儿童单纯型甘油激酶缺乏症2例临床及遗传学分析
收稿日期: 2024-07-17
录用日期: 2024-10-23
网络出版日期: 2025-06-01
基金资助
河南省重点研发专项(251111311300);河南省科技发展计划(232102311109);河南省儿童遗传代谢性疾病重点实验室开放课题(SS202205);河南省医学科技攻关计划联合共建项目(LHGJ20240560)
Clinical feature and genetic analysis of two children with isolation glycerol kinase deficiency
Received date: 2024-07-17
Accepted date: 2024-10-23
Online published: 2025-06-01
目的 探讨2例单纯型甘油激酶缺乏症(GKD)患儿的临床表型和基因变异,以提高临床医师对该病的认识。方法 收集2018年3月至2023年12月入院的2例单纯型GKD患儿的临床及基因检查资料,分析其临床特征和基因变异特点。结果 2例患儿均为男性,患儿1就诊时年龄为6岁7个月,表现为阵发性恶心呕吐,伴腹痛、纳差、精神差,存在反复低血糖、代谢性酸中毒、血中酮体和三酰甘油升高、尿中酮体、甘油浓度增高;患儿2就诊时年龄为3个月,出生后窒息、抽搐、昏迷、喂养困难,评估脑损伤住院治疗,发现血甘油三酯升高、尿甘油浓度增高。全外显子组基因检测发现患儿1的GK基因15号外显子存在1个c.1145C>T(p.A382V)半合子变异;患儿2的GK基因6号外显子存在1个c.422C>G(p.T141R)半合子变异,Sanger测序证实c.1145C>T和c.422C>G变异均来自表型正常的母亲,均被评级为临床意义未明,既往未见报道。结论 单纯型GKD急性期表现缺乏特异性,血三酰甘油三酯和尿甘油浓度增高有助于诊断,确诊依赖于GK基因检测。
张利明 , 刘磊 , 杨建伟 , 孙红启 , 杨俊梅 , 陈永兴 . 儿童单纯型甘油激酶缺乏症2例临床及遗传学分析[J]. 临床儿科杂志, 2025 , 43(6) : 458 -463 . DOI: 10.12372/jcp.2025.24e0723
Objective To investigate the clinical characteristics and genetic variations of two children with isolation glycerol kinase deficiency (GKD), fthereby enhancing clinicians' understanding of this the disease. Methods Clinical and genetic data were collected from two pediatric patients with isolated GKD admitted between March 2018 and December 2023.Their clinical manifestations and genetic variation profiles were analyzed systematically. Results Both patients were male. Patient 1 aged 6 years and 7 months, exhibited paroxysmal nausea, vomiting, abdominal pain, anorexia, and lethargy. Laboratory findings revealed recurrent hypoglycemia, metabolic acidosis, elevated blood ketone bodies and triglycerides, as well as increased urinary ketone bodies and glycerol concentrations. Patient 2 aged 3 months,experienced asphyxia, seizures, coma, and feeding difficulties shortly after birth, leading to hospitalization for brain injury assessment. Elevated blood triglycerides and increased urinary glycerol concentrations were detected.. The whole exon gene detection showed that there was a hemizygous variation c.1145C>T (p.A382V) in Exon 15 of GK gene in patient 1, and a hemizygous variation c.422C>G (p.T141R) in Exon 6 of GK gene in patient 2. Sanger sequencing confirmed that both the c.1145C>T and c.422C>G variants were from phenotypically normal mothers and classified as variants of uncertain significance according to the ACMG guidelines, with no prior reports. Conclusion The acute-phase symptoms of isolated GKD lack specificity. Elevated blood triglycerides and urinary glycerol concentrations can aid in diagnosis, while definitive diagnosis relies on GK gene testing.
Key words: glycerol kinase deficiency; hypoglycemia; GK gene; triglycerides; child
[1] | Ribeiro AI, Pinto S, Ayres-Pereira I, et al. Deficiencia de glicerolcinasa: una causa metabolica de retraso global del desarrollo [Glycerol kinase deficiency: a metabolic cause of global developmental delay][J]. Rev Neurol, 2019, 68(4): 179-180. |
[2] | Tao N, Liu X, Chen Y, et al. Delayed diagnosis of complex glycerol kinase defciency in a Chinese male infant: a case report[J]. BMC Pediatr, 2022, 22(1): 517. |
[3] | Pizza A, Picillo E, Onore ME, et al. Xp21 contiguous gene deletion syndrome presenting as Duchenne muscular dystrophy and glycerol kinase deficiency associated with intellectual disability: case report and review literature[J]. Acta Myol, 2023, 42(1): 24-30. |
[4] | Diana Montoya-Williams, Meredith Mowitz. Cholestasis and hepatic iron deposition in an infant with complex glycerol kinase deficiency[J]. Pediatrics, 2017, 140(1): e20161479. |
[5] | Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. |
[6] | Itziar LM, Rocio MG, Jacinto FP, et al. Glycerol kinase deficiency in adults: description of 4 novel cases, systematic review and development of a clinical diagnostic score[J]. Atherosclerosis, 2020, 315: 24-32. |
[7] | Filingeri D, Mackey S, Soller H, et al. A novel GK Ala469Val variant resulting in glycerol kinase deficiency with concurrent hepatoblastoma: A case report[J]. Mol Genet Metab Rep, 2024, 38: 101058. |
[8] | 李秀珍, 刘丽, 梅慧芬, 等. 儿童复合型甘油激酶缺乏症[J]. 中国当代儿科杂志, 2007, 9(5): 441-444. |
Li XZ, Liu L, Mei HF, et al. Complex glycerol kinase deficiency in children[J]. Zhongguo Dangdai Erke Zazhi, 2007, 9(5): 441-444. | |
[9] | Heide S, Afenjar A, Edery P. Xp21 deletion in female patients with intellectual disability: Two new cases and a review of the literature[J]. Eur J Med Genet, 2015, 58(6-7): 341-345. |
[10] | 石淑娟, 乔凌燕, 李堂. 儿童单纯型甘油激酶缺乏症1例报告并文献复习[J]. 山东医药, 2021, 61(2): 59-62. |
Shi SJ, Qiao LY, Li T. Simple glycerol kinase deficiency in a child: a case report and literature review[J]. Shandong Yiyao, 2021, 61(2): 59-62. | |
[11] | Sjarif DR, Révész T, De Koning TJ, et al. Isolated glycerol kinase deficiency and Fanconi anemia[J]. Am J Med Genet, 2001, 99(2): 159-160. |
[12] | Sjarif DR, Sinke RJ, Duran M, et al. Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency[J]. J Med Genet, 1998, 35(8): 650-656. |
[13] | Zhang YH, Huang BL, Jialal I, et al. Asymptomatic isolated human glycerol kinase deficiency associated with splice-site mutations and nonsense-mediated decay of mutant RNA[J]. Pediatr Res, 2006, 59(4 Pt 1): 590-592. |
[14] | Hellerud C, Adamowicz M, Jurkiewicz D, et al. Clinical heterogeneity and molecular findings in five Polish patients with glycerol kinase deficiency: investigation of two splice site mutations with computerized splice junction analysis and Xp21 gene-specific mRNA analysis[J]. Mol Genet Metab, 2003, 79(3): 149-159. |
[15] | Illsinger S, Marquardt I, Lücke T, et al. Two cases of isolated glycerol kinase deficiency with heterogeneous neurological symptoms[J]. Dev Med Child Neurol, 2007, 49(5): 396-397. |
[16] | Sargent CA, Kidd A, Moore S, et al. Five cases of isolated glycerol kinase deficiency, including two families: failure to find genotype: phenotype correlation[J]. J Med Genet, 2000, 37(6): 434-441. |
[17] | Hellerud C, Wramner N, Erikson A, et al. Glycerol kinase deficiency: follow-up during 20 years, genetics, biochemistry and prognosis[J]. Acta Paediatr, 2004, 93(7): 911-921. |
[18] | Hellerud C, Burlina A, Gabelli C, et al. Glycerol metabolism and the determination of triglycerides-clinical, biochemical and molecular findings in six subjects[J]. Clin Chem Lab Med, 2003, 41(1): 46-55. |
[19] | Eriksson A, Lindstedt S, Ransn?s L, et al. Deficiency of glycerol kinase (EC 2.7.1.30)[J]. Clin Chem, 1983, 29(4): 718-722.. |
[20] | Sjarif DR, Dorland L, Sperl W, et al. Hyperketonaemia in glycerol kinase deficiency[J]. J Inherit Metab Dis, 2000, 23(7): 760-764. |
[21] | Blomquist HK, Dahl N, Gustafsson L, et al. Glycerol kinase deficiency in two brothers with and without clinical manifestations[J]. Case Reports Clin Genet, 1996, 50(5): 375-379. |
[22] | Ginns EI, Barranger JA, McClean SW, et al. A juvenile form of glycerol kinase deficiency with episodic vomiting, acidemia, and stupor[J]. J Pediatr, 1984, 104(5): 736-739. |
[23] | Zhang YH, Hove JL Van, McCabe ER, et al. Gestational diabetes associated with a novel mutation (378-379insTT) in the glycerol kinase gene[J]. Mol Genet Metab Rep, 2015, 4: 42-45. |
[24] | Romero FF, Bermúdez de la Vega JA, Martin CG, et al. Hyperglycerolemia, a pseudo-hypertriglyceridemia: a case report[J]. An Pediatr (Barc), 2009, 71(1): 68-71. |
[25] | 曾兰兰, 李浩贤, 梅利斌, 等. 甘油激酶缺乏症基因突变分析[C]. 第十四次全国医学遗传学学术会议论文汇编, 2015年. |
Zeng LL, Li HX, Mei LB, et al. Mutation analysis of the glycerol kinase deficiency gene[C]. Proceedings of the 14th National Academic Conference on Medical Genetics, 2015. | |
[26] | Lewis B, Harbord M, Keenan R, et al. Isolated glycerol kinase deficiency in a neonate[J]. J Child Neurol, 1994, 9(1): 70-73. |
[27] | Zhang Y, Dipple KM, Vilain E, et al.AluY insertion (IVS4-52ins316alu) in the glycerol kinase gene from an individual with benign glycerol kinase deficiency[J]. Hum Mutat, 2000, 15(4): 316-323. |
[28] | Rughani A, Blick K, Pang H, et al. Pseudo-hypertriglyceridemia: a novel case with important clinical implications[J]. Case Rep Pediatr, 2020: 1-4. |
[29] | 范瑞, 张一宁, 李小平, 等. 复合型甘油激酶缺乏症2例报告并文献复习[J]. 临床儿科杂志, 2018, 36(3): 197-201. |
Fan R, Zhang YN, Li XP, et al. Complex glycerol kinase deficiency: two cases report and literature review[J]. Lingchuang Erke Zazhi, 2018, 36(3): 197-201. | |
[30] | James MB, Thomas DD, Daniel MH, et al. Hypertriglyceridaemia unresponsive to multiple treatments[J]. BMJ Case Rep, 2015: bcr2015210788. |
[31] | Fu XW, Williamson CP, Bosfield K. Pseudo-hypertriglyceridemia in a 2-year-old male with global developmental delay, myopathy and adrenal hypoplasia[J]. J Mass Spectrom Adv Clin Lab, 2024, 32: 47-49. |
[32] | Gaudet D, Arsenault S, Pérusse L, et al. Glycerol as a correlate of impaired glucose tolerance: dissection of a complex system by use of a simple genetic trait[J]. Am J Hum Genet, 2000, 66(5): 1558-1568. |
[33] | Sjarif DR, Ploos van Amstel JK, Duran M, et al. Isolated and contiguous glycerol kinase gene disorders: a review[J]. J Inherit Metab Dis, 2000, 23(6): 529-547. |
[34] | Dipple KM, Zhang YH, Huang BL, et al. Glycerol kinase deficiency: evidence for complexity in a single gene disorder[J]. Hum Genet, 2001, 109(1): 55-62. |
/
〈 |
|
〉 |