CSF 5-Methyltetrahydrofolate Serial Monitoring to Guide Treatment of Congenital Folate Malabsorption Due to Proton-Coupled Folate Transporter (PCFT) Deficiency

Abstract

Hereditary folate malabsorption is characterized by folate deficiency with impaired folate transport into the central nervous system (CNS). This disease is characterized by megaloblastic anemia of early appearance, combined immunodeficiency, seizures, and cognitive impairment. The anemia and immunologic disease are responsive but neurological signs are refractory to folic-acid treatment. We report a 7-year-old girl who has congenital folate deficiency and SLC46A1 gene mutation who is unable to transport folate from her gut to the circulatory system and consequently from the blood to the cerebrospinal fluid (CSF). As a result she developed undetectable 5-methyltetrahydrofolate levels in her plasma and CSF and became immunocompromised and quite ill. Intramuscular treatment with 5-formyltetrahydrofolate (folinic acid) was therapeutic at her presentation and has been successful preventing other signs and symptoms of hereditary folate malabsorption even at relatively low CSF levels. Although difficult, early detection and diagnosis of cerebral folate deficiency are important because folinic acid at a pharmacologic dose may normalize outcome in PCFT gene defects, as well as bypass autoantibody-blocked folate receptors and enter the cerebrospinal fluid by way of the reduced folate carrier. This route elevates the 5-methyltetrahydrofolate level within the central nervous system and can prevent the neuropsychiatric disorder. CSF levels of 5-methyltetrahydrofolate between 18 and 46 nmol/L may be sufficient to eradicate CNS disease.

Treatment with Mefolinate (5-Methyltetrahydrofolate), but Not Folic Acid or Folinic Acid, Leads to Measurable 5-Methyltetrahydrofolate in Cerebrospinal Fluid in Methylenetetrahydrofolate Reductase Deficiency

“…A patient diagnosed at 4 years with congenital folate malabsorption, a disorder in which there is folate deficiency and impaired transport of folate into the CNS, had at the time of diagnosis undetectable levels of CSF 5-MTHF (Torres et al 2015). With twice daily intramuscular folinic acid, CSF levels increased to between 18 and 46 nmol/L.…”

Hereditary folate malabsorption due to a mutation in the external gate of the proton-coupled folate transporter SLC46A1

“…34 In this case, even when the peak blood folate level was 2242 nM, the CSF 5-methyltHF concentration was 1/50th at 43 nM. Although CSF 5-methylTHF levels of 40 to 50 nM are sufficient in adults, this is far lower than the much higher CSF 5-methylTHF levels in heathy infants and toddlers.…”

“…The challenge, irrespective of the folate type and mode of administration, is achieving adequate CSF folate levels. [1][2][3]34 HFM is a very rare disorder, and its presentation is often confusing. Hence, the diagnosis of HFM and its treatment are often delayed, 3 as was the case with this child.…”

Role of Intramuscular Levofolinate Administration in the Treatment of Hereditary Folate Malabsorption: Report of Three Cases

“…Even though anemia, immune dysfunction, and Ponto-cerebellar hypoplasia in addition to generalized lack of cerebral volume and myelination, bilateral symmetrical mature hemorrhagic infarction of the basal ganglia, symmetrical periventricular, and deep white matter change over the frontal lobes ( Fig. 1 No progression of prominent white matter changes and ponto-cerebellar volume reduction gastrointestinal symptoms are reversible with the oral or parenteral administration of folinic acid and normalization of blood folate levels is easily achieved, it has been proven that CSF levels remain suboptimal (Zhao et al 2017;Borzutzky et al 2009;Torres et al 2015;Min et al 2008;Erlacher et al 2015;Kishimoto et al 2014;Wang et al 2015). Thus, the major challenge remains to achieve normal CSF 5-MTHF levels for treatment of neurological disease (Zhao et al 2017).…”

“…Previous literature reports recommend high doses of oral or intramuscular (im) 5-formyltetrahydrofolate (5-formylTHF), also known as folinic acid, aiming to improve or normalize 5-MTHF CSF levels before irreversible damage occurs (Kronn and Goldman 2008;Zhao et al 2017). Nevertheless, those levels are difficult to achieve even in patients who have been receiving high doses of parenteral folinic acid (Torres et al 2015). The active isomer of 5-formylTHF, also known as levofolinic acid, is as well available for administration.…”