Contents lists available at ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme Genetic assessment and folate receptor autoantibodies in infantile-onset cerebral folate deficiency (CFD) syndrome V.Th. Ramaekers a, ⁎ , K. Segers a , J.M. Sequeira b , M. Koenig c , L. Van Maldergem d , V. Bours a , U. Kornak e , E.V. Quadros b a Center of Autism and Department of Genetics, University Hospital Liège (CHU), Belgium b Department of Medicine, SUNY-Downstate Medical Center, Brooklyn, New York, USA c EA7402 Institut Universitaire de Recherche Clinique, Montpellier, France d Center Human Genetics, Université de Franche-Comté, Besançon, France e Institut für Humangenetik, Charité-University Berlin, Berlin, Germany ARTICLE INFO Keywords: Folate receptor Autoimmunity Genetics Infantile CFD syndrome Differential diagnosis ABSTRACT Introduction: Cerebral folate deficiency (CFD) syndromes are defined as neuro-psychiatric conditions with low CSF folate and attributed to different causes such as autoantibodies against the folate receptor-alpha (FR) protein that can block folate transport across the choroid plexus, FOLR1 gene mutations or mitochondrial disorders. High-dose folinic acid treatment restores many neurologic deficits. Study aims and methods: Among 36 patients from 33 families the infantile-onset CFD syndrome was diagnosed based on typical clinical features and low CSF folate. All parents were healthy. Three families had 2 affected siblings, while parents from 4 families were first cousins. We analysed serum FR autoantibodies and the FOLR1 and FOLR2 genes. Among three consanguineous fa- milies homozygosity mapping attempted to identify a monogenetic cause. Whole exome sequencing (WES) was performed in the fourth consanguineous family, where two siblings also suffered from polyneuropathy as an atypical finding. Results: Boys (72%) outnumbered girls (28%). Most patients (89%) had serum FR autoantibodies fluctuating over 5–6 weeks. Two children had a genetic FOLR1 variant without pathological significance. Homozygosity mapping failed to detect a single autosomal recessive gene. WES revealed an autosomal recessive polynucleotide kinase 3´phosphatase (PNKP) gene abnormality in the siblings with polyneuropathy. Discussion: Infantile-onset CFD was characterized by serum FR autoantibodies as its predominant pathology whereas pathogenic FOLR1 gene mutations were absent. Homozygosity mapping excluded autosomal recessive inheritance of any single responsible gene. WES in one consanguineous family identified a PNKP gene ab- normality that explained the polyneuropathy and also its contribution to the infantile CFD syndrome because the PNKP gene plays a dual role in both neurodevelopment and immune-regulatory function. Further research for candidate genes predisposing to FRα-autoimmunity is suggested to include X-chromosomal and non-coding DNA regions. 1. Introduction Folates are essential cofactors for a multitude of biological processes such as homocysteine metabolism, one- carbon group transfer reac- tions, synthesis of neurotransmitters and of purines and thymidine [1–4]. The folate receptor (FOLR) genes are part of a gene family located on chromosome region 11q13.3-q13.5 including a so-called adult gene (FOLR1; folate receptor alpha), a foetal gene (FOLR2; folate receptor bèta) and pseudo-genes. FOLR1 and FOLR2 are functional and are char- acterized by alternative splicing and numerous tissue specific tran- scripts that show variation in the 5’UTR region [4–6]. The folate re- ceptor (FR) proteins are membrane proteins that are attached by a GPI anchor to the epithelial cell membrane at the basal side of choroid plexus and function to internalize folate by an endocytotic process for its transfer to the spinal fluid and neural tissues [8]. The transport of folate across the choroid plexus epithelial cells is reported to be mediated by exosomes containing the folate receptor, that are secreted https://doi.org/10.1016/j.ymgme.2018.03.001 Received 25 January 2018; Received in revised form 1 March 2018; Accepted 2 March 2018 ⁎ Corresponding author at: Center of Autism and Department of Neuropediatrics, CHU Liège, Rue de Gaillarmont 600, 4032 Chênée, Belgium. E-mail address: vramaekers@chuliege.be (V.T. Ramaekers). Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx 1096-7192/ © 2018 Elsevier Inc. All rights reserved. Please cite this article as: Ramaekers, V.T., Molecular Genetics and Metabolism (2018), https://doi.org/10.1016/j.ymgme.2018.03.001