The clinical and molecular spectrum of <i>ZFYVE26</i>-associated hereditary spastic paraplegia: SPG15
The clinical and molecular spectrum of <i>ZFYVE26</i>-associated hereditary spastic paraplegia: SPG15
复制标题
<i>ZFYVE26</i>相关遗传性痉挛性截瘫的临床和分子谱：SPG15
作者：
Safari A;Kellner M;Takiyama Y;et al.
在遗传性痉挛截瘫(HSP)领域，分子诊断学的进展需要转化为稳健的表型研究，以了解遗传和表型的异质性并支持干预性试验。ZFYVE26相关遗传性痉挛截瘫(HSP-ZFYVE26，SPG15)是一种罕见的、起病早的复合性HSP，其特征是进行性痉挛和各种其他神经症状。虽然以前的报告(通常在血缘关系比率较高的人群中)已经确定了一般的表型，但缺乏系统的调查，对症状的年龄相关性表现也缺乏了解。在这里，我们描述了来自36个家庭的44个个体的临床、神经影像和分子特征，这是迄今为止收集到的最大的队列。最后一次随访的中位年龄为23.8岁，涵盖了广泛的年龄范围(11-61岁)。虽然症状通常发生在儿童早期[中位数：24个月，四分位数范围(IQR)=24]，但分子诊断达到的中位年龄为18.8岁(IQR=8)，表明诊断明显延迟。我们证明，大多数患者存在运动和/或语言延迟或学习障碍。重要的是，这些发育症状早于运动症状的出现几年。进行性肢体痉挛是HSP-ZFYVE26的显著特征，通常出现在青春期，在近端进展之前累及远端肢体。上肢痉挛发生率为%。我们发现锥体外系运动障碍的发生率很高，包括小脑性共济失调(%)和肌张力障碍(11%)。帕金森病(16%)出现在一个亚组中，并且对左旋多巴没有持续的反应。在大多数患者中，随着时间的推移，认知能力下降和神经原性膀胱功能障碍会逐渐发展。对脑部MRI特征的系统分析显示了一个共同的诊断特征，包括前痂体变薄，前钳信号改变，以及非特异性皮质和小脑萎缩。分子谱包括45个不同的变体，分布在整个蛋白质结构中，没有突变热点。痉挛截瘫评定量表评分、SPATAX功能障碍评分和四阶段功能活动评分在反映病程和运动功能障碍之间的差异比例方面表现中等强度。所有患者的血浆神经丝轻链水平均显著升高(P<0.0001.0 1)，且与年龄呈负相关(Spearman‘s等级相关系数=−0.6 5，P=0.0 1)。总之，我们对广泛年龄段的HSP-ZFYVE26患者进行了系统的横断面分析，描绘了核心的临床、神经成像和分子特征，并确定了疾病严重程度的标志。这些结果提高了人们对这种罕见疾病的认识，有助于早期诊断，并为临床试验做好了准备。
In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic heterogeneity and to support interventional trials.ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11–61 years). While symptom onset often occurred in early childhood [median: 24 months, interquartile range (IQR) = 24], a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps and non-specific cortical and cerebellar atrophy. The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots. Spastic Paraplegia Rating Scale scores, SPATAX Disability Scores and the Four Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction. Plasma neurofilament light chain levels were significantly elevated in all patients (Mann–Whitney U-test,P< 0.0001) and were correlated inversely with age (Spearman’s rank correlation coefficientr= −0.65,P= 0.01). In summary, our systematic cross-sectional analysis of HSP-ZFYVE26patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.