Institut du Cerveau et de la Moelle épinière (ICM), INSERM, CNRS, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Pitié-Salpêtrière University Hospital, Paris, France.
Raymond Escourolle Department of Neuropathology, Pitié-Salpêtrière University Hospital, Paris, France.
Brain. 2018 Dec 1;141(12):3331-3342. doi: 10.1093/brain/awy285.
Hereditary spastic paraplegias (HSPs) are rare neurological disorders caused by progressive distal degeneration of the corticospinal tracts. Among the 79 loci and 65 spastic paraplegia genes (SPGs) involved in HSPs, mutations in SPAST, which encodes spastin, responsible for SPG4, are the most frequent cause of both familial and sporadic HSP. SPG4 is characterized by a clinically pure phenotype associated with restricted involvement of the corticospinal tracts and posterior columns of the spinal cord. It is rarely associated with additional neurological signs. However, both age of onset and severity of the disorder are extremely variable. Such variability is both intra- and inter-familial and may suggest incomplete penetrance, with some patients carrying mutations remaining asymptomatic for their entire life. We analysed a cohort of 842 patients with SPG4-HSP to assess genotype-phenotype correlations. Most patients were French (89%) and had a family history of SPG4-HSP (75%). Age at onset was characterized by a bimodal distribution, with high inter-familial and intra-familial variability, especially concerning first-degree relatives. Penetrance of the disorder was 0.9, complete after 70 years of age. Penetrance was lower in females (0.88 versus 0.94 in males, P = 0.01), despite a more diffuse phenotype with more frequent upper limb involvement. Seventy-seven per cent of pathogenic mutations (missense, frameshift, splice site, nonsense, and deletions) were located in the AAA cassette of spastin, impairing its microtubule-severing activity. A comparison of the missense and truncating mutations revealed a significantly lower age at onset for patients carrying missense mutations than those carrying truncating mutations, explaining the bimodal distribution of the age at onset. The age at onset for patients carrying missense mutations was often before 10 years, sometimes associated with intellectual deficiency. Neuropathological examination of a single case showed degeneration of the spinocerebellar and spinocortical tracts, as well as the posterior columns. However, there were numerous small-diameter processes among unusually large myelinated fibres in the corticospinal tract, suggesting marked regeneration. In conclusion, this large cohort of 842 individuals allowed us to identify a significantly younger age at onset in missense mutation carriers and lower penetrance in females, despite a more severe disorder. Neuropathology in one case showed numerous small fibres suggesting regeneration.
遗传性痉挛性截瘫（HSP）是一种罕见的神经退行性疾病，由皮质脊髓束进行性远端变性引起。在 79 个 HSP 相关基因座和 65 个痉挛性截瘫基因（SPG）中，编码 spastin 的 SPAST 基因突变是家族性和散发性 HSP 的最常见原因。SPG4 表现为一种临床纯表型，与皮质脊髓束和脊髓后柱的局限性受累相关，很少伴有其他神经体征。然而，发病年龄和疾病严重程度的变化极大。这种变异性在家族内和家族间均存在，可能提示不完全外显率，一些携带突变的患者终生无症状。我们分析了 842 例 SPG4-HSP 患者的队列，以评估基因型-表型相关性。大多数患者为法国人（89%），有 SPG4-HSP 的家族史（75%）。发病年龄呈双峰分布，家族内和家族间的变异性很大，尤其是一级亲属。该疾病的外显率为 0.9，70 岁后完全外显。女性的外显率较低（0.88 比男性 0.94，P=0.01），尽管表型更为弥散，上肢受累更为常见。77%的致病性突变（错义、移码、剪接位点、无义和缺失）位于 spastin 的 AAA 盒中，破坏其微管切割活性。对错义突变和截断突变的比较表明，携带错义突变的患者发病年龄明显早于携带截断突变的患者，这解释了发病年龄的双峰分布。携带错义突变的患者发病年龄常在 10 岁之前，有时伴有智力缺陷。单个病例的神经病理学检查显示，脊髓小脑和皮质脊髓束以及后柱变性。然而，在皮质脊髓束中异常大的有髓纤维之间有许多小直径的过程，提示明显的再生。总之，这项包含 842 例患者的大型队列研究表明，错义突变携带者的发病年龄明显更年轻，女性的外显率更低，尽管疾病更严重。一例神经病理学检查显示，大量小纤维提示再生。
