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Introduction <p>Cerebral folate deficiency syndrome (CFDS) is a rare neurometabolic disorder with clinical features including late infantile onset refractory seizures, ataxia, movement disorder, unexplained global developmental delay, and leukoencephalopathy. It is an autosomal recessive disorder characterized by low levels of the active form of folate (5- MTHF) in cerebrospinal fluid (CSF) caused by mutations in <i>FOLR1</i> gene. This gene encodes the membrane protein folate receptor "FRα,” which is a glycophosphatidylinositol (GPI)-anchored cell membrane protein that regulates folate transport into the cells.</p> Patients and methods <p>Here, we report a consanguineous family with a girl diagnosed with progressive encephalopathy. To determine the genetic cause of this disease, whole exome sequencing (WES) was performed on the affected individual. As a further analysis, molecular docking and bioinformatics predictions were performed.</p> Results <p>WES analysis revealed a novel homozygous frameshift mutation (c.466insT; p. Trp156LeufsTer12) in <i>FOLR1</i> gene. This mutation was present at homozygous state in the affected patient which inherited it from her heterozygous parents. It generates a truncated FRα protein leading to the missing of two important glycosylation sites at Asn139 and Asn179 and the loss of the GPI anchor at Ala204 affecting protein anchoring in the cell membrane. In addition, molecular docking showed that the truncating mutation disturbs the affinity of the FRα receptor to its substrate the folate caused by the loss of important residues in the RFα–folate interaction region. Further, low level of 5-methyltetrahydrofolate was detected in the blood and the CSF of the patient. The patient was then treated with a dose of 5 mg/kg/day of FA as a supplement to antiepileptic drug (AED) leading to mild improvement that was achieved in terms of reactivity and motor skills.</p> Conclusion <p>Based on the c.466insT; p. Trp156LeufsTer12 mutation segregation and low 5-methyltetrahydrofolate levels in the CSF, the studied patient was diagnosed with CFD.</p>

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A novel truncated mutation in folate receptor α (FRα) affecting its glycosylation and affinity for folate in a consanguineous family with progressive encephalopathy: follow up and treatment improvement

  • 期刊论文

  • 发表日期：

    2025年7月11日

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  • Felhi Rahma,
  • Alila-Fersi Olfa,
  • Bahri Mahjoub,
  • Mkaouar-Rebai Emna,
  • Chouchen Jihene,
  • Fahkfakh Faiza,
  • Tlili Abdelaziz

摘要

Introduction

Cerebral folate deficiency syndrome (CFDS) is a rare neurometabolic disorder with clinical features including late infantile onset refractory seizures, ataxia, movement disorder, unexplained global developmental delay, and leukoencephalopathy. It is an autosomal recessive disorder characterized by low levels of the active form of folate (5- MTHF) in cerebrospinal fluid (CSF) caused by mutations in FOLR1 gene. This gene encodes the membrane protein folate receptor "FRα,” which is a glycophosphatidylinositol (GPI)-anchored cell membrane protein that regulates folate transport into the cells.

Patients and methods

Here, we report a consanguineous family with a girl diagnosed with progressive encephalopathy. To determine the genetic cause of this disease, whole exome sequencing (WES) was performed on the affected individual. As a further analysis, molecular docking and bioinformatics predictions were performed.

Results

WES analysis revealed a novel homozygous frameshift mutation (c.466insT; p. Trp156LeufsTer12) in FOLR1 gene. This mutation was present at homozygous state in the affected patient which inherited it from her heterozygous parents. It generates a truncated FRα protein leading to the missing of two important glycosylation sites at Asn139 and Asn179 and the loss of the GPI anchor at Ala204 affecting protein anchoring in the cell membrane. In addition, molecular docking showed that the truncating mutation disturbs the affinity of the FRα receptor to its substrate the folate caused by the loss of important residues in the RFα–folate interaction region. Further, low level of 5-methyltetrahydrofolate was detected in the blood and the CSF of the patient. The patient was then treated with a dose of 5 mg/kg/day of FA as a supplement to antiepileptic drug (AED) leading to mild improvement that was achieved in terms of reactivity and motor skills.

Conclusion

Based on the c.466insT; p. Trp156LeufsTer12 mutation segregation and low 5-methyltetrahydrofolate levels in the CSF, the studied patient was diagnosed with CFD.