Vatanavicharn Nithiwat, Yamada Kenji, Aoyama Yuka, Fukao Toshiyuki, Densupsoontorn Narumon, Jirapinyo Pipop, Sathienkijkanchai Achara, Yamaguchi Seiji, Wasant Pornswan
Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Department of Pediatrics, Shimane University School of Medicine, Izumo, Shimane, Japan.
Brain Dev. 2015 Aug;37(7):698-703. doi: 10.1016/j.braindev.2014.10.005. Epub 2014 Nov 1.
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.
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.
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.
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.
线粒体脂肪酸氧化（FAO）障碍是急性脑病样或肌病样疾病的病因之一。肉碱 - 酰基肉碱转位酶（CACT）缺乏症是一种罕见的FAO障碍，表现为在长期禁食、发热性疾病或肌肉活动增加时能量产生不足。CACT缺乏症由SLC25A20基因突变引起。大多数患者在新生儿期出现严重的代谢失代偿，尽管积极治疗仍在婴儿期死亡。
我们在此报告两例无关的CACT缺乏症病例的临床发现，包括突变确认，以及使用体外探针酰基肉碱（IVP）测定法进行的体外苯扎贝特反应。患者1和患者2均为非近亲父母所生。两名患者均在出生后第3天发生心脏骤停，但在最初事件中幸存下来。他们的血液化学检查显示低血糖和代谢性酸中毒。两名患者的酰基肉碱谱均显示长链酰基肉碱增加，提示CACT或肉碱棕榈酰转移酶-2（CPT2）缺乏。
突变分析在两名患者的SLC25A20基因中均鉴定出纯合子IVS2-10T>G，确诊为CACT缺乏症。IVP测定显示培养的成纤维细胞中C16、C16:1增加，但C2减少，苯扎贝特可使其改善。患者1的苯扎贝特短期临床试验未显示临床改善，在试验开始6个月后死亡。
在其他亚洲人群中也发现了这种剪接突变，表明可能存在奠基者效应。培养的成纤维细胞的IVP测定可以确定对苯扎贝特治疗的反应。需要更多患者参与的长期临床试验来评估这种疗法。
