Researchers at University Medical Centre Gottingen, other centers in Germany, and Helsinki University Central Hospital, Finland screened 72 children with low 5-methyltetrahydrofolate (5-MTHF) concentrations in the CSF who developed neurological abnormalities after infancy. Ten individuals with developmental regression, ataxia, cerebral hypomyelination, and cerebellar atrophy had nucleotide alterations in the folate receptor 1 gene, FOLR1. These included novel pathogenic alleles in 4, one splice mutation and 3 missense mutations, with absence of cellular binding of folic acid. The molecular studies did not consistently explain the phenotypic variations among patients with cerebral folate transport deficiency, and additional factors must be contributory. Most patients had frequent myoclonic seizures or infantile spasms and benefited from oral folinic acid. (Folic acid must be converted to biologically active 5-MTHF and folinic acid is preferred). Response occurred within 2 months with reduced frequency of seizures and improved motor skills. The EEG showed a slow background rhythm and multifocal epileptiform activity. MRI showed delayed or hypomyelination of cerebral white matter and cerebellar atrophy. 
COMMENT. Cerebral folate deficiency is a progressive neurologic disorder of childhood amenable to treatment with folinic acid. Mutations in the FOLR1 gene are the most common and severe etiology of cerebral folate deficiency, and are associated with a characteristic phenotype with early onset (<3 years), developmental delay, ataxia, and seizures often resembling infantile spasms. Seizures may prove refractory to oral folinic acid, and parenteral or rarely intrathecal administration may be required.