Elsaid Mahmoud F, Ibrahim Khalid, Chalhoub Nader, Elsotouhy Ahmed, El Mudehki Noora, Abdel Aleem Alice
Pediatric Neurology Department, Hamad Medical Corporation, Doha, Qatar.
Neurogenetics Research program, Neurology Department, Weill Cornell Medical College, Qatar Foundation- Education City, 24144, Doha, Qatar.
BMC Med Genet. 2017 Mar 21;18(1):33. doi: 10.1186/s12881-017-0395-6.
Hereditary Spastic Paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative diseases. Thin Corpus Callosum (TCC) associated HSP is a distinguished subgroup of complex forms. Purines and pyrimidine, the basic DNA and RNA components, are regulating the cell metabolism, having roles in signal transduction, energy preservation and cellular repair. Genetic defects in nucleotide metabolism related genes have been only recently implicated in brain and neurodegenerative diseases' pathogenesis.
We present a consanguineous Qatari family with two brothers, 9 and 3 years, who displayed a characteristic phenotype of early onset and markedly-severe spasticity with tiptoe walking, delayed dysarthric speech, persistent truncal hypotonia, and multiple variable-sized areas of brownish skin discoloration appearing at different places on the body. A clinical diagnosis suggestive of complex hereditary spastic paraplegia (HSP) was set after the family had the second affected child. Whole genome sequencing identified a novel homozygous NT5C2 splice site mutation (NM_012229.4/NM_001134373.2: c.1159 + 1G > T) that recessively segregated in family members. Brain MRI revealed dysgenic and thin corpus callosum (TCC) with peri-trigonal white matter cystic changes in both affected boys, whereas a well-developed corpus callosum with normal white matter was shown in their apparently normal brother, who found to be a carrier for the mutant variant. This mutation led to skipping of exon 14 with removal of 58 amino acid residues at the C-terminal half. The aberrantly spliced NT5C2 showed substantial reduction in expression level in the in-vitro study, indicating marked instability of the mutant NT5C2 protein.
The present report expands the phenotypic spectrum of SPG45 and confirms NT5C2-SPG45 as a member of the rare TCC SPG-subtypes. Homozygous alteration in NT5C2 seems essential to produce central white matter developmental defects. The study highlights the importance of cytosolic II 5'-nucleotidase (NT5C2) in maintaining the normal balance of purines' pool in the brain, which seems to play a pivotal role in the normal development of central white matter structures.
遗传性痉挛性截瘫（HSP）是一组具有遗传异质性的神经退行性疾病。胼胝体变薄（TCC）相关的HSP是复杂形式的一个特殊亚组。嘌呤和嘧啶作为DNA和RNA的基本组成成分，参与细胞代谢调节，在信号转导、能量维持和细胞修复中发挥作用。核苷酸代谢相关基因的遗传缺陷直到最近才被认为与脑和神经退行性疾病的发病机制有关。
我们报告一个来自卡塔尔的近亲家庭，家中有两名兄弟，分别为9岁和3岁，他们表现出早发性和明显严重痉挛的特征性表型，伴有踮足行走、言语发育迟缓、持续性躯干肌张力减退，以及身体不同部位出现多个大小不一的褐色皮肤色素沉着区域。在这个家庭有了第二个患病孩子后，做出了提示复杂遗传性痉挛性截瘫（HSP）的临床诊断。全基因组测序鉴定出一个新的纯合NT5C2剪接位点突变（NM_012229.4/NM_001134373.2：c.1159 + 1G > T），该突变在家庭成员中呈隐性分离。脑部MRI显示，两名患病男孩的胼胝体发育不良且变薄（TCC），伴有三角区周围白质囊性改变，而他们看似正常的兄弟的胼胝体发育良好，白质正常，经检测该兄弟为突变变体的携带者。这种突变导致外显子14跳跃，C末端一半的58个氨基酸残基缺失。在体外研究中，异常剪接的NT5C2表达水平大幅降低，表明突变的NT5C2蛋白明显不稳定。
本报告扩展了SPG45的表型谱，并确认NT5C2 - SPG45是罕见的TCC SPG亚型之一。NT5C2的纯合改变似乎是产生中枢白质发育缺陷的必要条件。该研究强调了胞质II 5'-核苷酸酶（NT5C2）在维持脑中嘌呤池正常平衡方面的重要性，这似乎在中枢白质结构的正常发育中起关键作用。
