PDF(Pubmed)
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.
CONCLUSIONS: 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.
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.
CONCLUSIONS: 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.
摘要：
背景：脑叶酸转运缺乏引起的神经变性是一种罕见的常染色体隐性遗传疾病，由FOLR1的双等位基因致病变异引起。发病通常发生在婴儿期晚期，以精神运动回归为特征，癫痫,和磁共振成像显示的骨髓过多性脑白质营养不良。如果不及时治疗，发生进行性神经变性。然而,亚叶酸早期治疗可稳定或逆转神经系统特征.全世界已经描述了大约30名患者。这里,我们报道了前两例来自东南欧的基因证实的脑叶酸转运缺乏症，描述口服亚叶酸治疗对临床和神经放射学特征的影响，并回顾文献。
结果：两名兄弟姐妹在童年时期出现临床和放射学检查结果与骨髓过细的脑白质营养不良一致。外显子组测序揭示了FOLR1中的一种新的纯合致病变体（c.465_466delinsTG；p.W156G），确认由于脑叶酸转运缺乏而导致的神经变性的诊断。两名患者均迅速开始亚叶酸治疗。年幼的兄弟姐妹在2岁时在病程早期接受治疗，并证明临床和MRI特征完全恢复。年长的兄弟姐妹，诊断和治疗时的8岁，展示了部分但实质性的改进。
结论：我们提出了文献中的第一个说法，即早期开始口服亚叶酸单独治疗可导致脑叶酸缺乏引起的神经变性的临床和放射学异常完全恢复。此外，通过对这些患者的报告以及文献的回顾，我们提供有关疾病自然史的信息，并比较疾病进展不同阶段的治疗效果。该报告还强调了普遍获得基因检测的重要性，以确保及时诊断可治疗的疾病。
结果：两名兄弟姐妹在童年时期出现临床和放射学检查结果与骨髓过细的脑白质营养不良一致。外显子组测序揭示了FOLR1中的一种新的纯合致病变体（c.465_466delinsTG；p.W156G），确认由于脑叶酸转运缺乏而导致的神经变性的诊断。两名患者均迅速开始亚叶酸治疗。年幼的兄弟姐妹在2岁时在病程早期接受治疗，并证明临床和MRI特征完全恢复。年长的兄弟姐妹，诊断和治疗时的8岁，展示了部分但实质性的改进。
结论：我们提出了文献中的第一个说法，即早期开始口服亚叶酸单独治疗可导致脑叶酸缺乏引起的神经变性的临床和放射学异常完全恢复。此外，通过对这些患者的报告以及文献的回顾，我们提供有关疾病自然史的信息，并比较疾病进展不同阶段的治疗效果。该报告还强调了普遍获得基因检测的重要性，以确保及时诊断可治疗的疾病。
