GAMT基因变异导致脑肌酸缺乏综合征2型临床特征及预后研究

doi:10.12372/jcp.2024.24e0300

摘要/Abstract

摘要：

目的总结胍基乙酸甲基转移酶（GAMT）基因变异导致脑肌酸缺乏综合征2型患者的临床特征、影像学特点及病情转归。方法回顾性分析2016年1月至2024年3月5例GAMT基因变异导致脑肌酸缺乏综合征2型患儿的临床资料，总结患儿起病情况、临床表现、实验室检查、治疗及预后等资料。结果 5例患儿，男3例，女2例，发病年龄为1.5（1.0~1.5）岁，5例均以发育落后伴癫痫发作起病，其中表现为不同程度的运动发育落后、语言发育迟缓，4例为药物难治性癫痫，3例合并孤独症样行为。5例头颅磁共振波谱成像（MRS）均提示脑肌酸峰明显降低，2例头颅磁共振成像（MRI）示脑干伴或不伴基底节异常信号。所有患儿血或尿肌酸代谢检测均提示肌酸明显降低和胍基乙酸升高。4例患儿均接受了补充肌酸和鸟氨酸的治疗，癫痫发作完全控制，并减停抗癫痫发作药，同时运动和语言发育有不同程度的改善。结论 GAMT基因变异导致的脑肌酸缺乏综合征2型通常表现为发育落后伴药物难治性癫痫，部分合并孤独症样行为，临床特征缺乏特异性。头颅MRS和肌酸代谢物检测可协助基因诊断，补充肌酸和鸟氨酸的治疗可有效控制癫痫发作，改善预后。

关键词: 脑肌酸缺乏综合征, 智力障碍, 胍基乙酸甲基转移酶, 胍基乙酸, 难治性癫痫

Abstract:

Objective To analyse the clinical features, imaging characteristics and prognosis of patients diagnosed with cerebral creatine deficiency syndrome type 2 (CCDS2) caused by variations in the guanidinoacetate methyltransferase (GAMT) gene. Methods To retrospectively analyse the clinical data of five patients diagnosed with CCDS2 due to GAMT gene mutations from January 2016 to March 2024. The analysis focused on the age of disease onset, clinical symptoms, laboratory findings, treatment approaches, and prognosis. Results There were 3 males and 2 females, age of onset 1.5 (1.0-1.5) years old, all patients presented with developmental delay and seizures, with 4 cases exhibiting drug-refractory epilepsy and 3 cases also showing autistic-like behaviors. Brain magnetic resonance spectroscopy (MRS) showed a significant decrease in cerebral creatine peaks in all 5 cases, and 2 cases showed abnormal signals in the brainstem with or without basal ganglia on brain magnetic resonance imaging (MRI). In all patients, blood or urine creatine metabolism tests showed a significant decrease in creatine and an increase in guanidinoacetate. Four patients received treatment with creatine supplementation and guanidinoacetate-lowering therapy, resulting in complete seizure control after 2 weeks to 10 months, discontinuation of anti-seizure medications, and varying degrees of improvement in motor and speech development. Conclusion CCDS2 due to variants in the GAMT gene usually presents with developmental delay with drug refractory epilepsy, partly combined with autistic-like behavior, and lacks specificity. Brain MRS and creatine metabolite testing may aid in genetic diagnosis, and treatment with creatine supplementation and guanidinoacetate lowering may be effective in controlling seizures and improving prognosis.

Key words: cerebral creatine deficiency syndromes, intellectual disabilities, guanidinoacetate methyltransferase, guanidinoacetate, refractory epilepsy

杨蕾, 方方, 宋天羽, 徐超龙. GAMT基因变异导致脑肌酸缺乏综合征2型临床特征及预后研究[J]. 临床儿科杂志, 2024, 42(12): 1039-1046.

YANG Lei, FANG Fang, SONG Tianyu, XU Chaolong. A clinical and prognosis study of five patients with cerebral creatine deficiency syndrome 2 caused by GAMT gene mutations[J]. Journal of Clinical Pediatrics, 2024, 42(12): 1039-1046.

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中国GAMT缺乏症患儿临床资料"

患儿	性别	年龄	临床表现	头颅影像学检查	基因	代谢检查	治疗	预后
1^[8]	男	3岁	轻度发育迟缓、热性惊厥	脑白质发育异常、胼胝体发育异常；脑Cr↓	c.412C>T IVS4-1G>A	/	肌酸400 mg/（kg·d）	随访3月无惊厥发作
2^[9]	男	8岁	发育迟缓、癫痫、肌张力低	/	c.403G>A c.520T>C	GAA↑、Cr↓、游离肉碱↓、尿甲苯胺蓝3+	肌酸4g/d，左卡尼汀1g/d	随访1年无癫痫发作
3^[9]	女	4.5岁	发育迟缓	双侧苍白球异常信号	c.134G>A c.316C>T	GAA↑、Cr↓、Hcy?	肌酸2g/d，左卡尼汀1g/d	随访1月后可扶走
4^[9]	女	6.5岁	发育迟缓、癫痫、运动障碍	头MRI正常	c.491dup c.403G>A	GAA↑、Cr↓、尿酰基肉碱和多种有机酸升高	肌酸3g/d，左卡尼汀1g/d	治疗5月无癫痫发作
5^[9]	男	4.5岁	发育迟缓、孤独症样行为	/	c.181G>A c.158_181+7del	GAA↑、Cr↓	肌酸2g/d，左卡尼汀1g/d	治疗6月行为、脾气、语言有改善
6^[9]	女	2岁	发育落后、难治性癫痫	/	c.444_448del c.520T>C	GAA↑、Cr↓、酰基肉碱升高，尿多种有机酸升高	肌酸1.5g/d，左卡尼汀1g/d	治疗3年无癫痫发作
7^[10]	女	4岁	中度发育落后、癫痫、肌张力低、说2-3字	脑白质异常信号；脑Cr↓	c.564G>T c.491dupG	GAA↑、Cr↓	肌酸400mg/（kg·d），鸟氨酸300~400mg/（kg·d），低蛋白饮食	随访10年发育正常，治疗2年后无癫痫发作
8^[10]	女	20月龄	重度发育落后、无主动语言、癫痫	脑外间隙宽；脑Cr↓	c.289delC c.392-1G>C	GAA正常、Cr↓	肌酸400mg/（kg·d），鸟氨酸300~400mg/（kg·d），低蛋白饮食	随访2年运动、社交语言有改善，癫痫发作可药物控制
9^[10]	女	4岁	重度发育落后、无语言、癫痫	胼胝体薄；脑Cr↓	c.328-1G>A c.403G>A	GAA↑、Cr↓	肌酸400mg/（kg·d），鸟氨酸300~400mg/（kg·d），低蛋白饮食	随访2年运动、社交、语言有改善，癫痫治疗1年后无发作
10^[10]	女	6岁	中度发育落后、说2-3个字、难治性癫痫	脑白质异常信号；脑Cr?	c.328-1G>A c.114C>T	GAA↑、Cr↓	肌酸400mg/（kg·d），鸟氨酸300~400mg/（kg·d），低蛋白饮食	随访3年运动、社交语言改善，治疗2年后癫痫无发作
11^[10]	男	3岁	中度发育落后、说1-2个字	头MRI正常；脑Cr↓	c.328-2A>G c.115 A>G	GAA↑、Cr↓	肌酸400mg/（kg·d），鸟氨酸300~400mg/（kg·d），低蛋白饮食	随访7个月运动、语言、社交改善
12^[10]	男	1岁	轻度发育落后、说1-2个字	头MRI正常；脑Cr↓	/	GAA↑、Cr↓	肌酸400mg/（kg·d），鸟氨酸300~400mg/（kg·d），低蛋白饮食	随访7个月运动、语言、社交改善
13^[11]	女	3岁	发育落后、难治性癫痫	头MRI正常	c.491 dupG c.403G>A	/	肌酸300mg/（kg·d），鸟氨酸300~400mg/（kg·d）	随访4月运动语言改善不明显，治疗2月后癫痫发作控制

表3

参考文献 16

[1]	Mercimek-Andrews S, Salomons GS. Creatine Deficiency Disorders. 2009 Jan 15 [Updated 2022 Feb 10].//Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [EB/OL]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK3794/
[2]	Khaikin Y, Sidky S, Abdenur J, et al. Treatment outcome of twenty-two patients with guanidinoacetate methyltransferase deficiency: an international retrospective cohort study[J]. Eur J Paediatr Neurol, 2018, 22: 369-379.
[3]	Hart K, Rohrwasser A, Wallis H, et al. Prospective identification by neonatal screening of patients with guanidinoacetate methyltransferase deficiency[J]. Mol Genet Metab, 2021, 134(1-2): 60-64. doi: 10.1016/j.ymgme.2021.07.012 pmid: 34389248
[4]	Desroches CL, Patel J, Wang P, et al. Carrier frequency of guanidinoacetate methyltransferase deficiency in the general population by functional characterization of missense variants in the GAMT gene[J]. Mol Genet Genomics, 2015, 290(6): 2163-2171.
[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. doi: 10.1038/gim.2015.30 pmid: 25741868
[6]	Mulik C, Mercimek-Andrews S. Creatine deficiency disorders: phenotypes, genotypes, diagnosis, and treatment outcomes[J]. Turk Arch Pediatr, 2023, 58(2): 129-135.
[7]	杨蕾, 方方. GAMT基因变异导致肌酸缺乏综合征一例[J]. 中华儿科杂志, 2017, 55(4): 309-310.
[8]	张勇刚, 张丽芬, 周敏, 等. 一例肌酸缺乏综合征患儿的临床特征及遗传学分析[J]. 中华医学遗传学杂志, 2021, 38(7): 686-689.
[9]	Shen M, Yang G, Chen Z, et al. Identification of novel variations in SLC6A8 and GAMT genes causing cerebral creatine deficiency syndrome[J]. Clin Chim Acta, 2022, 532: 29-36.
[10]	Sun W, Wang Y, Wu M, et al. Fourteen cases of cerebral creatine deficiency syndrome in children: a cohort study in China[J]. Transl Pediatr, 2023, 12(5): 927-937. doi: 10.21037/tp-23-164 pmid: 37305710
[11]	宋冬梅, 李晓华, 庄蒙丽, 等. 肌酸缺乏综合征1例报告[J]. 中国实用儿科杂志, 2017, 32(4): 319-320.
[12]	Narayan V, Mahay SB, Verma IC, et al. Case series of creatine deficiency syndrome due to guanidinoacetate methyltransferase deficiency[J]. Ann Indian Acad Neurol, 2020, 23(3): 347-351.
[13]	Clark JF, Cecil KM. Diagnostic methods and reco-mmendations for the cerebral creatine deficiency syndromes[J]. Pediatr Res, 2015, 77(3): 398-405.
[14]	El-Gharbawy AH, Goldstein JL, Millington DS, et al. Elevation of guanidinoacetate in newborn dried blood spots and impact of early treatment in GAMT deficiency[J]. Mol Genet Metab, 2013, 109: 215-217. doi: 10.1016/j.ymgme.2013.03.003 pmid: 23583224
[15]	Viau KS, Ernst SL, Pasquali M, et al. Evidence-based treatment of guanidinoacetate methyltransferase (GAMT) deficiency[J]. Mol Genet Metab, 2013, 110: 255-262. doi: 10.1016/j.ymgme.2013.08.020 pmid: 24071436
[16]	Schulze A, Hoffmann GF, Bachert P, et al. Presymptomatic treatment of neonatal guanidinoacetate methyltransferase deficiency[J]. Neurology, 2006, 67: 719-721. pmid: 16924036

项目	例1	例2	例3	例4	例5
性别	男	男	男	女	女
起病年龄	8月龄	1.5岁	2岁	1岁	1.5岁
确诊年龄	9月龄	10岁	8岁	7岁	5岁
随访年龄	8岁	15岁	14岁	14岁	13岁
临床表现
运动发育落后	+	+	+	+	+
语言发育迟缓	+	+	+	+	+
孤独症样行为	-	+	-	+	+
癫痫发作	点头发作（肌阵挛可能）、全身强直阵挛发作	强直发作，不典型失神、肌阵挛	全身强直阵挛发作、不典型失神、肌阵挛	跌倒发作（肌阵挛可能）、全身强直阵挛发作	肌阵挛
EEG	9月龄正常	各导联可见高-极高波幅尖波、尖慢波发放	全导频发广泛性高-极高波幅不规则慢波夹杂少量尖棘波，双枕及后颞导联频发棘波、尖波、尖棘慢波	广泛高波幅慢波夹杂多灶性尖棘波	慢波活动增加，广泛多灶性痫样放电
抗癫痫药物	VPA	VPA，LEV	PHT，LEV，VPA	TPM，LEV	TPM，LEV，PB
头颅MRI	双侧苍白球和脑桥背侧对称性长T1长T2信号	正常	正常	正常	脑干背侧可见长T1长T2信号
头颅MRS	Cr降低	Cr降低	Cr降低	Cr降低	Cr降低
代谢检查*
血肌酐	/	9.1 μmol/L	18.6 μmol/L	7.7 μmol/L	8.5 μmol/L
尿肌酸	0.012 mmol/L	0.002 mmol/mmolCrn	0.002 mmol/mmolCrn	0.003 mmol/mmolCrn	0.003 mmol/mmolCrn
尿GAA	1.192 mmol/L	2.168 mmol/mmolCrn	0.744 mmol/mmolCrn	1.575 mmol/mmolCrn	1.374 mmol/mmolCrn
尿肌酐	0.802 mmol/L	/	/	/	/
尿GAA/肌酐	1.486	/	/	/	/
治疗后血肌酐	/	40.2μmol/L	42.0μmol/L	/	/
治疗后尿肌酸	/	3.624 mmol/mmolCrn	0.553 mmol/mmolCrn	/	/
治疗后尿GAA	/	0.368 mmol/mmolCrn	0.428 mmol/mmolCrn	/	/

患儿	核苷酸变异	氨基酸变异	来源	致病性	ACMG评级
例1	c.194T>C	p.L65P	父源	临床意义未明	PM2_Supporting+PP3
	c.467C>A	p.A156D	母源	临床意义未明	PM2_Supporting+PP3+PS3_Supporting
例2	c.158_181+7 del	splicing	父源	致病	PVS1+PM2_Supporting+PM3_Supporting
	c.158_181+7 del	splicing	母源	致病	PVS1+PM2_Supporting+PM3_Supporting
例3	c.418_419delTC	p.S140Gfs*50	父源	疑似致病	PVS1+PM2_Supporting
	c.212T>G	p.M71R	母源	临床意义未明	PM3+PM2_Supporting+PP3
例4	c.328-1G>A	splicing	父源	致病	PVS1+PM2_Supporting+PM3_Supporting
	c.328-1G>A	splicing	母源	致病	PVS1+PM2_Supporting+PM3_Supporting
例5	c.328-1G>A	splicing	父源	致病	PVS1+PM2_Supporting+PM3_Supporting
	c.328-1G>A	splicing	母源	致病	PVS1+PM2_Supporting+PM3_Supporting