Section of Metabolic Diseases, Beatrix Children's Hospital, University of Groningen, University Medical Centre, Groningen, The Netherlands.
Orphanet J Rare Dis. 2013 Mar 20;8:43. doi: 10.1186/1750-1172-8-43.
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of the mitochondrial fatty acid oxidation, caused by mutations in the ACADM gene. Since the introduction of neonatal screening for MCAD deficiency, a subgroup of newborns have been identified with variant ACADM genotypes that had never been identified before in clinically ascertained patients. In vitro residual MCAD enzyme activity has been found to facilitate risk-stratification. In this study we integrated results of in vitro (residual MCAD enzyme activities) and in vivo (clinical fasting tolerance tests, and phenylpropionic acid loading tests) tests in this subgroup of newborns, defining the consequences of variant ACADM genotypes.
Enzyme analyses were performed in leukocytes with: hexanoyl-CoA (C6-CoA) +/- butyryl-CoA (C4-CoA), and phenylpropionyl-CoA (PP-CoA). In vitro studies were performed in 9 subjects with variant ACADM genotypes, in vivo functional tests in 6 of these subjects.
Enzyme analyses with C6-CoA, C6-CoA + C4-CoA, and PP-CoA identified significantly higher residual MCAD enzyme activities in subjects with variant ACADM genotypes when compared to patients with classical ACADM genotypes.After prolonged fasting (range 15-18.5 hours) no hypoglycaemia was observed. Increasing concentrations of free fatty acids indicated lipolysis, and ketone body concentrations were sufficient for blood glucose concentrations in 5 out of 6 subjects. Phenylpropionic acid loading clearly demonstrated in vivo residual MCAD enzyme activity in all studied subjects.
Subjects with variant ACADM genotypes and residual MCAD enzyme activities >10% display residual MCAD enzyme activities in vitro and in vivo. Our findings support the hypothesis that the guidelines on maximal duration of fasting might be abandoned in subjects with residual MCAD enzyme activities >10% under normal conditions. An emergency regimen and parental instructions remain necessary in all subjects with MCAD deficiency, regardless of residual MCAD enzyme activity.
中链酰基辅酶 A 脱氢酶（MCAD）缺乏症是最常见的线粒体脂肪酸氧化遗传障碍，由 ACADM 基因突变引起。自从引入 MCAD 缺乏症的新生儿筛查以来，已经在以前从未在临床确定的患者中发现过的变异 ACADM 基因型的亚组新生儿中发现了这种情况。已经发现体外残留的 MCAD 酶活性有助于风险分层。在这项研究中，我们整合了该亚组新生儿的体外（残留的 MCAD 酶活性）和体内（临床禁食耐量试验和苯丙氨酸负荷试验）试验的结果，定义了变异 ACADM 基因型的后果。
使用：己酰基辅酶 A（C6-CoA）±丁酰基辅酶 A（C4-CoA）和苯丙酰基辅酶 A（PP-CoA）在白细胞中进行酶分析。在 9 名具有变异 ACADM 基因型的受试者中进行了体外研究，在其中 6 名受试者中进行了体内功能测试。
与具有经典 ACADM 基因型的患者相比，使用 C6-CoA、C6-CoA+C4-CoA 和 PP-CoA 进行的酶分析在具有变异 ACADM 基因型的受试者中鉴定出明显更高的残留 MCAD 酶活性。在延长的禁食（范围 15-18.5 小时）后未观察到低血糖。游离脂肪酸浓度的增加表明脂肪分解，酮体浓度在 6 名受试者中的 5 名足以维持血糖浓度。苯丙氨酸负荷清楚地表明了所有研究对象的体内残留 MCAD 酶活性。
残留 MCAD 酶活性>10％的具有变异 ACADM 基因型和残留 MCAD 酶活性的受试者在体外和体内均显示残留 MCAD 酶活性。我们的研究结果支持这样的假设，即在正常条件下，残留 MCAD 酶活性>10％的患者可能放弃禁食的最长时间指南。在所有 MCAD 缺乏症患者中，无论残留 MCAD 酶活性如何，都仍然需要应急方案和父母指导。
