Hypomyelination Caused by a Novel Homozygous Pathogenic Variant in FOLR1: Complete Clinical and Radiological Recovery with Oral Folinic Acid Therapy and Review of the Literature

Overview

Journal Orphanet J Rare Dis

Publisher Biomed Central

Specialty General Medicine

Date 2023 Jul 13

PMID 37443037

Authors

Ana Potic

Stefanie Perrier

Tijana Radovic

Svetlana Gavrilovic

Jelena Ostojic

Luan T Tran

Isabelle Thiffault

Tomi Pastinen

Raphael Schiffmann

Genevieve Bernard

Affiliations

Soon will be listed here.

Abstract

Background: Neurodegeneration due to cerebral folate transport deficiency is a rare autosomal recessive disorder caused by biallelic pathogenic variants in FOLR1. Onset typically occurs in late infancy and is characterized by psychomotor regression, epilepsy, and a hypomyelinating leukodystrophy on magnetic resonance imaging. If left untreated, progressive neurodegeneration occurs. However, early treatment with folinic acid has been shown to stabilize or reverse neurological features. Approximately thirty patients have been described worldwide. Here, we report the first two cases with genetically proven cerebral folate transport deficiency from South-Eastern Europe, describe the effect of oral folinic acid therapy on clinical and neuroradiological features and review the literature.

Results: Two siblings presented in childhood with clinical and radiological findings consistent with a hypomyelinating leukodystrophy. Exome sequencing revealed a novel homozygous pathogenic variant in FOLR1 (c.465_466delinsTG; p.W156G), confirming the diagnosis of neurodegeneration due to cerebral folate transport deficiency. Folinic acid treatment was promptly initiated in both patients. The younger sibling was treated early in disease course at 2 years of age, and demonstrated complete recovery in clinical and MRI features. The older sibling, who was 8 years of age at the time of diagnosis and treatment, demonstrated partial but substantial improvements.

Conclusion: We present the first account in the literature that early treatment initiation with oral folinic acid alone can result in complete neurological recovery of both clinical and radiological abnormalities in neurodegeneration due to cerebral folate deficiency. Moreover, through the report of these patients along with review of the literature, we provide information about the natural history of the disease with comparison of treatment effects at different stages of disease progression. This report also reinforces the importance of universal access to genetic testing to ensure prompt diagnoses for treatable disorders.

References

Soden S, Saunders C, Willig L, Farrow E, Smith L, Petrikin J . Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med. 2014; 6(265):265ra168. PMC: 4286868. DOI: 10.1126/scitranslmed.3010076. View

Karin I, Borggraefe I, Catarino C, Kuhm C, Hoertnagel K, Biskup S . Folinic acid therapy in cerebral folate deficiency: marked improvement in an adult patient. J Neurol. 2017; 264(3):578-582. DOI: 10.1007/s00415-016-8387-6. View

Ramaekers V, Segers K, Sequeira J, Koenig M, Van Maldergem L, Bours V . Genetic assessment and folate receptor autoantibodies in infantile-onset cerebral folate deficiency (CFD) syndrome. Mol Genet Metab. 2018; 124(1):87-93. DOI: 10.1016/j.ymgme.2018.03.001. View

Toelle S, Wille D, Schmitt B, Scheer I, Thony B, Plecko B . Sensory stimulus-sensitive drop attacks and basal ganglia calcification: new findings in a patient with FOLR1 deficiency. Epileptic Disord. 2014; 16(1):88-92. DOI: 10.1684/epd.2014.0629. View

Zhang C, Deng X, Wen Y, He F, Yin F, Peng J . First case report of cerebral folate deficiency caused by a novel mutation of FOLR1 gene in a Chinese patient. BMC Med Genet. 2020; 21(1):235. PMC: 7691102. DOI: 10.1186/s12881-020-01162-3. View

Mafi S, Laroche-Raynaud C, Chazelas P, Lia A, Derouault P, Sturtz F . Pharmacoresistant Epilepsy in Childhood: Think of the Cerebral Folate Deficiency, a Treatable Disease. Brain Sci. 2020; 10(11). PMC: 7690394. DOI: 10.3390/brainsci10110762. View

Tabassum S, Alasmari A, AlSaman A . Widening the phenotypic spectrum - Non epileptic presentation of folate transporter deficiency. J Clin Neurosci. 2018; 59:341-344. DOI: 10.1016/j.jocn.2018.10.075. View

Papadopoulou M, Dalpa E, Portokalas M, Katsanika I, Tirothoulaki K, Spilioti M . Cerebral folate deficiency in two siblings caused by biallelic variants including a novel mutation of gene: Intrafamilial heterogeneity following early treatment and the role of ketogenic diet. JIMD Rep. 2021; 60(1):3-9. PMC: 8260484. DOI: 10.1002/jmd2.12206. View

Brunetti S, Malerba L, Giordano L, Parrini E, Guerrini R, Palumbo G . Cerebral folate transporter deficiency syndrome in three siblings: Why genetic testing for developmental and epileptic encephalopathies should be performed early and include the FOLR1 gene. Am J Med Genet A. 2021; 185(8):2526-2531. DOI: 10.1002/ajmg.a.62345. View

10.

Delmelle F, Thony B, Clapuyt P, Blau N, Nassogne M . Neurological improvement following intravenous high-dose folinic acid for cerebral folate transporter deficiency caused by FOLR-1 mutation. Eur J Paediatr Neurol. 2016; 20(5):709-13. DOI: 10.1016/j.ejpn.2016.05.021. View

11.

Linnebank M, Moskau S, Semmler A, Widman G, Stoffel-Wagner B, Weller M . Antiepileptic drugs interact with folate and vitamin B12 serum levels. Ann Neurol. 2011; 69(2):352-9. DOI: 10.1002/ana.22229. View

12.

Ferreira P, Luco S, Sawyer S, Davila J, Boycott K, Dyment D . Late diagnosis of cerebral folate deficiency: Fewer seizures with folinic acid in adult siblings. Neurol Genet. 2016; 2(1):e38. PMC: 4817904. DOI: 10.1212/NXG.0000000000000038. View

13.

Hyland K, Shoffner J, Heales S . Cerebral folate deficiency. J Inherit Metab Dis. 2010; 33(5):563-70. DOI: 10.1007/s10545-010-9159-6. View

14.

Al-Baradie R, Chaudhary M . Diagnosis and management of cerebral folate deficiency. A form of folinic acid-responsive seizures. Neurosciences (Riyadh). 2014; 19(4):312-6. PMC: 4727671. View

15.

Steinfeld R, Grapp M, Kraetzner R, Dreha-Kulaczewski S, Helms G, Dechent P . Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet. 2009; 85(3):354-63. PMC: 2771535. DOI: 10.1016/j.ajhg.2009.08.005. View

16.

Opladen T, Blau N, Ramaekers V . Effect of antiepileptic drugs and reactive oxygen species on folate receptor 1 (FOLR1)-dependent 5-methyltetrahydrofolate transport. Mol Genet Metab. 2010; 101(1):48-54. DOI: 10.1016/j.ymgme.2010.05.006. View

17.

Grapp M, Just I, Linnankivi T, Wolf P, Lucke T, Hausler M . Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency. Brain. 2012; 135(Pt 7):2022-31. DOI: 10.1093/brain/aws122. View

18.

Saunders C, Miller N, Soden S, Dinwiddie D, Noll A, Alnadi N . Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Sci Transl Med. 2012; 4(154):154ra135. PMC: 4283791. DOI: 10.1126/scitranslmed.3004041. View

19.

Kobayashi Y, Tohyama J, Akiyama T, Magara S, Kawashima H, Akasaka N . Severe leukoencephalopathy with cortical involvement and peripheral neuropathy due to FOLR1 deficiency. Brain Dev. 2016; 39(3):266-270. DOI: 10.1016/j.braindev.2016.09.011. View

20.

Weng Q, Wang J, Wang J, Tan B, Wang J, Wang H . Folate Metabolism Regulates Oligodendrocyte Survival and Differentiation by Modulating AMPKα Activity. Sci Rep. 2017; 7(1):1705. PMC: 5431811. DOI: 10.1038/s41598-017-01732-1. View