Division of Neurology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Stockholm, Sweden.
Neurol Sci. 2023 Mar;44(3):947-959. doi: 10.1007/s10072-022-06516-8. Epub 2022 Nov 28.
Hereditary spastic paraplegia (HSP) is a rare genetic disorder associated with mutations in > 80 loci designated SPG (SPastic parapleGia). The phenotypic spectrum of HSP can extend to include other neurologic features, including movement disorders. Our aim was to investigate genotype-phenotype associations in HSP with a focus on movement disorders.
We performed a systematic review and individual participant data (IPD)-level meta-analysis by retrieving publications from Medline/EMBASE/Web of Science on HSP with a SPG genotype. Studies were included only if individual-level information was accessible and at least one patient with a movement disorder was reported for that genotype. Out of 21,957 hits, 192 manuscripts with a total of 1413 HSP cases were eligible. Data were compared between two HSP groups: manifested with (HSP-MD, n = 767) or without (HSP-nMD, n = 646) a movement disorder.
The HSP-MD group had an older age of onset (20.5 ± 16.0 vs. 17.1 ± 14.2 yr, p < 0.001) and less frequent autosomal dominant inheritance (7.6% vs. 30.1%, p < 0.001) compared to HSP-nMD. SPG7 (31.2%) and SPG11 (23.8%) were the most frequent genotypes in the HSP-MD group. HSP-MD with SPG7 had higher frequency of later onset during adulthood (82.9% vs. 8.5%), ataxia (OR = 12.6), extraocular movement disturbances (OR = 3.4) and seizure (OR = 3.7) compared to HSP-MD with SPG11. Conversely, SPG11 mutations were more frequently associated with consanguinity (OR = 4.1), parkinsonism (OR = 7.8), dystonia (OR = 5.4), peripheral neuropathy (OR = 26.9), and cognitive dysfunction (OR = 34.5).
This systematic IPD-level meta-analysis provides the largest data on genotype-phenotype associations in HSP-MD. Several clinically relevant phenotypic differences were found between various genotypes, which can possibly facilitate diagnosis in resource-limited settings.
遗传性痉挛性截瘫（HSP）是一种罕见的遗传疾病，与 80 多个指定为 SPG（痉挛性截瘫）的基因座的突变有关。HSP 的表型谱可扩展到包括其他神经系统特征，包括运动障碍。我们的目的是研究 HSP 中与运动障碍相关的基因型-表型关联。
我们通过检索 Medline/EMBASE/Web of Science 中 HSP 与 SPG 基因型相关的出版物，进行了系统评价和个体参与者数据（IPD）水平的荟萃分析。只有在可以获得个体水平信息并且至少有一名患有运动障碍的患者报告该基因型的情况下，才纳入研究。在 21957 个命中中，有 192 篇论文共有 1413 例 HSP 病例符合条件。数据在两组 HSP 之间进行比较：有运动障碍的 HSP（HSP-MD，n=767）和无运动障碍的 HSP（HSP-nMD，n=646）。
与 HSP-nMD 相比，HSP-MD 组的发病年龄更大（20.5±16.0 岁 vs. 17.1±14.2 岁，p<0.001），常染色体显性遗传的频率更低（7.6% vs. 30.1%，p<0.001）。SPG7（31.2%）和 SPG11（23.8%）是 HSP-MD 组中最常见的基因型。HSP-MD 中 SPG7 突变的发病年龄较晚（82.9% vs. 8.5%），成年期发病（OR=12.6）、眼球运动障碍（OR=3.4）和癫痫（OR=3.7）的频率更高，而 HSP-MD 中 SPG11 突变则更常与近亲婚配（OR=4.1）、帕金森病（OR=7.8）、肌张力障碍（OR=5.4）、周围神经病（OR=26.9）和认知功能障碍（OR=34.5）相关。
这项系统的 IPD 水平荟萃分析提供了 HSP-MD 中基因型-表型关联的最大数据。在不同的基因型之间发现了一些具有临床意义的表型差异，这可能有助于在资源有限的情况下进行诊断。
