Cerebral Folate Deficiency and It's Management Chaudhary MW, MD, MRCPCH, Al-Baradie RS, MD, ABMS, Pediatric Neurology, Neuroscience Center, King Fahad Specialist Hospital-Dammam ABSTRACT INTRODUCTION RESULTS DISCUSSION Folates are essential cofactors for one-carbon methyl transfer reactions which are crucial for several processes including synthesis and repair of DNA, regulation of gene expression and synthesis of amino acids and neurotransmitters. 5-MTHF is one of the physiologically active form of folate. 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 crucial role in this transport process across the blood-CSF barrier in the choroid plexus. This FRα defect causes cerebral folate transport deficiency (MIM 136430), a progressive neurological disorder of late infantile onset that is characterized by psychomotor delay/ regression, autistic features, and movement disturbances with chorea, dystonia and difficult ambulation with disturbed brain myelination as well as a depletion of white matter choline and often inositol. Neuroimaging shows brain atrophy and variable white matter abnormalities. Patient 1:- CSF 5-MTHF was low (7 nmol/l, normal: 40-128), with normal serum folate Patient 2:- CSF 5-MTHF levels of 11 nmol/L (normal=40-150) with normal serum folate. Both had homozygous novel mutation c.398C>A (p.Pro133His) in the FOLR1 gene Folinic acid-responsive seizures (FARS) are a rare treatable cause of neonatal epilepsy. They have mutations in the ALDH7A1 gene, characteristically found in pyridoxine-dependent epilepsy. Patients presenting with seizures at later age with folate deficiency due to different mechanisms have variable response to folinic acid supplementation. Here we report two siblings who presented with global developmental delay, ataxia, autistic features and intractable seizures. MRI brain revealed sub cortical white matter abnormal high intensity on T2 consistent with hypomyelination with cerebellar atrophy. EEG showed hypsarrythmia initially changing one year later to generalized slowing and multifocal epileptic discharges, with occasional attenuation of the EEG activity which correlated with clinical drop attacks. They had very low 5-methyltetrahydrofolate (5-MTHF) in CSF with no systemic folate deficiency. A homozygous novel mutation c.398C>A (p.Pro133His) in FOLR1 gene was found. 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. The possibility of this treatable condition should be considered early in appropriate clinical circumstances as diagnosis with favorable outcome depends on the specialized tests. Beyond neonatal period folinic acid-responsive seizures are caused by mainly two different mechanisms. Presentation is beyond first 6 months of life. The more common type is caused by the presence of the autoantibody to folate receptors The second type is FOLR1 gene mutation as seen in our patients-an autosomal recessive disorder. The lower the CSF 5-MTHF level, the higher are the chances of having a FOLR1 gene mutation, typical levels being <25% of the lower limit of normal for age. Autistic features are frequently seen in both the conditions. Less severe deficiency of CSF 5-MTHF are due to wide variety of other etiologies such as Rett syndrome,7 dihydropteridine reductase deficiency, and Kearns-Sayre syndrome, and may not respond so well to folinic acid treatment. Folic acid is contraindicated as it will worsen the cerebral folate deficiency by competing with the active form of folate, folinic acid, at the receptor level. Patient 1. ← MRI Axial T1 –generalized hypomyelination →Patient 2. SUBJECTS 38 yrs 8 yrs 6 yrs Patient 1. ← MRI Axial T2 –generalized hypomyelination →Patient 2. CONCLUSIONS Drug-resistant epilepsy beyond the neonatal period, especially in the setting of otherwise unexplained global developmental delay/ regression or of features consistent with autistic spectrum disorder, cerebral folate deficiency disorder should be considered in differential diagnosis as outcome is dramatic in those treated early. Both were born at term, uneventful NSVD, but were delayed globally from the first year of life. Both had seizure onset about 4 years of age as drop attacks & myoclonic seizures. Other features were-microcephaly, ataxia, tremors, wide-based gait, autistic features. Patient 1. ← MRI sagittal T1–cerebellar hypoplasia →Patient 2. METHODS REFERENCES CSF 5-methyltetrahydrofolate (5-MTHF) with serum folate levels Neurotransmitter metabolite chromatogram. DNA sequencing for the ALDH7A1 gene and folate receptor 1 (FOLR1) gene. Magnetic Resonance Image of brain EEG CONTACT Ramaekers VT, Rohtenberg SP, Sequeira JM. Auto antibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med 2005; 352: 1985-1991 Steinfeld R, Grapp M, Kraetzner R, et al. Folate receptor alpha defect causes cerebral folate transport deficiency: A treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet 2009; 85:354-63 Dr Mohammed Wajid Chaudhary King Fahad Specialist Hospital-Dammam Email: Mohammed.Chaudhary@kfsh.med.sa Phone: +966-559754904 Patient 1. EEG with burst suppression pattern