目的 探讨儿童L-2-羟基戊二酸尿症(L-2-HGA)的临床特征及基因诊断依据.方法 对2015年4月至2018年3月首都医科大学附属北京儿童医院诊治的4例L-2-HGA患儿的临床表现、辅助检查结果进行回顾性分析,并对其进行3个月 ～3年2个月的随访.结果 本组患儿男1例,女3例,其中2例为同胞姐弟,起病年龄8个月 ～3岁.4例患儿均以抽搐为首发症状,发育里程碑均正常,其中3例渐出现智力发育停滞,3例走路稍欠稳,2例持物轻抖,2例锥体束征阳性.4例患儿头颅磁共振成像(MRI)均示双侧大脑皮质下白质、基底核区及小脑齿状核对称性异常信号,1例有脑萎缩样改变.3例气相色谱-质谱法(GC/MS)尿有机酸分析均提示2-羟基戊二酸水平明显升高.4例患儿采用目标捕获高通量测序法均检测出L2HGDH基因的致病性变异,例1检测出复合杂合变异c.845G>A(p.Arg282Gln)及c.800_801delCA(p.Ser267Ter),例2、例3检测出纯合错义变异c.584A>G(p.Tyr195Cys),例4检测出纯合移码变异c.407delA(p.Lys136SerfsTer3),其中,c.800_801delCA及c.407delA为未见报道的新变异,家系验证显示4例患儿的父母均为杂合携带者.随访研究显示2例未接受特殊治疗的患儿病情相对稳定,另2例接受大剂量维生素B 2和左旋肉碱治疗的患儿无智力倒退,未再抽搐,共济失调表现略有好转.结论 智力发育迟滞、抽搐发作和共济失调是L-2-HGA的常见临床表现,头颅MRI示双侧大脑皮质下白质、基底核和小脑齿状核对称性异常信号是本病的特征性影像学表现,尿2-羟基戊二酸水平显著升高是本病的基本特点,基因诊断应作为确诊本病的金标准,大剂量维生素B2和左旋肉碱治疗可能对部分病例有效.%Objective To investigate the clinical features and gene diagnostic bases of childhood L-2 -hydroxyglutaric aciduria (L-2-HGA). Methods The clinical data involving manifestations,laboratory examinations of 4 children with L-2-HGA admitted to Beijing Children′s Hospital Affiliated to Capital Medical University from April 2015 to March 2018 were retrospectively analyzed. Each patient had a follow-up visit ranging from 3 months to 3 years and 2 months after initial examination. Results The 4 patients,of whom 2 were siblings,consisted of 1 male and 3 females,whose age of onset ranged from 8 months old to 3 years old. All of them presented with seizures as their initial symptom. The developmental milestones were all normal before onset,while 3 cases gradually became mentally stagnant. Other symptoms included unsteady gait in 3 cases,slight hand trembling when holding items in 2 cases,and pyramidal impairment in 2 cases. Bilateral symmetric abnormalities in subcortical white matter,basal ganglia and dentate nucleus were detected by cranial magnetic resonance imaging (MRI)in all patients,and cerebral and cerebellar atrophy was ob-served in 1 case. Organic acid analysis by gas chromatography/ mass spectrometry (GC/ MS)demonstrated notable ele-vation of urinary 2-hydroxyglutaric acid in 3 cases. Pathogenic mutations on L2HGDH gene were detected by target -capture high-throughput sequencing in all 4 patients. The compound heterozygous mutations of c. 845G > A (p. Arg282Gln)and c. 800_801delCA (p. Ser267Ter)were identified in case 1,the homozygous missense mutation of c. 584A > G (p. Tyr195Cys ) in case 2 and case 3,and the homozygous frameshift mutation of c. 407delA (p. Lys136SerfsTer3)in case 4. The variants of c. 800_801delCA and c. 407delA were novel mutations firstly reported in this study. Sanger sequencing verified that parents of the 4 cases were all heterozygous carriers. The follow-up study in 2 cases who were put on high dosage of vitamin B2 and L-carnitine had shown a relatively favorable outcome of mild remission in ataxia and absence of mental degradation and further seizures,while the other 2 cases without specific therapy remained relatively stable. Conclusions The main clinical manifestations of L-2-HGA are mental retarda-tion,seizures and ataxia. Bilateral symmetric abnormalities in subcortical white matter,basal ganglia and dentate nucleus are specific neuroimaging findings. Significant elevation of urinary 2-hydroxyglutaric acid is the basic feature of the disease,while gene assessment should be the gold standard in the diagnosis of L-2-HGA. Treatment with high dosage of vitamin B2 and L-carnitine might be effective to partial patients.
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