Tein I
Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Canada.
J Inherit Metab Dis. 2003;26(2-3):147-69. doi: 10.1023/a:1024481016187.
Early-onset dilatative and/or hypertrophic cardiomyopathy with episodic hypoglycaemic coma and very low serum and tissue concentrations of carnitine should alert the clinician to the probability of the plasmalemmal high-affinity carnitine transporter defect. The diagnosis can be established by demonstration of impaired carnitine uptake in cultured skin fibroblasts or lymphoblasts and confirmed by mutation analysis of the human OCTN2 gene in the affected child and obligate heterozygote parents. The institution of high-dose oral carnitine supplementation reverses the pathology in this otherwise lethal autosomal recessive disease of childhood, and carnitine therapy from birth in prospectively screened siblings may altogether prevent the development of the clinical phenotype. Heterozygotes may be at risk for cardiomyopathy in later adult life, particularly in the presence of additional risk factors such as hypertension and competitive pharmacological agents. OCTN2 belongs to a family of organic cation/carnitine transporters that function primarily in the elimination of cationic drugs and other xenobiotics in kidney, intestine, liver and placenta. The high- and low-affinity human carnitine transporters, OCTN2 and OCTN1, are multifunctional polyspecific organic cation transporters; therefore, defects in these transporters may have widespread implications for the absorption and/or elimination of a number of key pharmacological agents such as cephalosporins, verapamil, quinidine and valproic acid. A third organic/cation carnitine transporter with high specificity for carnitine, Octn3, has been cloned in mice. The juvenile visceral steatosis (jvs) mouse serves as an excellent clinical, biochemical and molecular model for the high-affinity carnitine transporter OCTN2 defect and is due to a spontaneous point mutation in the murine Octn2 gene on mouse chromosome 11, which is syntenic to the human locus at 5q31 that harbours the human OCTN2 gene.
早发性扩张型和/或肥厚型心肌病合并发作性低血糖昏迷以及血清和组织中肉碱浓度极低，应提醒临床医生注意存在质膜高亲和力肉碱转运体缺陷的可能性。通过证明培养的皮肤成纤维细胞或淋巴细胞中肉碱摄取受损可确立诊断，并通过对患病儿童及其 obligate 杂合子父母的人 OCTN2 基因进行突变分析加以证实。大剂量口服补充肉碱可逆转这种儿童期致死性常染色体隐性疾病的病理状况，对前瞻性筛查的同胞从出生就进行肉碱治疗可能完全预防临床表型的发展。杂合子在成年后期可能有患心肌病的风险，尤其是在存在高血压和竞争性药物等其他风险因素的情况下。OCTN2 属于有机阳离子/肉碱转运体家族，主要在肾脏、肠道、肝脏和胎盘中发挥消除阳离子药物和其他外源性物质的作用。高亲和力和低亲和力的人肉碱转运体 OCTN2 和 OCTN1 是多功能多特异性有机阳离子转运体；因此，这些转运体的缺陷可能对多种关键药物如头孢菌素、维拉帕米、奎尼丁和丙戊酸的吸收和/或消除产生广泛影响。已在小鼠中克隆出对肉碱具有高特异性的第三种有机/阳离子肉碱转运体 Octn3。幼年内脏脂肪变性（jvs）小鼠是高亲和力肉碱转运体 OCTN2 缺陷的出色临床、生化和分子模型，它是由于小鼠 11 号染色体上的鼠 Octn2 基因发生自发点突变所致，该基因与人类 5q31 位点同线，而人类 OCTN2 基因就位于该位点。
