Carnitine-acylcarnitine translocase deficiency: Two neonatal cases with common splicing mutation and in vitro bezafibrate response
Carnitine-acylcarnitine translocase deficiency: Two neonatal cases with common splicing mutation and in vitro bezafibrate response
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DOI：
10.1016/j.braindev.2014.10.005
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发表时间：
2015-08-01
影响因子：
1.7
通讯作者：
Wasant, Pornswan
中科院分区：
文献类型：
--
作者：
Vatanavicharn, Nithiwat;Yamada, Kenji;Wasant, Pornswan
背景。线粒体脂肪酸氧化（FAO）紊乱是导致急性脑病或肌病样疾病的原因之一。肉毒碱酰基肉毒碱转座酶缺乏症是一种罕见的FAO疾病，表现为长时间禁食、发热性疾病或肌肉活动增加时能量产生不足。CACT缺乏是由SLC25A20基因突变引起的。大多数患者在新生儿期出现严重的代谢失代偿，尽管进行了积极的治疗，但仍在婴儿期死亡。患者和方法：我们在此报告两例不相关的CACT缺乏症的临床发现，并证实突变，并使用体外探针酰基肉碱（IVP）测定体外贝扎菲特反应。患者1和2是非近亲父母的产物。两名患者在出生后第3天出现心脏骤停，但在最初的事件中幸存下来。他们的血液化学显示低血糖和代谢性酸中毒。两例患者的酰基肉碱谱显示长链酰基肉碱增加，提示CACT或肉碱棕榈酰基转移酶-2 （CPT2）缺乏。结果：突变分析在两例患者的SLC25A20基因中发现纯合子IVS2-10T>G，证实了CACT缺乏症的诊断。IVP实验显示，贝扎布特改善了培养成纤维细胞的C16， C16:1，但降低了C2。患者1的贝扎布特短期临床试验未见临床改善，开始试验6个月后死亡。结论：这种剪接突变已在其他亚洲人群中发现，表明可能存在奠基者效应。体外培养成纤维细胞的IVP试验可以确定对贝扎菲特治疗的反应。需要对更多入组患者进行长期临床试验来评估这种疗法。(C) 2014日本儿童神经病学学会。Elsevier B.V.版权所有。
Background. Mitochondrial fatty acid oxidation (FAO) disorders are among the causes of acute encephalopathy- or myopathy-like illness. Carnitine acylcarnitine translocase (CACT) deficiency is a rare FAO disorder, which represent an energy production insufficiency during prolonged fasting, febrile illness, or increased muscular activity. CACT deficiency is caused by mutations of the SLC25A20 gene. Most patients developed severe metabolic decompensation in the neonatal period and died in infancy despite aggressive treatment.Patients and methods: We herein report the clinical findings of two unrelated cases of CACT deficiency with mutation confirmation, and in vitro bezafibrate responses using in vitro probe acylcarnitine (IVP) assay. Patients 1 and 2 are products of nonconsanguineous parents. Both patients developed cardiac arrest at day 3 of life but survived the initial events. Their blood chemistry revealed hypoglycemia and metabolic acidosis. The acylcarnitine profiles in both patients demonstrated increased long-chain acylcarnitines, suggesting CACT or carnitine palmitoyltransferase-2 (CPT2) deficiency.Results: The mutation analysis identified homozygous IVS2-10T>G in the SLC25A20 gene in both patients, confirming the diagnosis of CACT deficiency. The IVP assay revealed increased C16, C16:1, but decreased C2 with improvement by bezafibrate in the cultured fibroblasts. The short-term clinical trial of bezafibrate in Patient 1 did not show clinical improvement, and died after starting the trial for 6 months.Conclusion: This splicing mutation has been identified in other Asian populations indicating a possible founder effect. IVP assay of cultured fibroblasts could determine a response to bezafibrate treatment. A long-term clinical trial of more enrolled patients is required for evaluation of this therapy. (C) 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.