Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort
Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort
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DOI：
10.1093/brain/aws224
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发表时间：
2012-10-01
期刊：
影响因子：
14.5
通讯作者：
van de Warrenburg, Bart P.
中科院分区：
文献类型：
--
作者：
van Gassen, Koen L. I.;van der Heijden, Charlotte D. C. C.;van de Warrenburg, Bart P.
痉挛性截瘫7型是一种常染色体隐性遗传性神经退行性疾病，主要特征是进行性双侧下肢痉挛，被称为遗传性痉挛性截瘫的一种形式。另外的疾病特征也可以作为更复杂的表型的一部分被观察到。许多不同的突变已经被确定，但迄今为止还没有发现基因型-表型相关性。从总共近800名接受检测的患者中，我们确定了60名SPG 7基因突变的患者。我们确定了14个以前未报告的突变，并检测到几个早期报告的突变的高复发率。我们能够收集49例患者的详细临床数据，这些患者根据纯与复杂表型、共济失调与无共济失调以及错义与无效突变进行排名。69%的患者发生了一般复杂的表型，并且与发病时的年轻年龄相关（趋势P = 0.07）。在所有患者中观察到57%的共济失调。我们发现无效突变与小脑共济失调的共同发生有关（趋势P = 0.06）。c.1409 G > A（p.Arg470Gln）突变在两个同胞中发现同源性，与特定的复杂表型相关，包括由于视神经萎缩导致的主要视力丧失。其中1例病例的神经病理学显示视系统严重变性，脊髓和小脑上行束变性不太严重。该队列中遇到的其他疾病特征包括颈部肌张力障碍、垂直凝视麻痹、上睑下垂和严重智力残疾。在这个大型的荷兰队列中，我们似乎已经确定了第一个基因型-表型相关性痉挛性截瘫7型通过观察小脑表型痉挛性截瘫7型和SPG 7无效等位基因之间的关联。与其生物学对应物AFG 3L 2重叠的表型呈现是明显的，当突变时引起脊髓小脑共济失调28型，并且可能表明SPG 7蛋白质的异常水平影响与小脑中的多种细胞活性-蛋白酶复合物（由SPG 7和AFG 3L 2形成）相关的线粒体ATP酶的功能。此外，外显子10中的错义突变导致主要的视神经萎缩，这可能表明该SPG 7变体与其底物OPA 1（视神经萎缩1型中的突变基因产物）的有害相互作用。功能研究需要进一步研究这些相互作用。
Spastic paraplegia type 7 is an autosomal recessive neurodegenerative disorder mainly characterized by progressive bilateral lower limb spasticity and referred to as a form of hereditary spastic paraplegia. Additional disease features may also be observed as part of a more complex phenotype. Many different mutations have already been identified, but no genotype-phenotype correlations have been found so far. From a total of almost 800 patients referred for testing, we identified 60 patients with mutations in the SPG7 gene. We identified 14 previously unreported mutations and detected a high recurrence rate of several earlier reported mutations. We were able to collect detailed clinical data for 49 patients, who were ranked based on a pure versus complex phenotype, ataxia versus no ataxia and missense versus null mutations. A generally complex phenotype occurred in 69% of all patients and was associated with a younger age at onset (trend with P = 0.07). Ataxia was observed in 57% of all patients. We found that null mutations were associated with the co-occurrence of cerebellar ataxia (trend with P = 0.06). The c.1409 G > A (p.Arg470Gln) mutation, which was found homozygously in two sibs, was associated with a specific complex phenotype that included predominant visual loss due to optical nerve atrophy. Neuropathology in one of these cases showed severe degeneration of the optic system, with less severe degeneration of the ascending tracts of the spinal cord and cerebellum. Other disease features encountered in this cohort included cervical dystonia, vertical gaze palsy, ptosis and severe intellectual disability. In this large Dutch cohort, we seem to have identified the first genotype-phenotype correlation in spastic paraplegia type 7 by observing an association between the cerebellar phenotype of spastic paraplegia type 7 and SPG7 null alleles. An overlapping phenotypic presentation with its biological counterpart AFG3L2, which when mutated causes spinocerebellar ataxia type 28, is apparent and possibly suggests that abnormal levels of the SPG7 protein impact the function of the mitochondrial ATPases associated with diverse cellular activities-protease complex (formed by SPG7 and AFG3L2) in the cerebellum. In addition, a missense mutation in exon 10 resulted in predominant optical nerve atrophy, which might suggest deleterious interactions of this SPG7 variant with its substrate OPA1, the mutated gene product in optic atrophy type 1. Functional studies are required to further investigate these interactions.