Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, 6500 HB, The Netherlands.
Brain. 2012 Oct;135(Pt 10):2994-3004. doi: 10.1093/brain/aws224. Epub 2012 Sep 10.
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.
7 型痉挛性截瘫是一种常染色体隐性神经退行性疾病，主要表现为进行性双侧下肢痉挛，也称为遗传性痉挛性截瘫的一种形式。还可能观察到其他一些疾病特征，这些特征构成了更为复杂的表型。已经发现了许多不同的突变，但迄今为止尚未发现基因型-表型相关性。在总共近 800 名接受检测的患者中，我们鉴定出 60 名 SPG7 基因突变患者。我们发现了 14 种以前未报道过的突变，并检测到几种以前报道过的突变的高复发率。我们能够收集 49 名患者的详细临床数据，这些患者根据纯合与复杂表型、共济失调与无共济失调以及错义与无义突变进行了排序。在所有患者中，约 69%表现出一般复杂表型，且发病年龄更早（趋势 P=0.07）。在所有患者中，57%存在共济失调。我们发现无义突变与小脑共济失调的共同发生相关（趋势 P=0.06）。在两个同胞中发现纯合的 c.1409 G > A(p.Arg470Gln)突变与特定的复杂表型相关，该表型包括视神经萎缩导致的主要视力丧失。其中一个病例的神经病理学显示视神经系统严重退化，脊髓和小脑的上行束退化程度较轻。该队列中遇到的其他疾病特征包括颈肌张力障碍、垂直凝视麻痹、上睑下垂和严重智力障碍。在这个大型荷兰队列中，我们似乎通过观察 7 型痉挛性截瘫的小脑表型与 SPG7 无义等位基因之间的关联，确定了 7 型痉挛性截瘫的首个基因型-表型相关性。与生物对应物 AFG3L2 的重叠表型表现明显，当 AFG3L2 突变时会导致脊髓小脑共济失调 28 型，这可能表明 SPG7 蛋白水平异常会影响与多种细胞活动相关的线粒体 ATP 酶的功能-蛋白酶复合物（由 SPG7 和 AFG3L2 组成）在小脑。此外，外显子 10 中的错义突变导致主要视神经萎缩，这可能表明该 SPG7 变体与其底物 OPA1（1 型视神经萎缩的突变基因产物）的有害相互作用。需要进行功能研究来进一步研究这些相互作用。
