Cerebral folate transporter deficiency syndrome in three siblings: Why genetic testing for developmental and epileptic encephalopathies should be performed early and include the FOLR1 gene.

Abstract

Cerebral folate transporter deficiency syndrome, caused by FOLR-1 mutations is characterized by late infantile onset, severe developmental regression, epilepsy, and leukodystrophy. An extremely low concentration of 5-methyltetrahydrofolate in the cerebrospinal fluid provides a crucial clue to its diagnosis and is a treatment target. Oral or intravenous folinic acid (5-formyltetrahydrofolate) administration improves clinical symptoms and brain magnetic resonance imaging (MRI) findings. We describe three siblings carrying a novel homozygous FOLR1 nonsense mutation, that were referred due to intractable epilepsy and progressive neurological decline. Brain MRI showed hypomyelination and cerebellar atrophy. Folinic acid (oral and intravenous) supplementation, initiated after over 15 years illness, has failed to result in any sizeable clinical or neurophysiological improvement. Cerebral folate transport deficiency bears overlapping clinical features with many severe developmental encephalopathies. It is crucial to recognize FOLR1 signs and establish an early clinical and molecular diagnosis in order to provide timely folinic acid treatment and improve outcome.

• Authors: Sara Brunetti, Laura Malerba, Lucio Giordano, Elena Parrini, Renzo Guerrini, Giovanni Palumbo, Cecilia Parazzini, Ilaria Bestetti, Patrizia Accorsi
• Journal: American journal of medical genetics. Part A (Am J Med Genet A) Vol. 185 Issue 8 Pg. 2526-2531 (08 2021) ISSN: 1552-4833 [Electronic] United States
• PMID: 34008900 (Publication Type: Case Reports)
• Copyright: © 2021 Wiley Periodicals LLC.

Chemical References

• FOLR1 protein, human
• Folate Receptor 1
• Folic Acid

Topics

• Adolescent
• Alleles
• Brain (diagnostic imaging, drug effects, pathology)
• Consanguinity
• Developmental Disabilities (diagnosis, genetics)
• Disease Management
• Epilepsy (diagnosis, genetics)
• Female
• Folate Receptor 1 (deficiency, genetics)
• Folic Acid (administration & dosage)
• Genetic Association Studies
• Genetic Predisposition to Disease
• Genetic Testing
• Genotype
• Humans
• Magnetic Resonance Imaging
• Male
• Mutation
• Neuroaxonal Dystrophies (diagnosis, genetics, therapy)
• Phenotype
• Siblings
• Syndrome
• Treatment Outcome