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Abstract：
BACKGROUND: 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.
METHODS: 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.
CONCLUSIONS: 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.
METHODS: 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.
CONCLUSIONS: 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.
摘要：
背景：SCARB2基因的双等位基因致病变异与行动肌阵挛性肾衰竭（AMRF）综合征有关。尽管据报道SCARB2相关表型包括典型的神经系统特征，根据致病变体的定位和特征，临床过程和演示文稿已被证明是不同的。
方法：全外显子组测序（WES）分析揭示了纯合截短变体（p。N45MfsX88)在SCARB2基因中的指标情况下，随后的sanger测序分析验证了该变异体在一个土耳其家庭的所有受影响的家庭成员中具有与AMRF和相关疾病相关的临床特征.家族内临床异质性的共同特征包括构音障碍，震颤和蛋白尿，和独特的特征，如周围神经病变（PNP），受影响病例之间的肌阵鸣和癫痫发作，在家庭中观察到。深入的文献综述能够详细研究与AMRF相关的已报道的变异，并表明虽然变异的类型对临床特征的过程没有重大影响，只有致病性变异体的C末端定位显着影响临床表现，特别是疾病的发病年龄（AO）。
结论：在这项研究中，我们表明双等位基因SCARB2致病变异可能导致一系列与AMRF相关的共同和独特特征。在这些特征中，常见特征包括肌阵挛症(100%)，共济失调（96%），强直阵挛性癫痫发作（82%），构音障碍（68%），震颤（65%），肾损害（62%），不常见的特征涉及PNP（17％），听力损失（6.8%），和认知障碍（13.7%）。已发现AO在p.G462DfsX34致病变体的携带者中明显更高。SCARB2致病变异不仅与AMRF有关，而且与帕金森病（PD）和戈谢病（GD）的发病机制有关。提示遗传和功能研究在临床和诊断环境中的重要性。鉴于SCARB2基因在AMRF发病机制中的作用，PD和GD具有广泛的临床症状，调查可能的修饰符，如前颗粒蛋白和HSP7，具有很大的重要性。
方法：全外显子组测序（WES）分析揭示了纯合截短变体（p。N45MfsX88)在SCARB2基因中的指标情况下，随后的sanger测序分析验证了该变异体在一个土耳其家庭的所有受影响的家庭成员中具有与AMRF和相关疾病相关的临床特征.家族内临床异质性的共同特征包括构音障碍，震颤和蛋白尿，和独特的特征，如周围神经病变（PNP），受影响病例之间的肌阵鸣和癫痫发作，在家庭中观察到。深入的文献综述能够详细研究与AMRF相关的已报道的变异，并表明虽然变异的类型对临床特征的过程没有重大影响，只有致病性变异体的C末端定位显着影响临床表现，特别是疾病的发病年龄（AO）。
结论：在这项研究中，我们表明双等位基因SCARB2致病变异可能导致一系列与AMRF相关的共同和独特特征。在这些特征中，常见特征包括肌阵挛症(100%)，共济失调（96%），强直阵挛性癫痫发作（82%），构音障碍（68%），震颤（65%），肾损害（62%），不常见的特征涉及PNP（17％），听力损失（6.8%），和认知障碍（13.7%）。已发现AO在p.G462DfsX34致病变体的携带者中明显更高。SCARB2致病变异不仅与AMRF有关，而且与帕金森病（PD）和戈谢病（GD）的发病机制有关。提示遗传和功能研究在临床和诊断环境中的重要性。鉴于SCARB2基因在AMRF发病机制中的作用，PD和GD具有广泛的临床症状，调查可能的修饰符，如前颗粒蛋白和HSP7，具有很大的重要性。
