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A Personalized Medicine Approach to the Diagnosis and Management of...
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A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder: Beyond Genetic Syndromes

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 (30 April 2024) | Viewed by 105775

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
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. Daniel Rossignol

E-Mail Website
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
Dr. Shannon Rose

E-Mail Website
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 Issue Information

Dear Colleagues,

Background: Autism spectrum disorder (ASD) now affects more than 2% of children, and its prevalence continues to grow. Currently, there is no curative treatment and current therapies provide suboptimal habilitation in many individuals that are affected, leading to a new framing of ASD as a lifelong disorder for many rather than simply a disorder isolated to childhood. The significant heterogeneity of ASD has made the development of diagnosis tools and treatments challenging. A majority of research on ASD concentrates on identifying the genetic syndrome, but there is a new understanding that the etiology of ASD is very complex and probably driven by genetic variations and vulnerabilities interacting with environmental exposures and triggers. Our two previous Special Issues have provided insight into applying personalized medicine to improve the diagnosis and detection of pathophysiological processes and predict treatment response in individuals with ASD. See: (https://www.mdpi.com/journal/jpm/special_issues/Personalized_Medicine_Approach_ASD).

Aim and scope: Our goal is to continue to publish high-impact articles describing a personalized medicine approach for the diagnosis, classification, and treatment of ASD. This year, we wish to focus on the emerging understanding of the role of environmental factors, their contribution to genetic variants and vulnerabilities, and their interaction with the environment.

History: ASD is a difficult disorder to diagnose and treat, both because its diagnosis is traditionally not based on objective biomarkers and because there are numerous underlying pathophysiological processes which may be difficult to detect. Treatment response is extremely variable, and biomarkers used to predict response are limited. Thus, a personalized medicine approach could greatly benefit this population. There is emerging evidence that the environment and genetic variants play an important role in the development of ASD.

Cutting-edge research: We encourage any submissions describing genetic, epigenetic, physiologic, metabolic, immunological, microbiome, behavior, educational, and societal factors that are involved in the etiology, diagnosis, management, and treatment of ASD.

What kind of papers we are soliciting: We encourage the submission of manuscripts that describe a personalized medicine approach for the diagnosis, classification, and treatment of ASD, particularly those that describe the influence of environmental factors and/or genetic variants.

Prof. Dr. Richard E. Frye
Dr. Richard G. Boles
Dr. Daniel Rossignol
Dr. Shannon Rose
Guest Editors

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 2600 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
  • genetic syndromes
  • autonomic dysfunction
  • autoimmunity
  • epigenetic
  • folate/B12 metabolism
  • gene expression
  • genetics
  • immunology
  • metabolomics
  • methylation
  • microRNA
  • mitochondrial dysfunction
  • neurophysiology
  • quantitative behavior
  • redox metabolism/oxidative stress
  • inflammation
  • seizures

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Published Papers (15 papers)

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Editorial

Jump to: Research, Review, Other

2 pages, 160 KiB  
Editorial
Synchrony 2022: The Role of Neuroinflammation in Behavioral Exacerbations in Autism Spectrum Disorder
by Jennifer Frankovich, Heer Nanda, Elizabeth D. Mellins, Harumi Jyonouchi, Richard G. Boles, Stephen J. Walker, John Gaitanis and Richard E. Frye
J. Pers. Med. 2023, 13(7), 1133; https://doi.org/10.3390/jpm13071133 - 13 Jul 2023
Cited by 1 | Viewed by 2059
Abstract
The BRAIN Foundation (Pleasanton, CA) hosted Synchrony 2022, a medical conference focusing on research for treatments to benefit individuals with neurodevelopmental disorders (NDD), including those with autism spectrum disorders (ASD) [...] Full article
(This article belongs to the Special Issue A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder: Beyond Genetic Syndromes)
2 pages, 164 KiB  
Editorial
Synchrony 2022: Roundtable Discussion on the Pathways and the Challenges of Getting Medications FDA Approved
by Gabriel Belfort, Heer Nanda, John C. Slattery, Joanna Sambor, John Rodakis and Richard E. Frye
J. Pers. Med. 2023, 13(5), 779; https://doi.org/10.3390/jpm13050779 - 30 Apr 2023
Viewed by 1128
Abstract
The BRAIN Foundation (Pleasanton, CA, USA) hosted a medicine conference, Synchrony 2022, for research into treatments to benefit individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorders (ASD) [...] Full article
(This article belongs to the Special Issue A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder: Beyond Genetic Syndromes)
7 pages, 203 KiB  
Editorial
Synchrony 2022: Catalyzing Research and Treatments to Benefit Individuals with Neurodevelopmental Disorders including Autism Spectrum Disorders
by Heer Nanda and Richard E. Frye
J. Pers. Med. 2023, 13(3), 490; https://doi.org/10.3390/jpm13030490 - 9 Mar 2023
Cited by 1 | Viewed by 2783
Abstract
A unique translational medicine conference for research into treatments that can benefit individuals with neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD), has been developed and hosted by The BRAIN Foundation (Pleasanton, CA, USA) since 2019 [...] Full article
(This article belongs to the Special Issue A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder: Beyond Genetic Syndromes)
4 pages, 195 KiB  
Editorial
A Paradigm Shift in Understanding the Pathological Basis of Autism Spectrum Disorder: From the Womb to the Tomb
by Yoshihiro Noda
J. Pers. Med. 2022, 12(10), 1622; https://doi.org/10.3390/jpm12101622 - 1 Oct 2022
Cited by 2 | Viewed by 1532
Abstract
Autism Spectrum Disorder (ASD) is currently diagnosed based on clinical assessment of behavioral characteristics [...] Full article
(This article belongs to the Special Issue A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder: Beyond Genetic Syndromes)

Research

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10 pages, 843 KiB  
Article
Folate Receptor Alpha Autoantibodies in the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Population
by Lindsey Wells, Nancy O’Hara, Richard E. Frye, Neeshi Hullavard and Erica Smith
J. Pers. Med. 2024, 14(2), 166; https://doi.org/10.3390/jpm14020166 - 31 Jan 2024
Cited by 2 | Viewed by 11325
Abstract
The folate receptor alpha autoantibodies (FRAAs) are associated with cerebral folate deficiency (CFD) and autism spectrum disorder (ASD). Both of these syndromes have overlapping characteristics with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Thus, we [...] Read more.
The folate receptor alpha autoantibodies (FRAAs) are associated with cerebral folate deficiency (CFD) and autism spectrum disorder (ASD). Both of these syndromes have overlapping characteristics with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Thus, we propose that the FRAAs may contribute to the symptomatology of PANS/PANDAS. To test this hypothesis, 1 mL of serum from 47 patients (age range = 6–18 years old) clinically diagnosed with PANS/PANDAS was sent to Vascular Strategies (Plymouth Meeting, PA, USA) for analysis of FRAAs. Moreover, 63.8% of PANS/PANDAS patients (male = 15; female = 15) were found to have either the blocking and/or blinding FRAAs, with 25 (83.3%; male = 14; female = 11) having binding FRAAs, two (6.7%; all female = 2) having blocking FRAAs, and 3 (10%; male = 1; female = 2) having both binding and blocking. Furthermore, surprisingly, ASD was associated with a 0.76 lower binding titer (p = 0.02), and severe tics were associated with a 0.90 higher binding titer (p = 0.01). A case of a FRAA-positive patient is provided to illustrate that a treatment plan including leucovorin can result in symptom improvement in patients with PANS/PANDAS who are FRAA-positive. These data, for the first time, demonstrate that PANS/PANDAS is associated with FRAAs and suggest folate metabolism abnormalities may contribute to PANS/PANDAS symptomatology. Further studies investigating the therapeutic nature of leucovorin in the treatment of PANS/PANDAS are needed. Such studies may open up an alternative, safe, and well-tolerated treatment for those with the PANS/PANDAS diagnosis. Full article
(This article belongs to the Special Issue A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder: Beyond Genetic Syndromes)
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12 pages, 1225 KiB  
Article
Binding Folate Receptor Alpha Autoantibody Is a Biomarker for Leucovorin Treatment Response in Autism Spectrum Disorder
by Richard E. Frye, Patrick J. McCarty, Brianna A. Werner, Adrienne C. Scheck, Heidi L. Collins, Steven J. Adelman, Daniel A. Rossignol and Edward V. Quadros
J. Pers. Med. 2024, 14(1), 62; https://doi.org/10.3390/jpm14010062 - 1 Jan 2024
Cited by 1 | Viewed by 5526
Abstract
Autism spectrum disorder (ASD) affects up to 1 in 36 children in the United States. It is a heterogeneous neurodevelopmental disorder with life-long consequences. Patients with ASD and folate pathway abnormalities have demonstrated improved symptoms after treatment with leucovorin (folinic acid), a reduced [...] Read more.
Autism spectrum disorder (ASD) affects up to 1 in 36 children in the United States. It is a heterogeneous neurodevelopmental disorder with life-long consequences. Patients with ASD and folate pathway abnormalities have demonstrated improved symptoms after treatment with leucovorin (folinic acid), a reduced form of folate. However, biomarkers for treatment response have not been well investigated and clinical trials are lacking. In this retrospective analysis, a cohort of prospectively collected data from 110 consecutive ASD clinic patients [mean (SD) age: 10.5 (6.2) years; 74% male] was examined. These patients all underwent testing for folate receptor alpha autoantibodies (FRAAs) and soluble folate binding proteins (sFBPs) biomarkers and were treated with leucovorin, if appropriate. Analyses examined whether these biomarkers could predict response to leucovorin treatment as well as the severity of ASD characteristics at baseline. The social responsiveness scale (SRS), a measure of core ASD symptoms, and the aberrant behavior checklist (ABC), a measure of disruptive behavior, were collected at each clinic visit. Those positive for sFBPs had more severe ASD symptoms, and higher binding FRAA titers were associated with greater ABC irritability. Treatment with leucovorin improved most SRS subscales with higher binding FRAA titers associated with greater response. Leucovorin treatment also improved ABC irritability. These results confirm and expand on previous studies, underscore the need for biomarkers to guide treatment of folate pathways in ASD, and suggest that leucovorin may be effective for children with ASD. Full article
(This article belongs to the Special Issue A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder: Beyond Genetic Syndromes)
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14 pages, 2458 KiB  
Article
From Data to Insights: Machine Learning Empowers Prognostic Biomarker Prediction in Autism
by Ecmel Mehmetbeyoglu, Abdulkerim Duman, Serpil Taheri, Yusuf Ozkul and Minoo Rassoulzadegan
J. Pers. Med. 2023, 13(12), 1713; https://doi.org/10.3390/jpm13121713 - 15 Dec 2023
Cited by 3 | Viewed by 1641
Abstract
Autism Spectrum Disorder (ASD) poses significant challenges to society and science due to its impact on communication, social interaction, and repetitive behavior patterns in affected children. The Autism and Developmental Disabilities Monitoring (ADDM) Network continuously monitors ASD prevalence and characteristics. In 2020, ASD [...] Read more.
Autism Spectrum Disorder (ASD) poses significant challenges to society and science due to its impact on communication, social interaction, and repetitive behavior patterns in affected children. The Autism and Developmental Disabilities Monitoring (ADDM) Network continuously monitors ASD prevalence and characteristics. In 2020, ASD prevalence was estimated at 1 in 36 children, with higher rates than previous estimates. This study focuses on ongoing ASD research conducted by Erciyes University. Serum samples from 45 ASD patients and 21 unrelated control participants were analyzed to assess the expression of 372 microRNAs (miRNAs). Six miRNAs (miR-19a-3p, miR-361-5p, miR-3613-3p, miR-150-5p, miR-126-3p, and miR-499a-5p) exhibited significant downregulation in all ASD patients compared to healthy controls. The current study endeavors to identify dependable diagnostic biomarkers for ASD, addressing the pressing need for non-invasive, accurate, and cost-effective diagnostic tools, as current methods are subjective and time-intensive. A pivotal discovery in this study is the potential diagnostic value of miR-126-3p, offering the promise of earlier and more accurate ASD diagnoses, potentially leading to improved intervention outcomes. Leveraging machine learning, such as the K-nearest neighbors (KNN) model, presents a promising avenue for precise ASD diagnosis using miRNA biomarkers. Full article
(This article belongs to the Special Issue A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder: Beyond Genetic Syndromes)
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27 pages, 3312 KiB  
Article
Predicting Problematic Behavior in Autism Spectrum Disorder Using Medical History and Environmental Data
by Jennifer Ferina, Melanie Kruger, Uwe Kruger, Daniel Ryan, Conor Anderson, Jenny Foster, Theresa Hamlin and Juergen Hahn
J. Pers. Med. 2023, 13(10), 1513; https://doi.org/10.3390/jpm13101513 - 21 Oct 2023
Cited by 3 | Viewed by 4659
Abstract
Autism spectrum disorder (ASD), characterized by social, communication, and behavioral abnormalities, affects 1 in 36 children according to the CDC. Several co-occurring conditions are often associated with ASD, including sleep and immune disorders and gastrointestinal (GI) problems. ASD is also associated with sensory [...] Read more.
Autism spectrum disorder (ASD), characterized by social, communication, and behavioral abnormalities, affects 1 in 36 children according to the CDC. Several co-occurring conditions are often associated with ASD, including sleep and immune disorders and gastrointestinal (GI) problems. ASD is also associated with sensory sensitivities. Some individuals with ASD exhibit episodes of challenging behaviors that can endanger themselves or others, including aggression and self-injurious behavior (SIB). In this work, we explored the use of artificial intelligence models to predict behavior episodes based on past data of co-occurring conditions and environmental factors for 80 individuals in a residential setting. We found that our models predict occurrences of behavior and non-behavior with accuracies as high as 90% for some individuals, and that environmental, as well as gastrointestinal, factors are notable predictors across the population examined. While more work is needed to examine the underlying connections between the factors and the behaviors, having reasonably accurate predictions for behaviors has the potential to improve the quality of life of some individuals with ASD. Full article
(This article belongs to the Special Issue A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder: Beyond Genetic Syndromes)
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22 pages, 4224 KiB  
Article
microRNA as a Maternal Marker for Prenatal Stress-Associated ASD, Evidence from a Murine Model
by Taeseon Woo, Candice King, Nick I. Ahmed, Madison Cordes, Saatvika Nistala, Matthew J. Will, Clark Bloomer, Nataliya Kibiryeva, Rocio M. Rivera, Zohreh Talebizadeh and David Q. Beversdorf
J. Pers. Med. 2023, 13(9), 1412; https://doi.org/10.3390/jpm13091412 - 20 Sep 2023
Cited by 2 | Viewed by 1519
Abstract
Autism Spectrum Disorder (ASD) has been associated with a complex interplay between genetic and environmental factors. Prenatal stress exposure has been identified as a possible risk factor, although most stress-exposed pregnancies do not result in ASD. The serotonin transporter (SERT) gene has been [...] Read more.
Autism Spectrum Disorder (ASD) has been associated with a complex interplay between genetic and environmental factors. Prenatal stress exposure has been identified as a possible risk factor, although most stress-exposed pregnancies do not result in ASD. The serotonin transporter (SERT) gene has been linked to stress reactivity, and the presence of the SERT short (S)-allele has been shown to mediate the association between maternal stress exposure and ASD. In a mouse model, we investigated the effects of prenatal stress exposure and maternal SERT genotype on offspring behavior and explored its association with maternal microRNA (miRNA) expression during pregnancy. Pregnant female mice were divided into four groups based on genotype (wildtype or SERT heterozygous knockout (Sert-het)) and the presence or absence of chronic variable stress (CVS) during pregnancy. Offspring behavior was assessed at 60 days old (PD60) using the three-chamber test, open field test, elevated plus-maze test, and marble-burying test. We found that the social preference index (SPI) of SERT-het/stress offspring was significantly lower than that of wildtype control offspring, indicating a reduced preference for social interaction on social approach, specifically for males. SERT-het/stress offspring also showed significantly more frequent grooming behavior compared to wildtype controls, specifically for males, suggesting elevated repetitive behavior. We profiled miRNA expression in maternal blood samples collected at embryonic day 21 (E21) and identified three miRNAs (mmu-miR-7684-3p, mmu-miR-5622-3p, mmu-miR-6900-3p) that were differentially expressed in the SERT-het/stress group compared to all other groups. These findings suggest that maternal SERT genotype and prenatal stress exposure interact to influence offspring behavior, and that maternal miRNA expression late in pregnancy may serve as a potential marker of a particular subtype of ASD pathogenesis. Full article
(This article belongs to the Special Issue A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder: Beyond Genetic Syndromes)
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17 pages, 1079 KiB  
Article
High-Risk Siblings without Autism: Insights from a Clinical and Eye-Tracking Study
by Valeria Costanzo, Antonio Narzisi, Sonia Cerullo, Giulia Crifaci, Maria Boncoddo, Marco Turi, Fabio Apicella, Raffaella Tancredi, Filippo Muratori, Sara Calderoni and Lucia Billeci
J. Pers. Med. 2022, 12(11), 1789; https://doi.org/10.3390/jpm12111789 - 29 Oct 2022
Viewed by 1862
Abstract
Joint attention (JA)—the human ability to coordinate our attention with that of other people—is impaired in the early stage of Autism Spectrum Disorder (ASD). However, little is known about the JA skills in the younger siblings of children with ASD who do not [...] Read more.
Joint attention (JA)—the human ability to coordinate our attention with that of other people—is impaired in the early stage of Autism Spectrum Disorder (ASD). However, little is known about the JA skills in the younger siblings of children with ASD who do not develop ASD at 36 months of age [high-risk (HR)-noASD]. In order to advance our understanding of this topic, a prospective multicenter observational study was conducted with three groups of toddlers (age range: 18–33 months): 17 with ASD, 19 with HR-noASD and 16 with typical development (TD). All subjects underwent a comprehensive clinical assessment and an eye-tracking experiment with pre-recorded stimuli in which the visual patterns during two tasks eliciting initiating joint attention (IJA) were measured. Specifically, fixations, transitions and alternating gaze were analyzed. Clinical evaluation revealed that HR-noASD subjects had lower non-verbal cognitive skills than TD children, while similar levels of restricted and repetitive behaviors and better social communication skills were detected in comparison with ASD children. Eye-tracking paradigms indicated that HR-noASD toddlers had visual patterns resembling TD in terms of target-object-to-face gaze alternations, while their looking behaviors were similar to ASD toddlers regarding not-target-object-to-face gaze alternations. This study indicated that high-risk, unaffected siblings displayed a shared profile of IJA-eye-tracking measures with both ASD patients and TD controls, providing new insights into the characterization of social attention in this group of toddlers. Full article
(This article belongs to the Special Issue A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder: Beyond Genetic Syndromes)
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34 pages, 7954 KiB  
Article
Metabolomic Signatures of Autism Spectrum Disorder
by Danielle Brister, Shannon Rose, Leanna Delhey, Marie Tippett, Yan Jin, Haiwei Gu and Richard E. Frye
J. Pers. Med. 2022, 12(10), 1727; https://doi.org/10.3390/jpm12101727 - 17 Oct 2022
Cited by 18 | Viewed by 5194
Abstract
Autism Spectrum Disorder (ASD) is associated with many variations in metabolism, but the ex-act correlates of these metabolic disturbances with behavior and development and their links to other core metabolic disruptions are understudied. In this study, large-scale targeted LC-MS/MS metabolomic analysis was conducted [...] Read more.
Autism Spectrum Disorder (ASD) is associated with many variations in metabolism, but the ex-act correlates of these metabolic disturbances with behavior and development and their links to other core metabolic disruptions are understudied. In this study, large-scale targeted LC-MS/MS metabolomic analysis was conducted on fasting morning plasma samples from 57 children with ASD (29 with neurodevelopmental regression, NDR) and 37 healthy controls of similar age and gender. Linear model determined the metabolic signatures of ASD with and without NDR, measures of behavior and neurodevelopment, as well as markers of oxidative stress, inflammation, redox, methylation, and mitochondrial metabolism. MetaboAnalyst ver 5.0 (the Wishart Research Group at the University of Alberta, Edmonton, Canada) identified the pathways associated with altered metabolic signatures. Differences in histidine and glutathione metabolism as well as aromatic amino acid (AAA) biosynthesis differentiated ASD from controls. NDR was associated with disruption in nicotinamide and energy metabolism. Sleep and neurodevelopment were associated with energy metabolism while neurodevelopment was also associated with purine metabolism and aminoacyl-tRNA biosynthesis. While behavior was as-sociated with some of the same pathways as neurodevelopment, it was also associated with alternations in neurotransmitter metabolism. Alterations in methylation was associated with aminoacyl-tRNA biosynthesis and branched chain amino acid (BCAA) and nicotinamide metabolism. Alterations in glutathione metabolism was associated with changes in glycine, serine and threonine, BCAA and AAA metabolism. Markers of oxidative stress and inflammation were as-sociated with energy metabolism and aminoacyl-tRNA biosynthesis. Alterations in mitochondrial metabolism was associated with alterations in energy metabolism and L-glutamine. Using behavioral and biochemical markers, this study finds convergent disturbances in specific metabolic pathways with ASD, particularly changes in energy, nicotinamide, neurotransmitters, and BCAA, as well as aminoacyl-tRNA biosynthesis. Full article
(This article belongs to the Special Issue A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder: Beyond Genetic Syndromes)
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8 pages, 365 KiB  
Article
Understanding Challenging Behaviors in Autism Spectrum Disorder: A Multi-Component, Interdisciplinary Model
by Stephen M. Edelson
J. Pers. Med. 2022, 12(7), 1127; https://doi.org/10.3390/jpm12071127 - 12 Jul 2022
Cited by 9 | Viewed by 7677
Abstract
A multi-component, interdisciplinary model is described which explains the presence of, and in other cases the lack of, many challenging behaviors associated with autism spectrum disorder (ASD). More specifically, the model expands the operant behavioral conditioning paradigm by taking into account medical comorbidities [...] Read more.
A multi-component, interdisciplinary model is described which explains the presence of, and in other cases the lack of, many challenging behaviors associated with autism spectrum disorder (ASD). More specifically, the model expands the operant behavioral conditioning paradigm by taking into account medical comorbidities and interoceptive processing. Full article
(This article belongs to the Special Issue A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder: Beyond Genetic Syndromes)
27 pages, 3071 KiB  
Article
Multivariate Analysis of Metabolomic and Nutritional Profiles among Children with Autism Spectrum Disorder
by Fatir Qureshi, James B. Adams, Tapan Audhya and Juergen Hahn
J. Pers. Med. 2022, 12(6), 923; https://doi.org/10.3390/jpm12060923 - 1 Jun 2022
Cited by 5 | Viewed by 3110
Abstract
There have been promising results regarding the capability of statistical and machine-learning techniques to offer insight into unique metabolomic patterns observed in ASD. This work re-examines a comparative study contrasting metabolomic and nutrient measurements of children with ASD (n = 55) against their [...] Read more.
There have been promising results regarding the capability of statistical and machine-learning techniques to offer insight into unique metabolomic patterns observed in ASD. This work re-examines a comparative study contrasting metabolomic and nutrient measurements of children with ASD (n = 55) against their typically developing (TD) peers (n = 44) through a multivariate statistical lens. Hypothesis testing, receiver characteristic curve assessment, and correlation analysis were consistent with prior work and served to underscore prominent areas where metabolomic and nutritional profiles between the groups diverged. Improved univariate analysis revealed 46 nutritional/metabolic differences that were significantly different between ASD and TD groups, with individual areas under the receiver operator curve (AUROC) scores of 0.6–0.9. Many of the significant measurements had correlations with many others, forming two integrated networks of interrelated metabolic differences in ASD. The TD group had 189 significant correlation pairs between metabolites, vs. only 106 for the ASD group, calling attention to underlying differences in metabolic processes. Furthermore, multivariate techniques identified potential biomarker panels with up to six metabolites that were able to attain a predictive accuracy of up to 98% for discriminating between ASD and TD, following cross-validation. Assessing all optimized multivariate models demonstrated concordance with prior physiological pathways identified in the literature, with some of the most important metabolites for discriminating ASD and TD being sulfate, the transsulfuration pathway, uridine (methylation biomarker), and beta-amino isobutyrate (regulator of carbohydrate and lipid metabolism). Full article
(This article belongs to the Special Issue A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder: Beyond Genetic Syndromes)
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Review

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15 pages, 8039 KiB  
Review
Folate Pathway Gene Single Nucleotide Polymorphisms and Neural Tube Defects: A Systematic Review and Meta-Analysis
by Ahmad K. Almekkawi, Marwa W. AlJardali, Hicham M. Daadaa, Alison L. Lane, Ashley R. Worner, Mohammad A. Karim, Adrienne C. Scheck and Richard E. Frye
J. Pers. Med. 2022, 12(10), 1609; https://doi.org/10.3390/jpm12101609 - 29 Sep 2022
Cited by 5 | Viewed by 2380
Abstract
Neural tube defects (NTDs) are congenital abnormalities in the central nervous system. The exact etiology of NTDs is still not determined, but several genetic and epigenetic factors have been studied. Folate supplementation during gestation is recommended to reduce the risk of NTDs. In [...] Read more.
Neural tube defects (NTDs) are congenital abnormalities in the central nervous system. The exact etiology of NTDs is still not determined, but several genetic and epigenetic factors have been studied. Folate supplementation during gestation is recommended to reduce the risk of NTDs. In this review we examine single nucleotide polymorphisms (SNPs) of the genes in the folate pathway associated with NTD. We reviewed the literature for all papers discussing both NTDs and SNPs in the folate pathway. Data were represented through five different genetic models. Quality assessment was performed using the Newcastle–Ottawa Scale (NOS) and Cohen’s Kappa inter-rater coefficient assessed author agreement. Fifty-nine papers were included. SNPs in MTHFR, MTRR, RFC genes were found to be highly associated with NTD risk. NOS showed that high quality papers were selected, and Kappa Q-test was 0.86. Our combined results support the notion that SNPs significantly influence NTDs across the population, particularly in Asian ethnicity. Additional high-quality research from diverse ethnicities is needed and meta-regression analysis based on a range of criteria may provide a more complete understanding of the role of folate metabolism in NTDs. Full article
(This article belongs to the Special Issue A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder: Beyond Genetic Syndromes)
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Other

15 pages, 931 KiB  
Case Report
Reversal of Autism Symptoms among Dizygotic Twins through a Personalized Lifestyle and Environmental Modification Approach: A Case Report and Review of the Literature
by Christopher R. D’Adamo, Josephine L. Nelson, Sara N. Miller, Maria Rickert Hong, Elizabeth Lambert and Heather Tallman Ruhm
J. Pers. Med. 2024, 14(6), 641; https://doi.org/10.3390/jpm14060641 - 15 Jun 2024
Viewed by 50926
Abstract
The prevalence of autism has been increasing at an alarming rate. Even accounting for the expansion of autism spectrum disorder diagnostic (ASD) criteria throughout the 1990’s, there has been an over 300% increase in ASD prevalence since the year 2000. The often debilitating [...] Read more.
The prevalence of autism has been increasing at an alarming rate. Even accounting for the expansion of autism spectrum disorder diagnostic (ASD) criteria throughout the 1990’s, there has been an over 300% increase in ASD prevalence since the year 2000. The often debilitating personal, familial, and societal sequelae of autism are generally believed to be lifelong. However, there have been several encouraging case reports demonstrating the reversal of autism diagnoses, with a therapeutic focus on addressing the environmental and modifiable lifestyle factors believed to be largely underlying the condition. This case report describes the reversal of autism symptoms among dizygotic, female twin toddlers and provides a review of related literature describing associations between modifiable lifestyle factors, environmental exposures, and various clinical approaches to treating autism. The twins were diagnosed with Level 3 severity ASD “requiring very substantial support” at approximately 20 months of age following concerns of limited verbal and non-verbal communication, repetitive behaviors, rigidity around transitions, and extensive gastrointestinal symptoms, among other common symptoms. A parent-driven, multidisciplinary, therapeutic intervention involving a variety of licensed clinicians focusing primarily on addressing environmental and modifiable lifestyle factors was personalized to each of the twin’s symptoms, labs, and other outcome measures. Dramatic improvements were noted within several months in most domains of the twins’ symptoms, which manifested in reductions of Autism Treatment Evaluation Checklist (ATEC) scores from 76 to 32 in one of the twins and from 43 to 4 in the other twin. The improvement in symptoms and ATEC scores has remained relatively stable for six months at last assessment. While prospective studies are required, this case offers further encouraging evidence of ASD reversal through a personalized, multidisciplinary approach focusing predominantly on addressing modifiable environmental and lifestyle risk factors. Full article
(This article belongs to the Special Issue A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder: Beyond Genetic Syndromes)
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