Roland Dominique, Jissendi-Tchofo Patrice, Briand Gilbert, Vamecq Joseph, Fontaine Monique, Ultré Vincent, Acquaviva-Bourdain Cécile, Mention Karine, Dobbelaere Dries
Centre Agréé des Maladies Héréditaires du Métabolisme, Centre de Génétique Humaine, Institute of Pathology and Genetics, Gosselies (Charleroi), Belgium.
Department of Neuroradiology, Roger Salengro Hospital, CHRU Lille, France.
Mol Genet Metab. 2017 Jun;121(2):111-118. doi: 10.1016/j.ymgme.2017.03.006. Epub 2017 Mar 30.
3-Hydroxy-3-Methylglutaryl-Coenzyme A (HMG-CoA) lyase deficiency is a rare inborn error of leucine metabolism and ketogenesis. Despite recurrent hypoglycemia and metabolic decompensations, most patients have a good clinical and neurological outcome contrasting with abnormal brain magnetic resonance imaging (MRI) signals and consistent abnormal brain proton magnetic resonance spectroscopy (H-MRS) metabolite peaks. Identifying these metabolites could provide surrogate markers of the disease and improve understanding of MRI-clinical discrepancy and follow-up of affected patients.
Urine samples, brain MRI and H-MRS in 5 patients with HMG-CoA lyase deficiency (4 boys and 1 girl aged from 25days to 10years) were, for each patient, obtained on the same day. Brain and urine spectroscopy were performed at the same pH by studying urine at pH 7.4. Due to pH-induced modifications in chemical shifts and because reference H NMR spectra are obtained at pH 2.5, spectroscopy of normal urine added with the suspected metabolite was further performed at this pH to validate the correct identification of compounds.
Mild to extended abnormal white matter MRI signals were observed in all cases. Brain spectroscopy abnormal peaks at 0.8-1.1ppm, 1.2-1.4ppm and 2.4ppm were also detected by urine spectroscopy at pH 7.4. Taking into account pH-induced changes in chemical shifts, brain abnormal peaks in patients were formally identified to be those of 3-hydroxyisovaleric, 3-methylglutaconic, 3-methylglutaric and 3-hydroxy-3-methylglutaric acids.
3-Methylglutaric, 3-hydroxyisovaleric and 3-hydroxy-3-methylglutaric acids identified on urine H-NMR spectra of 5 patients with HMG-CoA lyase deficiency are responsible for the cerebral spectroscopy signature seen in these patients, validating their local involvement in brain and putative contribution to brain neuropathology.
3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）裂解酶缺乏症是一种罕见的亮氨酸代谢和生酮先天性代谢缺陷病。尽管存在反复低血糖和代谢失代偿情况，但与脑磁共振成像（MRI）信号异常及脑质子磁共振波谱（H-MRS）代谢物峰持续异常形成对比的是，大多数患者具有良好的临床和神经学转归。识别这些代谢物可提供疾病的替代标志物，并有助于更好地理解MRI表现与临床情况不符的现象以及对受影响患者的随访。
对5例HMG-CoA裂解酶缺乏症患者（4例男孩和1例女孩，年龄从25天至10岁），在同一天采集尿液样本、进行脑MRI和H-MRS检查。通过在pH 7.4条件下研究尿液，在相同pH值下进行脑和尿液波谱分析。由于化学位移受pH影响，且参考氢核磁共振谱是在pH 2.5条件下获得的，因此还在该pH值下对添加了可疑代谢物的正常尿液进行波谱分析，以验证化合物的正确识别。
所有病例均观察到轻度至广泛的白质MRI信号异常。在pH 7.4条件下，尿液波谱分析也检测到脑波谱在0.8 - 1.1ppm、1.2 - 1.4ppm和2.4ppm处出现异常峰。考虑到化学位移受pH影响的变化，患者脑内异常峰被正式确定为3-羟基异戊酸、3-甲基戊烯二酸、3-甲基戊二酸和3-羟基-3-甲基戊二酸的峰。
在5例HMG-CoA裂解酶缺乏症患者尿液氢核磁共振谱中识别出的3-甲基戊二酸、3-羟基异戊酸和3-羟基-3-甲基戊二酸是这些患者脑波谱特征的原因，证实了它们在脑内的局部参与以及对脑神经病理学的潜在作用。
