Biochemical, molecular, and clinical characteristics of children with short chain acyl-CoA dehydrogenase deficiency detected by newborn screening in California
Biochemical, molecular, and clinical characteristics of children with short chain acyl-CoA dehydrogenase deficiency detected by newborn screening in California
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DOI：
10.1016/j.ymgme.2012.02.007
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发表时间：
2012-05-01
影响因子：
3.8
通讯作者：
Wang, Raymond Y.
中科院分区：
文献类型：
--
作者：
Gallant, Natalie M.;Leydiker, Karen;Wang, Raymond Y.
背景：短链酰辅酶A脱氢酶缺乏症(SCADD)是一种常染色体隐性遗传性线粒体脂肪酸氧化缺陷，具有高度可变的生化、遗传和临床特征。SCADD与丁酰辅酶A副产物在体液和组织中的积累有关，包括丁酰卡尼汀(C4)、丁基甘氨酸、乙基丙二酸(EMA)和甲基琥珀酸(MS)。经临床诊断的患者与经新生儿筛查确诊的患者之间的基因频率存在差异。此外，尽管临床诊断的患者有不同的临床表现，包括发育迟缓、酮症低血糖、癫痫和行为障碍，但研究表明，通过新生儿筛查诊断的患者大多没有症状。关于通过新生儿筛查确诊的SCADD患者的生化、遗传学和临床结局的信息很少。方法：我们收集了2005年9月至2010年4月期间加州新生儿筛查、随访的生化水平和ACADS突变数据。我们回顾了通过新生儿筛查确诊的SCADD病例的现有数据。结果：在研究期间，筛查了2,632,058名新生儿，确诊了76例SCADD病例。在所研究的76例患者中，未发现初始C4值与随访生化标记物(C4、EMA或MS水平)之间的相关性。我们发现尿EMA与MS显著相关，随访C4与尿EMA显著相关。在进行ACADS基因测序的22例患者中，7例具有两个或两个以上有害突变，8例为有害突变和常见变异的复合杂合子，7例为常见突变c.625G>；A的纯合子，1例为c.625G>；A的杂合子，发现两个或两个以上有害突变的患者尿EMA和MS水平明显高于突变杂合子或常见多态纯合子。31名患者获得了临床结果数据，随访时间从0.5个月到60个月不等。没有人出现癫痫或行为障碍，3名患者有孤立的语言延迟。两名患者出现低血糖，均发生在新生儿期。第一例患者伴有胎粪吸入；另一例患者表现为中枢性呼吸暂停、喂养不良和低眼压。后者是一例c.625G>；A纯合子，在短链和中链的酰基肉碱水平持续升高；此病例的诊断工作广泛且仍在进行中。结论：这项研究是迄今为止通过新生儿筛查确诊的SCADD患者中最大的一组。我们的结果表明，验证性试验可能有助于区分具有常见变异的患者和具有有害突变的患者。这项研究还提供了证据表明，即使与有害的突变有关，通过新生儿筛查诊断的SCADD在很大程度上是一种良性疾病。(C)2012 Elsevier Inc.保留所有权利。
Background: Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation with highly variable biochemical, genetic, and clinical characteristics. SCADD has been associated with accumulation of butyryl-CoA byproducts, including butyrylcarnitine (C4), butyrylglycine, ethylmalonic acid (EMA), and methylsuccinic acid (MS) in body fluid and tissues. Differences in genotype frequencies have been shown between patients diagnosed clinically versus those diagnosed by newborn screening. Moreover, while patients diagnosed clinically have a variable clinical presentation including developmental delay, ketotic hypoglycemia, epilepsy and behavioral disorders, studies suggest patients diagnosed by newborn screening are largely asymptomatic. Scant information is published about the biochemical, genetic and clinical outcome of SCADD patients diagnosed by newborn screening.Methods: We collected California newborn screening, follow-up biochemical levels, and ACADS mutation data from September, 2005 through April, 2010. We retrospectively reviewed available data on SCADD cases diagnosed by newborn screening for clinical outcomes.Results: During the study period, 2,632,058 newborns were screened and 76 confirmed SCADD cases were identified. No correlations between initial C4 value and follow-up biochemical markers (C4, EMA or MS levels) were found in the 76 cases studied. We found significant correlation between urine EMA versus MS, and correlation between follow-up C4 versus urine EMA. Of 22 cases where ACADS gene sequencing was performed: 7 had two or more deleterious mutations; 8 were compound heterozygotes for a deleterious mutation and common variant; 7 were homozygous for the common variant c.625G>A; and 1 was heterozygous for c.625G>A. Significant increases in mean urine EMA and MS levels were noted in patients with two or more deleterious mutations versus mutation heterozygotes or common polymorphism homozygotes. Clinical outcome data was available in 31 patients with follow-up extending from 0.5 to 60 months. None developed epilepsy or behavioral disorders, and three patients had isolated speech delay. Hypoglycemia occurred in two patients, both in the neonatal period. The first patient had concomitant meconium aspiration; the other presented with central apnea, poor feeding, and hypotonia. The latter, a c.625G>A homozygote, has had persistent elevations in both short- and medium-chain acylcarnitines; diagnostic workup in this case is extensive and ongoing.Conclusions: This study examines the largest series to date of SCADD patients identified by newborn screening. Our results suggest that confirmatory tests may be useful to differentiate patients with common variants from those with deleterious mutations. This study also provides evidence to suggest that, even when associated with deleterious mutations, SCADD diagnosed by newborn screening presents largely as a benign condition. (C) 2012 Elsevier Inc. All rights reserved.