Mitochondrial Disease in Autism Spectrum Disorder Patients: A Cohort Analysis

Previous reports indicate an association between autism spectrum disorders (ASD) and disorders of mitochondrial oxidative phosphorylation. One study suggested that children with both diagnoses are clinically indistinguishable from children with idiopathic autism. There are, however, no detailed analyses of the clinical and laboratory findings in a large cohort of these children. Therefore, we undertook a comprehensive review of patients with ASD and a mitochondrial disorder.We reviewed medical records of 25 patients with a primary diagnosis of ASD by DSM-IV-TR criteria, later determined to have enzyme- or mutation-defined mitochondrial electron transport chain (ETC) dysfunction. Twenty-four of 25 patients had one or more major clinical abnormalities uncommon in idiopathic autism. Twenty-one patients had histories of significant non-neurological medical problems. Nineteen patients exhibited constitutional symptoms, especially excessive fatigability. Fifteen patients had abnormal neurological findings. Unusual developmental phenotypes included marked delay in early gross motor milestones (32%) and unusual patterns of regression (40%). Levels of blood lactate, plasma alanine, and serum ALT and/or AST were increased at least once in 76%, 36%, and 52% of patients, respectively. The most common ETC disorders were deficiencies of complex I (64%) and complex III (20%). Two patients had rare mtDNA mutations of likely pathogenicity.Although all patients' initial diagnosis was idiopathic autism, careful clinical and biochemical assessment identified clinical findings that differentiated them from children with idiopathic autism. These and prior data suggest a disturbance of mitochondrial energy production as an underlying pathophysiological mechanism in a subset of individuals with autism

Frequency of MTHFR GENE C677T Polymorphism for Non-Syndromic Autism Spectrum Disorder Patients

Background: The folate metabolism is a pathway that may involve in the non-syndromic Autism Spectrum Disorder (ASD). Methylenetetrahydrofolate reductase enzyme has a key role in folate metabolism. The C677T polymorphism of MTHFR gene could reduce the effectiveness of the enzyme.Objectives: To evaluate the frequency of MTHFR geneC677T polymorphism for non-syndromic ASD patients.Method: Thirty-four DNA samples were taken from each group. PCR mixture was consisted of 1µL DNA, 2.5µL PCR buffer, 0.5µL dNTP, 1.5µL MgCL2, 0.125µLTaqenzyme, 0.5µLofforwardandreverseprimerandaquabidesttoreach a volume of 25 µL. The PCR profiles were initiation 95ºC for 5 min, denaturation 94ºC for 1min, annealing 55ºCfor 45 seconds, and elongation 72ºC for30 seconds. The cycles were done in 35 times an dfinal elongation was at 72ºC for 5min. The PCR product was 198bp, and then digested by the Hinfl enzyme for 16hours at 37°C, and visualized using2%agarosegeland then electrophoresed for 30 minutes at 100 volts.Result: Non-syndromic ASD samples showed none had homozygote mutant type (677TT), 3 (8.8%) samples had heterozygote (677CT)and 31 (91.2%) samples had wild type (677CC). Meanwhile, normal control showed only 1 (2.9%)sample had homozygote mutant type(677TT), 9 (26.5%) samples had heterozygote (677CT)and 24 (70.6%) samples had wild type (677CC).Conclusion: The frequency of MTHFR geneC677T polymorphism in patients with non-syndromic ASD and controls are not significantly different

Frequency of MTHFR GENE C677T Polymorphism for Non-Syndromic Autism Spectrum Disorder Patients

Background: The folate metabolism is a pathway that may involve in the non-syndromic Autism Spectrum Disorder (ASD). Methylenetetrahydrofolate reductase enzyme has a key role in folate metabolism. The C677T polymorphism of MTHFR gene could reduce the effectiveness of the enzyme.Objectives: To evaluate the frequency of MTHFR geneC677T polymorphism for non-syndromic ASD patients.Method: Thirty-four DNA samples were taken from each group. PCR mixture was consisted of 1µL DNA, 2.5µL PCR buffer, 0.5µL dNTP, 1.5µL MgCL2, 0.125µLTaqenzyme, 0.5µLofforwardandreverseprimerandaquabidesttoreach a volume of 25 µL. The PCR profiles were initiation 95ºC for 5 min, denaturation 94ºC for 1min, annealing 55ºCfor 45 seconds, and elongation 72ºC for30 seconds. The cycles were done in 35 times an dfinal elongation was at 72ºC for 5min. The PCR product was 198bp, and then digested by the Hinfl enzyme for 16hours at 37°C, and visualized using2%agarosegeland then electrophoresed for 30 minutes at 100 volts.Result: Non-syndromic ASD samples showed none had homozygote mutant type (677TT), 3 (8.8%) samples had heterozygote (677CT)and 31 (91.2%) samples had wild type (677CC). Meanwhile, normal control showed only 1 (2.9%)sample had homozygote mutant type(677TT), 9 (26.5%) samples had heterozygote (677CT)and 24 (70.6%) samples had  wild type (677CC).Conclusion: The frequency of MTHFR geneC677T polymorphism in patients with non-syndromic ASD and controls are not significantly different

Phenotypic categorization of putative pathogenic CNVs in a population of Autism Spectrum Disorder patients

All individuals in this study signed an informed consent.This work was supported by the fellowships SFRH/BPD/74739/2010 to ICC, SFRH/BPD/64281/2009 to CC and SFRH/BD/79081/2011 to BO from Fundação para a Ciência e a Tecnologia (Portugal)

The Positive Effects of Medical Cannabinoids on the Dysregulated Endocannabinoid System in Autism Spectrum Disorder Patients

Autism Spectrum Disorder (ASD) is a developmental disability. The symptoms include a lack of social skills, a need for repetitive patterns of life, difficulty in communication, speaking deficits and numerous other symptoms. While the specific cause is unknown, there is much research being done on mechanisms including dysregulations of the immune system, endocannabinoid system, and overall brain (Nez Govorova 2021, Pol 2021). The Endocannabinoid system is a recently discovered branch of the nervous system composed of endocannabinoids which are produced naturally in the body; lipid-based neurotransmitters that bind to cannabinoid receptors (CBRs) and cannabinoid receptor proteins that are expressed throughout the central nervous system but also found in the lungs, liver, kidneys, and immune system. It regulates homeostasis of the central and peripheral mechanisms of food intake, lipids synthesis and metabolism in muscle cells (Alexandre 2019, Dasran 2022, Su 2021, Finn 2102). Endogenous Cannabinoids are chemical compounds that are produced by the body and act on cannabinoid receptors and alter neurotransmitter release and/or activity in the endocannabinoid system in the brain. Exogenous Cannabinoids such as THC and CBD are extracted from the cannabis plant. CBD has a relaxing effect and THC has a psychoactive, euphoric effect. It has been found that patients with Autism have a lower CB1 receptor expression which releases neurotransmitters as their brain is not releasing enough endogenous cannabinoids to bind to CB1 receptors and results in a lack of homeostasis. This thesis will explore the Endocannabinoid system and target the receptors using mixtures of cannabinoids to alleviate symptoms and improve the overall life for Autistic Spectrum Disorder Patients. Current investigations explore multiple mouse models and use different cannabinoids to treat ASD-like symptoms including CBDV, CBD and THC. Using CBDV in VPA mouse models was found to reduce the symptoms of ASD including excessive grooming time and increased sociability (Zamberletti 2019). These help to decrease repetitive behavior and increase social interactions which were dysregulated in ASD models. Mouse studies have shown that the benefits of a tincture of CBD and THC with a low ratio of THC are significant, including regulating CB1 receptors, eliminating symptoms of ASD for ASD patients (Poleg 2021). In human studies there was a total alleviation of epilepsy for ASD patients with use of CBD:THC mixture and a decrease of at least one or more symptoms in each patient (Fleury-Teixeria, 2019)

Complex associations between genetic variants and clinical profiles in autism spectrum disorder patients: an integrative systems biology approach

A complexidade genética e clínica que caracterizam a per turbação do espetro do autismo (PEA) têm limitado o desenvolvimento de biomarcadores que permitam um diagnóstico precoce e um prognóstico fiável, assim como uma abordagem personalizada para a inter venção terapêutica. Neste estudo pretendeu-se desenvolver uma abordagem integrativa para predição da apresentação clínica baseada em informação de variantes genéticas (Copy Number Variants, CNVs), com aplicação clínica no diagnóstico e prognóstico na PEA. Para tal, técnicas de aprendizagem automática (machine learning) foram aplicadas a dados clínicos e genéticos de 2446 doentes com PEA, recrutados no âmbito do consórcio Autism Genome Project. Análise de clustering de dados clínicos multidimensionais definiu, nesta população, dois subgrupos de pacientes com per fis clínicos diferindo significativamente em termos de capacidade verbal, nível cognitivo, gravidade da doença e compor tamento adaptativo. A análise dos CNVs que afetam especificamente genes do cérebro, nos mesmos indivíduos, identificou 15 processos biológicos enriquecidos em genes alterados. A aplicação de um algoritmo de machine learning para classificação dos doentes com apresentação clínica mais disfuncional, com base nos processos biológicos alterados, mostrou que correlações entre fenótipo clínico e biologia subjacente são possíveis na PEA e que, para grupos populacionais com dados informativos, existe um poder preditivo razoável. Para implementação deste conceito na prática clínica serão necessários estudos mais alargados com dados clínicos e genómicos mais completos.The genetic and clinical complexity that characterize Autism Spectrum Disorder (ASD) has hindered the development of biomarkers for early diagnosis and reliable prognosis, as well as a personalized to therapeutic inter vention. This study aimed to develop an integrative approach for clinical presentation prediction based on Copy Number Variants (CNVs), with clinical application for diagnosis and prognosis of ASD. For this purpose, machine learning techniques were applied to a dataset of 2446 patients with ASD, recruited by the Autism Genome Project. Clustering analysis of multidimensional clinical data allowed the definition of two patient subgroups in this population, with clinical profiles dif fering significantly in verbal ability, cognitive level, disease severity and adaptive behavior. In the same subjects, analysis of CNVs specifically af fecting brain-expressed genes identified 15 biological processes enriched for the disrupted genes. A machine learning algorithm was trained and tested to classif y patients with more dysfunctional clinical presentation based on altered biological processes. The results showed that correlations between clinical phenotype and underlying biology can be established in ASD and that, for datasets with suf ficiently informative data, there is a reasonable predictive power. Fur ther studies with more complete clinical and genomic data are needed to implement this concept in clinical practice.info:eu-repo/semantics/publishedVersio

O paciente com autismo: a abordagem na consulta de medicina dentária e a importância da prevenção em saúde oral

Tese de mestrado, Medicina Dentária, Universidade de Lisboa, Faculdade de Medicina Dentária, 2015O número de casos diagnosticados com Perturbação de Espetro de Autismo (PEA) é cada vez maior, e, na população portuguesa, não se conhecem estudos sobre a saúde oral deste grupo de pacientes. Os objetivos deste trabalho são: a) Conhecer os comportamentos relacionados com as visitas ao profissional de saúde oral dos pacientes com PEA e os “obstáculos” relacionados com a consulta de medicina dentária; b) Estudar os comportamentos relacionados com a higiene oral e hábitos alimentares destes pacientes; c) Descrever, com base na revisão da literatura, um protocolo de atuação para profissionais de saúde oral no atendimento de pacientes com PEA. Foi aplicado um questionário a 45 pais/educadores de pacientes com PEA do distrito de Lisboa. Para a descrição do protocolo foi efetuada uma pesquisa bibliográfica realizada na PubMed, na BookFi.org e na biblioteca on-line. Relativamente aos cuidados com a saúde oral destes pacientes, foi referido pelos participantes que 47,4% dos indivíduos colaborava nos tratamentos dentários realizados, e que 62,8% visitavam o profissional de saúde oral regularmente, mesmo sem queixas. A primeira consulta a um profissional de saúde oral foi realizada antes dos três anos de idade em apenas 13,7% dos indivíduos com PEA. No que diz respeito aos comportamentos relacionados com a saúde oral, verificou-se que a escovagem dentária bidiária era realizada por 77,8% dos indivíduos. Apesar da ingestão de alimentos cariogénicos ser rara em 58,2% dos casos, verificou-se que 55,8% desta ingestão se fazia entre as refeições. Nos pacientes com PEA é bastante importante a atuação precoce de modo a investir na prevenção e no diagnóstico precoce das doenças orais, e na implementação das rotinas saudáveis desde cedo, sendo de primordial importância instruir os principais cuidadores destes pacientes sobre os cuidados a ter com a saúde oral, de modo a evitar tratamentos dentários mais complexos e dispendiosos.The number of cases diagnosticated with Autism Spectrum Disorder is increasing, and about the Portuguese population, there are not known studies on the oral health of this group of patients. The aims of this work are: a) Know the behavior related to visits to oral health professionals and the obstacles relative to the consultation of dental medicine of the patients with Autism Spectrum Disorder; b) Study behaviors related to oral hygiene and dietary habits of the patients with Autism Spectrum Disorder; c) Describe, based on literature revision, an protocol with guidlines for oral health professionals in caring autism spectrum disorder patients. A questionnaire was applied to 45 Autism Spectrum Disorder patients' parents / educators in Lisbon district. To the description of the protocol was made a bibliographic research in PubMed, in BookFi.org and in biblioteca on-line. With regard to oral health care of these patients, was answered that 47% of individuals collaborated in dental treatments and 62,8% of them visited the oral health professional regularly, even without complaints. Only 13,7% of the Autism Spectrum Disorder patients visited an oral health professional before 3 years old. Concerning behaviors related to oral health, it was verified that 77,8% of the individuals performed dental brushing twice a day. Although cariogenic food intake is rare in 58,2% of the cases, it was verified that 55,8% of that intake occurred between meals. It is very important an early action in the Autism Spectrum Disorder patients in order to prevent and make early oral diseases' diagnosis and to implement healthy routines, and it is of primary importance to educate this patients' primary care providers about the care of the oral health in order to avoid dental treatments more complex and costly

Is there any relationship between autism and pineal gland volume?

Purpose: Abnormalities in melatonin physiology and circadian rhythm are detected in patients with autism. Melatonin is produced predominantly in the pineal gland and the amount of melatonin released is proportional to the pineal gland volume. This study aimed to examine whether the pineal gland volume in children with autism is different from that in healthy children. Material and methods: Brain magnetic resonance images (MRI) of 120 paediatric patients with autism and 82 control paediatric subjects were examined; pineal parenchymal volume (PPV), pineal cyst rate (PCR), and total pineal gland volume (TPGV) were measured using a multimodality viewer (MMV), but only the TPGVs were measured using a tumour tracking (TT) method. Measurements were taken by 2 separate radiologists. Results: In patients with autism, the PPV and TPGV according to MMV, and the TPGV according to TT were significantly lower, and the PCR was significantly higher. Moreover, the ratio of PPV to TPGV was significantly lower in the autism patient group. In both groups, the TPGVs were significantly lower in the autism patient group than the controls among all age groups. Conclusions: Our study was the first to examine TPGVs in detail in paediatric patients with autism using 2 different methods. Low PPV-TPGV and high PCR have been observed in autism. This study also provides comparable reference values for pineal gland size in healthy children or autistic children aged 2-17 years. These results show promising potential for further research to understand the relationship between autism pathogenesis and the pineal gland