目的:报道遗传性原发性侧索硬化症(PLS)与进行性非流畅性失语症之间的关联。
方法:6名成员来自一个家族,有15名患病个体,跨越3代,患有痉挛而没有肌肉萎缩或肌束震颤,从下肢开始,扩散到上肢和延髓肌肉组织,接着是努力的演讲,不流利的语言和痴呆症,5名死者疾病发作是在生命的第六个十年,或稍后。小脑共济失调是两名患者的首发表现,和帕金森病,在另一个。
结果:两名患者的神经病理学检查显示脊髓外侧皮质脊髓束变性,没有脊髓的损失,脑干,或脑运动神经元。骶骨和腰椎皮质脊髓纤维损失更大,而不是在宫颈或髓质水平被证明,支持中央轴突死亡的致病机制。额叶中的髓鞘和神经纤维也明显减少。嗜银性谷物病和原发性年龄相关性tau蛋白病各1例,并考虑偶然发现。基因检测,包括针对PLS的外显子组测序,共济失调,遗传性痉挛性截瘫,额颞叶痴呆,针对显性脊髓小脑共济失调的三重重复引物聚合酶链反应,对人类基因组进行大规模测序,产生负面结果。
结论:中央型远端轴突病会影响皮质脊髓束,在显性遗传性PLS进行性非流畅性失语症关联中发挥了致病作用,此处描述。需要进一步的分子研究来确定该疾病的致病突变。
OBJECTIVE: To report a kindred with an association between hereditary primary lateral sclerosis (PLS) and progressive nonfluent aphasia.
METHODS: Six members from a kindred with 15 affected individuals spanning three generations, suffered from spasticity without muscle atrophy or fasciculation, starting in the lower limbs and spreading to the upper limbs and bulbar musculature, followed by effortful speech, nonfluent language and dementia, in 5 deceased members. Disease onset was during the sixth decade of life, or later. Cerebellar ataxia was the inaugural manifestation in two patients, and parkinsonism, in another.
RESULTS: Neuropathological examination in two patients demonstrated degeneration of lateral corticospinal tracts in the spinal cord, without loss of spinal, brainstem, or cerebral motor neurons. Greater loss of corticospinal fibers at sacral and lumbar, rather than at cervical or medullary levels was demonstrated, supporting a central axonal dying-back pathogenic mechanism. Marked reduction of myelin and nerve fibers in the frontal lobes was also present. Argyrophilic grain disease and primary age-related tauopathy were found in one case each, and considered incidental findings. Genetic testing, including exome sequencing aimed at PLS, ataxia, hereditary spastic paraplegia, and frontotemporal lobe dementia, triplet-repeated primed polymerase chain reaction aimed at dominant spinocerebellar ataxias, and massive sequencing of the human genome, yielded negative results.
CONCLUSIONS: A central distal axonopathy affecting the corticospinal tract, exerted a pathogenic role in the dominantly inherited PLS-progressive nonfluent aphasia association, described herein. Further molecular studies are needed to identify the causative mutation in this disease.