Spastic paraplegia type 5 (SPG5) is a rare subtype of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative disorders defined by progressive neurodegeneration of the corticospinal tract motor neurons. SPG5 is caused by recessive mutations in the gene CYP7B1 encoding oxysterol-7α-hydroxylase. This enzyme is involved in the degradation of cholesterol into primary bile acids. CYP7B1 deficiency has been shown to lead to accumulation of neurotoxic oxysterols. In this multicentre study, we have performed detailed clinical and biochemical analysis in 34 genetically confirmed SPG5 cases from 28 families, studied dose-dependent neurotoxicity of oxysterols in human cortical neurons and performed a randomized placebo-controlled double blind interventional trial targeting oxysterol accumulation in serum of SPG5 patients. Clinically, SPG5 manifested in childhood or adolescence (median 13 years). Gait ataxia was a common feature. SPG5 patients lost the ability to walk independently after a median disease duration of 23 years and became wheelchair dependent after a median 33 years. The overall cross-sectional progression rate of 0.56 points on the Spastic Paraplegia Rating Scale per year was slightly lower than the longitudinal progression rate of 0.80 points per year. Biochemically, marked accumulation of CYP7B1 substrates including 27-hydroxycholesterol was confirmed in serum (n = 19) and cerebrospinal fluid (n = 17) of SPG5 patients. Moreover, 27-hydroxycholesterol levels in serum correlated with disease severity and disease duration. Oxysterols were found to impair metabolic activity and viability of human cortical neurons at concentrations found in SPG5 patients, indicating that elevated levels of oxysterols might be key pathogenic factors in SPG5. We thus performed a randomized placebo-controlled trial (EudraCT 2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in 14 SPG5 patients with 27-hydroxycholesterol levels in serum as the primary outcome measure. Atorvastatin, but not placebo, reduced serum 27-hydroxycholesterol from 853 ng/ml [interquartile range (IQR) 683–1113] to 641 (IQR 507–694) (−31.5%, P = 0.001, Mann-Whitney U-test). Similarly, 25-hydroxycholesterol levels in serum were reduced. In cerebrospinal fluid 27-hydroxycholesterol was reduced by 8.4% but this did not significantly differ from placebo. As expected, no effects were seen on clinical outcome parameters in this short-term trial. In this study, we define the mutational and phenotypic spectrum of SPG5, examine the correlation of disease severity and progression with oxysterol concentrations, and demonstrate in a randomized controlled trial that atorvastatin treatment can effectively lower 27-hydroxycholesterol levels in serum of SPG5 patients. We thus demonstrate the first causal treatment strategy in hereditary spastic paraplegia.

中文翻译：

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遗传性痉挛性截瘫 5 型：自然史、生物标志物和随机对照试验


痉挛性截瘫 5 型 (SPG5) 是遗传性痉挛性截瘫的一种罕见亚型，是一组高度异质性的神经退行性疾病，定义为皮质脊髓束运动神经元的进行性神经退行性变。 SPG5 是由编码氧化甾醇-7α-羟化酶的基因CYP7B1的隐性突变引起的。这种酶参与将胆固醇降解为初级胆汁酸。 CYP7B1 缺乏已被证明会导致神经毒性氧甾醇的积累。在这项多中心研究中，我们对来自 28 个家庭的 34 例基因确诊的 SPG5 病例进行了详细的临床和生化分析，研究了氧甾醇对人类皮质神经元的剂量依赖性神经毒性，并进行了一项针对血清中氧甾醇积累的随机安慰剂对照双盲介入试验SPG5 患者。临床上，SPG5 出现在儿童期或青春期（中位 13 岁）。步态共济失调是一个常见特征。 SPG5 患者在中位病程 23 年后失去独立行走的能力，并在中位 33 年后变得依赖轮椅。痉挛性截瘫评定量表的总体横断面进展率为每年 0.56 分，略低于每年 0.80 分的纵向进展率。生化方面，在 SPG5 患者的血清 ( n = 19) 和脑脊液 ( n = 17) 中证实了 CYP7B1 底物（包括 27-羟基胆固醇）的显着积聚。此外，血清中27-羟基胆固醇水平与疾病严重程度和病程持续时间相关。 在 SPG5 患者中发现，氧甾醇的浓度会损害人类皮质神经元的代谢活动和活力，表明氧甾醇水平升高可能是 SPG5 的关键致病因素。因此，我们对 14 名 SPG5 患者进行了一项随机安慰剂对照试验 (EudraCT 2015-000978-35)，每天服用阿托伐他汀 40 毫克，持续 9 周，以血清 27-羟基胆固醇水平作为主要结果指标。阿托伐他汀（而非安慰剂）将血清 27-羟基胆固醇从 853 ng/ml [四分位距 (IQR) 683–1113] 降低至 641 (IQR 507–694)（−31.5%， P = 0.001，Mann-Whitney U 检验） 。同样，血清中的 25-羟基胆固醇水平也降低了。脑脊液中 27-羟基胆固醇降低了 8.4%，但这与安慰剂没有显着差异。正如预期的那样，在这项短期试验中没有发现对临床结果参数的影响。在这项研究中，我们定义了 SPG5 的突变和表型谱，检查了疾病严重程度和进展与氧甾醇浓度的相关性，并在随机对照试验中证明阿托伐他汀治疗可以有效降低 SPG5 患者血清中的 27-羟基胆固醇水平。因此，我们展示了遗传性痉挛性截瘫的第一个因果治疗策略。