Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.

痉挛性共济失调是一种罕见的神经遗传性疾病，涉及脊髓小脑和锥体束。许多基因都参与其中。其中，CAPN1发生突变时，会导致一种复杂的遗传形式的痉挛性截瘫 (SPG76)。我们报告了来自两所欧洲大学医院（巴黎和斯德哥尔摩）的 21 名新患者的最大系列，这些患者具有 9 种新的CAPN1致病变异及其临床特征。经过正式的临床检查，通过下一代测序确定了致病变异，并通过 Sanger 测序进行了确认。CAPN1变异是年轻成人发作的痉挛性共济失调的罕见原因（约 1.4%）；然而，连同所有已发表的病例，它们使我们能够更好地描述这种形式的临床和遗传谱。截断变异是最常见的，错义变异导致发病年龄较早，有利于产生额外的有害影响。伴有小脑萎缩、构音障碍和下肢无力的小脑性共济失调通常与痉挛有关。我们还建议应在 SPG76 病例的随访中专门评估认知障碍和抑郁症。