Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
German Center for Neurodegenerative Diseases (DZNE)-Tübingen, Tübingen, Germany.
BMC Neurol. 2022 Mar 28;22(1):122. doi: 10.1186/s12883-022-02628-y.
Biallelic pathogenic variants in the SCARB2 gene have been associated with action myoclonus-renal failure (AMRF) syndrome. Even though SCARB2 associated phenotype has been reported to include typical neurological characteristics, depending on the localization and the feature of the pathogenic variants, clinical course and the presentations have been shown to differ.
Whole exome sequencing (WES) analysis revealed a homozygous truncating variant (p.N45MfsX88) in SCARB2 gene in the index case, and subsequent sanger sequencing analysis validated the variant in all affected family members from a Turkish family with the clinical characteristics associated with AMRF and related disorders. Intrafamilial clinical heterogeneity with common features including dysarthria, tremor and proteinuria, and distinct features such as peripheral neuropathy (PNP), myoclonus and seizures between the affected cases, was observed in the family. In-depth literature review enabled the detailed investigation of the reported variants associated with AMRF and suggested that while the type of the variant did not have a major impact on the course of the clinical characteristics, only the C terminal localization of the pathogenic variant significantly affected the clinical presentation, particularly the age at onset (AO) of the disease.
In this study we showed that biallelic SCARB2 pathogenic variants might cause a spectrum of common and distinct features associated with AMRF. Of those features while the common features include myoclonus (100%), ataxia (96%), tonic clonic seizures (82%), dysarthria (68%), tremor (65%), and renal impairment (62%), the uncommon features involve PNP (17%), hearing loss (6.8%), and cognitive impairment (13.7%). AO has been found to be significantly higher in the carriers of the p.G462DfsX34 pathogenic variant. SCARB2 pathogenic variants have not been only implicated in AMRF but also in the pathogenesis of Parkinson's disease (PD) and Gaucher disease (GD), suggesting the importance of genetic and functional studies in the clinical and the diagnostic settings. Given the proven role of SCARB2 gene in the pathogenesis of AMRF, PD and GD with a wide spectrum of clinical symptoms, investigation of the possible modifiers, such as progranulin and HSP7, has a great importance.
SCARB2 基因的双等位致病性变异与动作性肌阵挛-肾衰竭（AMRF）综合征有关。尽管已经报道 SCARB2 相关表型包括典型的神经特征，但根据致病性变异的定位和特征，临床过程和表现已显示出不同。
全外显子组测序（WES）分析显示，索引病例的 SCARB2 基因中存在纯合截断变异（p.N45MfsX88），随后对来自土耳其家族的所有受影响家庭成员进行了 Sanger 测序分析，该家族具有与 AMRF 和相关疾病相关的临床特征。在该家族中观察到具有共同特征（包括构音障碍、震颤和蛋白尿）和不同特征（如周围神经病[PNP]、肌阵挛和癫痫）的受影响病例的家族内临床异质性。对文献的深入综述使我们能够详细研究与 AMRF 相关的报告变异，并表明尽管变异类型对临床特征的病程没有重大影响，但致病性变异的 C 末端定位仅显著影响临床表现，尤其是疾病的发病年龄（AO）。
在这项研究中，我们表明双等位 SCARB2 致病性变异可能导致与 AMRF 相关的一系列常见和不同的特征。在这些特征中，常见特征包括肌阵挛（100%）、共济失调（96%）、强直阵挛性癫痫发作（82%）、构音障碍（68%）、震颤（65%）和肾功能不全（62%），罕见特征包括周围神经病（17%）、听力损失（6.8%）和认知障碍（13.7%）。发现携带致病性变异 p.G462DfsX34 的携带者的 AO 明显更高。SCARB2 致病性变异不仅与 AMRF 有关，还与帕金森病（PD）和戈谢病（GD）的发病机制有关，这表明在临床和诊断环境中进行遗传和功能研究的重要性。鉴于 SCARB2 基因在 AMRF、PD 和 GD 发病机制中的重要作用，以及其广泛的临床症状，研究可能的修饰因子（如颗粒蛋白和 HSP7）具有重要意义。
