Rao K V, Qureshi I A
Division of Medical Genetics, Hõpital Sainte-Justine, University of Montréal, QC, Canada.
Can J Physiol Pharmacol. 1997 May;75(5):423-30.
BALB/cByJ mice have an autosomal recessive deficiency of short-chain acyl-CoA dehydrogenase (SCAD) and show elevated excretion of urinary butyrylglycine, ethylmalonate, and methylsuccinate, which resembles the SCAD deficiency disorder in children. These mice are clinically normal, perhaps because of an efficient acyl-CoA conjugation system. We attempted to decompensate the acyl-CoA metabolism in mutant mice by chronic treatment with a riboflavin-deficient diet for 3 weeks to potentiate the SCAD deficiency. We studied the urinary profiles of organic acids, acylglycines, hepatic and cerebral profiles of carnitines, and ammonia to assess the potentiation of this disorder. Cerebral activity of choline acetyltransferase (ChAT) was determined to study the effects of acyl-CoA accumulation on the cholinergic system. The results indicate that in riboflavin-deficient mutant mice, the excretion of ethylmalonate, methylsuccinate, butyrylglycine, and dicarboxylic acids was enhanced. Hepatic and cerebral free and esterified carnitines were reduced, indicating a potentiation of the secondary carnitine deficiency. Hepatic ammonia levels, but not cerebral ammonia or glutamine levels, were elevated, indicating a tendency towards secondary hyperammonemia. Brain choline acetyltransferase activity was significantly reduced in striatum, implying a reduced availability of cerebral acetyl-CoA or a decreased cerebral transport of choline: Most of these changes were partially or completely restored by a concomitant treatment with acetyl-L-carnitine (ALCAR). In summary, we conclude that BALB/cByJ mice with SCAD deficiency, but with a functional urea cycle, might have an adequate adaptive mechanism to adjust to an excessive acyl-CoA load without hyperammonemia at the cerebral level. However, any deficiency of vitamins or cofactors in the diet could disturb an adaptation to this disorder and produce an effect on the cholinergic system.
BALB/cByJ小鼠存在常染色体隐性短链酰基辅酶A脱氢酶（SCAD）缺陷，尿中丁酰甘氨酸、乙基丙二酸和甲基琥珀酸排泄增加，这类似于儿童的SCAD缺陷症。这些小鼠临床上正常，可能是因为有高效的酰基辅酶A结合系统。我们试图通过用缺乏核黄素的饮食对突变小鼠进行3周的长期治疗来使酰基辅酶A代谢失代偿，以增强SCAD缺陷。我们研究了有机酸、酰基甘氨酸的尿谱，肉碱的肝脏和大脑谱以及氨，以评估这种疾病的增强情况。测定胆碱乙酰转移酶（ChAT）的脑活性以研究酰基辅酶A积累对胆碱能系统的影响。结果表明，在缺乏核黄素的突变小鼠中，乙基丙二酸、甲基琥珀酸、丁酰甘氨酸和二羧酸的排泄增加。肝脏和大脑中的游离和酯化肉碱减少，表明继发性肉碱缺乏增强。肝脏氨水平升高，但脑氨或谷氨酰胺水平未升高，表明有继发性高氨血症的趋势。纹状体中脑胆碱乙酰转移酶活性显著降低，这意味着脑乙酰辅酶A的可用性降低或胆碱的脑转运减少：通过同时用乙酰-L-肉碱（ALCAR）治疗，这些变化大多部分或完全恢复。总之，我们得出结论，具有SCAD缺陷但尿素循环功能正常的BALB/cByJ小鼠可能有足够的适应性机制来适应过量的酰基辅酶A负荷，而不会在脑水平出现高氨血症。然而，饮食中任何维生素或辅因子的缺乏都可能干扰对这种疾病的适应并对胆碱能系统产生影响。
