[Hereditary folate malabsorption due to an SLC46A1 mutation with cerebral folate deficiency and refractory epilepsy:...

Hereditary folate malabsorption (HFM) is an autosomal recessive metabolic disorder caused by pathogenic variants in SLC46A1, the gene encoding the proton-coupled folate transporter. This defect impairs intestinal folate absorption and its transport into the central nervous system (CNS), leading to cerebral folate deficiency even with normal serum levels. Clinically, it presents with megaloblastic anemia, gastrointestinal symptoms, immunological alterations, and progressive neurological involvement. Measurement of 5-methyltetrahydrofolate (5-MTHF) in cerebrospinal fluid (CSF) is the specific diagnostic method, and treatment is based on folinic acid or levofolinic acid administration. Case: A male patient with early-onset microangiopathic anemia, developmental delay, refractory epilepsy, and hyperhomocysteinemia. Whole-exome sequencing identified a homozygous pathogenic variant in the SLC46A1 gene, c.981_982del (p.Tyr327Ter). Upon diagnosis, folic acid was discontinued and treatment with folinic acid was initiated, later replaced by intramuscular levofolinic acid due to clinical deterioration and decreased CSF 5-MTHF levels. The multimodal therapeutic approach achieved normalization of biomarkers and control of refractory epilepsy. This is the first report of an Argentine patient with HFM due to an SLC46A1 mutation associated with cerebral folate deficiency. Early-onset refractory epilepsy and hyperhomocysteinemia were key diagnostic clues. Monitoring of CSF 5-MTHF proved essential for assessing therapeutic response. Levofolinic acid showed superior clinical and biochemical efficacy compared to leucovorin. This case broadens the genotypic and phenotypic spectrum of this rare disease and underscores the importance of early diagnosis and individualized management to optimize neurological outcomes.