Intended for healthcare professionals

Clinical Review State of the Art Review

Autism spectrum disorder: advances in diagnosis and evaluation

BMJ 2018; 361 doi: (Published 21 May 2018) Cite this as: BMJ 2018;361:k1674

Re: Autism spectrum disorder: advances in diagnosis and evaluation

The article on autism spectrum disorders, presented as “State of the art review”, does not address an important and significant area of research that has provided a biomarker and a treatment for ASD. Even though a whole section is devoted to “advances in biomarker research” there is no mention of folate receptor autoantibodies. In this context, the authors as well as reviewers of this article, have failed the readers.

Folate plays a prominent role in fertility, pregnancy, pregnancy outcome, fetal development and brain development during fetal as well as neonatal life. Folate deficiency has been attributed to many of the pregnancy and fetal development disorders. The identification of folate receptor autoantibodies in a majority of mothers with a history of neural tube defect pregnancy (1) and more recently in mothers with an autistic child (2) has provided an explanation for folate deficiency in the fetus due to the autoantibody blocking folate transport from the mother to the fetus as well as antibody-mediated inflammation as factors contributing to abnormalities in fetal brain development. These autoantibodies in children have been associated with cerebral folate deficiency syndrome (3). Recent studies have identified the autoantibody in 70% of children diagnosed with ASD and folinic acid treatment has shown significant improvement in the core deficits associated with ASD (4). These initial observations were recently confirmed in a double-blind placebo-controlled trial, which showed significant improvement in language and speech in children positive for the folate receptor autoantibody (5). Thus identifying folate receptor autoantibodies in parents and children provides a marker for early intervention to treat as well as potentially prevent the pathological consequences, as recently shown in a rat model (6).

1: Rothenberg SP, da Costa MP, Sequeira JM, Cracco J, Roberts JL, Weedon J, Quadros EV. Autoantibodies against folate receptors in women with a pregnancy complicated by a neural-tube defect. N Engl J Med. 2004 Jan 8;350(2):134-42. PubMed PMID: 14711912.

2: Quadros EV, Sequeira JM, Brown WT, Mevs C, Marchi E, Flory M, Jenkins EC, Velinov MT, Cohen IL. Folate receptor autoantibodies are prevalent in children diagnosed with autism spectrum disorder, their normal siblings and parents. Autism Res. 2018 Feb 2. doi: 10.1002/aur.1934. [Epub ahead of print] PubMed PMID: 29394471.

3: Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N, Quadros EV, Selhub J. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med. 2005 May 12;352(19):1985-91. PubMed PMID: 15888699.

4: 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 Dec;38(6):276-81. doi: 10.1055/s-2008-1065354. PubMed PMID: 18461502.

5: 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. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry. 2018 Feb;23(2):247-256. doi: 10.1038/mp.2016.168. Epub 2016 Oct 18. PubMed PMID: 27752075; PubMed Central PMCID: PMC5794882.

6: Desai A, Sequeira JM, Quadros EV. Prevention of behavioral deficits in rats exposed to folate receptor antibodies: implication in autism. Mol Psychiatry. 2017 Sep;22(9):1291-1297. doi: 10.1038/mp.2016.153. Epub 2016 Sep 20. PubMed PMID: 27646260.

Competing interests: Dr. Quadros is an inventor listed in a US patent for the folate receptor autoantibody test issued to the State University of New York.

25 May 2018
Edward V Quadros
Research Professor
SUNY Downstate Medical Center
450 Clarkson Avenue, Brooklyn, NY 11203, USA