摘要 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。
Abstract：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.3006C > G (p.C1002W), and a paternal nonsense mutation, c.1256C > G (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.
JIANG Tie-Jia,JIANG Jing-Jing,XU Jia-Lu et al. Clinical and genetic analyses of a family with atypical nonketotic hyperglycinemia caused by compound heterozygous mutations in the GLDC gene[J]. CJCP, 2017, 19(10): 1087-1091.
Coughlin CR 2nd, Swanson MA, Kronquist K, et al. The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT[J]. Genet Med, 2017, 19(1):104-111.
[2]
Perry TL, Urquhart N, Maclean J, et al. Nonketotic hyperglycinemia. Glycine accumulation due to absence of glycerine cleavage in brain[J]. N Engl J Med, 1975, 292(24):1269-1273.
[3]
Baker PR 2nd, Friederich MW, Swanson MA, et al. Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5[J]. Brain, 2014, 137(Pt 2):366-379.
[4]
Brenton JN, Rust RS. Late-onset nonketotic hyperglycinemia with a heterozygous novel point mutation of the GLDC gene[J]. Pediatr Neurol, 2014, 50(5):536-538.
[5]
Dinopoulos A, Matsubara Y, Kure S, et al. Atypical variants of nonketotic hyperglycinemia[J]. Mol Genet Metab, 2005, 86(1-2):61-69.
Rahman S, Footitt EJ, Varadkar S, et al. Inborn errors of metabolism causing epilepsy[J]. Dev Med Child Neurol, 2013, 55(1):23-36.
[9]
Ezgu F, Çiftci B, Topçu B, et al. Diagnosis of glycine encephalopathy in a pediatric patient by detection of a GLDC mutation during initial next generation DNA sequencing[J]. Metab Brain Dis, 2014, 29(1):211-213.
[10]
Korman SH, Boneh A, Ichinohe A, et al. Persistent NKH with transient or absent symptoms and a homozygous GLDC mutation[J]. Ann Neurol, 2004, 56(1):139-143.
[11]
Swanson MA, Coughlin CR, Scharer GH, et al. Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia[J]. Ann Neurol, 2015, 78(4):606-618.
[12]
Van Hove JL, Vande KK, Hennermann JB, et al. Benzoate treatment and the glycine index in nonketotic hyperglycinaemia[J]. J Inherit Metab Dis, 2005, 28(5):651-663.
[13]
Suzuki Y, Kure S, Oota M, et al. Nonketotic hyperglycinemia:proposal of a diagnostic and treatment strategy[J]. Pediatr Neurol, 2010, 43(3):221-224.
[14]
Deutsch SI, Rosse RB, Mastropaolo J. Current status of NMDA antagonist interventions in the treatment of nonketotic hyperglycinemia[J]. Clin Neuropharmacol, 1998, 21(2):71-79.
[15]
Chien YH, Hsu CC, Huang A, et al. Poor outcome for neonatal-type nonketotic hyperglycinemia treated with high-dose sodium benzoate and dextromethorphan[J]. J Child Neurol, 2004, 19(1):39-42.
[16]
Korman SH, Wexler ID, Gutman A, et al. Treatment from birth of nonketotic hyperglycinemia due to a novel GLDC mutation[J]. Ann Neurol, 2006, 59(2):411-415.
[17]
Bjoraker KJ, Swanson MA, Christodoulou J, et al. Neurodevelopmental outcome and treatment efficacy of benzoate and dextromethorphan in siblings with attenuated nonketotic hyperglycinemia[J]. J Pediatr, 2016, 170:234-239.
[18]
Subramanian V, Kadiyala P, Hariharan P, et al. A rare case of glycine encephalopathy unveiled by valproate therapy[J]. J Pediatr Neurosci, 2015, 10(2):143-145.
