OBJECTIVE: We herein describe two sisters carrying a rare GRN mutation with extremely different clinical features and family history of dementia and behavioral disorders, with a novel presentation with stridor and dysphonia.
METHODS: Patients underwent a multidimensional assessment including neurological and neuropsychological evaluation, structural and functional imaging, and genetic screening.
RESULTS: The younger sister presented at the age of 64 with inspiratory stridor, dysphonia and exercise-induced dyspnea. Transnasal fiberoptic laryngoscopy showed bilateral adduction of the vocal cords at rest and paradoxical further adduction of the vocal cords during forced inspiration, suggesting the hypothesis of an adductor laryngeal dystonia. The older sister presented at the age of 63 with a rapidly progressive corticobasal syndrome. The only clinical feature common to both sisters was a dysexecutive syndrome. The c.893G > A mutation in exon 9 of GRN was found in heterozygosis in both sisters, causing a missense Arginine to Histidine substitution in position 298 of the protein (p.R298H).
CONCLUSIONS: Our report supports the pathogenicity of the GRN p.R298H mutation, which is first detected in two members from the same family, showing an extremely different phenotypes. Moreover, we report the first case of an FTD-associated mutation presenting with inspiratory stridor and dysphonia linked to adductor laryngeal dystonia, thus expanding the clinical spectrum of GRN-related disorders.
目的:我们在此描述了两姐妹携带一种罕见的GRN突变,具有极其不同的痴呆和行为障碍的临床特征和家族史,有喘鸣和发音障碍的新颖表现。
方法:患者接受了包括神经和神经心理学评估在内的多维评估,结构和功能成像,和基因筛查。
结果:妹妹在64岁时出现吸气喘鸣,发声困难和运动性呼吸困难。经鼻纤维喉镜检查显示声带在休息时的双侧内收,而在强迫吸气时声带的反常进一步内收。提示内收肌张力障碍的假说。姐姐在63岁时出现了快速进展的皮质基底综合征。两姐妹共同的唯一临床特征是执行功能障碍综合征。在两个姐妹的杂合中发现了GRN外显子9的c.893G>A突变,在蛋白质的298位引起错义精氨酸到组氨酸取代(p。R298H)。
结论:我们的报告支持GRNp.R298H突变的致病性,首先在来自同一个家庭的两个成员中检测到,表现出非常不同的表型。此外,我们报告了首例FTD相关突变,表现为与内收肌喉肌张力障碍相关的吸气性喘鸣和发声障碍,从而扩大了GRN相关疾病的临床范围。