Carnitine uptake defect due to a 5′UTR mutation in a pedigree with false positives and false negatives on Newborn screening
Carnitine uptake defect due to a 5′UTR mutation in a pedigree with false positives and false negatives on Newborn screening
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DOI：
10.1016/j.ymgme.2019.12.006
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发表时间：
2020-03-01
影响因子：
3.8
通讯作者：
Geraghty, Michael T.
中科院分区：
文献类型：
--
作者：
Verbeeten, Kate C.;Lamhonwah, Anne-Marie;Geraghty, Michael T.
肉毒碱摄取缺陷（CUD）是一种常染色体隐性遗传疾病，由于SLC 22 A5基因突变。典型的患者在婴儿期表现为严重的肌无力和心肌病，并有特征性的EKG表现。后期表现包括复发性低酮性低血糖、近端肢带肌病和/或复发性肌肉疼痛。新生儿筛查可检测到这些临床变异中的大多数，但除此之外，还可在无症状女性中发现母体CUD。我们描述了一个家庭确定通过3新生儿筛查（NBS）阳性婴儿被发现是不受影响的，但在其中的母亲（姐妹篇）受到影响。也有两个受影响的孩子出生的受影响的男性和他的杂合子妻子谁是假阴性的NBS，但增加了尿液中的游离肉毒碱排泄分数。对专门设计用于完全覆盖新生儿筛查疾病靶标的下一代测序组的分析显示五个先证者中的纯合变化（SLC 22 A5; NM_003060：c. 149G > A; p.？）.该突变与家族内的CUD分离。它位于5' UTR中，在gnomAd数据库中的频率为0.001198。血浆肉毒碱减少，游离肉毒碱的排泄分数增加，在所有受影响的个人。在培养的皮肤成纤维细胞的一个先证者的功能性肉毒碱摄取的研究表明，肉毒碱摄取在5 μ M浓度为6%的控制。通过qRT-PCR，先证者中OCTN 2 mRNA与β-肌动蛋白mRNA的相对表达相对于对照增加了465倍。蛋白质印迹法显示了一个120 kDa的蛋白质条带，以及一个较弱的240 kDa的带在先证者，其意义是未知的，在这个时候。
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 mu M 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.