Paquay Stéphanie, Bourillon Agnès, Pichard Samia, Benoist Jean-François, de Lonlay Pascale, Dobbelaere Dries, Fouilhoux Alain, Guffon Nathalie, Rouvet Isabelle, Labarthe François, Mention Karine, Touati Guy, Valayannopoulos Vassili, Ogier de Baulny Hélène, Elmaleh-Bergès Monique, Acquaviva-Bourdain Cécile, Vianey-Saban Christine, Schiff Manuel
Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, 48 Bd Sérurier, Paris, F-75935 Cedex 19, France.
Pediatric Neurology, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
J Inherit Metab Dis. 2017 May;40(3):415-422. doi: 10.1007/s10545-017-0021-y. Epub 2017 Mar 2.
Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency affects ketone body and isoleucine catabolism. Neurological impairment may occur secondary to ketoacidotic episodes. However, we observed neuromotor abnormalities without ketoacidotic events in two T2-deficient families. We hypothesized that the neurological signs were related to the genetic defect and may occur independently of ketoacidotic episodes. We therefore conducted a retrospective review on a French T2-deficient patient series searching for neuromotor impairment.
In total, 26 cases were retrospectively analysed for clinical, biological and neuroimaging data.
Neurological findings were observed for 6/26 (23%) patients. Among these, two had never experienced ketoacidotic episodes, though they developed extrapyramidal signs with putamen involvement. Two of the other four patients developed neurological abnormalities before the first ketoacidotic crisis, with putamen involvement in one case. The third patient developed extrapyramidal symptoms more than 10 years after the initial decompensation with globus pallidus involvement. The last patient developed extrapyramidal signs immediately after a severe ketoacidotic crisis with putaminal lesions.
Most T2-deficient patients achieved normal neurodevelopment. However, on account of the role of T2 in isoleucine catabolism, these patients are potentially exposed to accumulation of toxic isoleucine-derived metabolites, which may contribute to neurological impairment. Our findings confirm previous observations that neurological symptoms in T2 deficiency may occur unrelated to ketoacidosis. The role of protein restriction as a preventive measure against neurological symptoms could not be established in this study and deserves further evaluation. Long-term follow-up data on children diagnosed by newborn screening may clarify the pathogenesis of this neurometabolic association.
线粒体乙酰乙酰辅酶A硫解酶（T2）缺乏会影响酮体和异亮氨酸分解代谢。神经功能障碍可能继发于酮症酸中毒发作。然而，我们在两个T2缺乏的家系中观察到了无酮症酸中毒事件的神经运动异常。我们推测神经体征与基因缺陷有关，可能独立于酮症酸中毒发作而出现。因此，我们对一组法国T2缺乏患者进行了回顾性研究，以寻找神经运动障碍。
对26例患者的临床、生物学和神经影像学数据进行回顾性分析。
26例患者中有6例（23%）出现神经学表现。其中，2例从未经历过酮症酸中毒发作，但出现了累及壳核的锥体外系体征。另外4例患者中有2例在首次酮症酸中毒危机前出现神经异常，其中1例累及壳核。第3例患者在初次失代偿10多年后出现锥体外系症状，累及苍白球。最后1例患者在严重酮症酸中毒危机后立即出现锥体外系体征，伴有壳核病变。
大多数T2缺乏患者神经发育正常。然而，由于T2在异亮氨酸分解代谢中的作用，这些患者可能会接触到有毒的异亮氨酸衍生代谢物的积累，这可能导致神经功能障碍。我们的研究结果证实了先前的观察结果，即T2缺乏的神经症状可能与酮症酸中毒无关。本研究未能确定蛋白质限制作为预防神经症状的措施的作用，值得进一步评估。通过新生儿筛查诊断的儿童的长期随访数据可能会阐明这种神经代谢关联的发病机制。
