Lewis Connor J, Chipman Selby I, Johnston Jean M, Acosta Maria T, Toro Camilo, Tifft Cynthia J
Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, 10 Center Drive, Bethesda MD USA.
medRxiv. 2024 Dec 16:2024.12.13.24318793. doi: 10.1101/2024.12.13.24318793.
GM2 gangliosidosis is lysosomal storage disorder caused by deficiency of the heterodimeric enzyme β-hexosaminidase A. Tay-Sachs disease is caused by variants in encoding the α-subunit and Sandhoff disease is caused by variants in encoding the β-subunit. Due to shared clinical and biochemical findings, the two have been considered indistinguishable. We applied diffusion tensor imaging (DTI) and correlational fiber tractography to assess phenotypic differences in these two diseases. 40 DTI scans from 16 Late-Onset GM2 patients (NCT00029965) with either Sandhoff (n = 4), or Tay-Sachs (n = 12) disease. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), and quantitative anisotropy (QA) were calculated in fiber tracts throughout the whole brain, arcuate fasciculus, corpus callosum, and cerebellum. Correlational tractography was also performed to identify fiber tracts with group wide differences in DTI metrics between Tay-Sachs and Sandhoff patients. A linear mixed effects model was used to analyze the differences between Tay-Sachs and Sandhoff patients. Tay-Sachs patients had higher MD in the left cerebellum ( = 0.003703), right cerebellum ( = 0.003435), superior cerebellar peduncle (SCP, = 0.007332), and vermis ( = 0.01007). Sandhoff patients had higher FA in the left cerebellum ( = 0.005537), right cerebellum ( = 0.01905), SCP ( = 0.02844), and vermis ( = 0.02469). Correlational fiber tractography identified fiber tracts almost exclusively in cerebellar pathways with higher FA and QA, and lower MD, AD, and RD in Sandhoff patients compared to Tay-Sachs patients. Our study shows neurobiological differences between these two related disorders. To our knowledge, this is the first study using correlational tractography in a lysosomal storage disorder demonstrating these differences. This result indicates a greater burden of cerebellar pathology in Tay-Sachs patients compared with Sandoff patients.
GM2神经节苷脂贮积症是一种溶酶体贮积病，由异二聚体酶β-己糖胺酶A缺乏引起。泰-萨克斯病由编码α亚基的基因变异导致，桑德霍夫病由编码β亚基的基因变异导致。由于两者在临床和生化表现上有相似之处，一直被认为难以区分。我们应用扩散张量成像（DTI）和相关纤维束成像来评估这两种疾病的表型差异。对16例晚发型GM2患者（NCT00029965）进行了40次DTI扫描，其中4例为桑德霍夫病患者，12例为泰-萨克斯病患者。在全脑、弓状束、胼胝体和小脑中的纤维束中计算了DTI指标，包括分数各向异性（FA）、平均扩散率（MD）、径向扩散率（RD）、轴向扩散率（AD）和定量各向异性（QA）。还进行了相关纤维束成像，以确定泰-萨克斯病患者和桑德霍夫病患者之间DTI指标存在组间差异的纤维束。使用线性混合效应模型分析泰-萨克斯病患者和桑德霍夫病患者之间的差异。泰-萨克斯病患者在左侧小脑（P = 0.003703）、右侧小脑（P = 0.003435）上小脑脚（SCP，P = 0.007332）和蚓部（P = 0.01007）的MD较高。桑德霍夫病患者在左侧小脑（P = 0.005537）、右侧小脑（P = 0.01905）、SCP（P = 0.02844）和蚓部（P = 0.02469）的FA较高。相关纤维束成像几乎只在小脑通路中发现了纤维束，与泰-萨克斯病患者相比，桑德霍夫病患者的FA和QA较高，而MD、AD和RD较低。我们的研究显示了这两种相关疾病之间的神经生物学差异。据我们所知，这是第一项在溶酶体贮积病中使用相关纤维束成像来证明这些差异的研究。这一结果表明，与桑德霍夫病患者相比泰-萨克斯病患者的小脑病理负担更重。
