Genetic and phenotypic characterization of complex hereditary spastic paraplegia.
Genetic and phenotypic characterization of complex hereditary spastic paraplegia.
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DOI：
10.1093/brain/aww111
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发表时间：
2016-07
期刊：
影响因子：
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通讯作者：
Houlden H
中科院分区：
文献类型：
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作者：
Kara E;Tucci A;Manzoni C;Lynch DS;Elpidorou M;Bettencourt C;Chelban V;Manole A;Hamed SA;Haridy NA;Federoff M;Preza E;Hughes D;Pittman A;Jaunmuktane Z;Brandner S;Xiromerisiou G;Wiethoff S;Schottlaender L;Proukakis C;Morris H;Warner T;Bhatia KP;Korlipara LV;Singleton AB;Hardy J;Wood NW;Lewis PA;Houlden H
高通量下一代测序可以识别极其异质性疾病中的致病突变。Kara等人研究了97例复杂性遗传性痉挛性截瘫（HSP）的一系列指标病例。他们确定了30个家族中的SPG 11缺陷，以及其他HSP基因和与帕金森病等疾病相关的基因的突变。 高通量下一代测序可以识别极其异质性疾病中的致病突变。Kara等人研究了97例复杂性遗传性痉挛性截瘫（HSP）的一系列指标病例。他们确定了30个家族中的SPG 11缺陷，以及其他HSP基因和与帕金森病等疾病相关的基因的突变。 遗传性痉挛性截瘫是一组异质性退行性疾病，临床上可分为单纯性（主要为下肢痉挛）或复杂性（痉挛性截瘫并发其他神经学特征），并以常染色体显性、常染色体隐性或X连锁模式遗传。在40多个不同的基因中发现了遗传缺陷，总共有70多个位点。复杂的隐性痉挛性截瘫在过去经常与SPG 11（spatacsin），ZFYVE 26/SPG 15，SPG 7（paraplegin）和少数其他罕见基因的突变有关，但许多病例在遗传上仍不确定。与其他神经退行性疾病的重叠已在少数报告中得到暗示，但在较大的疾病系列中没有。这种缺陷主要是由于缺乏合适的高通量技术来研究疾病的遗传基础，但最近可用的下一代测序可以促进即使在极其异质性的疾病中致病突变的鉴定。我们调查了一系列的97个索引案件复杂痉挛性截瘫转介到三级转诊神经学中心在伦敦的诊断或管理。平均发病年龄为16岁（范围3至39岁）。首先分析SPG 11基因，揭示了30/97（30.9%）先证者的纯合或复合杂合突变，这是迄今为止报道的最大的SPG 11系列，也是迄今为止英国复杂痉挛性截瘫的最常见原因，具有严重和进行性临床特征和其他神经学表现，与磁共振成像缺陷有关。鉴于SPG 11突变的高频率，我们研究了8个受影响的SPG 11病例和对照成纤维细胞系对饥饿的自噬反应，但在我们的限制性研究中，我们没有观察到疾病状态与自噬或溶酶体标志物之间的相关性。在其余的病例中，进行了下一代测序，揭示了许多其他已知的复杂痉挛性截瘫基因中的变体，包括SPG 7中的5个（5/97），FA 2 H中的4个（也称为SPG 35）（4/97）和ZFYVE 26/SPG 15中的2个。在通常与单纯痉挛性截瘫相关的基因中，以及在帕金森病相关基因ATP 13 A2、神经元蜡样质脂褐质沉积症基因TPP 1和遗传性运动和感觉神经病DNMT 1基因中鉴定出变异体，突出了痉挛性截瘫的遗传异质性。在51%的先证者中没有发现合理的遗传原因，这可能表明存在尚未鉴定的基因。
High-throughput next-generation sequencing can identify disease-causing mutations in extremely heterogeneous disorders. Kara et al . investigate a series of 97 index cases with complex hereditary spastic paraplegia (HSP). They identify SPG11 defects in 30 families, as well as mutations in other HSP genes and genes associated with disorders including Parkinson’s disease. High-throughput next-generation sequencing can identify disease-causing mutations in extremely heterogeneous disorders. Kara et al . investigate a series of 97 index cases with complex hereditary spastic paraplegia (HSP). They identify SPG11 defects in 30 families, as well as mutations in other HSP genes and genes associated with disorders including Parkinson’s disease. The hereditary spastic paraplegias are a heterogeneous group of degenerative disorders that are clinically classified as either pure with predominant lower limb spasticity, or complex where spastic paraplegia is complicated with additional neurological features, and are inherited in autosomal dominant, autosomal recessive or X-linked patterns. Genetic defects have been identified in over 40 different genes, with more than 70 loci in total. Complex recessive spastic paraplegias have in the past been frequently associated with mutations in SPG11 (spatacsin), ZFYVE26/SPG15 , SPG7 (paraplegin) and a handful of other rare genes, but many cases remain genetically undefined. The overlap with other neurodegenerative disorders has been implied in a small number of reports, but not in larger disease series. This deficiency has been largely due to the lack of suitable high throughput techniques to investigate the genetic basis of disease, but the recent availability of next generation sequencing can facilitate the identification of disease-causing mutations even in extremely heterogeneous disorders. We investigated a series of 97 index cases with complex spastic paraplegia referred to a tertiary referral neurology centre in London for diagnosis or management. The mean age of onset was 16 years (range 3 to 39). The SPG11 gene was first analysed, revealing homozygous or compound heterozygous mutations in 30/97 (30.9%) of probands, the largest SPG11 series reported to date, and by far the most common cause of complex spastic paraplegia in the UK, with severe and progressive clinical features and other neurological manifestations, linked with magnetic resonance imaging defects. Given the high frequency of SPG11 mutations, we studied the autophagic response to starvation in eight affected SPG11 cases and control fibroblast cell lines, but in our restricted study we did not observe correlations between disease status and autophagic or lysosomal markers. In the remaining cases, next generation sequencing was carried out revealing variants in a number of other known complex spastic paraplegia genes, including five in SPG7 (5/97), four in FA2H (also known as SPG35 ) (4/97) and two in ZFYVE26 / SPG15 . Variants were identified in genes usually associated with pure spastic paraplegia and also in the Parkinson’s disease-associated gene ATP13A2 , neuronal ceroid lipofuscinosis gene TPP1 and the hereditary motor and sensory neuropathy DNMT1 gene, highlighting the genetic heterogeneity of spastic paraplegia. No plausible genetic cause was identified in 51% of probands, likely indicating the existence of as yet unidentified genes.