Abstracts

Rationale: Cerebral folate deficiency (CFD) is a condition in which there is low CSF 5-methyltetrahydrofolate compared to a normal folate in the periphery. Typically, it presents in children less than one year of age. Symptoms include movement disorders and epilepsy. Seizures are usually clonic or myoclonic. Cerebellar atrophy has been reported in some cases. These symptoms are not specific and diagnosis can be missed. Methods: We report a 19 year old patient with an atypical and severe presentation of CFD, which went under recognized for many years. He presented at 5 years of age with brief events of behavioral arrest that evolved later into dacrystic and gelastic seizures with a short tonic component. The ictal EEG showed generalized "electrodecrements", in addition to multifocal and generalized epileptiform discharges. He developed a waxing and waning, but progressive cognitive decline that rapidly worsened around 15 years of age. He developed cerebellar atrophy between 12-15 years of age which remained stable. He underwent extensive diagnostic testing at different institutions but no etiology was found. At 16 years of age he became almost mute and developed refractory status epilepticus with frequent tonic seizures, requiring mechanical ventilation. The EEG showed almost continuous, generalized discharges consistent with an epileptic encephalopathy. Results: CSF neurotransmitter testing showed low 5- methyltetrahydrofolate with a value of 25 (range between 40-120 nmol/L). Folate in RBCs was somewhat low at 249 (lower limit 280). Lactate and pyruvate in CSF were normal. ALDH7A1, FOLR 1 gene, lactose mediated folate receptor antibodies, folate receptor antibody assay and MTHFR were negative. Microarray yielded nonspecific results. Folinic acid and pyridoxine were added to his antiepileptic drugs. He experienced a rapid recovery with cessation of seizures, great improvement in cognition and normalization of the EEG. Follow up CSF samples showed normalization of 5-methyl tetrahydrofolate with a level of 78. After a seizure free period of six months, he experienced seizure recurrences but finally became seizure free. His EEG remains normal and he continues treatment with Leucovorin . Testing for congenital disorders of glycosylation (CDG) studies, mtDNA common mutations/deletions and buccal swab mito enzyme screening studies were negative with only signs of mitochondrial proliferation. Conclusions: This case emphasizes the importance of performing CSF testing in patients with frequent seizures and progressive cognitive decline of unknown cause. Because of the atypical features, CSF samples were not obtained and treatment with folinic acid was delayed. Despite this delay in treatment our patient experienced a rapid resolution of the epileptic encephalopathy, supporting the diagnosis. A secondary cause of CFD could be postulated, possibly due to mitochondrial dysfunction, as specific genetic testing generated negative results. There is some evidence supporting the association between low folate status and mitochondrial DNA (mtDNA) instability. References: Hyland K, Shoffner J, and Heales S. Cerebral folate deficiency. Journal of Inherited Metabolic Disorders 2010. 33:563-570. Gordon N. Cerebral folate deficiency. Developmental Medicine & Child Neurology 2009. 51(3): 180-182. Mercimek-Mahmutoglu S and Stockler-Ipsiroglu S. Cerebral folate deficiency and folinic acid treatment in hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) syndrome. The Tohoku Journal of Experimental Medicine 2007. 211: 95-96. Al-Baradie RS and Chudary MW. Diagnosis and management of cerebral folate deficiency. Neurosciences (Riyadh) 2014. 19(4): 312-316. Funding: None.