Department of Neurology, Hospital General Universitario Gregorio Marañon, Madrid, Spain.
Movement Disorders Unit, National Referral Center for rare diseases with Movement Disorders (CSUR), Hospital General Universitario Gregorio Marañon, Madrid, Spain.
Mov Disord. 2019 Oct;34(10):1547-1561. doi: 10.1002/mds.27812. Epub 2019 Aug 21.
Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA.
To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients.
Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction.
Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001).
Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families. © 2019 International Parkinson and Movement Disorder Society.
导致痉挛性截瘫 7 型的致病性变异引起复杂的遗传性痉挛性截瘫表型，伴有经典的线粒体疾病特征，包括共济失调、进行性眼外肌麻痹和线粒体 DNA 缺失。
通过对西班牙痉挛性截瘫 7 型患者的临床、遗传和功能分析，更好地描述痉挛性截瘫 7 型疾病。
通过下一代测序、全外显子组测序、靶向 Sanger 测序、多重连接依赖性探针分析，对怀疑遗传性痉挛性截瘫的患者和 1 例帕金森病和 Pisa 综合征患者进行基因分析，并通过定量聚合酶链反应测定血液线粒体 DNA 水平。
发现 35 例患者携带痉挛性截瘫 7 型基因的纯合或复合杂合致病性变异。发病年龄的平均值为 40 岁（范围 12-63 岁）；63%的痉挛性截瘫 7 型患者为男性，所有患者中有四分之三至少有一个等位基因携带有 c.1529C>T（p.Ala510Val）突变。80%的患者表现出复杂的表型，结合共济失调和进行性眼外肌麻痹（分别为 65%和 26%）。21%的病例出现帕金森病。血液线粒体 DNA 分析表明，痉挛性截瘫 7 型致病性变异的患者和携带者的线粒体 DNA 水平明显低于对照组（分别为 228 个单倍体核 DNA/573 个、176 个/573 个；P<0.001）。
帕金森病是痉挛性截瘫 7 型患者的常见表现。痉挛性截瘫 7 型致病性变异破坏线粒体 DNA 动态平衡，与突变等位基因的数量、变异类型、患者或携带者状态无关。因此，痉挛性截瘫 7 型支持线粒体 DNA 维持，该基因的变异可能由于线粒体 DNA 异常引起帕金森病。此外，线粒体 DNA 血液分析可能是检测高危家族的有用生物标志物。
