PDF(Pubmed)
Abstract：
Cerebral folate transport deficiency due to folate receptor 1 gene (FOLR1) gene mutation results from impaired folate transport across the blood: choroidplexus: cerebrospinal fluid (CSF) barrier. This leads to low CSF 5-methyltetrahydrofolate, the active folate metabolite. We are reporting two children with this treatable cerebral folate transport deficiency. Eight years and 9-month-old female presented with delayed milestones followed by regression, seizures, and intention tremors. On examination child had microcephaly, generalized hypotonia, hyperreflexia, unsteady gait, and incoordination. Magnetic resonance imaging (MRI) of brain revealed dilated ventricular system and cerebellar atrophy. Computed tomography (CT) of brain showed brain calcifications. Whole exome sequencing was finally performed, revealing homozygous nonsense pathogenic variant in FOLR1 gene in exon 3 c.C382T p.R128W, confirming the diagnosis of cerebral folate deficiency. Twelve-year-old female child presented with global developmental delay since birth, myoclonic jerks and cognitive regression. Child had generalized hypotonia and hyperreflexia. Her coordination was markedly affected with intention tremors andunbalanced gait. CT brain showed bilateral basal ganglia and periventricular calcifications with brain atrophic changes. MRI brain showed a prominent cerebellar folia with mild brain atrophic changes. Genetic testing showed a homozygous pathogenic variant was identified in FOLR1 C.327_328 delinsAC, p.Cys109Ter. Both patients were started on intramuscular folinic acid injections with a decrease in seizure frequency. However, their seizures did not stop completely due to late initiation of therapy. In conclusion, cerebral folate transport deficiency should be suspected in every child with global developmental delay, intractable myoclonic epilepsy, ataxia with neuroimaging suggesting cerebellar atrophy and brain calcifications. Response to folinic acid supplementation is partial if diagnosed late and treatment initiation is delayed.
摘要：
由于叶酸受体1基因（FOLR1）基因突变导致的脑叶酸转运缺陷是由于叶酸通过血液的转运受损：脉络丛：脑脊液（CSF）屏障。这导致低CSF5-甲基四氢叶酸，活性叶酸代谢产物。我们报告了两名患有这种可治疗的脑叶酸转运缺乏症的儿童。8岁9个月大的女性出现了延迟的里程碑，然后是回归，癫痫发作,和意图颤抖。经检查，孩子患有小头畸形，广泛性低张力,反射亢进,步态不稳定,和不协调。脑磁共振成像（MRI）显示心室系统扩张和小脑萎缩。脑计算机断层扫描（CT）显示脑钙化。最终进行了全外显子组测序，揭示FOLR1基因外显子3c.C382Tp.R128W的纯合无义致病变异，确认大脑叶酸缺乏的诊断。12岁的女性儿童自出生以来出现了全球发育迟缓，肌阵挛性抽搐和认知退化。儿童有广泛性张力减退和反射亢进。她的协调性明显受到有意震颤和步态不平衡的影响。头颅CT显示双侧基底节及脑室周围钙化伴脑萎缩性改变。MRI脑部显示突出的小脑叶，轻度脑萎缩性变化。遗传检测显示在FOLR1C.327_328delinsAC中鉴定出纯合致病变异体，p.Cys109Ter.两名患者均开始肌内注射亚叶酸，癫痫发作频率降低。然而,他们的癫痫发作没有完全停止,因为治疗开始较晚.总之,每个患有全球发育迟缓的儿童都应该怀疑大脑叶酸转运缺乏，顽固性肌阵挛性癫痫,共济失调，神经影像学提示小脑萎缩和脑钙化。如果诊断晚并且治疗开始延迟，对亚叶酸补充的反应是部分的。
