Candelo Estephania, Cochard Léa, Caicedo-Herrera Gabriela, Granados Ana M, Gomez Juan F, Díaz-Ordoñez Lorena, Ramirez-Montaño Diana, Pachajoa Harry
Congenital Abnormalities and Rare Diseases Research Center (CIACER), Faculty of Health Science, Universidad Icesi, Cali, Colombia.
MSc Biomaterials and Tissues Engineering and Genetics of Human Diseases, Bioscience Department, University College London, London, UK.
Intractable Rare Dis Res. 2019 Aug;8(3):187-193. doi: 10.5582/irdr.2019.01014.
3-Hydroxyisobutyryl-coenzyme A (CoA) hydrolase deficiency (HIBCHD; MIM: #250620) is a rare autosomal recessive inborn error of metabolism caused by a defect in the HIBCH enzyme, resulting in a deficiency of the conversion of 3-hydroxy-isobutyryl-CoA to 3-hydroxy-isobutyric acid, a critical step in valine catabolism. This neurodegenerative disease of infancy is associated with hypotonia, developmental delay, cerebral atrophy and lesions in the basal ganglia on magnetic resonance imaging (MRI). In this study, we describe two unrelated patients with infantile-onset progressive neurodegenerative disease and mutations in HIBCH identified using whole exome sequencing (WES). In Case 1, WES revealed a novel homozygous variant in the gene: c.808A>G (p.Ser270Gly). In Case 2, a novel compound heterozygous mutation in the gene is described: c.808A>G (p.Ser270Gly) and c.173A>G (p. Asn58Ser). Parent analysis revealed that c.808A>G (p.Ser270Gly) was inherited from the father and c.173A>G (p. Asn58Ser) from the mother. These novel mutations were predicted as a disease-causing mutation. Plasma acylcarnitine analysis was normal in both patients. Physical examination showed similar features, such as axial hypotonia and spastic hypertonia in the legs. The first patient presented with difficult-to-treat seizures, while the second patient has not yet experienced documented seizures. In conclusion, our findings would widen the mutation spectrum of HIBCH deficiency and the phenotypic spectrum of the disease. The potential genotype-phenotype correlation would be profitable for the correct diagnosis, treatment and integral management of patients with HIBCH deficiency.
3-羟基异丁酰辅酶A（CoA）水解酶缺乏症（HIBCHD；MIM：#250620）是一种罕见的常染色体隐性遗传代谢性先天性疾病，由HIBCH酶缺陷引起，导致3-羟基异丁酰辅酶A向3-羟基异丁酸的转化缺乏，这是缬氨酸分解代谢中的关键步骤。这种婴儿期神经退行性疾病与肌张力减退、发育迟缓、脑萎缩以及磁共振成像（MRI）显示的基底神经节病变有关。在本研究中，我们描述了两名患有婴儿期起病的进行性神经退行性疾病且通过全外显子组测序（WES）鉴定出HIBCH突变的无关患者。在病例1中，WES显示该基因存在一个新的纯合变异：c.808A>G（p.Ser270Gly）。在病例2中，描述了该基因一个新的复合杂合突变：c.808A>G（p.Ser270Gly）和c.173A>G（p.Asn58Ser）。亲本分析显示，c.808A>G（p.Ser270Gly）来自父亲，c.173A>G（p.Asn58Ser）来自母亲。这些新突变被预测为致病突变。两名患者的血浆酰基肉碱分析均正常。体格检查显示出相似特征，如轴性肌张力减退和腿部痉挛性高张力。第一名患者出现难治性癫痫发作，而第二名患者尚未有癫痫发作记录。总之，我们的发现将拓宽HIBCH缺乏症的突变谱和该疾病的表型谱。潜在的基因型-表型相关性将有助于对HIBCH缺乏症患者进行正确诊断、治疗和综合管理。
