Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management.
Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management.
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DOI：
10.1186/1750-1172-7-68
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发表时间：
2012-09-18
影响因子：
3.7
通讯作者：
El-Hattab AW
中科院分区：
文献类型：
--
作者：
Magoulas PL;El-Hattab AW
系统性原发性肉碱缺乏症（CDSP）是一种常染色体隐性肉碱运输障碍。 CDSP 的临床表现在发病年龄、器官受累和症状严重程度方面差异很大，但典型特征是婴儿中出现低酮性低血糖、肝肿大、转氨酶升高和高氨血症；儿童期骨骼肌病、肌酸激酶（CK）升高和心肌病；或成年后出现心肌病、心律失常或易疲劳。新生儿筛查可怀疑该诊断，但需通过血浆游离肉碱浓度低（<5 μM，正常为 25-50 μM）、成纤维细胞肉碱转运减少（<对照的 10%）以及 SLC22A5 基因的分子检测来确定。 CDSP 的发病率因种族而异；然而，根据新生儿筛查数据，美国的这一频率估计约为五万分之一。 CDSP 是由 SLC22A5 基因隐性突变引起的。该基因编码 2 型有机阳离子转运蛋白 (OCTN2)，可跨细胞膜转运肉碱。据报道，该基因存在 100 多种突变，其中 c.136C > T (p.P46S) 突变是最常见的突变。 CDSP应与肉碱缺乏的次要原因如各种有机酸血症和脂肪酸氧化缺陷相鉴别。 CDSP 是一种常染色体隐性遗传疾病；因此每次妊娠的复发风险为25%。应通过对 SLC22A5 基因进行靶向突变分析来对高危个体和家庭成员进行携带者筛查，因为血浆肉碱分析不足以确定携带者状态。如果已知 SLC22A5 基因的两种突变，则可以通过从绒毛膜绒毛取样或羊膜穿刺术中提取的 DNA 进行分子遗传学检测，对 CDSP 风险增加的妊娠进行产前诊断。一旦确诊个体 CDSP，应进行超声心动图、心电图、CK 浓度、肝脏转氨酶测量和餐前血糖水平进行基线评估。主要治疗包括补充口服左卡尼汀（L-肉碱），剂量为 50-400 毫克/公斤/天，分为三剂。迄今为止，尚未制定针对 CDSP 个体的正式监测指南，但建议采取以下筛查建议：在急性疾病期间可以考虑每年进行超声心动图和心电图、频繁的血浆肉碱水平以及 CK 和肝脏转氨酶测量。计划怀孕或正在怀孕的患有 CDSP 的成年女性最好在受孕前与代谢或遗传专家会面，讨论怀孕期间肉碱水平的管理，因为怀孕期间肉碱水平通常较低。 CDSP 患者的预后取决于诊断时的年龄、表现和症状的严重程度；然而，只要个体继续补充肉碱，长期预后就会良好。
Systemic primary carnitine deficiency (CDSP) is an autosomal recessive disorder of carnitine transportation. The clinical manifestations of CDSP can vary widely with respect to age of onset, organ involvement, and severity of symptoms, but are typically characterized by episodes of hypoketotic hypoglycemia, hepatomegaly, elevated transaminases, and hyperammonemia in infants; skeletal myopathy, elevated creatine kinase (CK), and cardiomyopathy in childhood; or cardiomyopathy, arrhythmias, or fatigability in adulthood. The diagnosis can be suspected on newborn screening, but is established by demonstration of low plasma free carnitine concentration (<5 μM, normal 25-50 μM), reduced fibroblast carnitine transport (<10% of controls), and molecular testing of the SLC22A5 gene. The incidence of CDSP varies depending on ethnicity; however the frequency in the United States is estimated to be approximately 1 in 50,000 individuals based on newborn screening data. CDSP is caused by recessive mutations in the SLC22A5 gene. This gene encodes organic cation transporter type 2 (OCTN2) which transport carnitine across cell membranes. Over 100 mutations have been reported in this gene with the c.136C > T (p.P46S) mutation being the most frequent mutation identified. CDSP should be differentiated from secondary causes of carnitine deficiency such as various organic acidemias and fatty acid oxidation defects. CDSP is an autosomal recessive condition; therefore the recurrence risk in each pregnancy is 25%. Carrier screening for at-risk individuals and family members should be obtained by performing targeted mutation analysis of the SLC22A5 gene since plasma carnitine analysis is not a sufficient methodology for determining carrier status. Antenatal diagnosis for pregnancies at increased risk of CDSP is possible by molecular genetic testing of extracted DNA from chorionic villus sampling or amniocentesis if both mutations in SLC22A5 gene are known. Once the diagnosis of CDSP is established in an individual, an echocardiogram, electrocardiogram, CK concentration, liver transaminanses measurement, and pre-prandial blood sugar levels, should be performed for baseline assessment. Primary treatment involves supplementation of oral levocarnitine (L-carnitine) at a dose of 50–400 mg/kg/day divided into three doses. No formal surveillance guidelines for individuals with CDSP have been established to date, however the following screening recommendations are suggested: annual echocardiogram and electrocardiogram, frequent plasma carnitine levels, and CK and liver transaminases measurement can be considered during acute illness. Adult women with CDSP who are planning to or are pregnant should meet with a metabolic or genetic specialist ideally before conception to discuss management of carnitine levels during pregnancy since carnitine levels are typically lower during pregnancy. The prognosis for individuals with CDSP depends on the age, presentation, and severity of symptoms at the time of diagnosis; however the long-term prognosis is favorable as long as individuals remain on carnitine supplementation.
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DOI：
10.1196/annals.1320.004
发表时间：
2004-01-01
期刊：
CARNITINE: THE SCIENCE BEHIND A CONDITIONALLY ESSENTIAL NUTRIENT
影响因子：
--
作者：
Stanley, CA
通讯作者：
Stanley, CA
影响因子：
158.5
作者：
Wilcken, B;Wiley, V;Carpenter, K
通讯作者：
Carpenter, K
影响因子：
4.2
作者：
Spiekerkoetter, U;Huener, G;Mayatepek, E
通讯作者：
Mayatepek, E
影响因子：
4.2
作者：
Vijay, S.;Patterson, A.;Walter, J. H.
通讯作者：
Walter, J. H.
影响因子：
3.9
作者：
Erguven, Muferet;Yilmaz, Oznur;Dolunay, Gulderen
通讯作者：
Dolunay, Gulderen