The clinical phenotype and outcome of mitochondrial acetoacetyl-CoA thiolase deficiency (beta-ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation-defined patients.
The clinical phenotype and outcome of mitochondrial acetoacetyl-CoA thiolase deficiency (beta-ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation-defined patients.
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26 名经酶法证实和突变定义的患者线粒体乙酰乙酰辅酶 A 硫解酶缺乏症（β-酮硫解酶或 T2 缺乏症）的临床表型和结果。
DOI：
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发表时间：
2001
影响因子：
3.8
通讯作者：
N. Kondo
中科院分区：
文献类型：
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作者：
T. Fukao;Charles R. Scriver;N. Kondo
线粒体乙酰乙酰辅酶A硫解酶（T2酶）缺乏症（MIM 203750）是一种常染色体隐性遗传的异亮氨酸和酮体代谢疾病。我们在皮肤成纤维细胞酶活性、蛋白质完整性和DNA核苷酸序列水平上确定了26例患者T2酶缺乏症的分子基础。确定了30种不同的疾病相关等位基因。根据这些数据，我们预测，T2在26例患者中的6例将对酶蛋白产生轻度影响，20例将因其突变基因型而产生严重影响。通过访谈和问卷调查的方式收集两组患者的相关临床资料。我们发现基因型不能预测临床严重程度，突变的同胞可以有不同的临床表型; T2活性无效或残留基因型患者之间的临床严重程度没有一致的差异;只有酮症酸中毒期间没有或尿中低排泄的tiglycine与轻度基因型相关。总的来说，T2缺乏具有良好的结局，26例患者中有23例发育正常; 1例在首次酮症酸中毒发作期间死亡，2例发育迟缓。首次酮症酸中毒发作时的中位年龄为15个月（范围为3天至48个月）。发作频率随年龄而福尔斯，最后一次发生在10岁时; 11例患者仅发作1次，3例患者无发作。我们的结论是，T2缺乏症的临床后果是可以避免的早期诊断，酮症酸中毒的适当管理，和适度的蛋白质限制。
Mitochondrial acetoacetyl-CoA thiolase (T2 enzyme) deficiency (MIM 203750) is an autosomal recessive disorder of isoleucine and ketone-body metabolism. We determined the molecular basis of T2 enzyme deficiency in 26 patients at the levels of skin fibroblast enzyme activity, protein integrity, and DNA nucleotide sequence. Thirty different disease-associated alleles were identified. From these data we predicted that T2 in 6 of the 26 patients would have a mild effect on the enzyme protein and 20 would have a severe effect from their mutant genotypes. The corresponding clinical data were collected (by interviews and questionnaires) for the patients in the two groups. We found that genotype does not predict clinical severity and mutant sibs can have different clinical phenotypes; there were no consistent differences in clinical severity between patients with null-conferring or residual-conferring genotypes for T2 activity; only the absence of or a low urinary excretion of tiglyglycine during ketoacidosis correlated with a mild genotype. In general, T2 deficiency has a favorable outcome and 23 of 26 patients developed normally; one died during the first ketoacidotic episode and two have developmental delay. The median age at onset for the first ketoacidotic episode is 15 months (range 3 days to 48 months). The frequency of attacks falls with age, the last in our series occurring at 10 years of age; 11 patients had only one episode and 3 patients had none. We conclude that clinical consequences of T2 deficiency are avoidable with early diagnosis, appropriate management of ketoacidosis, and modest protein restriction.