Carnitine transport and fatty acid oxidation.
Carnitine transport and fatty acid oxidation.
复制标题
DOI：
10.1016/j.bbamcr.2016.01.023
复制
发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Pasquali M
中科院分区：
文献类型：
--
作者：
Longo N;Frigeni M;Pasquali M
肉碱对于长链脂肪酸通过线粒体内膜的转移以及随后的β氧化是必不可少的。它可以由身体合成，也可以通过饮食从肉类和乳制品中合成。肉碱生物合成缺陷通常不会导致血浆肉碱水平降低。肉碱是一种高亲和力的有机阳离子转运蛋白，专门作用于肉碱，由细胞积累并由肾脏使用OCTN2保留。OCTN2肉碱转运体缺陷导致常染色体隐性遗传性原发肉碱缺乏症，其特征是细胞内肉碱蓄积减少，尿中肉碱损失增加，以及血清肉碱水平降低。患者可能在生命早期出现低酮症低血糖和肝性脑病，或在生命后期出现骨骼肌病和心肌病，或因心律失常而猝死，通常由禁食或分解代谢状态触发。这种疾病对口服肉碱有反应，在药理剂量下，肉碱通过氨基酸转运蛋白B0，+进入细胞。可从临床表现怀疑原发性肉碱缺乏，或通过新生儿筛查中低水平的游离肉碱(C0)来确定。一些成年患者是在新生儿筛查中肉碱水平非常低的未受影响的孩子出生后被诊断出来的。通过测量患者成纤维细胞对肉碱摄取的低水平或编码OCTN2肉碱转运体的SLC22A5基因的DNA序列，可以确认诊断。一些突变是特定种族背景特有的，但大多数是私人的，只在个别家庭中发现。尽管该基因型别通常与原发性肉碱缺乏症患者的代谢或心脏损害无关，但成年患者往往至少有一个错义突变保留了残留活性。
Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. It can be synthesized by the body or assumed with the diet from meat and dairy products. Defects in carnitine biosynthesis do not routinely result in low plasma carnitine levels. Carnitine is accumulated by the cells and retained by kidneys using OCTN2, a high affinity organic cation transporter specific for carnitine. Defects in the OCTN2 carnitine transporter results in autosomal recessive primary carnitine deficiency characterized by decreased intracellular carnitine accumulation, increased losses of carnitine in the urine, and low serum carnitine levels. Patients can present early in life with hypoketotic hypoglycemia and hepatic encephalopathy, or later in life with skeletal and cardiac myopathy or sudden death from cardiac arrhythmia, usually triggered by fasting or catabolic state. This disease responds to oral carnitine that, in pharmacological doses, enters cells using the amino acid transporter B0,+. Primary carnitine deficiency can be suspected from the clinical presentation or identified by low levels of free carnitine (C0) in the newborn screening. Some adult patients have been diagnosed following the birth of an unaffected child with very low carnitine levels in the newborn screening. The diagnosis is confirmed by measuring low carnitine uptake in the patients’ fibroblasts or by DNA sequencing of the SLC22A5 gene encoding the OCTN2 carnitine transporter. Some mutations are specific for certain ethnic backgrounds, but the majority are private and identified only in individual families. Although the genotype usually does not correlate with metabolic or cardiac involvement in primary carnitine deficiency, patients presenting as adults tend to have at least one missense mutation retaining residual activity.