First case report of cerebral folate deficiency caused by a novel mutation of FOLR1 gene in a Chinese patient
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CASE REPORT
Open Access
First case report of cerebral folate deficiency caused by a novel mutation of FOLR1 gene in a Chinese patient Ciliu Zhang1, Xiaolu Deng1, Yafei Wen2, Fang He1, Fei Yin1 and Jing Peng1*
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. 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 (5MTHF), 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, * Correspondence: [email protected] 1 Xiangya Hospital Central South University, 87 Xiangya Road, Changsha, Hunan 410008, P.R. China Full list of author information is available at the end of the article
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 r
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