Abstract：
BACKGROUND: Spinocerebellar ataxia 4 (SCA4), characterized in 1996, features adult-onset ataxia, polyneuropathy, and linkage to chromosome 16q22.1; its underlying mutation has remained elusive.
OBJECTIVE: To explore the radiological and neuropathological abnormalities in the entire neuroaxis in SCA4 and search for its mutation.
METHODS: Three Swedish families with undiagnosed ataxia went through clinical, neurophysiological, and neuroimaging tests, including PET studies and genetic investigations. In four cases, neuropathological assessments of the neuroaxis were performed. Genetic testing included short read whole genome sequencing, short tandem repeat analysis with ExpansionHunter de novo, and long read sequencing.
RESULTS: Novel features for SCA4 include dysautonomia, motor neuron affection, and abnormal eye movements. We found evidence of anticipation; neuroimaging demonstrated atrophy in the cerebellum, brainstem, and spinal cord. [18F]FDG-PET demonstrated brain hypometabolism and [11C]Flumazenil-PET reduced binding in several brain lobes, insula, thalamus, hypothalamus, and cerebellum. Moderate to severe loss of Purkinje cells in the cerebellum and of motor neurons in the anterior horns of the spinal cord along with pronounced degeneration of posterior tracts was also found. Intranuclear, mainly neuronal, inclusions positive for p62 and ubiquitin were sparse but widespread in the CNS. This finding prompted assessment for nucleotide expansions. A polyglycine stretch encoding GGC expansions in the last exon of the zink finger homeobox 3 gene was identified segregating with disease and not found in 1000 controls.
CONCLUSIONS: SCA4 is a neurodegenerative disease caused by a novel GGC expansion in the coding region of ZFHX3, and its spectrum is expanded to include dysautonomia and neuromuscular manifestations.
OBJECTIVE: To explore the radiological and neuropathological abnormalities in the entire neuroaxis in SCA4 and search for its mutation.
METHODS: Three Swedish families with undiagnosed ataxia went through clinical, neurophysiological, and neuroimaging tests, including PET studies and genetic investigations. In four cases, neuropathological assessments of the neuroaxis were performed. Genetic testing included short read whole genome sequencing, short tandem repeat analysis with ExpansionHunter de novo, and long read sequencing.
RESULTS: Novel features for SCA4 include dysautonomia, motor neuron affection, and abnormal eye movements. We found evidence of anticipation; neuroimaging demonstrated atrophy in the cerebellum, brainstem, and spinal cord. [18F]FDG-PET demonstrated brain hypometabolism and [11C]Flumazenil-PET reduced binding in several brain lobes, insula, thalamus, hypothalamus, and cerebellum. Moderate to severe loss of Purkinje cells in the cerebellum and of motor neurons in the anterior horns of the spinal cord along with pronounced degeneration of posterior tracts was also found. Intranuclear, mainly neuronal, inclusions positive for p62 and ubiquitin were sparse but widespread in the CNS. This finding prompted assessment for nucleotide expansions. A polyglycine stretch encoding GGC expansions in the last exon of the zink finger homeobox 3 gene was identified segregating with disease and not found in 1000 controls.
CONCLUSIONS: SCA4 is a neurodegenerative disease caused by a novel GGC expansion in the coding region of ZFHX3, and its spectrum is expanded to include dysautonomia and neuromuscular manifestations.
摘要：
背景：脊髓小脑共济失调4（SCA4），1996年以成人共济失调为特征，多发性神经病,与染色体16q22.1连锁；其潜在的突变仍然难以捉摸。
目的：探讨SCA4中整个神经轴的放射学和神经病理学异常，并寻找其突变。
方法：三个未确诊共济失调的瑞典家庭经历了临床，神经生理学，和神经影像学检查，包括PET研究和基因调查。在四个案例中，对神经轴进行了神经病理学评估.基因检测包括短阅读全基因组测序，用ExpansionHunter从头进行短串联重复分析，和长读取测序。
结果：SCA4的新功能包括自主神经失调，运动神经元的影响，和异常的眼球运动。我们发现了预期的证据；神经影像学显示小脑萎缩，脑干,和脊髓。[18F]FDG-PET显示脑代谢低，[11C]氟马西尼-PET降低了几个脑叶的结合，脑岛,丘脑,下丘脑,还有小脑.还发现了小脑中的Purkinje细胞和脊髓前角中的运动神经元的中度至重度损失以及后束的明显变性。核内,主要是神经元，p62和泛素阳性的包涵体稀疏，但在中枢神经系统中分布广泛。这一发现促使评估核苷酸扩增。在zink手指同源盒3基因的最后一个外显子中编码GGC扩增的聚甘氨酸延伸被鉴定为与疾病隔离，在1000个对照中未发现。
结论：SCA4是一种由ZFHX3编码区的新型GGC扩增引起的神经退行性疾病，其范围扩大到包括自主神经失调和神经肌肉表现。
目的：探讨SCA4中整个神经轴的放射学和神经病理学异常，并寻找其突变。
方法：三个未确诊共济失调的瑞典家庭经历了临床，神经生理学，和神经影像学检查，包括PET研究和基因调查。在四个案例中，对神经轴进行了神经病理学评估.基因检测包括短阅读全基因组测序，用ExpansionHunter从头进行短串联重复分析，和长读取测序。
结果：SCA4的新功能包括自主神经失调，运动神经元的影响，和异常的眼球运动。我们发现了预期的证据；神经影像学显示小脑萎缩，脑干,和脊髓。[18F]FDG-PET显示脑代谢低，[11C]氟马西尼-PET降低了几个脑叶的结合，脑岛,丘脑,下丘脑,还有小脑.还发现了小脑中的Purkinje细胞和脊髓前角中的运动神经元的中度至重度损失以及后束的明显变性。核内,主要是神经元，p62和泛素阳性的包涵体稀疏，但在中枢神经系统中分布广泛。这一发现促使评估核苷酸扩增。在zink手指同源盒3基因的最后一个外显子中编码GGC扩增的聚甘氨酸延伸被鉴定为与疾病隔离，在1000个对照中未发现。
结论：SCA4是一种由ZFHX3编码区的新型GGC扩增引起的神经退行性疾病，其范围扩大到包括自主神经失调和神经肌肉表现。
