摘要目的 探讨遗传性叶酸吸收障碍的临床、生化、影像及基因突变特点.方法 对2013-2015年北京大学第一医院儿科收治的2例遗传性叶酸吸收障碍患儿的临床表现、实验室检查、治疗及家系SLC46A1基因进行分析,并回顾2016年9月之前报道的文献.总结遗传性叶酸吸收障碍的临床和遗传学特点.结果 2例患儿于婴儿期出现大细胞贫血,幼儿期出现抽搐发作,智力、运动发育落后伴倒退.例l 平均红细胞容积100 fl,血叶酸9.96 nmol/L,脑脊液叶酸0,脑脊液5-甲基四氢叶酸0.01 nmol/L.例2 平均红细胞容积93.9 fl,血清叶酸4.49 nmol/L,脑脊液叶酸和5-甲基四氢叶酸为0.头颅CT示双侧对称性多发颅内钙化,进行性加重.2例患儿及父母SLC46A1基因均检出两个复合杂合突变,支持遗传性叶酸吸收障碍的诊断.例1 携带c.1238T＞ C(L413P)和c.194-195insG(p.Cys66LeufsX99),其中c.1238T＞ C(L413P)为新突变.例2存在c.1A＞T(M1L)和c.194-195insG(p.Cys66LeufsX99)均为已知突变.确诊后给予大剂量亚叶酸钙治疗(60～120 mg/d),智力、运动逐渐改善,1个月后贫血纠正,脑脊液叶酸和5-甲基四氢叶酸较前显著升高.检索国内外文献,共报道遗传性叶酸吸收障碍37例,30例明确SLC46A1基因突变(1例中国病例);100％婴儿期起病,男女比为1:1.5,表现为大细胞贫血(77％),喂养困难(50％)和腹泻(27％)、智力运动发育落后(63.6％)和癫痫(27％)、呼吸系统感染(46％);血和脑脊液叶酸浓度降低(73％和64％).27％出现低免疫球蛋白血症.SLC46A1基因p.65至p.68区域为突变高发区,以缺失/插入突变或终止密码突变为主.口服和(或)静脉或肌注亚叶酸钙治疗可缓解症状.结论 遗传性叶酸吸收障碍表现为大细胞贫血、消化和神经系统异常及免疫功能低下易反复感染,血清和脑脊液叶酸降低和SLC46A1基因分析明确诊断,早期亚叶酸钙治疗可改善预后.

abstractsObjective This study aimed to investigate the clinical,biochemical and genetic features of two Chinese children with hereditary folate malabsorption.Method Clinical features,laboratory examinations,treatment and SLC46A1 gene of two cases were studied.Reports on hereditary folate malabsorption utill September of 2016 were searched and the clinical and genetic characteristics of reported cases were summarized.Result The two patients presented with megaloblastic anemia from their infant period and seizures,psychomotor retardation and regression.In casel,mean corpuscular volume (MCV) was 100 ft.Serum folate was 9.96 nmol/L.Folate and 5-methylenetetrahydrofolate in cerebrospinal fluid were 0 and 0.01 separately.In case 2,MCV was 93.9 ft.Serum folate was 4.49 nmol/L.The concentration of folate and 5-methylenetetrahydrofolate in cerebrospinal fluid were both zero.On their brain CT,progressive bilateral symmetrical calcification was observed.On their SLC46A1 gene,four mutations were identified.Case 1 had one novel mutation,c.1238T ＞C (L413P) and c.194-195 insG (p.Cys66LeufsX99).From Case 2,two reported mutations,c.1A ＞ T (M1L) and c.194-195insG (p.Cys66LeufsX99) were identified.The administration of folinic acid (60 to 120 mg per day) was initiated after diagnosis.Clinical improvement and normalized hematologic markers were observed after treatment.Totally 37 cases were reported in reviewed English literature,including 30 cases with mutations on SLC46A1 gene (only one Chinese patient).All the cases had the onset in infancy.The ratio of boys to girls was 1 to 1.5.Main manifestations were characterized by megaloblastic anemia (77％),failure to thrive (50％),diarrhea (27％),psychomotor retardation (63.6％),epilepsy (27％),and infection of respiratory system (45.5％).The concentration of folate in both serum and cerebrospinal fluid was decreased (72.7％ and 63.6％ respectively).Hypoimmunoglobulinemia accounted for 27.3％.Most of mutations in HFM were distributed between p.65 and p.68 (c.194-c.204),mainly due to insertion-or deletion-related frame shifts or generation of stop codons.Oral and parenteral folinic acid treatment was effective.Conclusion Hereditary folate malabsorption often presented with megaloblastic anemia,abnormalities of digestive and nervous system,and hypoimmunoglobulinemia with recurrent infections.Low level of serum and CSF folate and screening SLC46A1 gene are keys to the etiologic study of the patients.Early supplement with folinic acid is beneficial to the prognosis.