First case report of cerebral folate deficiency caused by a novel mutation of FOLR1 gene in a Chinese patient

Abstract

Background Cerebral folate deficiency (CFD) is a neurological disease, hallmarked by remarkable low concentrations of 5-methyltetrahydrofolic acid (5-MTHF) in cerebrospinal fluid (CSF). The primary causes of CFD include the presence of folate receptor (FR) autoantibodies, defects of FR encoding gene FOLR1, mitochondrial diseases and congenital abnormalities in folate metabolism. Case presentation Here we first present a Chinese male CFD patient whose seizure onset at 2 years old with convulsive status epilepticus. Magnetic Resonance Imaging (MRI) revealed the development of encephalomalacia, laminar necrosis in multiple lobes of the brain and cerebellar atrophy. Whole Exome Sequencing (WES) uncovered a homozygous missense variant of c.524G > T (p.C175F) in FOLR1 gene. Further laboratory tests demonstrated the extremely low level of 5-MTHF in the CSF from this patient, which was attributed to cerebral folate transport deficiency. Following the intravenous and oral treatment of calcium folinate, the concentrations of 5-MTHF in CSF were recovered to the normal range and seizure symptoms were relieved as well. Conclusions One novel variation of FOLR1 was firstly identified from a Chinese male patient with tonic-clonic seizures, developmental delay, and ataxia. The WES and laboratory results elucidated the etiology of the symptoms. Clinical outcomes were improved by early diagnosis and proper treatment.

Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis

“…Dysfunction of the FRα can occur through several mechanisms. In only rare cases, genetic mutations in the gene encoding for FRα (FOLR1) is a cause of CFD [22,23]. Two other mechanisms are more prevalent in causing FRα dysfunction.…”

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

“…They were not documented in three reported patients [ 1 , 13 , 15 ], while all the other patients manifested various combinations of myoclonic, atonic, tonic–clonic, tonic, absence seizures, epileptic spasms [ 10 , 13 ], and/or focal seizures with and without impaired awareness. The most common were myoclonic seizures, observed in all but four patients [ 2 , 13 , 16 , 17 ]. The seizures were commonly described as drug-resistant, of high frequency, and frequently evolving to status epilepticus.…”

“…Four patients had accompanied bulbar signs [ 14 , 18 ], and 13 patients had accompanied pyramidal signs [ 1 , 2 , 9 , 10 , 18 , 19 ]. Autistic behavioral features were observed in 18 patients [ 1 , 2 , 12 , 13 , 17 , 19 – 22 ]. Congenital microcephaly was described in one patient [ 2 ], while acquired microcephaly was noted in five patients [ 2 , 17 , 21 ].…”

“…Autistic behavioral features were observed in 18 patients [ 1 , 2 , 12 , 13 , 17 , 19 – 22 ]. Congenital microcephaly was described in one patient [ 2 ], while acquired microcephaly was noted in five patients [ 2 , 17 , 21 ]. Head circumference was normal in all other patients.…”

Microcephaly in Neurometabolic Diseases

“…Impaired functioning of the FR⍺ most often results from the presence of autoantibodies blinding to the FR⍺, which disrupts its function, or results from a rare mutation in the FOLR1 gene, which can lead to an autosomal recessive genetic condition that disrupts FR⍺ function. The receptor becomes dysfunctional so that hardly any folic acid or MTHF can be properly transported to the brain, which leads to many neurological consequences [ 50 , 51 , 52 ]. Fewer than 20 individuals with CFD have been reported in scientific literature.…”