Special Issue "A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder"

A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Mechanisms of Diseases".

Deadline for manuscript submissions: closed (5 June 2021) | Viewed by 48868

Special Issue Editors

Prof. Dr. Richard E. Frye
E-Mail Website
Guest Editor
1. Department of Child Health, College of Medicine—Phoenix, University of Arizona, Phoenix, AZ 85004, USA
2. Section on Neurodevelopmental Disorders, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ 85016, USA
Interests: neurodevelopment disorders; metabolic disorders; autism; mitochondrial disorders; folate metabolism; redox metabolism
Special Issues, Collections and Topics in MDPI journals
Dr. Richard G. Boles
E-Mail Website1 Website2
Co-Guest Editor
Mitochondrial and Molecular Medicine, 630 S Raymond Ave, Unit 310, Pasadena, CA 91105, USA
Interests: mitochondrial medicine; functional disease (including cyclic vomiting syndrome, other atypical forms of migraine, and chronic fatigue syndrome); autism spectrum disorders
Special Issues, Collections and Topics in MDPI journals
Dr. Shannon Rose
E-Mail Website
Co-Guest Editor
Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children’s Research Institute, Little Rock, AR, USA
Interests: oxidative stress; mitochondrial abnormalities; autism spectrum disorders (ASD)
Special Issues, Collections and Topics in MDPI journals
Dr. Daniel Rossignol
E-Mail Website
Co-Guest Editor
Rossignol Medical Center, Irvine, CA, USA
Interests: autism spectrum disorders; cerebral palsy; neurological and developmental disorders; PANS/PANDAS; ADD/ADHD; pediatric special needs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Background: Autism spectrum disorder (ASD) presents with a spectrum of symptoms and is believed to be caused by a variety of etiologies. Additionally, response to treatment for individuals with ASD is very variable and unpredictable. Furthermore, the diagnosis of ASD is based on behavioral observation rather than an objective metric.

Aim and scope: We aim to publish articles describing a personalized medicine approach to the diagnosis, classification, and treatment of ASD.

History: ASD is a difficult disorder to diagnosis and treat, both because its diagnosis is traditionally not based on objective biomarkers and because there are many underlying causes which are difficult to identify. This results in each individuals with ASD having a unique presentation. Thus, a personalized medicine approach could greatly benefit this population.

Cutting-edge research: Quantitative behavioral measurements as well as genetic, epigenetic, physiologic, metabolic, and proteomic biomarkers have been investigated for use in the management of ASD.

What kind of papers we are soliciting: We encourage the submission of manuscripts which describe a personalized medicine approach to the diagnosis, classification, and treatment approach to ASD.

Prof. Richard E. Frye
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Autism Spectrum Disorder
  • Quantitative Behavior
  • Neurophysiology
  • Genetic
  • Epigenetic
  • Metabolomics
  • Mitochondria
  • Redox Metabolism
  • Methylation
  • Autonomic Dysfunction
  • Folate Metabolism

Published Papers (22 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review, Other

Editorial
A Personalized Approach to Evaluating and Treating Autism Spectrum Disorder
J. Pers. Med. 2022, 12(2), 147; https://doi.org/10.3390/jpm12020147 - 24 Jan 2022
Viewed by 952
Abstract
The most recent Center for Disease Control and Prevention estimates suggest that 1 in every 44 children (>2%) in the United States (US) is affected by autism spectrum disorder (ASD) [...] Full article

Research

Jump to: Editorial, Review, Other

Article
Transdermal Electrical Neuromodulation for Anxiety and Sleep Problems in High-Functioning Autism Spectrum Disorder: Feasibility and Preliminary Findings
J. Pers. Med. 2021, 11(12), 1307; https://doi.org/10.3390/jpm11121307 - 06 Dec 2021
Cited by 2 | Viewed by 1295
Abstract
Background: Autism spectrum disorder (ASD) is associated with anxiety and sleep problems. We investigated transdermal electrical neuromodulation (TEN) of the cervical nerves in the neck as a safe, effective, comfortable and non-pharmacological therapy for decreasing anxiety and enhancing sleep quality in ASD. Methods: [...] Read more.
Background: Autism spectrum disorder (ASD) is associated with anxiety and sleep problems. We investigated transdermal electrical neuromodulation (TEN) of the cervical nerves in the neck as a safe, effective, comfortable and non-pharmacological therapy for decreasing anxiety and enhancing sleep quality in ASD. Methods: In this blinded, sham-controlled study, seven adolescents and young adults with high-functioning ASD underwent five consecutive treatment days, one day of the sham followed by four days of subthreshold TEN for 20 min. Anxiety-provoking cognitive tasks were performed after the sham/TEN. Measures of autonomic nervous system activity, including saliva α-amylase and cortisol, electrodermal activity, and heart rate variability, were collected from six participants. Results: Self-rated and caretaker-rated measures of anxiety were significantly improved with TEN treatment as compared to the sham, with effect sizes ranging from medium to large depending on the rating scale. Sleep scores from caretaker questionnaires also improved, but not significantly. Performance on two of the three anxiety-provoking cognitive tasks and heart rate variability significantly improved with TEN stimulation as compared to the sham. Four of the seven (57%) participants were responders, defined as a ≥ 30% improvement in self-reported anxiety. Salivary α-amylase decreased with more TEN sessions and decreased from the beginning to the end of the session on TEN days for responders. TEN was well-tolerated without significant adverse events. Conclusions: This study provides preliminary evidence that TEN is well-tolerated in individuals with ASD and can improve anxiety. Full article
Show Figures

Figure 1

Article
Pregnant Mothers’ Medical Claims and Associated Risk of Their Children being Diagnosed with Autism Spectrum Disorder
J. Pers. Med. 2021, 11(10), 950; https://doi.org/10.3390/jpm11100950 - 24 Sep 2021
Cited by 1 | Viewed by 821
Abstract
A retrospective analysis of administrative claims containing a diverse mixture of ages, ethnicities, and geographical regions across the United States was conducted in order to identify medical events that occur during pregnancy and are associated with autism spectrum disorder (ASD). The dataset used [...] Read more.
A retrospective analysis of administrative claims containing a diverse mixture of ages, ethnicities, and geographical regions across the United States was conducted in order to identify medical events that occur during pregnancy and are associated with autism spectrum disorder (ASD). The dataset used in this study is comprised of 123,824 pregnancies of which 1265 resulted in the child being diagnosed with ASD during the first five years of life. Logistic regression analysis revealed significant relationships between several maternal medical claims, made during her pregnancy and segmented by trimester, and the child’s diagnosis of ASD. Having a biological sibling with ASD, maternal use of antidepressant medication and psychiatry services as well as non-pregnancy related claims such hospital visits, surgical procedures, and radiology exposure were related to an increased risk of ASD regardless of trimester. Urinary tract infections during the first trimester and preterm delivery during the second trimester were also related to an increased risk of ASD. Preventative and obstetrical care were associated with a decreased risk for ASD. A better understanding of the medical factors that increase the risk of having a child with ASD can lead to strategies to decrease risk or identify those children who require increased surveillance for the development of ASD to promote early diagnosis and intervention. Full article
Show Figures

Graphical abstract

Article
Ratings of the Effectiveness of Nutraceuticals for Autism Spectrum Disorders: Results of a National Survey
J. Pers. Med. 2021, 11(9), 878; https://doi.org/10.3390/jpm11090878 - 31 Aug 2021
Cited by 2 | Viewed by 1552
Abstract
Autism spectrum disorder (ASD) often involves a wide range of co-occurring medical conditions (“comorbidities”) and biochemical abnormalities such as oxidative stress and mitochondrial dysfunction. Nutritional supplements (“Nutraceuticals”) are often used to treat both core ASD symptoms and comorbidities, but some have not yet [...] Read more.
Autism spectrum disorder (ASD) often involves a wide range of co-occurring medical conditions (“comorbidities”) and biochemical abnormalities such as oxidative stress and mitochondrial dysfunction. Nutritional supplements (“Nutraceuticals”) are often used to treat both core ASD symptoms and comorbidities, but some have not yet been formally evaluated in ASD. The potential biological mechanisms of nutraceuticals include correction of micronutrient deficiencies due to a poor diet and support for metabolic processes such as redox regulation, mitochondrial dysfunction and melatonin production. This paper reports on the results of the National Survey on Treatment Effectiveness for Autism, focusing on nutraceuticals. The Survey involved 1286 participants from across the United States. Participants rated the overall perceived benefits and adverse effects of each nutraceutical, and also indicated the specific symptoms changed and adverse effects. From these ratings the top-rated nutraceuticals for each of 24 symptoms are listed. Compared to psychiatric and seizure medications rated through the same Survey, on average nutraceuticals had significantly higher ratings of Overall Benefit (1.59 vs. 1.39, p = 0.01) and significantly lower ratings of Overall Adverse Effects (0.1 vs. 0.9, p < 0.001). Folinic acid and vitamin B12 were two of the top-rated treatments. This study suggests that nutraceuticals may have clinical benefits and favorable adverse effect profiles. Full article
Show Figures

Figure 1

Article
Locked-in Intact Functional Networks in Children with Autism Spectrum Disorder: A Case-Control Study
J. Pers. Med. 2021, 11(9), 854; https://doi.org/10.3390/jpm11090854 - 28 Aug 2021
Cited by 2 | Viewed by 886
Abstract
Resting-state functional magnetic resonance imaging (rs-fMRI) has the potential to investigate abnormalities in brain network structure and connectivity on an individual level in neurodevelopmental disorders, such as autism spectrum disorder (ASD), paving the way toward using this technology for a personalized, precision medicine [...] Read more.
Resting-state functional magnetic resonance imaging (rs-fMRI) has the potential to investigate abnormalities in brain network structure and connectivity on an individual level in neurodevelopmental disorders, such as autism spectrum disorder (ASD), paving the way toward using this technology for a personalized, precision medicine approach to diagnosis and treatment. Using a case-control design, we compared five patients with severe regressive-type ASD to five patients with temporal lobe epilepsy (TLE) to examine the association between brain network characteristics and diagnosis. All children with ASD and TLE demonstrated intact motor, language, and frontoparietal (FP) networks. However, aberrant networks not usually seen in the typical brain were also found. These aberrant networks were located in the motor (40%), language (80%), and FP (100%) regions in children with ASD, while children with TLE only presented with aberrant networks in the motor (40%) and language (20%) regions, in addition to identified seizure onset zones. Fisher’s exact test indicated a significant relationship between aberrant FP networks and diagnosis (p = 0.008), with ASD and atypical FP networks co-occurring more frequently than expected by chance. Despite severe cognitive delays, children with regressive-type ASD may demonstrate intact typical cortical network activation despite an inability to use these cognitive facilities. The functions of these intact cognitive networks may not be fully expressed, potentially because aberrant networks interfere with their long-range signaling, thus creating a unique “locked-in network” syndrome. Full article
Show Figures

Figure 1

Article
Mitochondrial Fatty Acid β-Oxidation and Resveratrol Effect in Fibroblasts from Patients with Autism Spectrum Disorder
J. Pers. Med. 2021, 11(6), 510; https://doi.org/10.3390/jpm11060510 - 04 Jun 2021
Cited by 2 | Viewed by 1393
Abstract
Patients with autism spectrum disorder (ASD) may have an increase in blood acyl-carnitine (AC) concentrations indicating a mitochondrial fatty acid β-oxidation (mtFAO) impairment. However, there are no data on systematic mtFAO analyses in ASD. We analyzed tritiated palmitate oxidation rates in fibroblasts from [...] Read more.
Patients with autism spectrum disorder (ASD) may have an increase in blood acyl-carnitine (AC) concentrations indicating a mitochondrial fatty acid β-oxidation (mtFAO) impairment. However, there are no data on systematic mtFAO analyses in ASD. We analyzed tritiated palmitate oxidation rates in fibroblasts from patients with ASD before and after resveratrol (RSV) treatment, according to methods used for the diagnosis of congenital defects in mtFAO. ASD participants (N = 10, 60%; male; mean age (SD) 7.4 (3.2) years) were divided in two age-equivalent groups based on the presence (N = 5) or absence (N = 5) of elevated blood AC levels. In addition, electron transport chain (ETC) activity in fibroblasts and muscle biopsies and clinical characteristics were compared between the ASD groups. Baseline fibroblast mtFAO was not significantly different in patients in comparison with control values. However, ASD patients with elevated AC exhibited significantly decreased mtFAO rates, muscle ETC complex II activity, and fibroblast ETC Complex II/III activity (p < 0.05), compared with patients without an AC signature. RSV significantly increased the mtFAO activity in all study groups (p = 0.001). The highest mtFAO changes in response to RSV were observed in fibroblasts from patients with more severe symptoms on the Social Responsiveness Scale total (p = 0.001) and Awareness, Cognition, Communication and Motivation subscales (all p < 0.01). These findings suggested recognition of an ASD patient subset characterized by an impaired mtFAO flux associated with abnormal blood AC. The study elucidated that RSV significantly increased fibroblast mtFAO irrespective of plasma AC status, and the highest changes to RSV effects on mtFAO were observed in the more severely affected patients. Full article
Show Figures

Figure 1

Article
Evaluation of Chromosome Microarray Analysis in a Large Cohort of Females with Autism Spectrum Disorders: A Single Center Italian Study
J. Pers. Med. 2020, 10(4), 160; https://doi.org/10.3390/jpm10040160 - 09 Oct 2020
Cited by 3 | Viewed by 1231
Abstract
Autism spectrum disorders (ASD) encompass a heterogeneous group of neurodevelopmental disorders resulting from the complex interaction between genetic and environmental factors. Thanks to the chromosome microarray analysis (CMA) in clinical practice, the accurate identification and characterization of submicroscopic deletions/duplications (copy number variants, CNVs) [...] Read more.
Autism spectrum disorders (ASD) encompass a heterogeneous group of neurodevelopmental disorders resulting from the complex interaction between genetic and environmental factors. Thanks to the chromosome microarray analysis (CMA) in clinical practice, the accurate identification and characterization of submicroscopic deletions/duplications (copy number variants, CNVs) associated with ASD was made possible. However, the widely acknowledged excess of males on the autism spectrum reflects on a paucity of CMA studies specifically focused on females with ASD (f-ASD). In this framework, we aim to evaluate the frequency of causative CNVs in a single-center cohort of idiopathic f-ASD. Among the 90 f-ASD analyzed, we found 20 patients with one or two potentially pathogenic CNVs, including those previously associated with ASD (located at 16p13.2 16p11.2, 15q11.2, and 22q11.21 regions). An exploratory genotype/phenotype analysis revealed that the f-ASD with causative CNVs had statistically significantly lower restrictive and repetitive behaviors than those without CNVs or with non-causative CNVs. Future work should focus on further understanding of f-ASD genetic underpinnings, taking advantage of next-generation sequencing technologies, with the ultimate goal of contributing to precision medicine in ASD. Full article
Show Figures

Figure 1

Article
Digitized ADOS: Social Interactions beyond the Limits of the Naked Eye
J. Pers. Med. 2020, 10(4), 159; https://doi.org/10.3390/jpm10040159 - 08 Oct 2020
Cited by 3 | Viewed by 2254
Abstract
The complexity and non-linear dynamics of socio-motor phenomena underlying social interactions are often missed by observation methods that attempt to capture, describe, and rate the exchange in real time. Unknowingly to the rater, socio-motor behaviors of a dyad exert mutual influence over each [...] Read more.
The complexity and non-linear dynamics of socio-motor phenomena underlying social interactions are often missed by observation methods that attempt to capture, describe, and rate the exchange in real time. Unknowingly to the rater, socio-motor behaviors of a dyad exert mutual influence over each other through subliminal mirroring and shared cohesiveness that escape the naked eye. Implicit in these ratings nonetheless is the assumption that the other participant of the social dyad has an identical nervous system as that of the interlocutor, and that sensory-motor information is processed similarly by both agents’ brains. What happens when this is not the case? We here use the Autism Diagnostic Observation Schedule (ADOS) to formally study social dyadic interactions, at the macro- and micro-level of behaviors, by combining observation with digital data from wearables. We find that integrating subjective and objective data reveals fundamentally new ways to improve standard clinical tools, even to differentiate females from males using the digital version of the test. More generally, this work offers a way to turn a traditional, gold-standard clinical instrument into an objective outcome measure of human social behaviors and treatment effectiveness. Full article
Show Figures

Graphical abstract

Article
Multivariate Analysis of Fecal Metabolites from Children with Autism Spectrum Disorder and Gastrointestinal Symptoms before and after Microbiota Transfer Therapy
J. Pers. Med. 2020, 10(4), 152; https://doi.org/10.3390/jpm10040152 - 02 Oct 2020
Cited by 8 | Viewed by 2811
Abstract
Fecal microbiota transplant (FMT) holds significant promise for patients with Autism Spectrum Disorder (ASD) and gastrointestinal (GI) symptoms. Prior work has demonstrated that plasma metabolite profiles of children with ASD become more similar to those of their typically developing (TD) peers following this [...] Read more.
Fecal microbiota transplant (FMT) holds significant promise for patients with Autism Spectrum Disorder (ASD) and gastrointestinal (GI) symptoms. Prior work has demonstrated that plasma metabolite profiles of children with ASD become more similar to those of their typically developing (TD) peers following this treatment. This work measures the concentration of 669 biochemical compounds in feces of a cohort of 18 ASD and 20 TD children using ultrahigh performance liquid chromatography-tandem mass spectroscopy. Subsequent measurements were taken from the ASD cohort over the course of 10-week Microbiota Transfer Therapy (MTT) and 8 weeks after completion of this treatment. Univariate and multivariate statistical analysis techniques were used to characterize differences in metabolites before, during, and after treatment. Using Fisher Discriminant Analysis (FDA), it was possible to attain multivariate metabolite models capable of achieving a sensitivity of 94% and a specificity of 95% after cross-validation. Observations made following MTT indicate that the fecal metabolite profiles become more like those of the TD cohort. There was an 82–88% decrease in the median difference of the ASD and TD group for the panel metabolites, and among the top fifty most discriminating individual metabolites, 96% report more comparable values following treatment. Thus, these findings are similar, although less pronounced, as those determined using plasma metabolites. Full article
Show Figures

Figure 1

Review

Jump to: Editorial, Research, Other

Review
Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis
J. Pers. Med. 2021, 11(11), 1141; https://doi.org/10.3390/jpm11111141 - 03 Nov 2021
Cited by 7 | Viewed by 3006 | Correction
Abstract
The cerebral folate receptor alpha (FRα) transports 5-methyltetrahydrofolate (5-MTHF) into the brain; low 5-MTHF in the brain causes cerebral folate deficiency (CFD). CFD has been associated with autism spectrum disorders (ASD) and is treated with d,l-leucovorin (folinic acid). One cause of CFD [...] Read more.
The cerebral folate receptor alpha (FRα) transports 5-methyltetrahydrofolate (5-MTHF) into the brain; low 5-MTHF in the brain causes cerebral folate deficiency (CFD). CFD has been associated with autism spectrum disorders (ASD) and is treated with d,l-leucovorin (folinic acid). One cause of CFD is an autoantibody that interferes with the function of the FRα. FRα autoantibodies (FRAAs) have been reported in ASD. A systematic review was performed to identify studies reporting FRAAs in association with ASD, or the use of d,l-leucovorin in the treatment of ASD. A meta-analysis examined the prevalence of FRAAs in ASD. The pooled prevalence of ASD in individuals with CFD was 44%, while the pooled prevalence of CFD in ASD was 38% (with a significant variation across studies due to heterogeneity). The etiology of CFD in ASD was attributed to FRAAs in 83% of the cases (with consistency across studies) and mitochondrial dysfunction in 43%. A significant inverse correlation was found between higher FRAA serum titers and lower 5-MTHF CSF concentrations in two studies. The prevalence of FRAA in ASD was 71% without significant variation across studies. Children with ASD were 19.03-fold more likely to be positive for a FRAA compared to typically developing children without an ASD sibling. For individuals with ASD and CFD, meta-analysis also found improvements with d,l-leucovorin in overall ASD symptoms (67%), irritability (58%), ataxia (88%), pyramidal signs (76%), movement disorders (47%), and epilepsy (75%). Twenty-one studies (including four placebo-controlled and three prospective, controlled) treated individuals with ASD using d,l-leucovorin. d,l-Leucovorin was found to significantly improve communication with medium-to-large effect sizes and have a positive effect on core ASD symptoms and associated behaviors (attention and stereotypy) in individual studies with large effect sizes. Significant adverse effects across studies were generally mild but the most common were aggression (9.5%), excitement or agitation (11.7%), headache (4.9%), insomnia (8.5%), and increased tantrums (6.2%). Taken together, d,l-leucovorin is associated with improvements in core and associated symptoms of ASD and appears safe and generally well-tolerated, with the strongest evidence coming from the blinded, placebo-controlled studies. Further studies would be helpful to confirm and expand on these findings. Full article
Show Figures

Figure 1

Review
Parental Quality of Life and Involvement in Intervention for Children or Adolescents with Autism Spectrum Disorders: A Systematic Review
J. Pers. Med. 2021, 11(9), 894; https://doi.org/10.3390/jpm11090894 - 08 Sep 2021
Cited by 7 | Viewed by 1457
Abstract
Previous research has examined several parental, child-related, and contextual factors associated with parental quality of life (QoL) among parents with a child or an adolescent with autism spectrum disorders (ASD); however, no systematic review has examined the relationship between parental QoL and parental [...] Read more.
Previous research has examined several parental, child-related, and contextual factors associated with parental quality of life (QoL) among parents with a child or an adolescent with autism spectrum disorders (ASD); however, no systematic review has examined the relationship between parental QoL and parental involvement in intervention. To fill this gap, a systematic review was conducted using four electronic databases and checked reference lists of retrieved studies. Records were included in the systematic review if they presented original data, assessed parental QoL, and involvement in intervention for children or adolescents with ASD, were published in peer-reviewed journals between 2000 and 2020, and were written in English. Among the 96 screened full-texts, 17 articles met the eligibility criteria. The selected studies included over 2000 parents of children or adolescents with ASD. Three categories of parental involvement (i.e., none, indirect, direct) were identified, which varied across studies, although most had direct parental involvement. The results from this review show that increased parental involvement in the intervention for children or adolescents with ASD may be one way to promote their QoL. However, further research specifically focused on parental involvement during the intervention for children and adolescents with ASD is warranted. Full article
Show Figures

Figure 1

Review
Ways to Address Perinatal Mast Cell Activation and Focal Brain Inflammation, including Response to SARS-CoV-2, in Autism Spectrum Disorder
J. Pers. Med. 2021, 11(9), 860; https://doi.org/10.3390/jpm11090860 - 29 Aug 2021
Cited by 3 | Viewed by 1783
Abstract
The prevalence of autism spectrum disorder (ASD) continues to increase, but no distinct pathogenesis or effective treatment are known yet. The presence of many comorbidities further complicates matters, making a personalized approach necessary. An increasing number of reports indicate that inflammation of the [...] Read more.
The prevalence of autism spectrum disorder (ASD) continues to increase, but no distinct pathogenesis or effective treatment are known yet. The presence of many comorbidities further complicates matters, making a personalized approach necessary. An increasing number of reports indicate that inflammation of the brain leads to neurodegenerative changes, especially during perinatal life, “short-circuiting the electrical system” in the amygdala that is essential for our ability to feel emotions, but also regulates fear. Inflammation of the brain can result from the stimulation of mast cells—found in all tissues including the brain—by neuropeptides, stress, toxins, and viruses such as SARS-CoV-2, leading to the activation of microglia. These resident brain defenders then release even more inflammatory molecules and stop “pruning” nerve connections, disrupting neuronal connectivity, lowering the fear threshold, and derailing the expression of emotions, as seen in ASD. Many epidemiological studies have reported a strong association between ASD and atopic dermatitis (eczema), asthma, and food allergies/intolerance, all of which involve activated mast cells. Mast cells can be triggered by allergens, neuropeptides, stress, and toxins, leading to disruption of the blood–brain barrier (BBB) and activation of microglia. Moreover, many epidemiological studies have reported a strong association between stress and atopic dermatitis (eczema) during gestation, which involves activated mast cells. Both mast cells and microglia can also be activated by SARS-CoV-2 in affected mothers during pregnancy. We showed increased expression of the proinflammatory cytokine IL-18 and its receptor, but decreased expression of the anti-inflammatory cytokine IL-38 and its receptor IL-36R, only in the amygdala of deceased children with ASD. We further showed that the natural flavonoid luteolin is a potent inhibitor of the activation of both mast cells and microglia, but also blocks SARS-CoV-2 binding to its receptor angiotensin-converting enzyme 2 (ACE2). A treatment approach should be tailored to each individual patient and should address hyperactivity/stress, allergies, or food intolerance, with the introduction of natural molecules or drugs to inhibit mast cells and microglia, such as liposomal luteolin. Full article
Show Figures

Figure 1

Review
The Effectiveness of Cobalamin (B12) Treatment for Autism Spectrum Disorder: A Systematic Review and Meta-Analysis
J. Pers. Med. 2021, 11(8), 784; https://doi.org/10.3390/jpm11080784 - 11 Aug 2021
Cited by 5 | Viewed by 2532
Abstract
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder affecting 2% of children in the United States. Biochemical abnormalities associated with ASD include impaired methylation and sulphation capacities along with low glutathione (GSH) redox capacity. Potential treatments for these abnormalities include cobalamin (B12). [...] Read more.
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder affecting 2% of children in the United States. Biochemical abnormalities associated with ASD include impaired methylation and sulphation capacities along with low glutathione (GSH) redox capacity. Potential treatments for these abnormalities include cobalamin (B12). This systematic review collates the studies using B12 as a treatment in ASD. A total of 17 studies were identified; 4 were double-blind, placebo-controlled studies (2 examined B12 injections alone and 2 used B12 in an oral multivitamin); 1 was a prospective controlled study; 6 were prospective, uncontrolled studies, and 6 were retrospective (case series and reports). Most studies (83%) used oral or injected methylcobalamin (mB12), while the remaining studies did not specify the type of B12 used. Studies using subcutaneous mB12 injections (including 2 placebo-controlled studies) used a 64.5–75 µg/kg/dose. One study reported anemia in 2 ASD children with injected cyanocobalamin that resolved with switching to injected mB12. Two studies reported improvements in markers of mitochondrial metabolism. A meta-analysis of methylation metabolites demonstrated decreased S-adenosylhomocysteine (SAH), and increased methionine, S-adenosylmethionine (SAM), SAM/SAH ratio, and homocysteine (with small effect sizes) with mB12. Meta-analysis of the transsulfuration and redox metabolism metabolites demonstrated significant improvements with mB12 in oxidized glutathione (GSSG), cysteine, total glutathione (GSH), and total GSH/GSSG redox ratio with medium to large effect sizes. Improvements in methylation capacity and GSH redox ratio were significantly associated with clinical improvements (with a mean moderate effect size of 0.59) in core and associated ASD symptoms, including expressive communication, personal and domestic daily living skills, and interpersonal, play-leisure, and coping social skills, suggesting these biomarkers may predict response to B12. Other clinical improvements observed with B12 included sleep, gastrointestinal symptoms, hyperactivity, tantrums, nonverbal intellectual quotient, vision, eye contact, echolalia, stereotypy, anemia, and nocturnal enuresis. Adverse events identified by meta-analysis included hyperactivity (11.9%), irritability (3.4%), trouble sleeping (7.6%), aggression (1.8%), and worsening behaviors (7.7%) but were generally few, mild, not serious, and not significantly different compared to placebo. In one study, 78% of parents desired to continue mB12 injections after the study conclusion. Preliminary clinical evidence suggests that B12, particularly subcutaneously injected mB12, improves metabolic abnormalities in ASD along with clinical symptoms. Further large multicenter placebo-controlled studies are needed to confirm these data. B12 is a promising treatment for ASD. Full article
Show Figures

Figure 1

Review
Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorders: Diagnosis, Treatment and Prevention
J. Pers. Med. 2021, 11(8), 710; https://doi.org/10.3390/jpm11080710 - 24 Jul 2021
Cited by 3 | Viewed by 1808
Abstract
Folate deficiency and folate receptor autoimmune disorder are major contributors to infertility, pregnancy related complications and abnormal fetal development including structural and functional abnormalities of the brain. Food fortification and prenatal folic acid supplementation has reduced the incidence of neural tube defect (NTD) [...] Read more.
Folate deficiency and folate receptor autoimmune disorder are major contributors to infertility, pregnancy related complications and abnormal fetal development including structural and functional abnormalities of the brain. Food fortification and prenatal folic acid supplementation has reduced the incidence of neural tube defect (NTD) pregnancies but is unlikely to prevent pregnancy-related complications in the presence of folate receptor autoantibodies (FRAb). In pregnancy, these autoantibodies can block folate transport to the fetus and in young children, folate transport to the brain. These antibodies are prevalent in neural tube defect pregnancies and in developmental disorders such as cerebral folate deficiency (CFD) syndrome and autism spectrum disorder (ASD). In the latter conditions, folinic acid treatment has shown clinical improvement in some of the core ASD deficits. Early testing for folate receptor autoantibodies and intervention is likely to result in a positive outcome. This review discusses the first identification of FRAb in women with a history of neural tube defect pregnancy and FRAb’s association with sub-fertility and preterm birth. Autoantibodies against folate receptor alpha (FRα) are present in about 70% of the children with a diagnosis of ASD, and a significant number of these children respond to oral folinic acid with overall improvements in speech, language and social interaction. The diagnosis of folate receptor autoimmune disorder by measuring autoantibodies against FRα in the serum provides a marker with the potential for treatment and perhaps preventing the pathologic consequences of folate receptor autoimmune disorder. Full article
Show Figures

Figure 1

Review
Rationale of an Advanced Integrative Approach Applied to Autism Spectrum Disorder: Review, Discussion and Proposal
J. Pers. Med. 2021, 11(6), 514; https://doi.org/10.3390/jpm11060514 - 04 Jun 2021
Cited by 2 | Viewed by 3045
Abstract
The rationale of an Advanced Integrative Model and an Advanced Integrative Approach is presented. In the context of Allopathic Medicine, this model introduces the evaluation, clinical exploration, diagnosis, and treatment of concomitant medical problems to the diagnosis of Autism Spectrum Disorder. These may [...] Read more.
The rationale of an Advanced Integrative Model and an Advanced Integrative Approach is presented. In the context of Allopathic Medicine, this model introduces the evaluation, clinical exploration, diagnosis, and treatment of concomitant medical problems to the diagnosis of Autism Spectrum Disorder. These may be outside or inside the brain. The concepts of static or chronic, dynamic encephalopathy and condition for Autism Spectrum Disorder are defined in this model, which looks at the response to the treatments of concomitant medical problemsto the diagnosis of Autism Spectrum Disorder. (1) Background: Antecedents and rationale of an Advanced Integrative Model and of an Advanced Integrative Approach are presented; (2) Methods: Concomitant medical problems to the diagnosis of Autism Spectrum Disorder and a discussion of the known responses of their treatments are presented; (3) Results: Groups in Autism are defined and explained, related to the responses of the treatments of the concomitant medical problems to ASD and (4) Conclusions: The analysis in the framework of an Advanced Integrative Model of three groups including the concepts of static encephalopathy; chronic, dynamic encephalopathy and condition for Autism Spectrum Disorder explains findings in the field, previously not understood. Full article
Show Figures

Figure 1

Review
A Systematic Review and Meta-Analysis of Immunoglobulin G Abnormalities and the Therapeutic Use of Intravenous Immunoglobulins (IVIG) in Autism Spectrum Disorder
J. Pers. Med. 2021, 11(6), 488; https://doi.org/10.3390/jpm11060488 - 30 May 2021
Cited by 10 | Viewed by 2050
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting approximately 2% of children in the United States. Growing evidence suggests that immune dysregulation is associated with ASD. One immunomodulatory treatment that has been studied in ASD is intravenous immunoglobulins (IVIG). This systematic review [...] Read more.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting approximately 2% of children in the United States. Growing evidence suggests that immune dysregulation is associated with ASD. One immunomodulatory treatment that has been studied in ASD is intravenous immunoglobulins (IVIG). This systematic review and meta-analysis examined the studies which assessed immunoglobulin G (IgG) concentrations and the therapeutic use of IVIG for individuals with ASD. Twelve studies that examined IgG levels suggested abnormalities in total IgG and IgG 4 subclass concentrations, with concentrations in these IgGs related to aberrant behavior and social impairments, respectively. Meta-analysis supported possible subsets of children with ASD with low total IgG and elevated IgG 4 subclass but also found significant variability among studies. A total of 27 publications reported treating individuals with ASD using IVIG, including four prospective, controlled studies (one was a double-blind, placebo-controlled study); six prospective, uncontrolled studies; 2 retrospective, controlled studies; and 15 retrospective, uncontrolled studies. In some studies, clinical improvements were observed in communication, irritability, hyperactivity, cognition, attention, social interaction, eye contact, echolalia, speech, response to commands, drowsiness, decreased activity and in some cases, the complete resolution of ASD symptoms. Several studies reported some loss of these improvements when IVIG was stopped. Meta-analysis combining the aberrant behavior checklist outcome from two studies demonstrated that IVIG treatment was significantly associated with improvements in total aberrant behavior and irritability (with large effect sizes), and hyperactivity and social withdrawal (with medium effect sizes). Several studies reported improvements in pro-inflammatory cytokines (including TNF-alpha). Six studies reported improvements in seizures with IVIG (including patients with refractory seizures), with one study reporting a worsening of seizures when IVIG was stopped. Other studies demonstrated improvements in recurrent infections, appetite, weight gain, neuropathy, dysautonomia, and gastrointestinal symptoms. Adverse events were generally limited but included headaches, vomiting, worsening behaviors, anxiety, fever, nausea, fatigue, and rash. Many studies were limited by the lack of standardized objective outcome measures. IVIG is a promising and potentially effective treatment for symptoms in individuals with ASD; further research is needed to provide solid evidence of efficacy and determine the subset of children with ASD who may best respond to this treatment as well as to investigate biomarkers which might help identify responsive candidates. Full article
Review
Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder
J. Pers. Med. 2021, 11(3), 218; https://doi.org/10.3390/jpm11030218 - 18 Mar 2021
Cited by 8 | Viewed by 1717
Abstract
We propose that the mitochondrion, an essential cellular organelle, mediates the long-term prenatal environmental effects of disease in autism spectrum disorder (ASD). Many prenatal environmental factors which increase the risk of developing ASD influence mitochondria physiology, including toxicant exposures, immune activation, and nutritional [...] Read more.
We propose that the mitochondrion, an essential cellular organelle, mediates the long-term prenatal environmental effects of disease in autism spectrum disorder (ASD). Many prenatal environmental factors which increase the risk of developing ASD influence mitochondria physiology, including toxicant exposures, immune activation, and nutritional factors. Unique types of mitochondrial dysfunction have been associated with ASD and recent studies have linked prenatal environmental exposures to long-term changes in mitochondrial physiology in children with ASD. A better understanding of the role of the mitochondria in the etiology of ASD can lead to targeted therapeutics and strategies to potentially prevent the development of ASD. Full article
Show Figures

Figure 1

Review
Paving the Way toward Personalized Medicine: Current Advances and Challenges in Multi-OMICS Approach in Autism Spectrum Disorder for Biomarkers Discovery and Patient Stratification
J. Pers. Med. 2021, 11(1), 41; https://doi.org/10.3390/jpm11010041 - 13 Jan 2021
Cited by 9 | Viewed by 2178
Abstract
Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder characterized by impairments in two main areas: social/communication skills and repetitive behavioral patterns. The prevalence of ASD has increased in the past two decades, however, it is not known whether the evident rise in [...] Read more.
Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder characterized by impairments in two main areas: social/communication skills and repetitive behavioral patterns. The prevalence of ASD has increased in the past two decades, however, it is not known whether the evident rise in ASD prevalence is due to changes in diagnostic criteria or an actual increase in ASD cases. Due to the complexity and heterogeneity of ASD, symptoms vary in severity and may be accompanied by comorbidities such as epilepsy, attention deficit hyperactivity disorder (ADHD), and gastrointestinal (GI) disorders. Identifying biomarkers of ASD is not only crucial to understanding the biological characteristics of the disorder, but also as a detection tool for its early screening. Hence, this review gives an insight into the main areas of ASD biomarker research that show promising findings. Finally, it covers success stories that highlight the importance of precision medicine and the current challenges in ASD biomarker discovery studies. Full article
Show Figures

Graphical abstract

Review
The Relationship between Autism and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders
J. Pers. Med. 2020, 10(4), 260; https://doi.org/10.3390/jpm10040260 - 01 Dec 2020
Cited by 15 | Viewed by 8848
Abstract
Considerable interest has arisen concerning the relationship between hereditary connective tissue disorders such as the Ehlers-Danlos syndromes (EDS)/hypermobility spectrum disorders (HSD) and autism, both in terms of their comorbidity as well as co-occurrence within the same families. This paper reviews our current state [...] Read more.
Considerable interest has arisen concerning the relationship between hereditary connective tissue disorders such as the Ehlers-Danlos syndromes (EDS)/hypermobility spectrum disorders (HSD) and autism, both in terms of their comorbidity as well as co-occurrence within the same families. This paper reviews our current state of knowledge, as well as highlighting unanswered questions concerning this remarkable patient group, which we hope will attract further scientific interest in coming years. In particular, patients themselves are demanding more research into this growing area of interest, although science has been slow to answer that call. Here, we address the overlap between these two spectrum conditions, including neurobehavioral, psychiatric, and neurological commonalities, shared peripheral neuropathies and neuropathologies, and similar autonomic and immune dysregulation. Together, these data highlight the potential relatedness of these two conditions and suggest that EDS/HSD may represent a subtype of autism. Full article
Show Figures

Figure 1

Other

Case Report
Resting State Functional Magnetic Resonance Imaging Elucidates Neurotransmitter Deficiency in Autism Spectrum Disorder
J. Pers. Med. 2021, 11(10), 969; https://doi.org/10.3390/jpm11100969 - 28 Sep 2021
Cited by 3 | Viewed by 746
Abstract
Resting-state functional magnetic resonance imaging provides dynamic insight into the functional organization of the brains’ intrinsic activity at rest. The emergence of resting-state functional magnetic resonance imaging in both the clinical and research settings may be attributed to recent advancements in statistical techniques, [...] Read more.
Resting-state functional magnetic resonance imaging provides dynamic insight into the functional organization of the brains’ intrinsic activity at rest. The emergence of resting-state functional magnetic resonance imaging in both the clinical and research settings may be attributed to recent advancements in statistical techniques, non-invasiveness and enhanced spatiotemporal resolution compared to other neuroimaging modalities, and the capability to identify and characterize deep brain structures and networks. In this report we describe a 16-year-old female patient with autism spectrum disorder who underwent resting-state functional magnetic resonance imaging due to late regression. Imaging revealed deactivated networks in deep brain structures involved in monoamine synthesis. Monoamine neurotransmitter deficits were confirmed by cerebrospinal fluid analysis. This case suggests that resting-state functional magnetic resonance imaging may have clinical utility as a non-invasive biomarker of central nervous system neurochemical alterations by measuring the function of neurotransmitter-driven networks. Use of this technology can accelerate and increase the accuracy of selecting appropriate therapeutic agents for patients with neurological and neurodevelopmental disorders. Full article
Show Figures

Figure 1

Case Report
Genomics as a Clinical Decision Support Tool: Successful Proof of Concept for Improved ASD Outcomes
J. Pers. Med. 2021, 11(7), 596; https://doi.org/10.3390/jpm11070596 - 24 Jun 2021
Cited by 3 | Viewed by 1512
Abstract
Considerable evidence is emerging that Autism Spectrum Disorder (ASD) is most often triggered by a range of different genetic variants that interact with environmental factors such as exposures to toxicants and changes to the food supply. Up to 80% of genetic variations that [...] Read more.
Considerable evidence is emerging that Autism Spectrum Disorder (ASD) is most often triggered by a range of different genetic variants that interact with environmental factors such as exposures to toxicants and changes to the food supply. Up to 80% of genetic variations that contribute to ASD found to date are neither extremely rare nor classified as pathogenic. Rather, they are less common single nucleotide polymorphisms (SNPs), found in 1–15% or more of the population, that by themselves are not disease-causing. These genomic variants contribute to ASD by interacting with each other, along with nutritional and environmental factors. Examples of pathways affected or triggered include those related to brain inflammation, mitochondrial dysfunction, neuronal connectivity, synapse formation, impaired detoxification, methylation, and neurotransmitter-related effects. This article presents information on four case study patients that are part of a larger ongoing pilot study. A genomic clinical decision support (CDS) tool that specifically focuses on variants and pathways that have been associated with neurodevelopmental disorders was used in this pilot study to help develop a targeted, personalized prevention and intervention strategy for each child. In addition to an individual’s genetic makeup, each patient’s personal history, diet, and environmental factors were considered. The CDS tool also looked at genomic SNPs associated with secondary comorbid ASD conditions including attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), anxiety, and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections/pediatric acute-onset neuropsychiatric syndrome (PANDAS/PANS). The interpreted genomics tool helped the treating clinician identify and develop personalized, genomically targeted treatment plans. Utilization of this treatment approach was associated with significant improvements in socialization and verbal skills, academic milestones and intelligence quotient (IQ), and overall increased ability to function in these children, as measured by autism treatment evaluation checklist (ATEC) scores and parent interviews. Full article
Case Report
The Temple Grandin Genome: Comprehensive Analysis in a Scientist with High-Functioning Autism
J. Pers. Med. 2021, 11(1), 21; https://doi.org/10.3390/jpm11010021 - 29 Dec 2020
Cited by 3 | Viewed by 3021
Abstract
Autism spectrum disorder (ASD) is a heterogeneous condition with a complex genetic etiology. The objective of this study is to identify the complex genetic factors that underlie the ASD phenotype and other clinical features of Professor Temple Grandin, an animal scientist and woman [...] Read more.
Autism spectrum disorder (ASD) is a heterogeneous condition with a complex genetic etiology. The objective of this study is to identify the complex genetic factors that underlie the ASD phenotype and other clinical features of Professor Temple Grandin, an animal scientist and woman with high-functioning ASD. Identifying the underlying genetic cause for ASD can impact medical management, personalize services and treatment, and uncover other medical risks that are associated with the genetic diagnosis. Prof. Grandin underwent chromosomal microarray analysis, whole exome sequencing, and whole genome sequencing, as well as a comprehensive clinical and family history intake. The raw data were analyzed in order to identify possible genotype-phenotype correlations. Genetic testing identified variants in three genes (SHANK2, ALX1, and RELN) that are candidate risk factors for ASD. We identified variants in MEFV and WNT10A, reported to be disease-associated in previous studies, which are likely to contribute to some of her additional clinical features. Moreover, candidate variants in genes encoding metabolic enzymes and transporters were identified, some of which suggest potential therapies. This case report describes the genomic findings in Prof. Grandin and it serves as an example to discuss state-of-the-art clinical diagnostics for individuals with ASD, as well as the medical, logistical, and economic hurdles that are involved in clinical genetic testing for an individual on the autism spectrum. Full article
Back to TopTop