Tein I, Sloane A E, Donner E J, Lehotay D C, Millington D S, Kelley R I
Division of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada.
Pediatr Neurol. 1995 Jan;12(1):21-30. doi: 10.1016/0887-8994(94)00100-g.
The purpose of this study was to further identify and quantify the fatty acid oxidation abnormalities in spinal muscular atrophy, correlate these with disease severity, and identify specific underlying defect(s). Fifteen children with spinal muscular atrophy (3 type I, 8 type II, 4 type III) were studied. Serum carnitine total/free ratios demonstrated a tendency toward an increased esterified fraction ranging 35-58% of total carnitine (normal: 25-30% of total) in younger children with types I and II. The remaining type II and III patients, older than 23 months of age at sampling, had normal esterified carnitine levels. Urinary organic acid analysis demonstrated mild to moderate medium-chain dicarboxylic aciduria in type I patients and normal, mild, or moderate increases in short-chain and medium-chain organic acids in type II patients. In the type III group, the organic acids were normal except for one patient with mild medium-chain dicarboxylic aciduria. Muscle intramitochondrial beta-oxidation was measured in 5 children (2 type I, 2 type II, and 1 type III) and a significant reduction in the activities of short-chain L-3-hydroxyacyl-CoA dehydrogenase, long-chain L-3-hydroxyacyl-CoA dehydrogenase, acetoacetyl-CoA thiolase, and 3-ketoacyl-CoA thiolase were found; however, normal crotonase activity was documented. Most strikingly, there was a marked increase (3- to 5-fold) in the activity ratios of crotonase to L-3-hydroxyacyl-CoA dehydrogenase and thiolase activities with both short- and long-chain substrates. The combined abnormalities suggest a defect in a mitochondrial multifunctional enzyme complex, distinct from the trifunctional enzyme. These abnormalities may be either primary or secondary and may respond to dietary measures to reduce the dependence on fatty acid oxidation.
本研究的目的是进一步识别和量化脊髓性肌萎缩症中脂肪酸氧化异常，将这些异常与疾病严重程度相关联，并确定具体的潜在缺陷。对15名脊髓性肌萎缩症患儿（3名I型、8名II型、4名III型）进行了研究。血清肉碱总/游离比值显示，I型和II型的年幼儿童中，酯化部分有增加的趋势，占总肉碱的35 - 58%（正常：占总肉碱的25 - 30%）。其余II型和III型患者在采样时年龄超过23个月，其酯化肉碱水平正常。尿有机酸分析显示，I型患者有轻度至中度的中链二羧酸尿症，II型患者短链和中链有机酸有正常、轻度或中度增加。在III型组中，除一名有轻度中链二羧酸尿症的患者外，有机酸均正常。对5名儿童（2名I型、2名II型和1名III型）的肌肉线粒体内β-氧化进行了测量，发现短链L-3-羟基酰基辅酶A脱氢酶、长链L-3-羟基酰基辅酶A脱氢酶、乙酰乙酰辅酶A硫解酶和3-酮酰基辅酶A硫解酶的活性显著降低；然而，巴豆酸酶活性记录正常。最显著的是，巴豆酸酶与L-3-羟基酰基辅酶A脱氢酶的活性比值以及短链和长链底物的硫解酶活性均有显著增加（3至5倍）。这些综合异常表明线粒体多功能酶复合物存在缺陷，不同于三功能酶。这些异常可能是原发性的或继发性的，可能对饮食措施有反应，以减少对脂肪酸氧化的依赖。
