RESUMO
BACKGROUND: Autism spectrum disorder (ASD) is a complex, heterogeneous neurodevelopmental disorder with onset during early childhood. Most studies have reported an elevation in platelet serotonin in persons with autism. The serotonin (5-hydroxytryptamine; 5-HT) transporter in the brain uptakes 5-HT from extracellular spaces. It is also present in platelets, where it takes up 5-HT from plasma. Polymorphisms in serotonin transporter gene (SLC6A4) were frequently studied in many neuropsychiatric disorders. MATERIALS AND METHODS: We have measured the plasma 5-HT levels in 20 autistic male children and 20 control male children by the enzyme-linked immunosorbent assay (ELISA) method. In addition, the SLC6A4 promoter region (5-HTTLPR) insertion/deletion (I/D) polymorphism was studied, using whole genomic DNA. RESULTS: Plasma serotonin was significantly low in autistic children compared to control (P = 0.001), although correlation to severity of autism was not significant. The frequency of short (S) allele in autism cases was 10% and in the control group it was absent. CONCLUSION: Our study demonstrated an increased prevalence of 5-HTTLPR S allele in autism subjects. Significantly decreased plasma serotonin was detected in autism subjects, with no significant relationship between 5-HTTLPR genotype and plasma 5-HT being evident.
RESUMO
Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 × 10(-9)), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.
Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Mutação da Fase de Leitura , Deleção de Sequência , Criança , Transtornos Globais do Desenvolvimento Infantil/sangue , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , DNA/sangue , DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Proteínas de Ligação ao GTP/genética , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Linhagem , Fenótipo , Fatores SexuaisRESUMO
Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1α subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1α phosphorylation, and plasma branched-chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome.
Assuntos
3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/administração & dosagem , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/genética , Transtorno Autístico/dietoterapia , Transtorno Autístico/genética , Epilepsia/dietoterapia , Epilepsia/genética , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/deficiência , Adolescente , Aminoácidos de Cadeia Ramificada/administração & dosagem , Aminoácidos de Cadeia Ramificada/sangue , Aminoácidos de Cadeia Ramificada/deficiência , Animais , Arginina/genética , Transtorno Autístico/enzimologia , Sequência de Bases , Encéfalo/metabolismo , Criança , Pré-Escolar , Dieta , Epilepsia/enzimologia , Feminino , Homozigoto , Humanos , Deficiência Intelectual/dietoterapia , Deficiência Intelectual/enzimologia , Deficiência Intelectual/genética , Masculino , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Mutação , Linhagem , Fosforilação , Dobramento de Proteína , Estrutura Terciária de Proteína , RNA Mensageiro/metabolismo , Adulto JovemRESUMO
OBJECTIVE: Estimation of free polyunsaturated fatty acids (PUFAs) in blood and evaluation of behavior of autistic children before and after taking fish oil (Efalex) were performed. DESIGN AND METHODS: 30 autistic children (18 males and 12 females) aged 3-11 years and 30 healthy children as control group were included in this study. Tandem mass spectrometry and CARS were used to estimate the free PUFAs from dried blood spot and to evaluate the autistic behavior respectively. RESULTS: Before taking Efalex, linolenic acid showed a significant reduction (71%), followed by docosahexaenoic acid (65%) and arachidonic acid (45%), while linoleic acid was the least affected PUFA (32%). After taking Efalex, 66% of autistic children showed clinical and biochemical improvement, linolenic acid and docosahexaenoic acid showed the highest levels after Efalex supplementation. CONCLUSION: PUFA supplementation may play an important role in ameliorating the autistic behavior.