Genetic assessment and folate receptor autoantibodies in infantile-onset cerebral folate deficiency (CFD) syndrome

[en] 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 families 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 abnormality 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. © 2018 Elsevier Inc.

Disciplines :

Genetics & genetic processes

Author, co-author :

RAMAEKERS, Vincent ; Centre Hospitalier Universitaire de Liège - CHU > Département de Pédiatrie > Centre de référence de l'autisme de Liège (CRAL)

SEGERS, Karin ; Centre Hospitalier Universitaire de Liège - CHU > Unilab > Centre d'oncogénétique

Sequeira, J. M.; Department of Medicine, SUNY-Downstate Medical Center, New York, Brooklyn, United States

Koenig, M.; EA7402 Institut Universitaire de Recherche Clinique, Montpellier, France

Van Maldergem, L.; Center Human Genetics, Université de Franche-Comté, Besançon, France

Bours, Vincent ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Génétique humaine

Kornak, U.; Institut für Humangenetik, Charité-University Berlin, Berlin, Germany

Quadros, E. V.; Department of Medicine, SUNY-Downstate Medical Center, New York, Brooklyn, United States

Language :

English

Title :

Genetic assessment and folate receptor autoantibodies in infantile-onset cerebral folate deficiency (CFD) syndrome

Publication date :

2018

Journal title :

Molecular Genetics and Metabolism

ISSN :

1096-7192

eISSN :

1096-7206

Publisher :

Academic Press Inc.

Volume :

124

Issue :

Pages :

87-93

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

Autism Speaks [US-NY] [US-NY]

Available on ORBi :

since 21 December 2018

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