Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration
Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration
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DOI：
10.1093/brain/awm293
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发表时间：
2008-03-01
期刊：
影响因子：
14.5
通讯作者：
Durr, Alexandra
中科院分区：
文献类型：
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作者：
Stevanin, Giovanni;Azzedine, Hamid;Durr, Alexandra
遗传性痉挛性截瘫（HSP）是一种以下肢痉挛为主要特征的神经退行性疾病，伴有复杂的神经系统症状。我们分析了一个大系列的指数患者（n = 76），无论是从家庭与常染色体隐性遗传（n = 43）或孤立的患者（n = 33），在最近确定的SPGII基因突变。我们发现了22个截短突变，包括前四个剪接位点突变，在7个孤立病例和13个家族中分离。19个突变是新的。在葡萄牙和北非患者中发现了两个复发性突变，表明这些人群中的创始人效应。突变频率根据表型而变化，从41%，在HSP患者中表现为薄胼胝体（TCC）可视化的MRI，4.5%，在没有TCC的精神障碍患者。疾病发作发生在第一至第三个十年期间，主要是由于步态和/或智力迟钝的问题。在平均病程14.9 +/- 6.6年后，38例SPGII患者的表型为重度，53%的患者坐轮椅或卧床不起。除了精神发育迟滞外，80%的患者表现出认知功能下降伴执行功能障碍。有趣的是，表型还经常包括下运动神经元变性（81%）和消瘦（53%）。在病程较长的患者中也观察到轻微的眼部小脑体征。除了TCC（95%），脑MRI显示白色改变（69%）和皮质萎缩（81%），随着疾病持续时间的推移而恶化。总之，我们的研究揭示了HSP、TCC和认知障碍患者（包括孤立患者）中SPGII突变的高频率，并扩展了相关表型。
Hereditary spastic paraplegias (HSP) are neurodegenerative diseases mainly characterized by lower limb spasticity associated, in complicated forms, with additional neurological signs. We have analysed a large series of index patients (n = 76) with this condition, either from families with an autosomal recessive inheritance (n = 43) or isolated patients (n = 33), for mutations in the recently identified SPGII gene. We found 22 truncating mutations, including the first four splice-site mutations, segregating in seven isolated cases and 13 families. Nineteen mutations were novel. Two recurrent mutations were found in Portuguese and North-African patients indicating founder effects in these populations. The mutation frequency varied according to the phenotype, from 41%, in HSP patients presenting with a thin corpus callosum (TCC) visualized by MRI, to 4.5%, in patients with mental impairment without a TCC. Disease onset occurred during the first to the third decade mainly by problems with gait and/or mental retardation. After a mean disease duration of 14.9 +/- 6.6 years, the phenotype of 38 SPGII patients was severe with 53% of patients wheelchair bound or bedridden. In addition to mental retardation, 80% of the patients showed cognitive decline with executive dysfunction. Interestingly, the phenotype also frequently included lower motor neuron degeneration (81%) with wasting (53%). Slight ocular cerebellar signs were also noted in patients with long disease durations. In addition to a TCC (95%), brain MRI revealed white matter alterations (69%) and cortical atrophy (81%), which worsened with disease duration. In conclusion, our study reveals the high frequency of SPGII mutations in patients with HSP, a TCC and cognitive impairment, including in isolated patients, and extends the associated phenotype.