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Novel ACOX1 mutations in two siblings with peroxisomal acyl-CoA oxidase deficiency
Brain and Development ( IF 1.7 ) Pub Date : 2021-03-01 , DOI: 10.1016/j.braindev.2020.10.011
Atsushi Morita 1 , Takashi Enokizono 1 , Tatsuyuki Ohto 2 , Mai Tanaka 1 , Shiena Watanabe 1 , Yui Takada 3 , Kazuhiro Iwama 4 , Takeshi Mizuguchi 4 , Naomichi Matsumoto 4 , Masashi Morita 5 , Shigeo Takashima 6 , Nobuyuki Shimozawa 6 , Hidetoshi Takada 2
Affiliation  

Peroxisomal acyl-CoA oxidase (ACOX1) deficiency is a rare autosomal recessive single enzyme deficiency characterized by hypotonia, seizures, failure to thrive, developmental delay, and neurological regression starting from approximately 3 years of age. Here, we report two siblings with ACOX1 deficiency born to non-consanguineous Japanese parents. They showed mild global developmental delay from infancy and began to regress at 5 years 10 months and 5 years 6 months of age respectively. They gradually manifested with cerebellar ataxia, dysarthria, pyramidal signs, and dysphasia. Brain MRI revealed T2 high-intensity areas in the cerebellar white matter, bilateral middle cerebellar peduncle, and transverse tracts of the pons, followed by progressive atrophy of these areas. Intriguingly, the ratios of C24:0, C25:0, and C26:0 to C22:0 in plasma, which usually increase in ACOX1 deficiency were within normal ranges in both patients. On the other hand, whole exome sequencing revealed novel compound heterozygous variants in ACOX1: a frameshift variant (c.160delC:p.Leu54Serfs*18) and a missense variant (c.1259 T > C:p.Phe420Ser). The plasma concentration of individual very long chain fatty acids (C24:0, C25:0, and C26:0) was elevated, and we found that peroxisomes in fibroblasts of the patients were larger in size and fewer in number as previously reported in patients with ACOX1 deficiency. Furthermore, the C24:0 β-oxidation activity was dramatically reduced. Our findings suggest that the elevation of individual plasma very long chain fatty acids concentration, genetic analysis including whole exome analysis, and biochemical studies on the patient's fibroblasts should be considered for the correct diagnosis of ACOX1 deficiency.

中文翻译:

过氧化物酶体酰基辅酶A氧化酶缺乏症的两个兄弟姐妹的新ACOX1突变

过氧化物酶体酰基辅酶 A 氧化酶 (ACOX1) 缺乏症是一种罕见的常染色体隐性单酶缺乏症,其特征是肌张力减退、癫痫发作、发育迟缓、发育迟缓和从大约 3 岁开始的神经系统退化。在这里,我们报告了非近亲日本父母所生的 ACOX1 缺陷的两个兄弟姐妹。他们从婴儿时期就表现出轻微的整体发育迟缓,并分别在 5 岁 10 个月和 5 岁 6 个月大时开始退化。他们逐渐表现为小脑性共济失调、构音障碍、锥体体征和语言障碍。脑部 MRI 显示小脑白质、双侧小脑中脚和脑桥横束中的 T2 高强度区域,随后这些区域进行性萎缩。有趣的是,血浆中 C24:0、C25:0 和 C26:0 与 C22:0 的比率,两个患者的 ACOX1 缺乏通常增加都在正常范围内。另一方面,全外显子组测序揭示了 ACOX1 中新的复合杂合变体:移码变体 (c.160delC:p.Leu54Serfs*18) 和错义变体 (c.1259 T > C:p.Phe420Ser)。单个极长链脂肪酸(C24:0、C25:0 和 C26:0)的血浆浓度升高,我们发现患者成纤维细胞中的过氧化物酶体较大,数量较少,如先前在患者中报道的那样ACOX1 缺乏症。此外,C24:0 β-氧化活性显着降低。我们的研究结果表明,个体血浆极长链脂肪酸浓度的升高、包括全外显子组分析在内的遗传分析以及对患者的生化研究
更新日期:2021-03-01
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