title: Thyroid dysfunction in children with autism spectrum disorder is associated with folate receptor α autoimmune disorder.
abstract: Folate receptor α (FRα) autoantibodies (FRAAs) are prevalent in autism spectrum disorder (ASD). FRAAs disrupt folate transport across the blood-brain barrier by binding to the FRα. Thyroid dysfunction is frequently found in children with ASD. We measured blocking and binding FRAAs and thyroid-stimulating hormone (TSH), free thyroxine (T4) (FT4), total triiodothyronine (T3) (TT3), reverse T3 (rT3), thyroid-releasing hormone (TRH) and other metabolites in 87 children with ASD, 84 of whom also underwent behaviour and cognition testing and in 42 of whom FRAAs, TSH and FT4 were measured at two time points. To better understand the significance of the FRα in relation to thyroid development, we examined FRα expression on prenatal and postnatal thyroid. TSH, TT3 and rT3 were above the normal range in 7%, 33% and 51% of the participants and TRH was below the normal range in 13% of the participants. FT4 was rarely outside the normal range. TSH concentration was positively and the FT4/TSH, TT3/TSH and rT3/TSH ratios were inversely related to blocking FRAA titres. On repeated measurements, changes in TSH and FT4/TSH ratio were found to correspond to changes in blocking FRAA titres. TSH and the FT4/TSH, TT3/TSH and rT3/TSH ratios were related to irritability on the Aberrant Behavior Checklist and several scales of the Social Responsiveness Scale (SRS), whereas TT3 was associated with SRS subscales and TRH was related to Vineland Adaptive Behavior Scale subscales. The thyroid showed significant FRα expression during the early prenatal period, although expression decreased significantly in later gestation and postnatal thyroid tissue. The results of the present study suggest that thyroid dysfunction in ASD may be related to blocking FRAA. The high expression of FRα in the early foetal thyroid suggests that foetal and neonatal exposure to maternal FRAAs could affect the development of the thyroid and may contribute to the pathology in ASD.
authors.affiliation: Department of Pediatrics, Arkansas Children's Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: R E
authors.identifier: 0000-0003-4442-2937
authors.initials: RE
authors.lastname: Frye
authors.affiliation: Department of Pediatrics, Arkansas Children's Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: R
authors.initials: R
authors.lastname: Wynne
authors.affiliation: Department of Pediatrics, Arkansas Children's Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rose
authors.affiliation: Department of Pediatrics, Arkansas Children's Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: J
authors.initials: J
authors.lastname: Slattery
authors.affiliation: Department of Pediatrics, Arkansas Children's Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: L
authors.initials: L
authors.lastname: Delhey
authors.affiliation: Department of Pediatrics, Arkansas Children's Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tippett
authors.affiliation: Department of Pediatrics, Arkansas Children's Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Kahler
authors.affiliation: Department of Pediatrics, Arkansas Children's Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Bennuri
authors.affiliation: Department of Pediatrics, Arkansas Children's Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: S
authors.initials: S
authors.lastname: Melnyk
authors.affiliation: Department of Medicine, State University of New York - Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Sequeira
authors.affiliation: Department of Medicine, State University of New York - Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: E V
authors.initials: EV
authors.lastname: Quadros
mesh_terms: D000067877:Autism Spectrum Disorder / Q000097:blood / Q000150:complications / Q000453:epidemiology*; D001323:Autoantibodies / Q000097:blood*; D001327:Autoimmune Diseases / Q000097:blood / Q000150:complications / Q000453:epidemiology*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D058975:Folate Receptor 1 / Q000276:immunology*; D006801:Humans; D008297:Male; D013959:Thyroid Diseases / Q000097:blood / Q000150:complications / Q000453:epidemiology*; D013960:Thyroid Function Tests; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
chemical_list: D001323:Autoantibodies; C548696:FOLR1 protein, human; D058975:Folate Receptor 1; D014284:Triiodothyronine; D013972:Thyrotropin; D013974:Thyroxine
keywords: autism spectrum disorders; folate receptor autoantibody; free T4; thyroid function; thyroid-stimulating hormone