Research Department, Hospital Universitari Institut Pere Mata, E43206 Reus, Spain.
Institut d'Investigació Sanitària Pere Virgili (IISPV), E43204 Reus, Catalonia, Spain.
Hum Mol Genet. 2018 Mar 1;27(5):891-900. doi: 10.1093/hmg/ddy009.
Clinical conditions commonly associated with mitochondrial disorders (CAMDs) are often present in autism spectrum disorders (ASD) and intellectual disability (ID). Therefore, the mitochondrial dysfunction hypothesis has been proposed as a transversal mechanism that may function in both disorders. Here, we investigated the presence of conditions associated with mitochondrial disorders and mitochondrial DNA (mtDNA) alterations in 122 subjects who presented ASD with ID (ASD group), 115 subjects who presented ID but not ASD (ID group) and 112 healthy controls (HC group). We assessed in the three study groups the presence of the clinical conditions through a questionnaire and the mtDNA content of two mitochondrial genes, MT-ND1 and MT-ND4, by qPCR. The mtDNA sequences of 98 ASD and 95 ID subjects were obtained by mtDNA-targeted next generation sequencing and analysed through the MToolBox pipeline to identify mtDNA mutations. Subjects with ASD and ID showed higher frequencies of constipation, edema, seizures, vision alterations, strabismus and sphincter incontinence than HCs subjects. ASD and ID subjects showed significantly lower mtDNA content than HCs in both MT-ND1 and MT-ND4 genes. In addition, we identified 49 putative pathogenic variants with a heteroplasmy level higher than 60%: 8 missense, 29 rRNA and 12 tRNA variants. A total of 28.6% of ASD and 30.5% of ID subjects carried at least one putative pathogenic mtDNA mutation. The high frequency of CAMDs, the low mtDNA content and the presence of putative pathogenic mtDNA mutations observed in both ASD and ID subjects are evidence of mitochondrial dysfunction in ASD and ID.
临床上常与线粒体疾病（CAMDs）相关的病症常存在于自闭症谱系障碍（ASD）和智力障碍（ID）中。因此，线粒体功能障碍假说被提出作为一种可能在这两种疾病中发挥作用的跨领域机制。在这里，我们研究了 122 名既有 ASD 又有 ID 的受试者（ASD 组）、115 名只有 ID 而没有 ASD 的受试者（ID 组）和 112 名健康对照者（HC 组）中与线粒体疾病相关的病症和线粒体 DNA（mtDNA）改变的存在情况。我们通过问卷调查评估了三组研究对象的临床病症的存在情况，并用 qPCR 评估了两个线粒体基因 MT-ND1 和 MT-ND4 的 mtDNA 含量。通过 mtDNA 靶向下一代测序获得了 98 名 ASD 和 95 名 ID 受试者的 mtDNA 序列，并通过 MToolBox 分析流程对其进行分析，以鉴定 mtDNA 突变。与 HC 组相比，ASD 和 ID 组的受试者更频繁地出现便秘、水肿、癫痫发作、视力改变、斜视和括约肌失禁。与 HC 组相比，ASD 和 ID 组的 MT-ND1 和 MT-ND4 基因的 mtDNA 含量显著降低。此外，我们还发现了 49 种可能致病性的变体，其异质性水平高于 60%：8 种错义突变、29 种 rRNA 变体和 12 种 tRNA 变体。共有 28.6%的 ASD 和 30.5%的 ID 受试者携带至少一种可能致病性的 mtDNA 突变。在 ASD 和 ID 受试者中观察到 CAMDs 的高频率、mtDNA 含量低以及存在可能致病性的 mtDNA 突变，这表明 ASD 和 ID 中存在线粒体功能障碍。
