Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations
Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations
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DOI：
10.1136/jnnp.2009.201103
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发表时间：
2010-10-01
影响因子：
11
通讯作者：
Scheffer, H.
中科院分区：
文献类型：
--
作者：
de Bot, S. T.;van den Elzen, R. T. M.;Scheffer, H.
背景在遗传性痉挛截瘫(HSPs)的临床和遗传异质性组中，SPAST基因突变最为常见，可导致一种纯常染色体显性遗传形式。目的了解SPAST突变所致荷兰HSP患者的临床和遗传学特征。结果151例突变携带者携带60种不同的spast基因突变，其中1例为已知多态，27例为新发现。错义突变最常见(39%)。临床资料来自72名突变携带者。发病年龄从1岁到63岁不等，第一个十年呈双峰型分布，30岁以上。以单纯痉挛型截瘫为主的患者有近50%伴有深度感觉障碍和括约肌问题。另有10%的患者出现手部震颤。有错义突变和外显子缺失的患者没有表现出明显的表型。结论荷兰SPAST突变携带者具有广泛的突变谱，在本系列中有27个新突变。SPG4的发病年龄呈双峰型分布，并伴有震颤。讨论了S44L的致病性，第一外显子4突变，以及一种可能的常染色体隐性遗传方式。
Background In the clinically and genetically heterogeneous group of the hereditary spastic paraplegias (HSPs), mutations in the SPAST gene are most frequently found and cause a pure autosomal dominant form.Objective To provide the clinical and genetic characteristics of Dutch patients with HSP due to a SPAST mutation (SPG4).Methods SPAST mutation carriers were identified through a comprehensive national database search. Available medical records were reviewed.Results 151 mutation carriers carried 60 different changes in the SPAST gene, of which one was a known polymorphism, and 27 were novel. Missense mutations were most frequently found (39%). Clinical information was available from 72 mutation carriers. Age at onset ranged from 1 to 63 years with a bimodal peak distribution in the first decade and above age 30. The predominantly pure spastic paraplegia was accompanied by deep sensory disturbances and sphincter problems in almost 50%. An additional hand tremor was found in 10%. Patients with missense mutations and exon deletions did not reveal a distinctive phenotype.Conclusions Dutch SPAST mutation carriers show a broad mutation spectrum, with 27 novel mutations in the present series. A bimodal peak distribution in age at onset was found and an accompanying tremor as peculiar feature of SPG4. The pathogenicity of S44L, the first exon 4 mutation, and a possible autosomal recessive mode of inheritance are discussed.