Already in 2004 researcher at the University Children’s Hospital in Zurich discovered a folate deficiency in the brain of children with delayed neurological development and called their finding Cerebral Folate Deficiency (CFD). The affected children had a low/very low level of Folate in their cerebrospinal fluid independent of a normal Folate-level outside the nervous system, in the blood. The conclusion at this time was that CFD could result from either disturbed folate transport or from increased folate turnover within the central nervous system (CNS). Later on the autoantibody FRA was identified and a corresponding test was developed. The autoantibody FRA hampers or blocks the Folate-transport across the Blood-Brain Barrier (BBB) via the Folate-receptor-alpha (FRɑ). In 2016 Dr. Frye published the result of a study with autistic children which were treated with a high dose of Leucovorin over 12 weeks. Most of these children had an elevated FRA-value and responded favorably to the treatment with improved verbal communication. With the high dose Folate-treatment the alternate Folate-transporter (RFC) can be activated for the improvement of the Folate-level in the brain.

In December 2018 Dr. Frye received an award (750 TUSD) from the US-autism advocacy organisation Autism Speaks for a further study with small children. In this study a patented Aprofol-technology will be used. Compared to the 2016-study only half the dose will be necessary. The Levoleucovorin-Solution can be provided as drops added to a drink and allows a precise and convenient dosing based on the body weight of the children. The study has startet first quarter 2021. Aprofol AG is providing the medication.