Cinical treatment of 3-hydroxy-3-methylglutaric aciduria and a novel mutation on 3-hydroxy-3-methylglutaryl-coenzyme A lyase gene

doi:10.3877/cma.j.issn.1673-5250.2016.01.013

Objective

To investigate the clinical manifestations and biochemical characteristics of 3-hydroxy-3-methylglutaric aciduria, and discuss results of 3-hydroxy-3-methylglutaryl-coenzyme A lyase (HMGCL) gene mutation.

Methods

The clinical data of a boy with 3-hydroxy-3-methylglutaric aciduria who was treated at Peking University First Hospital on December 7th 2014 was collected into this study. The admission examination, auxiliary examination, diagnosis and treatment, gene detection and follow-up of this boy were retrospectively analyzed. The study protocol was approved by the Ethical Review Board of Investigation in Human Being of Peking University First Hospital. Informed consents were obtained from patient's parents.

Results

The boy complained of unexplained diarrhea, vomiting, repeated hematemesis, fever 2 d and coma 3 h. The admission examination and auxiliary examination results showed increased white blood cell count, liver damage, electrolyte imbalance, low blood sugar, blood clotting abnormalities, low-protein, high ammonia, metabolic acidosis. Cranial MRI result showed that abnormal signal could be found in bilateral lateral ventricle and double fronto-temporal parietal cortex. The final diagnosis of the boy was 3-hydroxy-3-methylglutaric aciduria. By limiting protein intake, intravenous infusion of glucose and L-carnitine treatment, the symptom alleviated gradually. Genetic analysis results showed that exon region of HMGCL was found two heterozygous mutation point: c. 509G> T and c. 348 + 1 G>C, where c. 509G> T was heterozygous mutation from the mother, c. 348 + 1 G>C emerged in child homozygous mutation, the mutation site of c. 348+ 1G>C splice site mutation caused amino acid changes p. Cys170Phe, splicing (cysteine phenylalanine, shear mutation). After discharge, the six months follow-up results showed as follow. Psychomotor developed slightly behind the health children, but no significant setback. The boy lived in good general condition, and biochemical markers and the level of urinary 3-hydroxy-3-methylpentyl reduce to normal range.

Conclusions

3-hydroxy-3-methylglutaric aciduria is one of rare autosomal recessive genetic disease. Genetic gene detection and genetic analysis of HMGCL was helpful not only to diagnose the disease, but also crucial important to genetic counseling for family guidance and prenatal diagnosis.

Key words: 3-Hydroxy-3-methylglutaric aciduria, 3-Hydroxy-3-methylglutaryl-coenzyme A lyase gene, Organic acid, Metabolic diseases, Child

表1 患儿治疗前、后及随访6个月时血清生化检查结果

项目	治疗前	治疗后	随访6个月时	参考范围
丙氨酸转氨酶(IU/L)	314	67	27	0～40
天冬氨酸转氨酶(IU/L)	179	84	18	0～45
白蛋白(g/L)	33	37	42	38～54
尿素氮(mmol/L)	7.98	7.3	6.2	1.7～8.3
肌酐(μmol/L)	14	53	68	59～104
尿酸(μmol/L)	96	186	216	202～416
血糖(mmol/L)	2.70	3.40	4.50	4.11～6.05
血清Ca^2＋(mmol/L)	1.86	2.90	3.10	2.25～2.75
血清K^＋(mmol/L)	2.6	3.6	4.1	3.5～5.0
血清Na^＋(mmol/L)	127.5	132	139	136～145
血清Cl^－(mmol/L)	96.3	99	102	98～110
血氨(μmol/L)	89	54	34	18～72
乳酸(mmol/L)	1.63	1.54	1.40	0.50～2.20
丙酮酸(μmol/L)	32	36	44	20～100

表1 患儿治疗前、后及随访6个月时血清生化检查结果

项目	治疗前	治疗后	随访6个月时	参考范围
丙氨酸转氨酶(IU/L)	314	67	27	0～40
天冬氨酸转氨酶(IU/L)	179	84	18	0～45
白蛋白(g/L)	33	37	42	38～54
尿素氮(mmol/L)	7.98	7.3	6.2	1.7～8.3
肌酐(μmol/L)	14	53	68	59～104
尿酸(μmol/L)	96	186	216	202～416
血糖(mmol/L)	2.70	3.40	4.50	4.11～6.05
血清Ca^2＋(mmol/L)	1.86	2.90	3.10	2.25～2.75
血清K^＋(mmol/L)	2.6	3.6	4.1	3.5～5.0
血清Na^＋(mmol/L)	127.5	132	139	136～145
血清Cl^－(mmol/L)	96.3	99	102	98～110
血氨(μmol/L)	89	54	34	18～72
乳酸(mmol/L)	1.63	1.54	1.40	0.50～2.20
丙酮酸(μmol/L)	32	36	44	20～100

图1 患儿入院时头颅MRI检查结果(综合各序列所见，双侧侧脑室后角旁可见片状长T1长T2高信号，双侧额颞顶皮层下见小片状等T1长T2高信号)

表2 患儿治疗前、后及随访6个月时血、尿代谢结果

项目		治疗前	治疗后	随访6个月时	参考范围
尿液有机酸(mg/g)
	3-羟基-3-甲基戊二酸	408	341	203	0～25.7
	戊二酸	67	58	42	0～4
	3-甲基戊二酸	1095	876	560	0～2.9
	3-羟基戊二酸	45	48	32	0
	丙酰甘氨酸	43	36	28	0
	异戊酰甘氨酸	263	234	132	0～0.4
	3甲基巴豆酰甘氨酸	48	46	42	0
血液氨基酸(μmol/L)
	精氨酸	7.5	7.1	6.4	5～60
	瓜氨酸	9.2	8.7	7.3	5～50
	亮氨酸/异亮氨酸	87	83	78	50～150
	蛋氨酸	18	14	8.7	13～60
血液肉碱谱(μmol/L)
	羟异戊酰肉碱	1.33	1.30	1.12	0.07～0.50
	游离肉碱	275	198	146	20～60
	乙酰肉碱	128	116	89	6～30

表2 患儿治疗前、后及随访6个月时血、尿代谢结果

项目		治疗前	治疗后	随访6个月时	参考范围
尿液有机酸(mg/g)
	3-羟基-3-甲基戊二酸	408	341	203	0～25.7
	戊二酸	67	58	42	0～4
	3-甲基戊二酸	1095	876	560	0～2.9
	3-羟基戊二酸	45	48	32	0
	丙酰甘氨酸	43	36	28	0
	异戊酰甘氨酸	263	234	132	0～0.4
	3甲基巴豆酰甘氨酸	48	46	42	0
血液氨基酸(μmol/L)
	精氨酸	7.5	7.1	6.4	5～60
	瓜氨酸	9.2	8.7	7.3	5～50
	亮氨酸/异亮氨酸	87	83	78	50～150
	蛋氨酸	18	14	8.7	13～60
血液肉碱谱(μmol/L)
	羟异戊酰肉碱	1.33	1.30	1.12	0.07～0.50
	游离肉碱	275	198	146	20～60
	乙酰肉碱	128	116	89	6～30

图2 患儿及其母亲的HMGCL基因测序结果(图2A：母亲为HMGCL基因c.509G>T杂合突变携带者；图2B：患儿HMGCL基因存在c.348＋1G>C纯合突变)

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