GLDC基因复合杂合突变致非经典型非酮性高甘氨酸血症家系的临床和遗传学分析

Clinical and genetic analyses of a family with atypical nonketotic hyperglycinemia caused by compound heterozygous mutations in the GLDC gene

非酮性高甘氨酸血症(NKH)是由甘氨酸裂解系统缺陷引起的常染色体隐性遗传疾病,分经典型和非经典型,而非经典型表现复杂多样,诊断较为困难。该文报道1个NKH家系,父母表型正常,兄妹均非新生儿期起病,哥哥表现为难治性癫癎、严重的双侧痉挛性瘫痪和智力低下,血和脑脊液的甘氨酸浓度增高,尿甘氨酸与肌酐的比值增高,脑脊液与血甘氨酸浓度的比增高;妹妹表现为语言发育迟缓、共济失调、舞蹈病和发热诱发的精神行为异常和肌张力减退,脑脊液甘氨酸浓度增高、脑脊液与血甘氨酸浓度比增高。高通量测序提示兄妹均存在GLDC基因母源c.3006C>G(p.C1002W)错义突变和父源c.1256C>G(p.S419X)无义突变,生物学软件预测均提示致病突变。转染两种突变体GLDC基因的H293T细胞甘氨酸脱羧酶活性均有下调。NKH表型多样,二代高通量测序有利于疑似病例的确认,非经典NKH与基因突变导致的甘氨酸脱羧酶活性下调相关。

Nonketotic hyperglycinemia（NKH） is an autosomal recessive hereditary disease caused by a defect in the glycine cleavage system and is classified into typical and atypical NKH. Atypical NKH has complex manifestations and is difficult to diagnose in clinical practice. This article reports a family of NKH. The parents had normal phenotypes, and the older brother and the younger sister developed this disease in the neonatal period. The older brother manifested as intractable epilepsy, severe spastic diplegia, intellectual disability, an increased level of glycine in blood and cerebrospinal fluid, an increased glycine/creatinine ratio in urine, and an increased ratio of glycine concentration in cerebrospinal fluid and blood. The younger sister manifested as delayed language development, ataxia, chorea, mental and behavior disorders induced by pyrexia, hypotonia, an increased level of glycine in cerebrospinal fluid, and an increased ratio of glycine concentration in cerebrospinal fluid and blood. High-throughput sequencing found a maternal missense mutation, c.3006CG（p.C1002W）, and a paternal nonsense mutation, c.1256CG（p.S419X）, in the GLDC gene in both patients. These two mutations were thought to be pathogenic mutations by a biological software. H293T cells transfected with these two mutants of the GLDC gene had a down-regulated activity of glycine decarboxylase. NKH has various phenotypes, and high-throughput sequencing helps to make a confirmed diagnosis. Atypical NKH is associated with the downregulated activity of glycine decarboxylase caused by gene mutations.