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

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 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.

• Authors: V Th Ramaekers, K Segers, J M Sequeira, M Koenig, L Van Maldergem, V Bours, U Kornak, E V Quadros
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 124 Issue 1 Pg. 87-93 (05 2018) ISSN: 1096-7206 [Electronic] United States
• PMID: 29661558 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Autoantibodies
• FOLR1 protein, human
• FOLR2 protein, human
• Folate Receptor 1
• Folate Receptor 2
• Folic Acid
• PNKP protein, human
• Phosphotransferases (Alcohol Group Acceptor)
• DNA Repair Enzymes

Topics

• Adolescent
• Autoantibodies (blood)
• Brain Diseases, Metabolic, Inborn (cerebrospinal fluid, diagnosis, genetics)
• Child
• Child, Preschool
• Consanguinity
• DNA Repair Enzymes (genetics)
• Diagnosis, Differential
• Family
• Female
• Folate Receptor 1 (genetics, immunology)
• Folate Receptor 2 (genetics)
• Folic Acid (cerebrospinal fluid)
• Folic Acid Deficiency (cerebrospinal fluid, diagnosis, genetics)
• Humans
• Infant
• Male
• Phosphotransferases (Alcohol Group Acceptor) (genetics)
• Polyneuropathies (etiology)
• Exome Sequencing
• Young Adult