PDF(Sci-hub)
Abstract：
Short/branched chain acyl-CoA dehydrogenase deficiency (SBCADD), also called 2-methylbutyryl CoA dehydrogenase deficiency (2-MBCDD), is a disorder of l-isoleucine metabolism of uncertain clinical significance. SBCADD is inadvertently detected on expanded newborn screening by elevated 2-methylbutyrylcarnitine (C5), which has the same mass to charge (m/s) on tandem mass spectrometry (MS/MS) as isovalerylcarnitine (C5), an analyte that is elevated in isovaleric acidemia (IVA), a disorder in leucine metabolism. SBCADD cases identified in the Hmong-American population have been found in association with the c.1165 A>G mutation in the ACADSB gene. The purposes of this study were to: (a) estimate the prevalence of SBCADD and carrier frequency of the c.1165 A>G mutation in the Hmong ethnic group; (b) determine whether the c.1165 A>G mutation is common to all Hmong newborns screening positive for SBCADD; and (c) evaluate C5 acylcarnitine cut-off values to detect and distinguish between SBCADD and IVA diagnoses. During the first 10years of expanded newborn screening using MS/MS in Wisconsin (2001-2011), 97 infants had elevated C5 values (≥0.44μmol/L), of whom five were Caucasian infants confirmed to have IVA. Of the remaining 92 confirmed SBCADD cases, 90 were of Hmong descent. Mutation analysis was completed on an anonymous, random sample of newborn screening cards (n=1139) from Hmong infants. Fifteen infants, including nine who had screened positive for SBCADD based on a C5 acylcarnitine concentration ≥0.44μmol/L, were homozygous for the c.1165 A>G mutation. This corresponds to a prevalence in this ethnic group of being homozygous for the mutation of 1.3% (95% confidence interval 0.8-2.2%) and of being heterozygous for the mutation of 21.8% (95% confidence interval 19.4-24.3%), which is consistent with the Hardy-Weinberg equilibrium. Detection of homozygous individuals who were not identified on newborn screening suggests that the C5 screening cut-off would need to be as low as 0.20μmol/L to detect all infants homozygous for the ACADSB c.1165 A>G mutation. However, lowering the screening cut-off to 0.20 would also result in five \"false positive\" (non-homozygous) screening results in the Hmong population for every c.1165 A>G homozygote detected. Increasing the cut-off to 0.60μmol/L and requiring elevated C5/C2 (acetylcarnitine) and C5/C3 (propionylcarnitine) ratios to flag a screen as abnormal would reduce the number of infants screening positive, but would still result in an estimated 5 infants with SBCADD per year who would require follow-up and additional biochemical testing to distinguish between SBCADD and IVA diagnoses. Further research is needed to determine the clinical outcomes of SBCADD detected on newborn screening and the c.1165 A>G mutation before knowing whether the optimal screening cut-off would minimize true positives or false negatives for SBCADD associated with this mutation.
摘要：
短/支链酰基辅酶A脱氢酶缺乏症（SBCADD），也称为2-甲基丁酰基辅酶A脱氢酶缺乏症（2-MBCDD），是一种临床意义不确定的l-异亮氨酸代谢障碍。SBCADD在扩大新生儿筛查中被2-甲基丁酰肉碱（C5）升高而无意中检测到，在串联质谱（MS/MS）上与异戊酰基肉碱（C5）具有相同的质荷比（m/s），在异戊酸血症（IVA）中升高的分析物，亮氨酸代谢紊乱.在苗族美国人群中发现的SBCADD病例与ACADSB基因中的c.1165A>G突变有关。这项研究的目的是：（a）估计苗族人群中SBCADD的患病率和c.1165A>G突变的载波频率；（b）确定c.1165A>G突变是否在所有对SBCADD筛查阳性的苗族新生儿中常见；（c）评估C5酰基肉碱的临界值，以检测和区分SBCADD和IVA诊断。在威斯康星州（2001-2011年）使用MS/MS进行扩大新生儿筛查的前10年期间，97例婴儿C5值升高（≥0.44μmol/L），其中5名是确认患有IVA的白种人婴儿。在其余92例确诊的SBCADD病例中，90人是苗族后裔。突变分析是在一个匿名的人身上完成的，从苗族婴儿中随机抽取新生儿筛查卡（n=1139）。15个婴儿,包括9名基于C5酰基肉碱浓度≥0.44μmol/L的SBCADD筛查阳性，对于c.1165A>G突变是纯合的。这对应于该种族群体中1.3%的突变纯合(95%置信区间0.8-2.2%)和21.8%的突变杂合(95%置信区间19.4-24.3%)的患病率。这与哈代-温伯格均衡是一致的。未在新生儿筛查中鉴定的纯合子个体的检测表明，C5筛查截止值需要低至0.20μmol/L，以检测所有纯合子婴儿的ACADSBc.1165A>G突变。然而,将筛选截止值降低至0.20还将导致在每检测到c.1165A>G纯合子的苗族人群中出现5个“假阳性”（非纯合子）筛选结果。将截止值增加至0.60μmol/L并要求升高C5/C2（乙酰肉碱）和C5/C3（丙酰肉碱）比率以标记异常的筛查将减少筛查阳性的婴儿数量，但仍将导致每年估计有5名婴儿患有SBCADD,他们需要随访和额外的生化检测来区分SBCADD和IVA诊断.需要进一步的研究来确定在新生儿筛查中检测到的SBCADD的临床结果和c.1165A>G突变，然后才知道最佳筛查截止值是否会使与该突变相关的SBCADD的真阳性或假阴性最小化。
