Abstracts

Rationale: Folate is an essential cofactor for a number of cellular processes including methylation, nucleic acid metabolism, and amino acid synthesis. Cerebral folate deficiency leads to a spectrum of neurodegeneration, developmental delay, cerebellar ataxia, spastic paraplegia, and seizures. Diagnosis is based on low cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF) with concurrent normal serum folate, and is most commonly associated with autoantibodies to the folate receptor alpha (FRa) or mutations in the corresponding gene FOLR1 (OMIM #613068). Folate movement across the choroid plexus is also mediated by the reduced folate carrier (RFC). However, mutations in RFC have never before been reported as a cause of cerebral folate deficiency.     Methods: We describe a case of a previously healthy, normally developing boy presenting to the hospital at 4 months of age with apneic episodes, episodes of staring and abnormal arm movements with corresponding EEG suggestive of focal seizures, and abnormal MRI thought to be consistent with ADEM. He was treated with steroids, IVIG, and plasmapheresis. After a prolonged hospital stay, EEG improved and he was stable until a new decompensation and onset of treatment-resistant myoclonic seizures at 3 years old. MRI and EEG findings were compared across hospitalizations and treatment. Whole exome sequencing was performed for the child and his parents. CSF studies including neurotransmitters, 5MTHF, and anti-FRa antibodies were obtained.  Results: MRI at illness onset at 4 months showed areas of restricted diffusion of the periaqueductal gray region, midbrain, superior colliculus, and thalamus, which resolved with treatment. However, repeat imaging showed persistent, diffuse cortical atrophy. EEG for new onset of seizures at 3 years of age showed moderate to severe background slowing, abundant generalized epileptiform discharges, with/without associated myoclonic seizures. Serum folate was within normal limits, but CSF 5MTHF was undetectable. Whole exome sequencing identified compound heterozygous mutations p.S46N and p.F141del in SCL19A1 encoding RFC inherited in trans, one from each neurologically normal parent. Therefore, treatment with IV folinic acid was initiated, and a mild increase of CSF 5MTHF level was detected. Treatment with metabolic supplements and IV folinic acid remains ongoing.    Conclusions: Here we describe the first reported case of cerebral folate deficiency likely secondary to inherited compound heterozygous mutations in SCL19A1. Clinical features include developmental regression with focal seizures and MRI thought to mimic ADEM, which without folate supplementation progressed to refractory myoclonic seizures. These findings suggest that RFC plays a more dynamic role in CSF and brain 5MTHF homeostasis than previously appreciated. Autosomal recessive RFC mutations represent a new, potentially treatable form of cerebral folate deficiency.    Funding: None