Mitochondrial HMG-CoA synthase deficiency

IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM
Bram Decru , Marine Lys , Kobe Truijens , Nathalie Mercier , Jean Papadopoulos , Daisy Rymen , Dominique Roland , Joseph P. Dewulf , Pieter Vermeersch
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Abstract

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) deficiency is a rare, potentially life-threatening autosomal recessive disorder resulting from mutations in the HMGCS2 gene, leading to impaired ketogenesis. We systematically reviewed the clinical presentations, biochemical and genetic abnormalities in 93 reported cases and 2 new patients diagnosed based on biochemical findings. Reported onset ages ranged from 3 months to 6 years, mostly before the age of 3. Children younger than one year old are more prone to a severe clinical course. In most patients, the initial metabolic decompensation occurs after an episode of gastroenteritis or gastroenteritis-like symptoms. Other commonly observed symptoms during the first clinical episode included poor intake, altered consciousness, dyspnea, seizures and hepatomegaly. Severity was correlated with the number of truncating mutations. Most patients presented with acute metabolic decompensation with hypoglycemia, dicarboxyluria and inadequate ketonuria. Dicarboxylic acid levels were elevated in 54/56 cases. The organic acid 4-hydroxy-6-methyl-2-pyrone (4HMP) was detected in 33/35 urine samples taken during the acute episodes, but typically only retrospectively. The plasma C2/C0 acylcarnitine ratio was abnormal in 16/18 (88.9 %) of acute plasma samples, but only in 2/6 (33 %) of DBS samples. Other metabolites that have been reported are hydroxyhexenoic acid, 3,5-dihydroxyhexanoic (1,5 lactone), glutaric acidand 3-OH-isovaleric acid.
Laboratories should look for 4HMP in urinary organic acid analysis and an increased plasma C2/C0 acylcarnitine ratio to facilitate the diagnosis of HMGCS2 deficiency, especially in cases of metabolic decompensation with dicarboxyluria without adequate ketonuria.
线粒体HMG-CoA合成酶缺乏。
线粒体3-羟基-3-甲基戊二酰辅酶a合成酶2 (HMGCS2)缺乏症是一种罕见的、可能危及生命的常染色体隐性遗传病,由HMGCS2基因突变引起,导致生酮功能受损。我们系统地回顾了93例报告病例的临床表现,生化和遗传异常以及2例基于生化结果诊断的新患者。报告的发病年龄从3个月到6岁不等,大多在3岁之前。一岁以下的儿童更容易出现严重的临床病程。在大多数患者中,最初的代谢失代偿发生在肠胃炎或肠胃炎样症状发作后。首次临床发作时常见的其他症状包括摄入不良、意识改变、呼吸困难、癫痫发作和肝肿大。严重程度与截断突变的数量相关。大多数患者表现为急性代谢失代偿,伴有低血糖、二羧基尿和酮尿不足。56例患者中有54例二羧酸水平升高。有机酸4-羟基-6-甲基-2-吡酮(4HMP)在33/35例急性发作时的尿液样本中检测到,但通常只是回顾性的。血浆C2/C0酰基肉碱比值在16/18(88.9%)急性血浆标本中异常,而在DBS标本中仅在2/6(33%)异常。其他已报道的代谢物有羟基己烯酸、3,5-二羟基己烯酸(1,5内酯)、戊二酸和3- oh -异戊酸。实验室应在尿有机酸分析中寻找4HMP和血浆C2/C0酰基肉碱比值的升高,以促进HMGCS2缺乏症的诊断,特别是在代谢失代偿伴二羧基尿而无足酮尿的病例中。
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来源期刊
Molecular genetics and metabolism
Molecular genetics and metabolism 生物-生化与分子生物学
CiteScore
5.90
自引率
7.90%
发文量
621
审稿时长
34 days
期刊介绍: Molecular Genetics and Metabolism contributes to the understanding of the metabolic and molecular basis of disease. This peer reviewed journal publishes articles describing investigations that use the tools of biochemical genetics and molecular genetics for studies of normal and disease states in humans and animal models.
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