Beta-Ketothiolase Deficiency Presenting with Metabolic Stroke After a Normal Newborn Screen in Two Individuals
Beta-Ketothiolase Deficiency Presenting with Metabolic Stroke After a Normal Newborn Screen in Two Individuals
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DOI：
10.1007/8904_2017_45
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发表时间：
2018-01-01
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影响因子：
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通讯作者：
Agrawal, Pankaj B.
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作者：
Wojcik, Monica H.;Wierenga, Klaas J.;Agrawal, Pankaj B.
-酮硫酶（线粒体乙酰乙酰辅酶a硫酶）缺乏症是一种遗传性疾病，其特征是异亮氨酸分解代谢和酮体利用受损，易发生偶发性酮酸中毒。它是由编码线粒体β -酮硫酶的ACAT1基因的双等位致病变异引起的。我们报告两例β -酮硫酶缺乏表现为急性酮症酸中毒和“代谢性中风”。第一个病人在28个月大时出现代谢性酸中毒和苍白性中风，在发热性胃肠道疾病的设置。虽然尿中存在2-甲基-3-羟基丁酸和微量的替甘氨酸，但由于戊二酸和3-羟基戊二酸的存在，最初怀疑诊断为戊二酸血症I型。通过全外显子组测序发现ACAT1存在复合杂合变异，最终诊断为β -酮硫酶缺乏症。成纤维细胞对β -酮硫酶活性的研究得到了证实。第二例患者在6个月大时出现酮症酸中毒，发现尿中2-甲基-3-羟基丁酸、2-甲基乙酰乙酸和甲酰甘氨酸升高。ACAT1的测序证实了复合杂合推定的致病变异。患者在急性代谢失代偿2个月后出现舞蹈病。这些病例强调，与许多其他有机酸血症和线粒体疾病类似，β -酮硫酶缺乏症可出现代谢性中风。他们还说明了临床表现、影像学和生化评估的可变性，使得这种罕见疾病的筛查和诊断具有挑战性，并进一步证明了全外显子组测序在代谢性疾病诊断中的价值。
Beta-ketothiolase (mitochondrial acetoacetylCoA thiolase) deficiency is a genetic disorder characterized by impaired isoleucine catabolism and ketone body utilization that predisposes to episodic ketoacidosis. It results from biallelic pathogenic variants in the ACAT1 gene, encoding mitochondrial beta-ketothiolase. We report two cases of beta-ketothiolase deficiency presenting with acute ketoacidosis and "metabolic stroke." The first patient presented at 28 months of age with metabolic acidosis and pallidal stroke in the setting of a febrile gastrointestinal illness. Although 2-methyl-3-hydroxybutyric acid and trace quantities of tiglylglycine were present in urine, a diagnosis of glutaric acidemia type I was initially suspected due to the presence of glutaric and 3-hydroxyglutaric acids. A diagnosis of beta-ketothiolase deficiency was ultimately made through whole exome sequencing which revealed compound heterozygous variants in ACAT1. Fibroblast studies for beta-ketothiolase enzyme activity were confirmatory. The second patient presented at 6 months of age with ketoacidosis, and was found to have elevations of urinary 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, and tiglylglycine. Sequencing of ACAT1 demonstrated compound heterozygous presumed causative variants. The patient exhibited choreoathethosis 2 months after the acute metabolic decompensation. These cases highlight that, similar to a number of other organic acidemias and mitochondrial disorders, beta-ketothiolase deficiency can present with metabolic stroke. They also illustrate the variability in clinical presentation, imaging, and biochemical evaluation that make screening for and diagnosis of this rare disorder challenging, and further demonstrate the value of whole exome sequencing in the diagnosis of metabolic disorders.