糖原累积症Ⅸ型12例临床、病理特点及基因突变位点分析

Clinical and pathological features and gene mutation analysis in 12 Chinese patients with glycogen storage disease type Ⅸ

目的探讨糖原累积症Ⅸ型(Glycogen storage disease typeⅨ,GSDⅨ)的临床、病理和基因突变特点。方法回顾性分析2015年10月至2017年10月在解放军第三○二医院青少年肝病诊疗与研究中心住院治疗的12例经基因检测确诊为GSDⅨ型的患者,总结其临床、病理特点及与基因突变的关系。结果 12例GSDⅨ型患者根据基因突变位点的不同分为三类,其中GSDⅨa型10例,均为男性,GSDⅨb型1例,女性,GSDⅨc型1例,女性。发病年龄中位数为2.1岁。所有患者均有肝大和肝功能异常,伴不同程度的低血糖10例,生长发育落后7例,伴有尿酮体阳性6例、高三酰甘油3例、高乳酸4例。12例患者肝脏病理炎症程度均为G1-2,纤维化程度S1-2 8例,S2-3 3例,肝硬化S4 1例。所有的肝脏病理糖原染色阳性。12例患者共检测出13个糖原磷酸化酶激酶基因突变位点,包括11个错义突变,1个缺失突变,1个剪切突变。其中5个为新发现的突变,分别为PHKA2三个:c.3597-3598del(p.F1199fs),c.1039C>T (p.Q347X),c.749C>T (p.s250L);PHKB一个:c.1776+1G>T (splicing);PHKG2一个:c.925 C>T (p.R309 W)。经生玉米淀粉口服等干预治疗,患儿症状可减轻。结论肝大并转氨酶异常的患儿需考虑GSDⅨ型诊断,确诊及分型依赖于基因检测。GSDⅨ型尽早干预可改善预后。

Objective To analyze the clinical, pathological features and gene mutations of glycogen storage disease type IX （GSD IX） for improving clinical understanding of the disease. Methods Data of 12 pediatric patients who had been genetically diagnosed of GSD IX and hospitalized in our hospital from October 2015 to October 2017 were analyzed retrospectively. Results According to gene mutations, 12 patients were divided into 3 types, including 10 boys diagnosed of GSD IRa, 1 girl diagnosed of GSD IX b and 1 girl diagnosed of GSD IX c. The median onset age was 2. 1 years old. All patients had elevated transaminase levels and hepatomegaly （100%, 12/12）. Most patients had different degrees of hypoglycemia （83.3%, 10/12） and growth retardation （58.3%, 7/12）. Some patients were with positive urine ketone bodies （50%, 6/12）, hypertriglyceridemia （25%, 3/12） and hyperlactacidemia （33.3%, 4/12）. All patients were with mild inflammation （G1 2） histologically, among which 8 （66.7%） were in $1 2, 3 （25%） were in $2 3, and 1 （8.3%） was in $4. All cases （12/12） were positive stained with periodic acid Schiff reaction. There were 13 phosphorylase kinase （PHK） gene mutations detected in the 12 patients, including 11 missense mutation, 1 deletion mutation and 1 shear mutation. Five novel mutations were identified, including 3 in PHKA2 （p. Fl199fs, p. Q347X and p. s250L）, 1 in PHKB （c. 1776 ＋ 1G^T） and 1 in PHKG2 （p. R309W）. Raw cornstarch therapy could alleviate the symptoms in most of these patients. Conclusion GSD IX should be considered in pediatric patients with hepatomegaly and elevated transaminase levels. The accurate diagnosis and classification of GSD IX depend on genetic test. Intervention should be performed as early as possible to improve the prognosis.