Lesch-Nyhan综合征8例临床特征及HPRT1基因变异分析

doi:10.12372/jcp.2023.22e1637

摘要/Abstract

摘要：

目的分析Lesch-Nyhan综合征的临床特征及HPRT1基因变异特点，以提升对该病的认识。方法回顾性分析2015年7月至2019年11月诊断并随访的8例患儿的临床表现、实验室检查及基因检测结果，总结患儿的临床特征及HPRT1基因变异特点。结果 8例患儿均为男性，于3月龄至11月龄起病，主因发育落后就诊，同时有锥体系及锥体外系症状，4例在就诊前已出现自残行为，4例目前尚未出现自残行为，血清尿酸不同程度增高。HPRT1基因检测出6种变异（c.609+5G>A、exon 2-3 del、c.131G>A、exon7-8 del、c.384+2T>A、c.212G>A）。经口服碳酸氢钠片、别嘌呤醇片、巴氯芬及家庭康复等治疗后，5例患儿脑损伤症状缓解，1例窒息死亡，1例死于肺部感染，1例未规律服药和复查，病情加重。结论 Lesch-Nyhan综合征患者的临床症状轻重不一，主要临床特征为神经系统功能障碍、自残行为、高尿酸血症，基因测序是确诊的关键，对症治疗可改善症状。

关键词: Lesch-Nyhan综合征, 次黄嘌呤-鸟嘌呤磷酸核糖转移酶, 自残行为, 高尿酸血症, HPRT1基因

Abstract:

Objective To analyze the clinical features and HPRT1 gene variation characteristics of Lesch-Nyhan syndrome in children and to improve the understanding for the disease. Methods The clinical manifestations, laboratory examination and genetic test results of 8 children diagnosed with Lesch-Nyhan syndrome and followed up from July 2015 to November 2019 were retrospectively analyzed, and the clinical characteristics and HPRT1 gene variation characteristics of the children were analyzed and summarized. Results All the 8 patients were male, and the onset of disease was from 3 months to 11 months old. The patients mainly visited because of developmental retardation, accompanied by pyramidal and extrapyramidal symptoms. Four patients had self-mutilation behavior before seeing a doctor, another 4 patients did not have at present, and the blood uric acid increased in different degrees. Six variations (c.609+5G>A, exon 2-3 del, c.131G>A, exon7-8 del, c.384+2T>A and c.212G>A) were detected in their HPRT1 gene. After oral sodium bicarbonate, allopurinol and baclofen and home-based rehabilitation, the symptoms of brain injury were relieved in 5 patients. One patient died of asphyxia, 1 died of pulmonary infection, and 1 was aggravated without regular medication and reexamination. Conclusions The clinical symptoms of Lesch Nyhan syndrome are complex. The main characteristics are nervous system dysfunction, self-mutilation behavior and hyperuricemia. Gene sequencing is the key to diagnosis. Symptomatic treatment can improve symptoms of the patients.

Key words: Lesch Nyhan syndrome, hypoxanthine guanine phosphoribosyltransferase, self- mutilation behavior, hyperuricemia, HPRT1 gene

卢婷婷, 陆相朋, 廉文君, 张尧, 郑宏, 杨艳玲. Lesch-Nyhan综合征8例临床特征及HPRT1基因变异分析[J]. 临床儿科杂志, 2023, 41(12): 931-936.

LU Tingting, LU Xiangpeng, LIAN Wenjun, ZHANG Yao, ZHENG Hong, YANG Yanling. Clinical features and HPRT1 gene variations of 8 patients with Lesch Nyhan syndrome[J]. Journal of Clinical Pediatrics, 2023, 41(12): 931-936.

图/表 1

表1

8例患儿主要临床表现和实验室特点"

病例	发病年龄 /月	神经系统症状	自残行为/出现年龄	确诊年龄	血清尿酸 /μmol·L	尿结晶 /个·μL^-1	泌尿系彩超	脑电图	头颅MRI	HPRT1变异	治疗	转归
1	12	运动发育落后，扭转痉挛、手足徐动，肌力低，哭闹不安	咬口唇/ 11个月	1岁3 个月	974	197	右肾内多发小结石	基本脑波节律慢化，睡眠期仅可见少量睡眠纺锤波，睡眠周期不易区分	无异常	c.609+5G>A	别嘌呤醇，碳酸氢钠，巴氯芬	29个月死亡（肺部感染）
2	3	运动发育落后，肌张力障碍，腱反射亢进，肌力低，烦躁，易激惹	咬口唇/ 6个月	1岁6 个月	968	85	双肾内多发小结石，右肾盂分离	无异常	脑白质髓鞘化落后	Exon 2-3del	别嘌呤醇，碳酸氢钠，巴氯芬，家庭训练，防护器具	好转
3	7	运动发育落后，肌张力障碍，腱反射亢进	无	9个月	447	无异常	无异常	无异常	无异常	C.131G>A	别嘌呤醇，碳酸氢钠，巴氯芬，家庭训练、防护器具	1岁窒息死亡
4	9	运动发育落后，肌张力障碍，手足徐动，易激惹	咬口唇、撞头/ 不详	6岁7 个月	578	无异常	无异常	未做	未做	C.131G>A	别嘌呤醇，碳酸氢钠，巴氯芬，家庭训练	好转
5	3	运动发育落后，肌张力障碍，腱反射亢进，肌力低	无	1岁2 个月	855	30	左肾积水，双肾锥体回声异常，皮质回声轻度增高，右肾体积较小，血流减少	界限性脑电图，浅睡期前头部尖-慢复合波散在出现，有时左右不同步	无异常	Exon 7-8del	别嘌呤醇，碳酸氢钠，巴氯芬，家庭训练	好转
6	6	运动发育落后，肌张力障碍，腱反射亢进，病理征阳性，肌力低，易激惹	咬手、咬口唇/ 5个月	2岁4 个月	726.3	无异常	双肾内多发小结石	未做	双侧额、颞、顶部脑外间隙增宽，皮质发育差，脑沟宽深	c.384+2T>A	别嘌呤醇，碳酸氢钠，巴氯芬，家庭训练	好转
7	4	运动发育落后，肌张力障碍，腱反射亢进，肌力低，易激惹	无	8个月	>1 000	无异常	无异常	无异常	无异常	c.212G>A	别嘌呤醇，碳酸氢钠，巴氯芬，家庭训练	好转
8	8	运动发育落后，肌张力障碍，腱反射亢进，病理征阳性，肌张力高，易激惹	无	1岁1 个月	776	无异常	无异常	无异常	无异常	C.131G>A	别嘌呤醇，碳酸氢钠，巴氯芬，家庭训练	不稳定

表1

参考文献 30

[1]	Kim SH, Moores JC, David D, et al. The organization of the human HPRT gene[J]. Nucleic Acids Res, 1986, 14(7): 3103-3118. pmid: 3008106
[2]	Torres RJ, Puig JG. Hypoxanthine-guanine pho-sophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome[J]. Orphanet J Rare Dis, 2007, 2: 48. pmid: 18067674
[3]	Stur E, Reis RS, Agostini LP, et al. HPRTYale proposed as a pathogenic variant for Lesch-Nyhan syndrome: a case report[J]. Genet Mol Res, 2016, 15(2).
[4]	唐久来, 秦炯, 邹丽萍, 等. 中国脑性瘫痪康复指南 (2015): 第一部分[J]. 中国康复医学杂志, 2015, 21(7): 161.
[5]	李逢潮, 章印红, 吕涛, 等. HPRT1基因变异致Lesch-Nyhan综合征1例报告[J]. 临床儿科杂志, 2022, 40(6): 465-468.
[6]	Fu R, Ceballos-Picot I, Torres RJ, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder[J]. Brain, 2014, 137(Pt 5): 1282-1303. doi: 10.1093/brain/awt202 pmid: 23975452
[7]	Fu R, Sutcliffe D, Zhao H, et al. Clinical severity in Lesch-Nyhan disease: the role of residual enzyme and compensatory pathways[J]. Mol Genet Metab, 2015, 114(1): 55-61. doi: 10.1016/j.ymgme.2014.11.001 pmid: 25481104
[8]	Nguyen KV, Naviaux RK, Nyhan WL. Novel mutation in the human HPRT1 gene and the Lesch-Nyhan disease[J]. Nucleosides Nucleotides Nucleic Acids, 2017, 36(11): 704-711. doi: 10.1080/15257770.2017.1395037 pmid: 29185864
[9]	Vargiami E, Printza N, Papadimiditriou E, et al. Nephrocalcinosis and renal failure in Lesch-Nyhan syndrome: report of two familial cases and review of the literature[J]. Urology, 2016, 97: 194-196. doi: S0090-4295(16)30065-6 pmid: 27079129
[10]	Mishima E, Mori T, Nakajima Y, et al. HPRT-related hyperuricemia with a novel p.V35M mutation in HPRT1 presenting familial juvenile gout[J]. CEN Case Rep, 2020, 9(3): 210-214. doi: 10.1007/s13730-020-00459-9
[11]	Tschirner SK, Gutzki F, Schneider EH, et al. Neuro-transmitter and their metabolite concentrations in different areas of the HPRT knockout mouse brain[J]. J Neurol Sci, 2016, 365: 169-174. doi: 10.1016/j.jns.2016.04.025 pmid: 27206901
[12]	Gasperini S, Stagi S, Gasperini U, et al. Orange-colored diapers as first sign of Lesch-Nyhan disease in an asymptomatic infant[J]. Pediatr Nephrol, 2010, 25(11): 2373-2374. doi: 10.1007/s00467-010-1557-3 pmid: 20517618
[13]	Wong H, Feber J, Chakraborty P, et al. Novel HGPRT 293 A>G point mutation presenting as neonatal acute renal failure[J]. Pediatr Nephrol, 2008, 23(2): 317-321. doi: 10.1007/s00467-007-0612-1
[14]	Jinnah HA, Sabina RL, Van Den Berghe G. Metabolic disorders of purine metabolism affecting the nervous system[J]. Handb Clin Neurol, 2013, 113: 1827-1836. doi: 10.1016/B978-0-444-59565-2.00052-6 pmid: 23622405
[15]	Jinnah HA, Visser JE, Harris JC, et al. Delineation of the motor disorder of Lesch-Nyhan disease[J]. Brain, 2006, 129(Pt 5): 1201-1217. pmid: 16549399
[16]	Robey KL, Reck JF, Giacomini KD, et al. Modes and patterns of self-mutilation in persons with Lesch-Nyhan disease[J]. Dev Med Child Neurol, 2003, 45(3): 167-171. doi: 10.1017/s001216220300032x pmid: 12613772
[17]	Campolo González A, Vargas Díaz A, Fontboté Riesco D, et al. Oral self-mutilation in Lesch-Nyhan syndrome. Case report[J]. Rev Chil Pediatr, 2018, 89(1): 86-91. doi: S0370-41062018000100086 pmid: 29664508
[18]	Keough DT, McConachie LA, Gordon RB, et al. Human hypoxanthine-guanine phosphoribosyltransferase. Development of a spectrophotometric assay and its use in detection and characterization of mutant forms[J]. Clin Chim Acta, 1987, 163(3): 301-308. pmid: 3581473
[19]	Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and central nervous system function[J]. Am J Med, 1964, 36: 561-570. pmid: 14142409
[20]	Fu R, Ceballos-Picot I, Torres RJ, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder[J]. Brain, 2014, 137(Pt 5): 1282-1303. doi: 10.1093/brain/awt202 pmid: 23975452
[21]	Seegmiller JE, Rosenbloom FM, Kelley WN. Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis[J]. Science, 1967, 155(3770): 1682-1684. pmid: 6020292
[22]	Wirths O, Walter S, Kraus I, et al. N-truncated Aβ4-x peptides in sporadic Alzheimer's disease cases and transgenic Alzheimer mouse models[J]. Alzheimers Res Ther, 2017, 9(1): 80. doi: 10.1186/s13195-017-0309-z
[23]	Thinakaran G, Koo EH. Amyloid precursor protein trafficking, processing, and function[J]. J Biol Chem, 2008, 283(44): 29615-29619. doi: 10.1074/jbc.R800019200 pmid: 18650430
[24]	Turner PR, O'Connor K, Tate WP, et al. Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory[J]. Prog Neurobiol, 2003, 70(1): 1-32. doi: 10.1016/s0301-0082(03)00089-3 pmid: 12927332
[25]	Nguyen KV. Epigenetic regulation in amyloid precursor protein with genomic rearrangements and the Lesch-Nyhan syndrome[J]. Nucleosides Nucleotides Nucleic Acids, 2015, 34(10): 674-690. doi: 10.1080/15257770.2015.1071844 pmid: 26398526
[26]	Sikora P, Pijanowska M, Majewski M, et al. Acute renal failure due to bilateral xanthine urolithiasis in a boy with Lesch-Nyhan syndrome[J]. Pediatr Nephrol, 2006, 21(7): 1045-1047. pmid: 16773422
[27]	Ng N, Kaur A, Shenoy M. Recurrent kidney stones in a child with Lesch-Nyhan syndrome, answers[J]. Pediatr Nephrol, 2019, 34(3): 425-427. doi: 10.1007/s00467-018-4037-9
[28]	Piedimonte F, Andreani JC, Piedimonte L, et al. Remarkable clinical improvement with bilateral globus pallidus internus deep brain stimulation in a case of Lesch-Nyhan disease: five-year follow-up[J]. Neuromodulation, 2015, 18(2): 118-122. doi: 10.1111/ner.12261 pmid: 25603976
[29]	Kállay K, Liptai Z, Benyó G, et al. Successful unrelated umbilical cord blood transplantation in Lesch-Nyhan syndrome[J]. Metab Brain Dis, 2012, 27(2): 193-196. doi: 10.1007/s11011-012-9279-9 pmid: 22350962
[30]	季涛云, 吴晔, 王静敏, 等. 检测不明原因智力障碍/脑发育迟缓儿染色体亚端粒重组突变[J]. 国外医学计划生育/生殖健康分冊, 2011, 30(3): 173-177.