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

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.