Cerebral folate receptor autoantibodies in autism spectrum disorder - PubMed (original) (raw)
Controlled Clinical Trial
doi: 10.1038/mp.2011.175. Epub 2012 Jan 10.
Affiliations
- PMID: 22230883
- PMCID: PMC3578948
- DOI: 10.1038/mp.2011.175
Free PMC article
Controlled Clinical Trial
Cerebral folate receptor autoantibodies in autism spectrum disorder
R E Frye et al. Mol Psychiatry. 2013 Mar.
Free PMC article
Abstract
Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg(-1) per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted.
Figures
Figure 1
The prevalence of blocking and binding folate receptor autoantibodies in ASD. (a) The prevalence of children with ASD for negative, low, medium and high titers of the folate receptor-blocking autoantibody. (b) The prevalence of children with ASD for negative, low, medium and high titers of the folate receptor-binding autoantibody. (c) The prevalence of being negative for both the binding and the blocking autoantibodies, being positive for only the blocking or the binding autoantibody and being positive for both the binding and the blocking autoantibodies. (d) The blocking folate receptor autoantibody titer was found to significantly decrease with age. ASD, autism spectrum disorder.
Figure 2
The relationship between cerebrospinal fluid 5-methyltetrahydrofolate concentrations and blocking folate receptor autoantibody titers. Lower cerebrospinal fluid 5-methyltetrahydrofolate concentrations are associated with higher blocking folate receptor autoantibody titers.
Figure 3
Improvement ratings for nine cognitive-behavioral dimensions for children treated with leucovorin calcium compared with the no-treatment group (a-i). Improvement is rated on a 7-point scale ranging from much worse (−3) to much better (+3). For each cognitive-behavioral dimension, we provide the score for each child treated with leucovorin on the right of each graph (filled circles), and the score for each control child who did not undergo treatment (unfilled circles). The median for each group is given by a thick line, and the mean for each group is provided by diamonds. The _P_-value for the Mann–Whitney _U_-test is provided at the middle bottom of each graph and the _P_-value for the _t_-test is provided at the middle top of each graph.
Figure 4
The relationship between improvement ratings in verbal communication (a, b) and expressive language (c, d) and age for children with (b, d) and without (a, c) binding folate receptor autoantibody. (a, c) For children without the binding autoantibody, improvements in verbal communication and expressive language are higher for older children than for younger children. (b, d) For children with the binding autoantibody, improvements in verbal communication and expressive language are higher for younger children than for older children. Correlation coefficients are provided for the relationship between improvement and age for each graph; hence, the _P_-value for these correlations are not provided.
Similar articles
- Treatment of Folate Metabolism Abnormalities in Autism Spectrum Disorder.
Frye RE, Rossignol DA, Scahill L, McDougle CJ, Huberman H, Quadros EV. Frye RE, et al. Semin Pediatr Neurol. 2020 Oct;35:100835. doi: 10.1016/j.spen.2020.100835. Epub 2020 Jun 25. Semin Pediatr Neurol. 2020. PMID: 32892962 Free PMC article. Review. - Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial.
Frye RE, Slattery J, Delhey L, Furgerson B, Strickland T, Tippett M, Sailey A, Wynne R, Rose S, Melnyk S, Jill James S, Sequeira JM, Quadros EV. Frye RE, et al. Mol Psychiatry. 2018 Feb;23(2):247-256. doi: 10.1038/mp.2016.168. Epub 2016 Oct 18. Mol Psychiatry. 2018. PMID: 27752075 Free PMC article. Clinical Trial. - Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies.
Ramaekers VT, Thöny B, Sequeira JM, Ansseau M, Philippe P, Boemer F, Bours V, Quadros EV. Ramaekers VT, et al. Mol Genet Metab. 2014 Dec;113(4):307-14. doi: 10.1016/j.ymgme.2014.10.002. Epub 2014 Oct 12. Mol Genet Metab. 2014. PMID: 25456743 - The diagnostic utility of folate receptor autoantibodies in blood.
Sequeira JM, Ramaekers VT, Quadros EV. Sequeira JM, et al. Clin Chem Lab Med. 2013 Mar 1;51(3):545-54. doi: 10.1515/cclm-2012-0577. Clin Chem Lab Med. 2013. PMID: 23314538 Review.
Cited by
- Unveiling the Therapeutic Potential of Folate-Dependent One-Carbon Metabolism in Cancer and Neurodegeneration.
Sobral AF, Cunha A, Silva V, Gil-Martins E, Silva R, Barbosa DJ. Sobral AF, et al. Int J Mol Sci. 2024 Aug 28;25(17):9339. doi: 10.3390/ijms25179339. Int J Mol Sci. 2024. PMID: 39273288 Free PMC article. Review. - Evaluating the Role of Susceptibility Inducing Cofactors and of Acetaminophen in the Etiology of Autism Spectrum Disorder.
Jones JP 3rd, Williamson L, Konsoula Z, Anderson R, Reissner KJ, Parker W. Jones JP 3rd, et al. Life (Basel). 2024 Jul 23;14(8):918. doi: 10.3390/life14080918. Life (Basel). 2024. PMID: 39202661 Free PMC article. - Autism spectrum disorder: pathogenesis, biomarker, and intervention therapy.
Zhuang H, Liang Z, Ma G, Qureshi A, Ran X, Feng C, Liu X, Yan X, Shen L. Zhuang H, et al. MedComm (2020). 2024 Mar 2;5(3):e497. doi: 10.1002/mco2.497. eCollection 2024 Mar. MedComm (2020). 2024. PMID: 38434761 Free PMC article. Review. - The Dangers of Acetaminophen for Neurodevelopment Outweigh Scant Evidence for Long-Term Benefits.
Parker W, Anderson LG, Jones JP, Anderson R, Williamson L, Bono-Lunn D, Konsoula Z. Parker W, et al. Children (Basel). 2023 Dec 29;11(1):44. doi: 10.3390/children11010044. Children (Basel). 2023. PMID: 38255358 Free PMC article. Review.
References
- Ramaekers VT, Hausler M, Opladen T, Heimann G, Blau N. Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution. Neuropediatrics. 2002;33:301–308. - PubMed
- Ramaekers VT, Blau N. Cerebral folate deficiency. Dev Med Child Neurol. 2004;46:843–851. - PubMed
- Ramaekers VT, Blau N, Sequeira JM, Nassogne MC, Quadros EV. Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits. Neuropediatrics. 2007;38:276–281. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous