Mignarri Andrea, Rubegni Anna, Tessa Alessandra, Stefanucci Stefano, Malandrini Alessandro, Cardaioli Elena, Meschini Maria Chiara, Stromillo Maria Laura, Doccini Stefano, Federico Antonio, Santorelli Filippo Maria, Dotti Maria Teresa
Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy.
Unit of Molecular Medicine, IRCCS Stella Maris, Pisa, Italy.
J Neurol Sci. 2016 Mar 15;362:287-91. doi: 10.1016/j.jns.2016.02.007. Epub 2016 Feb 4.
Mutations in DDHD1 cause the SPG28 subtype of hereditary spastic paraplegia (HSP). Recent studies suggested that mitochondrial dysfunction occurs in SPG28. Here we describe two siblings with SPG28, and report evidence of mitochondrial impairment in skeletal muscle and skin fibroblasts. Patient 1 (Pt1) was a 35-year-old man with spastic paraparesis and urinary incontinence, while his 25-year-old brother (Pt2) had gait spasticity and motor axonal neuropathy. In these patients we identified the novel homozygous c.1429C>T/p.R477* mutation in DDHD1, using a next-generation sequencing (NGS) approach. Histochemical analyses in muscle showed mitochondrial alterations, and multiple mitochondrial DNA (mtDNA) deletions were evident. In Pt1, respiratory chain enzyme activities were altered in skeletal muscle, mitochondrial ATP levels reduced, and analysis of skin fibroblasts revealed mitochondrial fragmentation. It seems possible that the novel nonsense mutation identified abolishes DDHD1 protein function thus altering oxidative metabolism. Qualitative alterations of mtDNA could have a pathogenetic significance. We suggest to perform DDHD1 analysis in patients with multiple mtDNA deletions.
DDHD1基因的突变会导致遗传性痉挛性截瘫（HSP）的SPG28亚型。最近的研究表明，SPG28患者存在线粒体功能障碍。在此，我们描述了两名患有SPG28的同胞，并报告了骨骼肌和皮肤成纤维细胞中线粒体损伤的证据。患者1（Pt1）是一名35岁男性，患有痉挛性截瘫和尿失禁，而他25岁的弟弟（Pt2）有步态痉挛和运动性轴索性神经病。我们采用下一代测序（NGS）方法，在这些患者中鉴定出DDHD1基因新的纯合c.1429C>T/p.R477*突变。肌肉组织化学分析显示线粒体改变，且存在多个线粒体DNA（mtDNA）缺失。在Pt1中，骨骼肌呼吸链酶活性改变，线粒体ATP水平降低，皮肤成纤维细胞分析显示线粒体碎片化。新发现的无义突变似乎可能使DDHD1蛋白功能丧失，从而改变氧化代谢。mtDNA的定性改变可能具有致病意义。我们建议对存在多个mtDNA缺失的患者进行DDHD1分析。
