Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies V.T. Ramaekers a,b, ⁎, B. Thöny c , J.M. Sequeira f , M. Ansseau d , P. Philippe b , F. Boemer e , V. Bours e , E.V. Quadros f a Division of Paediatric Neurology, Centre Hospitalier Universitaire de Liège, Liège, Belgium b Centre for Autism Liège, Centre Hospitalier Universitaire de Liège, Liège, Belgium c Division of Metabolism, University Children's Hospital Zurich, Switzerland d Department of Psychiatry, Centre Hospitalier Universitaire de Liège, Liège, Belgium e Department of Human Genetics and Metabolism, Centre Hospitalier Universitaire de Liège, Liège, Belgium f Department of Medicine, SUNY Downstate Medical Center, Brooklyn, NY, USA abstract article info Article history: Received 29 July 2014 Received in revised form 30 September 2014 Accepted 1 October 2014 Available online xxxx Keywords: Autoimmunity Folate receptor Treatment Schizophrenia Cerebral folate deficiency Background: Auto-antibodies against folate receptor alpha (FRα) at the choroid plexus that block N 5 - methyltetrahydrofolate (MTHF) transfer to the brain were identified in catatonic schizophrenia. Acoustic hallu- cinations disappeared following folinic acid treatment. Folate transport to the CNS prevents homocysteine accu- mulation and delivers one-carbon units for methyl-transfer reactions and synthesis of purines. The guanosine derivative tetrahydrobiopterin acts as common co-factor for the enzymes producing dopamine, serotonin and ni- tric oxide. Methods: Our study selected patients with schizophrenia unresponsive to conventional treatment. Serum from these patients with normal plasma homocysteine, folate and vitamin B12 was tested for FR autoantibodies of the blocking type on serial samples each week. Spinal fluid was analyzed for MTHF and the metabolites of pterins, dopamine and serotonin. The clinical response to folinic acid treatment was evaluated. Results: Fifteen of 18 patients (83.3%) had positive serum FR auto-antibodies compared to only 1 in 30 controls (3.3%) (χ 2 = 21.6; p b 0.0001). FRα antibody titers in patients fluctuated over time varying between negative and high titers, modulating folate flux to the CNS, which explained low CSF folate values in 6 and normal values in 7 patients. The mean ± SD for CSF MTHF was diminished compared to previously established controls (t-test: 3.90; p = 0.0002). A positive linear correlation existed between CSF MTHF and biopterin levels. CSF dopamine and serotonin metab- olites were low or in the lower normal range. Administration of folinic acid (0.3–1 mg/kg/day) to 7 participating patients during at least six months resulted in clinical improvement. Conclusion: Assessment of FR auto-antibodies in serum is recommended for schizophrenic patients. Clinical neg- ative or positive symptoms are speculated to be influenced by the level and evolution of FRα antibody titers which determine folate flux to the brain with up- or down-regulation of brain folate intermediates linked to met- abolic processes affecting homocysteine levels, synthesis of tetrahydrobiopterin and neurotransmitters. Folinic acid intervention appears to stabilize the disease process. © 2014 Elsevier Inc. All rights reserved. 1. Introduction Schizophrenia is a severe mental illness affecting 1% of the popula- tion. Clinical recognition is characterized by the presence of phases with positive symptoms (delusions, hallucinations, disorganization of thoughts and speech, catatonic behavior), phases with negative symp- toms (affective flattening, alogia, avolition) and cognitive impairment [1,2]. Some neuro-imaging studies documented progressive gray matter loss over 5–10 years [3]. Schizophrenia is a multifactorial disorder car- rying a predominant genetic risk as reflected by a positive family histo- ry, in addition to environmental risk factors like obstetric complications, social isolation, migrant status and urban life and early exposure to drug abuse like cocaine, amphetamines and cannabis. Schizophrenia fits the model of a complex disorder in which multiple genes interact along with environmental influences, to produce the schizophrenic pheno- type. In addition to susceptibility genes involving growth factors partic- ipating in nerve growth and development, the encoded proteins by most of the strongest candidate genes are involved in dopamine and glutamate signaling [4–6]. Beyond the older dopamine hypothesis, the NMDA glutamate receptor hypofunction hypothesis has recently gained more interest [7–9]. Molecular Genetics and Metabolism xxx (2014) xxx–xxx ⁎ Corresponding author at: Division of Paediatric Neurology, Centre Hospitalier Universitaire Liège, Rue de Gaillarmont 600, B-4032 Chênée (Liège), Belgium. E-mail address: vramaekers@skynet.be (V.T. Ramaekers). YMGME-05818; No. of pages: 8; 4C: http://dx.doi.org/10.1016/j.ymgme.2014.10.002 1096-7192/© 2014 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme Please cite this article as: V.T. Ramaekers, et al., Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies, Mol. Gen- et. Metab. (2014), http://dx.doi.org/10.1016/j.ymgme.2014.10.002