Carnitine Uptake Defect (CUD) is an autosomal recessive disorder due to mutations in the SLC22A5 gene. Classically patients present in infancy with profound muscle weakness and cardiomyopathy with characteristic EKG findings. Later presentations include recurrent hypoketotic hypoglycemia, proximal limb girdle myopathy,and/or recurrent muscle pain. Newborn screening detects most of these clinical variants but in addition has identified maternal CUD often in asymptomatic women. We describe a family ascertained through 3 newborn screening (NBS) positive infants found to be unaffected themselves but in whom the mothers (sisters) were affected. There were also two affected children born to an affected male and his heterozygous wife who were false negatives on NBS but had increased fractional excretion of free carnitine in the urine. Analysis on a Next Generation Sequencing panel specifically designed to fully cover newborn screening disease targets showed a homozygous change in the five probands (SLC22A5; NM_003060:c.-149G > A; p.?). The mutation segregates with the CUD within the family. It is in the 5' UTR and has a frequency within the gnomAd database of 0.001198. Plasma carnitine was decreased and fractional excretion of free carnitine was increased in all affected individuals. Functional carnitine uptake studies in cultured skin fibroblasts of one proband showed carnitine uptake at the 5 μM concentration to be 6% of controls. Relative expression of OCTN2 mRNA to beta-actin mRNA by qRT-PCR was increased in a proband relative to controls by a factor of 465-fold. Western blotting revealed a 120 kDa protein band, as well as a weaker 240 kDa band in the proband, the significance of which is unknown at this time.

中文翻译：

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由于新生儿筛查中的假阳性和假阴性的血统中的5'UTR突变而导致的肉碱摄取缺陷。

肉碱摄取缺陷（CUD）是由于SLC22A5基因突变而引起的常染色体隐性遗传疾病。典型地，婴儿期患者表现为严重的肌无力和心肌病，并伴有典型的心电图表现。以后的表现包括复发性低酮症性低血糖症，近端腰带肌病和/或复发性肌肉痛。新生儿筛查可以检测到大多数这些临床变异，但此外，通常可以在无症状的女性中识别出孕妇的CUD。我们描述了一个通过3个新生儿筛查（NBS）阳性婴儿确定的家庭，这些婴儿被发现自己没有受到影响，但是母亲（姐妹）受到了影响。还有两个受影响的孩子，由一个受影响的男性和他的杂合子妻子所生，他们在NBS上为假阴性，但尿中游离肉碱的分数排泄增加。在专门设计为完全覆盖新生儿筛查疾病目标的下一代测序小组的分析中，发现五个先证者发生了纯合变化（SLC22A5； NM_003060：c.-149G> A； p。？）。突变与家族中的CUD隔离。它位于5'UTR中，在gnomAd数据库中的频率为0.001198。在所有受影响的个体中，血浆肉碱减少，游离肉碱的分数排泄增加。在一个先证者的培养皮肤成纤维细胞中进行的功能性肉碱摄取研究表明，浓度为5μM的肉碱摄取量为对照组的6％。通过qRT-PCR，OCTN2 mRNA与β-actinmRNA的相对表达在先证者中相对于对照增加了465倍。Western印迹显示先证者中有一个120 kDa的蛋白条带，以及一个较弱的240 kDa的条带，