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

Ciliu Zhang, Xiaolu Deng, Yafei Wen, Fang He, Fei Yin, and Jing Peng

1 Xiangya Hospital Central South University, 87 Xiangya Road, Changsha, Hunan 410008 P.R. China 2 XiangYa School of Medicine of Central South University, 172 Tongzipo Road, Changsha, Hunan 410013 P.R. China Jing Peng, Email: moc.361@6434gnijgnep.

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.

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

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.

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

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.

Keywords: Seizures, FOLR1, 5-MTHF, Calcium folinate

Background

As defined in 2004 by Ramaekers and Blau, Cerebral Folate Deficiency (CFD) encompasses a collection of neurological syndromes associated with low cerebrospinal fluid (CSF) concentrations of 5-methyltetrahydrofolate (5-MTHF), the normal folate metabolism in nervous system [1]. The circumstantial evidence show that CFD is caused by congenital metabolic disorders and the acquired folic acid deficiency [2, 3]. The most common cause of CFD is the presence of folate receptor (FR) autoantibodies [4]. In addition, defects of FR encoding gene FOLR1, mitochondrial diseases and congenital abnormalities in folate metabolism could also lead to CFD. FOLR1 (OMIM#613068), located in the long arm of chromosome 11, encodes for folate receptor α (FRα) [5]. Binding of FRα with 5-MTHF in high affinity is essential for the transportation of folate to the brain [6, 7]. Thus, pathogenic variants of FOLR1 could result in brain-specific 5-MTHF deficiency, and ultimately cause a series of neuropsychiatric symptoms [5]. Normally, the onset of CFD caused by mutated FOLR1 begins from late infancy [8], with the major clinical manifestations including developmental retardation, dyskinesia, epileptic seizure, leukodystrophy and slow EEG background activity. In infant patients, 5-MTHF concentration in cerebrospinal fluid is also extremely low, but remains normal in peripheral nervous system, indicating that the cerebral 5-MTHF deficiency is the underlying mechanism for infant CFD.

Case presentation

Patient

The Chinese patient was born at full term through normal vaginal delivery, weighting 3.25 kg that fell in the normal range of newborn weights. He showed developmental delay and mental retardation since one and half years old. He was able to raise his head at 3 months, sit at 6 ~ 7 months, walk at 24 months, and learn limited vocabulary at 12 months. The patient was in poor physical health since he was 2 years old.