Diagnosis and management of cerebral folate deficiency: A form of folinic acid-responsive seizures

Folinic acid-responsive seizures (FARS) are a rare treatable cause of neonatal epilepsy. They have characteristic peaks on CSF monoamine metabolite analysis, and have mutations in the ALDH7A1 gene, characteristically found in pyridoxine-dependent epilepsy. There are case reports of patients presenting with seizures at a later age, and with folate deficiency due to different mechanisms with variable response to folinic acid supplementation. Here, we report 2 siblings who presented with global developmental delay and intractable seizures who responded clinically to folinic acid therapy. Their work-up included metabolic and genetic testing. The DNA sequencing was carried out for the ALDH7A1 gene, and the folate receptor 1 (FOLR1) gene. They had very low 5-methyltetrahydrofolate (5-MTHF) in CSF with no systemic folate deficiency and no characteristic peaks on neurotransmitter metabolite chromatogram. A novel mutation in the FOLR1 gene was found. The mutation in this gene is shown to affect CSF folate transport leading to cerebral folate deficiency. The response to treatment with folinic acid was dramatic with improvement in social interaction, mobility, and complete seizure control. We should consider the possibility of this treatable condition in appropriate clinical circumstances early, as diagnosis with favorable outcome depends on the specialized tests.Folinic acid-responsive seizures (FARS) are a well-recognized cause of vitamin-responsive neonatal epilepsy.1 Patients present with seizures, either myoclonic or clonic, apnea, and irritability within 5 days after birth. Neuroimaging shows brain atrophy and variable white matter abnormalities. Some patients respond to pyridoxine alone, or have an initial response to it, only to become resistant later on and responding to folinic acid. The response to treatment has been variable. Gallagher et al2 reported that all surviving patients were developmentally delayed and 5 of 10 reported cases were deceased. Subsequently, it was demonstrated that FARS and pyridoxine-dependent epilepsy (PDE) are allelic; indeed, the molecular genetic basis of the 2 conditions is identical in at least some cases. Cerebrospinal fluid 5-methyltetrahydrofolate (5-MTHF) analysis was carried out in one of 7 cases, and reported normal in Hyland & Arnold’s study.1 A few cases of cerebral folate deficiency (CFD) presenting with seizures onset beyond the neonatal period (7 months to 11 years of age) have recently been reported with severe developmental regression,3 and movement disturbances with chorea,4 dystonia, and difficult ambulation.3,4 Neuroimaging showed brain atrophy and variable white matter abnormalities.3,4 The CSF biogenic metabolite did not show characteristic peaks, CSF 5-MTHF levels were found low,4 and FOLR1 gene mutations were reported.3,4 Mutations in the FOLR1 gene are associated with severely reduced concentrations of CSF 5-MTHF indicating that its gene product, folate receptor alpha (FRα), plays a crucial role in this transport process. This FRα defect causes a cerebral folate transport deficiency (MIM 136430), a progressive neurological disorder of late infantile onset that is characterized by psychomotor regression, epilepsy, and disturbed brain myelination as well as a depletion of white matter choline and often inositol.3 All of the cases responded to folinic acid supplementation becoming seizure free, or with better seizure control, and disappearance of chorea, and dystonia with better ambulation.3,4 Our objective in presenting these cases is to highlight that FARS is not uncommon. Early diagnosis and management can lead to better outcome.