背景:氨基甲酰磷酸合成酶1(CPS1)缺乏症(OMIM237300),常染色体隐性遗传罕见和严重的尿素循环障碍,与高氨血症和高死亡率有关。
方法:本文介绍了2014年9月至2023年8月北京大学第一医院儿童医学中心收治的7例临床特征良好的中国CPS1缺乏症患者的12种遗传变异。
结果:7名患者(2名男性和5名女性患者,包括2名姐妹)在2天至13岁之间出现症状,他们在2个月至20年间被诊断为CPS1缺乏症。血氨的峰值水平范围为160至1,000µmol/L。3例患者出现早发性CPS1缺乏症,用苯丁酸钠治疗后只有一人存活,N-氨基甲酰基-L-谷氨酸,在4个月时进行肝移植,显示出有利的结果。其余4例患者有迟发性CPS1缺乏症,表现出智力迟钝,精神症状,和自我选择的低蛋白饮食。在这些患者中确定的12种CPS1变体中,10是小说,所有患者均表现出CPS1突变等位基因的复合杂合性。七个变体(c.149T>C,c.616A>T,c.1145C>T,c.1294G>A,c.3029C>T,c.3503A>T,和c.3793C>T)导致单个氨基酸取代。三个移码变体(c.2493del,c.3067dup,和c.3241del)被确定,导致酶截短。一个突变(c.3506_3508del)导致框内单氨基酸缺失,而另一个(c.2895+2T>C)导致异常剪接。
结论:除了两个已知的变体,所有其他变体均被鉴定为新型变体.在患者中未观察到热点变异。我们的数据有助于扩展CPS1的突变谱。
BACKGROUND: Carbamoyl phosphate synthetase 1 (CPS1) deficiency (OMIM 237300), an autosomal recessive rare and severe urea cycle disorder, is associated with hyperammonemia and high mortality.
METHODS: Herein we present 12 genetic variants identified in seven clinically well-characterized Chinese patients with CPS1 deficiency who were admitted to the Children\'s Medical Center of Peking University First Hospital from September 2014 to August 2023.
RESULTS: Seven patients (two male and five female patients including two sisters) experienced symptoms onset between 2 days and 13 years of age, and they were diagnosed with CPS1 deficiency between 2 months and 20 years. Peak blood ammonia levels ranged from 160 to 1,000 µmol/L. Three patients showed early-onset CPS1 deficiency, with only one surviving after treatment with sodium phenylbutyrate, N-carbamoyl-L-glutamate, and liver transplantation at 4 months, showing a favorable outcome. The remaining four patients had late-onset CPS1 deficiency, presenting with mental retardation, psychiatric symptoms, and self-selected low-protein diets. Among the 12 CPS1 variants identified in these patients, 10 were novel, with all patients exhibiting compound heterozygosity for CPS1 mutant alleles. Seven variants (c.149T > C, c.616 A > T, c.1145 C > T, c.1294G > A, c.3029 C > T, c.3503 A > T, and c.3793 C > T) resulted in single amino acid substitutions. Three frameshift variations (c.2493del, c.3067dup, and c.3241del) were identified, leading to enzyme truncation. One mutation (c.3506_3508del) caused an in-frame single amino acid deletion, while another (c.2895 + 2T > C) resulted in aberrant splicing.
CONCLUSIONS: Except for two known variants, all other variants were identified as novel. No hotspot variants were observed among the patients. Our data contribute to expanding the mutation spectrum of CPS1.