Department of Pediatrics, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 777, Rochester, NY 14642, USA.
Mol Genet Metab. 2010 Mar;99(3):263-8. doi: 10.1016/j.ymgme.2009.10.188. Epub 2009 Nov 1.
Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most common inborn errors of metabolism. Affected patients have impaired ability to break down medium chain fatty acids during fasting, and typically present in the early years of life with hypoketotic hypoglycemia, Reye syndrome-like symptoms, brain damage or death. The development of newborn screening (NBS) for MCAD deficiency has greatly improved outcome, but some patients still appear at risk for severe complications. We reviewed the outcome of patients identified with MCAD deficiency by the New York State NBS process to identify biochemical or genotypic markers which might predict outcome.
All eight NBS follow-up centers in New York State contributed the cases of MCAD deficiency diagnosed by newborn screen, who received diagnostic and follow-up care in their clinic. Data reviewed included gender, age, birthweight, initial NBS octanoylcarnitine level (C8) and C8/C2 ratio, follow-up C8 and hexanoylglycine, race/ethnicity, and presence of neonatal or later symptoms.
We identified 53 cases of MCAD deficiency. More than one quarter of patients had a post-neonatal symptomatic admission (predominantly lethargy associated with an intercurrent illness). No genotype or C8 level was protective for neonatal or later symptoms. There was a relationship between initial C8 level or C8/C2 ratio and occurrence of later symptoms (7.3 micromol/L in the asymptomatic vs. 19.1 micromol/L in the symptomatic, p<0.0002 for C8, and 0.26 vs. 0.6, respectively, for C8/C2 ratio, p<0.012). Four infants had initial C8 level >30 micromol/L; these infants had a high rate of symptomatic or multiple symptomatic episodes or a history of sibling death from "SIDS", and typically had deletion, nonsense or splice sites mutations. Infants having a history of a symptomatic episode were more likely to have higher initial C8 on NBS and a genotype predicted to strongly affect protein function. In our ethnically diverse group of patients, the c.985A>G mutation was rarely found in non-Caucasians.
No genotype or metabolite profile is protective from symptoms. The strong relationship between initial C8 level and outcome suggests that in at least some cases neonates having high initial C8 levels may be demonstrating an increased susceptibility to catabolic stress, and may merit additional precautions. Our data also suggest that these infants are more likely to carry severe mutations including homozygosity for the common mutation, deletions, nonsense or splice site mutations. The reports of significant lethargy or hypoglycemia during intercurrent illness in over one quarter of cases even when early medical intervention is recommended (and even when initial C8 is not profoundly elevated) underscores the importance of continued vigilance to prevent stressful fasting in this disorder.
中链酰基辅酶 A 脱氢酶（MCAD）缺乏症是最常见的先天性代谢缺陷之一。受影响的患者在禁食期间分解中链脂肪酸的能力受损，通常在生命的早期表现为低酮低血糖、类似瑞氏综合征的症状、脑损伤或死亡。新生儿筛查（NBS）对 MCAD 缺乏症的发展极大地改善了预后，但仍有一些患者存在严重并发症的风险。我们回顾了纽约州 NBS 过程中发现的 MCAD 缺乏症患者的结果，以确定可能预测结局的生化或基因型标志物。
纽约州的所有八个 NBS 随访中心都提供了通过新生儿筛查诊断的 MCAD 缺乏症病例，这些患者在其诊所接受了诊断和随访护理。回顾的数据包括性别、年龄、出生体重、初始 NBS 辛酰肉碱水平（C8）和 C8/C2 比值、随访的 C8 和己酰基甘氨酸、种族/民族以及是否存在新生儿期或后期症状。
我们确定了 53 例 MCAD 缺乏症患者。超过四分之一的患者有新生儿期后出现症状的住院治疗（主要是与急性病相关的昏睡）。没有基因型或 C8 水平可预防新生儿期或后期症状。初始 C8 水平或 C8/C2 比值与后期症状的发生有关（无症状患者为 7.3 微摩尔/升，有症状患者为 19.1 微摩尔/升，C8 水平差异有统计学意义，p<0.0002；C8/C2 比值分别为 0.26 和 0.6，差异有统计学意义，p<0.012）。有 4 名婴儿的初始 C8 水平>30 微摩尔/升；这些婴儿有症状或多次症状发作的高发生率，或有兄弟姐妹因“婴儿猝死综合征”（SIDS）死亡的病史，且通常存在缺失、无义或剪接位点突变。有症状发作病史的婴儿在 NBS 时更有可能有较高的初始 C8 值，且基因型预测对蛋白质功能有强烈影响。在我们种族多样化的患者群体中，c.985A>G 突变在非高加索人中很少见。
没有基因型或代谢物谱可预防症状。初始 C8 水平与结局之间的强关系表明，在至少一些情况下，初始 C8 水平较高的新生儿可能表现出对分解代谢应激的增加易感性，因此可能需要额外的预防措施。我们的数据还表明，这些婴儿更有可能携带严重的突变，包括常见突变的纯合子、缺失、无义或剪接位点突变。超过四分之一的病例在急性病期间出现明显的昏睡或低血糖，即使建议进行早期医疗干预（即使初始 C8 未显著升高），这突出表明在这种疾病中，继续保持警惕以防止禁食期间的应激至关重要。
