Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7

Objective: We took advantage of a large multinational recruitment to delineate genotype-phenotype correlations in a large, trans-European multicenter cohort of patients with spastic paraplegia gene 7 (SPG7). Methods: We analyzed clinical and genetic data from 241 patients with SPG7, integrating neurologic follow-up data. One case was examined neuropathologically. Results: Patients with SPG7 had a mean age of 35.5 ± 14.3 years (n = 233) at onset and presented with spasticity (n = 89), ataxia (n = 74), or both (n = 45). At the first visit, patients with a longer disease duration (>20 years, n = 62) showed more cerebellar dysarthria (p < 0.05), deep sensory loss (p < 0.01), muscle wasting (p < 0.01), ophthalmoplegia (p < 0.05), and sphincter dysfunction (p < 0.05) than those with a shorter duration (<10 years, n = 93). Progression, measured by Scale for the Assessment and Rating of Ataxia evaluations, showed a mean annual increase of 1.0 ± 1.4 points in a subgroup of 30 patients. Patients homozygous for loss of function (LOF) variants (n = 65) presented significantly more often with pyramidal signs (p < 0.05), diminished visual acuity due to optic atrophy (p < 0.0001), and deep sensory loss (p < 0.0001) than those with at least 1 missense variant (n = 176). Patients with at least 1 Ala510Val variant (58%) were older (age 37.6 ± 13.7 vs 32.8 ± 14.6 years, p < 0.05) and showed ataxia at onset (p < 0.05). Neuropathologic examination revealed reduction of the pyramidal tract in the medulla oblongata and moderate loss of Purkinje cells and substantia nigra neurons. Conclusions: This is the largest SPG7 cohort study to date and shows a spasticity-predominant phenotype of LOF variants and more frequent cerebellar ataxia and later onset in patients carrying at least 1 Ala510Val variant.

研究目标：本研究依托一项大型跨国招募项目，针对横跨欧洲的多中心大型痉挛性截瘫7型（spastic paraplegia gene 7, SPG7）患者队列，阐明其基因型与表型的关联。
研究方法：本研究分析了241例SPG7患者的临床与遗传学数据，并整合神经科随访数据；另有1例患者接受了神经病理学检查。
研究结果：SPG7患者的平均发病年龄为35.5±14.3岁（n=233），临床表现为痉挛状态（n=89）、共济失调（n=74）或二者兼具（n=45）。在首次就诊时，病程较长（＞20年，n=62）的患者相比病程较短（＜10年，n=93）的患者，更易出现小脑性构音障碍（p＜0.05）、深感觉缺失（p＜0.01）、肌肉萎缩（p＜0.01）、眼肌麻痹（p＜0.05）及括约肌功能障碍（p＜0.05）。对30例患者亚组采用共济失调评定量表（Scale for the Assessment and Rating of Ataxia, SARA）评分评估疾病进展，结果显示其平均年评分增幅为1.0±1.4分。携带纯合功能丧失（loss of function, LOF）变异的患者（n=65）相比至少携带1个错义变异的患者（n=176），更常出现锥体束征（p＜0.05）、视神经萎缩所致视力减退（p＜0.0001）及深感觉缺失（p＜0.0001）。至少携带1个Ala510Val变异的患者（占比58%）发病年龄更大（37.6±13.7岁 vs 32.8±14.6岁，p＜0.05），且起病时即表现为共济失调（p＜0.05）。神经病理学检查显示，延髓内锥体束减少，浦肯野细胞与黑质神经元呈中度丢失。
研究结论：本研究为目前规模最大的SPG7队列研究，结果显示功能丧失变异以痉挛表型为主，而携带至少1个Ala510Val变异的患者更易出现小脑性共济失调，且发病年龄更晚。