Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients
Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients
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DOI：
10.1002/ana.24611
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发表时间：
2016-04-01
影响因子：
11.2
通讯作者：
Schoels, Ludger
中科院分区：
文献类型：
--
作者：
Schuele, Rebecca;Wiethoff, Sarah;Schoels, Ludger
遗传性痉挛性截瘫（HSP）是一种以进行性痉挛性步态障碍为特征的遗传性疾病。为了调查表型谱，预后因素，和基因型特异性差异，我们分析了基线数据从一个连续的，前瞻性cohol.MethodsWe招募了608 HSP病例519个家庭，主要是德国血统。采用痉挛性截瘫评定量表评估临床严重程度。并发症的症状记录了一个标准化inventory. ResultsFamilyhistory表明显性（43%），隐性（10%），和单纯（47%）疾病。我们观察到一个显着的男性优势，特别是在单纯的情况下，没有基因诊断。疾病严重程度随病程增加而增加。较早的疾病发作与较轻的疾病有关。特定的并发症特征，包括认知功能障碍、锥体外系或外周运动受累和共济失调，与疾病严重程度相关。疾病的严重程度也取决于基因型。HSP病例的中位病程为22年，能够独立行走。早发病例能够保持自由行走显着更长的时间，并在较低的风险，成为轮椅dependent.InterpretationThis横断面队列研究提供了第一个大规模的数据，疾病的表现，进展和修改因素，与咨询HSP家庭和规划未来的横断面和自然史研究的相关性。晚发病年龄，特定的并发症特征，SPG 11基因型与更严重的疾病密切相关。未来的干预性研究将需要对本研究中确定的疾病进展修饰因子进行分层。前瞻性纵向研究将验证本基线分析中计算的进展率。神经学年鉴2016;79：646-658
ObjectiveHereditary spastic paraplegias (HSPs) are genetically driven disorders with the hallmark of progressive spastic gait disturbance. To investigate the phenotypic spectrum, prognostic factors, and genotype-specific differences, we analyzed baseline data from a continuous, prospective cohort.MethodsWe recruited 608 HSP cases from 519 families of mostly German origin. Clinical severity was assessed by the Spastic Paraplegia Rating Scale. Complicating symptoms were recorded by a standardized inventory.ResultsFamily history indicated dominant (43%), recessive (10%), and simplex (47%) disease. We observed a significant male predominance, particularly in simplex cases without a genetic diagnosis. Disease severity increased with disease duration. Earlier disease onset was associated with less severe disease. Specific complicating features including cognitive impairment, extrapyramidal or peripheral motor involvement, and ataxia were associated with worse disease severity. Disease severity also depended on the genotype. HSP cases maintained the ability to walk independently for a median disease duration of 22 years. Early onset cases were able to maintain free walking significantly longer and were at less risk to become wheelchair dependent.InterpretationThis cross-sectional cohort study provides the first large-scale data on disease manifestation, progression, and modifying factors, with relevance for counseling of HSP families and planning of future cross-sectional and natural history studies. Later age of onset, specific complicating features, and the SPG11 genotype are strongly associated with more severe disease. Future interventional studies will require stratification for modifiers of disease progression identified in this study. Prospective longitudinal studies will verify progression rates calculated in this baseline analysis. Ann Neurol 2016;79:646-658