Frye Richard E, Cohen Ira L, Sequeira Jeffrey M, Hill Zoe, Espinoza Alina, Brown W Ted, Mevs Clifford, Marchi Elaine, Flory Michael, Jenkins Edmund C, Velinov Milen T, Quadros Edward V
Autism Discovery and Treatment Foundation, Phoenix, AZ 85050, USA.
Department of Psychology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Int J Mol Sci. 2025 Aug 26;26(17):8293. doi: 10.3390/ijms26178293.
Autism Spectrum Disorder (ASD) affects an estimated prevalence of 1 in 31 children but the cause in most cases is unknown. Human and animal studies have linked ASD to Folate Receptor Alpha Autoantibodies (FRAAs). Our previous studies demonstrated that FRAAs are more common, on average, in families with children with ASD. This study reanalyzed data from a previous study which included 82 children diagnosed with ASD, 53 unaffected siblings, 70 mothers, 65 fathers, and 52 typically developing controls who did not have a history of ASD in their family. This study investigates the association of FRAA titers with ASD risk factors and explores the relationship of FRAA titers across generations. Several known risk factors for ASD, including multiplex ASD families, multiple birth pregnancies, and increased maternal and paternal ages at birth, were related to offspring FRAA titers. Multiplex ASD families demonstrated higher FRAA titers. Significant correlation were found between maternal and offspring blocking FRAA titers. FRAA titers increased across generations, although the increase in blocking FRAA titers was only seen in multiplex families. The proband with ASD showed higher blocking but not higher binding, FRAA titers compared to their non-affected siblings. Paternal FRAA titers are associated with several measures of offspring behavior and cognitive development. This research highlights the potential transgenerational transmission of FRAAs and their role in ASD. This supports the notion that heritable non-genetic factors may be important in the etiology of ASD and that FRAAs may demonstrate anticipation (worsening across generations), especially in multiplex families. FRAAs may provide one example of the possibility that susceptibility to autoimmune processes may contribute to disrupted brain development and function in ASD.
据估计，自闭症谱系障碍（ASD）在每31名儿童中的患病率为1，但在大多数情况下病因不明。人类和动物研究已将ASD与α-叶酸受体自身抗体（FRAAs）联系起来。我们之前的研究表明，平均而言，FRAAs在患有ASD儿童的家庭中更为常见。本研究重新分析了之前一项研究的数据，该研究包括82名被诊断为ASD的儿童、53名未受影响的兄弟姐妹、70名母亲、65名父亲以及52名家庭中无ASD病史的正常发育对照。本研究调查了FRAA滴度与ASD风险因素的关联，并探讨了FRAA滴度在几代人之间的关系。ASD的几个已知风险因素，包括多重ASD家庭、多胞胎妊娠以及父母生育年龄增加，都与后代的FRAA滴度有关。多重ASD家庭显示出更高的FRAA滴度。在母亲和后代的阻断性FRAA滴度之间发现了显著相关性。FRAA滴度在几代人之间有所增加，尽管阻断性FRAA滴度的增加仅在多重家庭中可见。与未受影响的兄弟姐妹相比，患有ASD的先证者显示出更高的阻断性但不是更高的结合性FRAA滴度。父亲的FRAA滴度与后代行为和认知发展的多项指标相关。这项研究突出了FRAAs潜在的跨代传递及其在ASD中的作用。这支持了这样一种观点，即遗传性非遗传因素可能在ASD的病因中起重要作用，并且FRAAs可能表现出遗传早现（几代人之间病情恶化），尤其是在多重家庭中。FRAAs可能提供了一个例子，说明自身免疫过程的易感性可能导致ASD中大脑发育和功能的破坏。
