Receptor Complexes, (3) Neural Cell Adhesion Molecules, (4) DISC1 and Interactors and (5) Functional and Positional Candidates. Thirty-one novel loss-of-function (LoF) variants that are predicted to severely disrupt protein-coding sequence were detected among 2 861 rare variants. We found an excess of LoF variants in the combined cases compared with controls (P=0.02). This effect was stronger when analysis was limited to singleton LoF variants (P=0.0007) and the excess was present in both SZ (P=0.002) and ASD (P=0.001). As an individual gene category, Neurexin and Neuroligin Interacting Proteins carried an excess of LoF variants in cases compared with controls (P=0.05). A de novo nonsense variant in GRIN2B was identified in an ASD case adding to the growing evidence that this is an important risk gene for the disorder. These data support synapse formation and maintenance as key molecular mechanisms for SZ and ASD.

PMID: 24126926 [PubMed - indexed for MEDLINE]

Think about it: FMR1 gene mosaicism.

May 12, 2015 - 8:45am
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Think about it: FMR1 gene mosaicism.

J Child Neurol. 2014 Sep;29(9):NP74-7

Authors: Bonarrigo FA, Russo S, Vizziello P, Menni F, Cogliati F, Giorgini V, Monti F, Milani D

Abstract
Fragile X syndrome (FXS) is one of the most frequent causes of mental retardation, intellectual disability, and autism. Most cases are the result of an expansion of the CGG trinucleotide repeat in the 5' untranslated region of the FMR1 gene and the subsequent functional loss of the related protein. We describe the case of a 4-year-old boy who clinically presents mild psychomotor delay without any major clinical dysmorphisms. Molecular analysis of the FMR1 gene showed mosaicism in terms of size and methylation, with one normal and 1 fully mutated allele, which is very rare in this syndrome. Physicians should therefore consider a diagnosis of FXS even if the patient's phenotype is mild. Although rare, diagnosing this condition has important consequences for the patient's rehabilitation and the family planning of parents and relatives.

PMID: 24065579 [PubMed - indexed for MEDLINE]

Common DNA methylation alterations in multiple brain regions in autism.

May 12, 2015 - 8:45am
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Common DNA methylation alterations in multiple brain regions in autism.

Mol Psychiatry. 2014 Aug;19(8):862-71

Authors: Ladd-Acosta C, Hansen KD, Briem E, Fallin MD, Kaufmann WE, Feinberg AP

Abstract
Autism spectrum disorders (ASD) are increasingly common neurodevelopmental disorders defined clinically by a triad of features including impairment in social interaction, impairment in communication in social situations and restricted and repetitive patterns of behavior and interests, with considerable phenotypic heterogeneity among individuals. Although heritability estimates for ASD are high, conventional genetic-based efforts to identify genes involved in ASD have yielded only few reproducible candidate genes that account for only a small proportion of ASDs. There is mounting evidence to suggest environmental and epigenetic factors play a stronger role in the etiology of ASD than previously thought. To begin to understand the contribution of epigenetics to ASD, we have examined DNA methylation (DNAm) in a pilot study of postmortem brain tissue from 19 autism cases and 21 unrelated controls, among three brain regions including dorsolateral prefrontal cortex, temporal cortex and cerebellum. We measured over 485,000 CpG loci across a diverse set of functionally relevant genomic regions using the Infinium HumanMethylation450 BeadChip and identified four genome-wide significant differentially methylated regions (DMRs) using a bump hunting approach and a permutation-based multiple testing correction method. We replicated 3/4 DMRs identified in our genome-wide screen in a different set of samples and across different brain regions. The DMRs identified in this study represent suggestive evidence for commonly altered methylation sites in ASD and provide several promising new candidate genes.

PMID: 23999529 [PubMed - indexed for MEDLINE]

A rare mutation of CACNA1C in a patient with bipolar disorder, and decreased gene expression associated with a bipolar-associated common SNP of CACNA1C in brain.

May 12, 2015 - 8:45am
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A rare mutation of CACNA1C in a patient with bipolar disorder, and decreased gene expression associated with a bipolar-associated common SNP of CACNA1C in brain.

Mol Psychiatry. 2014 Aug;19(8):890-4

Authors: Gershon ES, Grennan K, Busnello J, Badner JA, Ovsiew F, Memon S, Alliey-Rodriguez N, Cooper J, Romanos B, Liu C

Abstract
Timothy Syndrome (TS) is caused by very rare exonic mutations of the CACNA1C gene that produce delayed inactivation of Cav1.2 voltage-gated calcium channels during cellular action potentials, with greatly increased influx of calcium into the activated cells. The major clinical feature of this syndrome is a long QT interval that results in cardiac arrhythmias. However, TS also includes cognitive impairment, autism and major developmental delays in many of the patients. We observed the appearance of bipolar disorder (BD) in a patient with a previously reported case of TS, who is one of the very few patients to survive childhood. This is most interesting because the common single-nucleotide polymorphism (SNP) most highly associated with BD is rs1006737, which we show here is a cis-expression quantitative trait locus for CACNA1C in human cerebellum, and the risk allele (A) is associated with decreased expression. To combine the CACNA1C perturbations in the presence of BD in this patient and in patients with the common CACNA1C SNP risk allele, we would propose that either increase or decrease in calcium influx in excitable cells can be associated with BD. In treatment of BD with calcium channel blocking drugs, we would predict better response in patients without the risk allele, because they have increased CACNA1C expression.

PMID: 23979604 [PubMed - indexed for MEDLINE]

Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients.

May 11, 2015 - 6:54am

Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients.

Brain Dev. 2015 May 6;

Authors: Yang Z, Matsumoto A, Nakayama K, Jimbo EF, Kojima K, Nagata KI, Iwamoto S, Yamagata T

Abstract
BACKGROUND: The genetic background of autism spectrum disorder (ASD) is considered a multi-genetic disorder with high heritability. Autistic children present with a higher prevalence of sleep disorders than has been observed in children with normal development. Some circadian-relevant genes have been associated with ASD (e.g., PER1, PER2, NPAS2, MTNR1A, and MTNR1B).
METHODS: We analyzed 28 ASD patients (14 with sleep disorders and 14 without) and 23 control subjects of Japanese descent. The coding regions of 18 canonical clock genes and clock-controlled genes were sequenced. Detected mutations were verified by direct sequencing analysis, and additional control individuals were screened.
RESULTS: Thirty-six base changes with amino acid changes were detected in 11 genes. Six missense changes were detected only in individuals with ASD with sleep disturbance: p.F498S in TIMELESS, p.S20R in NR1D1, p.R493C in PER3, p.H542R in CLOCK, p.L473S in ARNTL2, and p.A325V in MTNR1B. Six missense changes were detected only in individuals with ASD without sleep disturbance: p.S1241N in PER1, p.A325T in TIMELESS, p.S13T in ARNTL, p.G24E in MTNR1B, p.G24E in PER2, and p.T1177A in PER3. The p.R493C mutation in PER3 was detected in both groups. One missense change, p.P932L in PER2, was detected only in the control group. Mutations in NR1D1, CLOCK, and ARNTL2 were detected only in individuals with ASD with sleep disorder. The prevalence of the mutations detected only single time differed significantly among all ASD patients and controls (p=0.003). Two kinds of mutations detected only in individuals with ASD with sleep disorder, p.F498S in TIMELESS and p.R366Q in PER3, were considered to affect gene function by three different methods: PolyPhen-2, scale-invariant feature transform (SIFT) prediction, and Mutation Taster (www.mutationtaster.org). The mutations p.S20R in NR1D1, p.H542R in CLOCK, p.L473S in ARNTL2, p.A325T in TIMELESS, p.S13T in ARNTL, and p.G24E in PER2 were diagnosed to negatively affect gene function by more than one of these methods.
CONCLUSION: Mutations in circadian-relevant genes affecting gene function are more frequent in patients with ASD than in controls. Circadian-relevant genes may be involved in the psychopathology of ASD.

PMID: 25957987 [PubMed - as supplied by publisher]

Spatiotemporal dynamics of the postnatal developing primate brain transcriptome.

May 9, 2015 - 7:25am

Spatiotemporal dynamics of the postnatal developing primate brain transcriptome.

Hum Mol Genet. 2015 May 7;

Authors: Bakken TE, Miller JA, Luo R, Bernard A, Bennett JL, Lee CK, Bertagnolli D, Parikshak NN, Smith KA, Sunkin SM, Amaral DG, Geschwind DH, Lein ES

Abstract
Developmental changes in the temporal and spatial regulation of gene expression drive the emergence of normal mature brain function, while disruptions in these processes underlie many neurodevelopmental abnormalities. To solidify our foundational knowledge of such changes in a primate brain with an extended period of postnatal maturation like in human, we investigated the whole-genome transcriptional profiles of rhesus monkey brains from birth to adulthood. We found that gene expression dynamics are largest from birth through infancy, after which gene expression profiles transition to a relatively stable state by young adulthood. Biological pathway enrichment analysis revealed that genes more highly expressed at birth are associated with cell adhesion and neuron differentiation, while genes more highly expressed in juveniles and adults are associated with cell death. Neocortex showed significantly greater differential expression over time than sub-cortical structures, and this trend likely reflects the protracted postnatal development of the cortex. Using network analysis, we identified 27 co-expression modules containing genes with highly correlated expression patterns that are associated with specific brain regions, ages, or both. In particular, one module with high expression in neonatal cortex and striatum that decreases during infancy and juvenile development was significantly enriched for autism spectrum disorder (ASD)-related genes. This network was enriched for genes associated with axon guidance and interneuron differentiation, consistent with a disruption in the formation of functional cortical circuitry in ASD.

PMID: 25954031 [PubMed - as supplied by publisher]

Synaptic synthesis, dephosphorylation, and degradation: a novel paradigm for an activity-dependent neuronal control of CDKL5.

May 9, 2015 - 7:25am
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Synaptic synthesis, dephosphorylation, and degradation: a novel paradigm for an activity-dependent neuronal control of CDKL5.

J Biol Chem. 2015 Feb 13;290(7):4512-27

Authors: La Montanara P, Rusconi L, Locarno A, Forti L, Barbiero I, Tramarin M, Chandola C, Kilstrup-Nielsen C, Landsberger N

Abstract
Mutations in the X-linked CDKL5 (cyclin-dependent kinase-like 5) gene have been associated with several forms of neurodevelopmental disorders, including atypical Rett syndrome, autism spectrum disorders, and early infantile epileptic encephalopathy. Accordingly, loss of CDKL5 in mice results in autistic-like features and impaired neuronal communication. Although the biological functions of CDKL5 remain largely unknown, recent pieces of evidence suggest that CDKL5 is involved in neuronal plasticity. Herein, we show that, at all stages of development, neuronal depolarization induces a rapid increase in CDKL5 levels, mostly mediated by extrasomatic synthesis. In young neurons, this induction is prolonged, whereas in more mature neurons, NMDA receptor stimulation induces a protein phosphatase 1-dependent dephosphorylation of CDKL5 that is mandatory for its proteasome-dependent degradation. As a corollary, neuronal activity leads to a prolonged induction of CDKL5 levels in immature neurons but to a short lasting increase of the kinase in mature neurons. Recent results demonstrate that many genes associated with autism spectrum disorders are crucial components of the activity-dependent signaling networks regulating the composition, shape, and strength of the synapse. Thus, we speculate that CDKL5 deficiency disrupts activity-dependent signaling and the consequent synapse development, maturation, and refinement.

PMID: 25555910 [PubMed - indexed for MEDLINE]

Mutations in the TTDN1 gene are associated with a distinct trichothiodystrophy phenotype.

May 9, 2015 - 7:25am
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Mutations in the TTDN1 gene are associated with a distinct trichothiodystrophy phenotype.

J Invest Dermatol. 2015 Mar;135(3):734-41

Authors: Heller ER, Khan SG, Kuschal C, Tamura D, DiGiovanna JJ, Kraemer KH

Abstract
Trichothiodystrophy (TTD) is a rare multisystem disorder, characterized by sulfur-deficient hair with alternating dark and light "tiger tail" banding on polarized light microscopy. TTD is caused by mutations in DNA repair/transcription genes XPD, XPB or TTDA, and in TTDN1, a gene of unknown function. Although most of the TTD patients are photosensitive, patients with TTDN1 mutations were reported to be nonphotosensitive. We followed a cohort of 36 TTD patients from 2001 to 2013. We describe five patients from four families with defects in the TTDN1 gene: four had no photosensitivity, and one patient exhibited cutaneous burning. Deep phenotyping of our cohort revealed differences between the patients with and without TTDN1 mutations. Delayed bone age and seizure disorders were overrepresented in the TTDN1 group (P=0.009 and P=0.024, respectively), whereas some characteristic TTD clinical, laboratory, and imaging findings were absent. The three oldest TTDN1 patients displayed autistic behaviors in contrast to the characteristic friendly, socially interactive personality in the other patients. DNA sequencing revealed deletion mutations in TTDN1 ranging in size from a single base pair to over 120 kb. These data identify a distinct phenotype relationship in TTD caused by TTDN1 mutations and suggest a different mechanism of disease.

PMID: 25290684 [PubMed - indexed for MEDLINE]

Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports.

May 8, 2015 - 8:37am

Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports.

BMC Psychiatry. 2015 May 7;15(1):107

Authors: Serret S, Thümmler S, Dor E, Vesperini S, Santos A, Askenazy F

Abstract
BACKGROUND: Phelan-Mc Dermid syndrome is a contiguous disorder resulting from 22q13.3 deletion implicating the SHANK3 gene. The typical phenotype includes neonatal hypotonia, moderate to severe intellectual disability, absent or delayed speech, minor dysmorphic features and autism or autistic-like behaviour. Recently, point mutations or micro-deletions of the SHANK3 gene have been identified, accompanied by a phenotype different from the initial clinically description in Phelan McDermid syndrome.
CASE PRESENTATION: Here we present two case studies with similar psychiatric and genetic diagnosis as well as similar clinical history and evolution. The two patients were diagnosed with autism spectrum disorders in childhood and presented regression with catatonia features and behavioural disorders after a stressful event during adolescence. Interestingly, both patients presented mutation/microdeletion of the SHANK3 gene, inducing a premature stop codon in exon 21. Different pharmacological treatments (antipsychotics, benzodiazepines, mood stabilizer drugs, antidepressants, and methylphenidate) failed to improve clinical symptoms and lead to multiple adverse events. In contrast, lithium therapy reversed clinical regression, stabilized behavioural symptoms and allowed patients to recover their pre-catatonia level of functioning, without significant side effects.
CONCLUSION: These cases support the hypothesis of a specific SHANK3 phenotype. This phenotype might be linked to catatonia-like deterioration for which lithium use could be an efficient treatment. Therefore, these cases provide an important contribution to the field of autism research, clinical genetics and possible pharmacological answers.

PMID: 25947967 [PubMed - as supplied by publisher]

Recent advances in the genetics of autism spectrum disorder.

May 8, 2015 - 8:37am

Recent advances in the genetics of autism spectrum disorder.

Curr Neurol Neurosci Rep. 2015 Jun;15(6):553

Authors: De Rubeis S, Buxbaum JD

Abstract
Autism spectrum disorder (ASD) is a devastating neurodevelopmental disorder with high prevalence in the population and a pronounced male preponderance. ASD has a strong genetic basis, but until recently, a large fraction of the genetic factors contributing to liability was still unknown. Over the past 3 years, high-throughput next-generation sequencing on large cohorts has exposed a heterogeneous and complex genetic landscape and has revealed novel risk genes. Here, we provide an overview of the recent advances on the ASD genetic architecture, with an emphasis on the estimates of heritability, the contribution of common variants, and the role of inherited and de novo rare variation. We also examine the genetic components of the reported gender bias. Finally, we discuss the emerging findings from sequencing studies and how they illuminate crucial aspects of ASD pathophysiology.

PMID: 25946996 [PubMed - in process]

Autistic Children Exhibit Decreased Levels of Essential Fatty Acids in Red Blood Cells.

May 7, 2015 - 7:16am

Autistic Children Exhibit Decreased Levels of Essential Fatty Acids in Red Blood Cells.

Int J Mol Sci. 2015;16(5):10061-10076

Authors: Brigandi SA, Shao H, Qian SY, Shen Y, Wu BL, Kang JX

Abstract
Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) are essential nutrients for brain development and function. However, whether or not the levels of these fatty acids are altered in individuals with autism remains debatable. In this study, we compared the fatty acid contents between 121 autistic patients and 110 non-autistic, non-developmentally delayed controls, aged 3-17. Analysis of the fatty acid composition of red blood cell (RBC) membrane phospholipids showed that the percentage of total PUFA was lower in autistic patients than in controls; levels of n-6 arachidonic acid (AA) and n-3 docosahexaenoic acid (DHA) were particularly decreased (p < 0.001). In addition, plasma levels of the pro-inflammatory AA metabolite prostaglandin E2 (PGE2) were higher in a subset of the autistic participants (n = 20) compared to controls. Our study demonstrates an alteration in the PUFA profile and increased production of a PUFA-derived metabolite in autistic patients, supporting the hypothesis that abnormal lipid metabolism is implicated in autism.

PMID: 25946342 [PubMed - as supplied by publisher]

Deletion of 15q11.2(BP1-BP2) region: Further evidence for lack of phenotypic specificity in a pediatric population.

May 7, 2015 - 7:16am

Deletion of 15q11.2(BP1-BP2) region: Further evidence for lack of phenotypic specificity in a pediatric population.

Am J Med Genet A. 2015 May 6;

Authors: Hashemi B, Bassett A, Chitayat D, Chong K, Feldman M, Flanagan J, Goobie S, Kawamura A, Lowther C, Prasad C, Siu V, So J, Tung S, Speevak M, Stavropoulos DJ, Carter MT

Abstract
Microdeletion of the BP1-BP2 region at 15q11.2 is a recurrent copy number variant (CNV) frequently found in patients undergoing chromosomal microarray (CMA). Genetic counselling regarding this CNV is challenging due to the wide range of phenotypic presentation in reported patients and lack of general population-based data. As one of the most common reasons for CMA is childhood developmental delay, clinicians need to be cognizant of the inherent ascertainment bias in the literature. We performed a detailed medical record review for 55 patients with this 15q11.2 microdeletion and report the clinical features of the 35 patients for whom information was available. We compared our results to the recent report by Cafferkey et al. in this journal. Our conclusion is that the phenotypic spectrum is too broad and non-specific to constitute a bona fide "syndrome" and that further research must be done to delineate the contribution of this CNV to phenotype. © 2015 Wiley Periodicals, Inc.

PMID: 25946043 [PubMed - as supplied by publisher]

Autism occurrence by MMR vaccine status among US children with older siblings with and without autism.

May 6, 2015 - 6:17am
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Autism occurrence by MMR vaccine status among US children with older siblings with and without autism.

JAMA. 2015 Apr 21;313(15):1534-40

Authors: Jain A, Marshall J, Buikema A, Bancroft T, Kelly JP, Newschaffer CJ

Abstract
IMPORTANCE: Despite research showing no link between the measles-mumps-rubella (MMR) vaccine and autism spectrum disorders (ASD), beliefs that the vaccine causes autism persist, leading to lower vaccination levels. Parents who already have a child with ASD may be especially wary of vaccinations.
OBJECTIVE: To report ASD occurrence by MMR vaccine status in a large sample of US children who have older siblings with and without ASD.
DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study using an administrative claims database associated with a large commercial health plan. Participants included children continuously enrolled in the health plan from birth to at least 5 years of age during 2001-2012 who also had an older sibling continuously enrolled for at least 6 months between 1997 and 2012.
EXPOSURES: MMR vaccine receipt (0, 1, 2 doses) between birth and 5 years of age.
MAIN OUTCOMES AND MEASURES: ASD status defined as 2 claims with a diagnosis code in any position for autistic disorder or other specified pervasive developmental disorder (PDD) including Asperger syndrome, or unspecified PDD (International Classification of Diseases, Ninth Revision, Clinical Modification 299.0x, 299.8x, 299.9x).
RESULTS: Of 95,727 children with older siblings, 994 (1.04%) were diagnosed with ASD and 1929 (2.01%) had an older sibling with ASD. Of those with older siblings with ASD, 134 (6.9%) had ASD, vs 860 (0.9%) children with unaffected siblings (P < .001). MMR vaccination rates (≥1 dose) were 84% (n = 78,564) at age 2 years and 92% (n = 86,063) at age 5 years for children with unaffected older siblings, vs 73% (n = 1409) at age 2 years and 86% (n = 1660) at age 5 years for children with affected siblings. MMR vaccine receipt was not associated with an increased risk of ASD at any age. For children with older siblings with ASD, at age 2, the adjusted relative risk (RR) of ASD for 1 dose of MMR vaccine vs no vaccine was 0.76 (95% CI, 0.49-1.18; P = .22), and at age 5, the RR of ASD for 2 doses compared with no vaccine was 0.56 (95% CI, 0.31-1.01; P = .052). For children whose older siblings did not have ASD, at age 2, the adjusted RR of ASD for 1 dose was 0.91 (95% CI, 0.67-1.20; P = .50) and at age 5, the RR of ASD for 2 doses was 1.12 (95% CI, 0.78-1.59; P = .55).
CONCLUSIONS AND RELEVANCE: In this large sample of privately insured children with older siblings, receipt of the MMR vaccine was not associated with increased risk of ASD, regardless of whether older siblings had ASD. These findings indicate no harmful association between MMR vaccine receipt and ASD even among children already at higher risk for ASD.

PMID: 25898051 [PubMed - indexed for MEDLINE]

Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses.

May 2, 2015 - 8:22am
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Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses.

Proc Natl Acad Sci U S A. 2015 Feb 24;112(8):2551-6

Authors: Bemben MA, Nguyen QA, Wang T, Li Y, Nicoll RA, Roche KW

Abstract
Autism spectrum disorders (ASDs) comprise a highly heritable, multifarious group of neurodevelopmental disorders, which are characterized by repetitive behaviors and impairments in social interactions. Point mutations have been identified in X-linked Neuroligin (NLGN) 3 and 4X genes in patients with ASDs and all of these reside in their extracellular domains except for a single point mutation in the cytoplasmic domain of NLGN4X in which an arginine is mutated to a cysteine (R704C). Here we show that endogenous NLGN4X is robustly phosphorylated by protein kinase C (PKC) at T707, and R704C completely eliminates T707 phosphorylation. Endogenous NLGN4X is intensely phosphorylated on T707 upon PKC stimulation in human neurons. Furthermore, a phospho-mimetic mutation at T707 has a profound effect on NLGN4X-mediated excitatory potentiation. Our results now establish an important interplay between a genetic mutation, a key posttranslational modification, and robust synaptic changes, which can provide insights into the synaptic dysfunction of ASDs.

PMID: 25675530 [PubMed - indexed for MEDLINE]

New Genes for Focal Epilepsies with Speech and Language Disorders.

April 30, 2015 - 8:47am

New Genes for Focal Epilepsies with Speech and Language Disorders.

Curr Neurol Neurosci Rep. 2015 Jun;15(6):554

Authors: Turner SJ, Morgan AT, Perez ER, Scheffer IE

Abstract
The last 2 years have seen exciting advances in the genetics of Landau-Kleffner syndrome and related disorders, encompassed within the epilepsy-aphasia spectrum (EAS). The striking finding of mutations in the N-methyl-D-aspartate (NMDA) receptor subunit gene GRIN2A as the first monogenic cause in up to 20 % of patients with EAS suggests that excitatory glutamate receptors play a key role in these disorders. Patients with GRIN2A mutations have a recognizable speech and language phenotype that may assist with diagnosis. Other molecules involved in RNA binding and cell adhesion have been implicated in EAS; copy number variations are also found. The emerging picture highlights the overlap between the genetic determinants of EAS with speech and language disorders, intellectual disability, autism spectrum disorders and more complex developmental phenotypes.

PMID: 25921602 [PubMed - as supplied by publisher]

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