预约演示

更新于：2025-05-07

Spinocerebellar Ataxia, Autosomal Recessive, With Axonal Neuropathy

常染色体隐性遗传性脊髓小脑性共济失调伴轴索型神经病

更新于：2025-05-07

基本信息

别名

SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY、Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy、脊髓小脑性共济失调，常染色体隐性遗传，伴轴索神经病

简介-

关联

项与常染色体隐性遗传性脊髓小脑性共济失调伴轴索型神经病相关的临床试验

NCT01793168

/ RecruitingN/A

Coordination of Rare Diseases at Sanford

CoRDS, or the Coordination of Rare Diseases at Sanford, is based at Sanford Research in Sioux Falls, South Dakota. It provides researchers with a centralized, international patient registry for all rare diseases. This program allows patients and researchers to connect as easily as possible to help advance treatments and cures for rare diseases. The CoRDS team works with patient advocacy groups, individuals and researchers to help in the advancement of research in over 7,000 rare diseases. The registry is free for patients to enroll and researchers to access. Visit sanfordresearch.org/CoRDS to enroll.

开始日期2010-07-01

申办/合作机构

Sanford Health Corp.

[+9]

100 项与常染色体隐性遗传性脊髓小脑性共济失调伴轴索型神经病相关的临床结果

登录后查看更多信息

100 项与常染色体隐性遗传性脊髓小脑性共济失调伴轴索型神经病相关的转化医学

登录后查看更多信息

0 项与常染色体隐性遗传性脊髓小脑性共济失调伴轴索型神经病相关的专利（医药）

登录后查看更多信息

项与常染色体隐性遗传性脊髓小脑性共济失调伴轴索型神经病相关的文献（医药）

2025-03-01·Pediatric Neurology

Genetic Homogeneity of a TDP1 Variant, c.1478A>G, as the Main Disease-Causing Variant of Spinocerebellar Ataxia With Axonal Neuropathy 1 (SCAN1) in the Middle East: A Systematic Review

Review

作者: Gharebaghian, Hadi ; Alavi, Afagh ; Mohammadi, Mahsa ; Ravanbod, Moez ; Nafissi, Shahriar ; Ghasemi, Aida

BACKGROUNDSpinocerebellar ataxia with axonal neuropathy 1 (SCAN1) is an ultrarare neurodegenerative disorder inherited in an autosomal recessive manner, mainly marked by progressive ataxia and axonal polyneuropathy. SCAN1 is mainly caused by the c.1478A>G:p.His493Arg mutation in the TDP1 gene. In this study, we present the first Iranian family, and the fifth family totally, diagnosed with the SCAN1, which carries the common variant c.1478A>G. Additionally, we conducted a systematic review to identify all reported probably disease-related variants of TDP1.METHODSWhole exome sequencing was performed on the proband, who was initially diagnosed with axonal neuropathy. The data were analyzed, and the variant was confirmed via Sanger sequencing. Cosegregation analysis was used to validate the variant within the family. Following PRISMA 2020 guidelines, we performed a systematic review using the terms TDP1, tyrosyl-DNA phosphodiesterase, SCAN1, and spinocerebellar ataxia with axonal neuropathy in four major databases.RESULTSWhole exome sequencing results identified the known TDP1:c.1478A>G variant, which correlated with the disease status in the family. Clinical and paraclinical findings were consistent with SCAN1. Our systematic review identified 16 variants in 20 families associated with various neurological or non-neurological disorders. Among these families, four were SCAN1. Although four of five families with SCAN1, including our family, shared the same TDP1 variant, c.1478A>G, they exhibited some clinical heterogeneity.CONCLUSIONSGiven that all these cases were from the Middle East, we suggested this mutation may be a founder mutation in this region. Since only a few families with SCAN1 have been reported, further research is needed to fully understand this disorder.

2021-11-01·Molecular Diversity3区 · 化学

Dehydroabietylamine-based thiazolidin-4-ones and 2-thioxoimidazolidin-4-ones as novel tyrosyl-DNA phosphodiesterase 1 inhibitors

3区 · 化学

Article

作者: Yarovaya, Olga ; Salakhutdinov, Nariman ; Mamontova, Evgeniya ; Lavrik, Olga ; Zakharova, Olga ; Kovaleva, Kseniya ; Zakharenko, Alexandra

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a DNA repair enzyme that plays a key role in repairing damage caused by various antitumor drugs. It is a promising target in medicinal chemistry for the creation of cancer adjuvant therapy. Inhibition of this enzyme together with the use of anticancer chemotherapy enhances the effect of the latter. The natural mutant of TDP1, TDP1(H493R), causes severe neurodegenerative disease spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1). Inhibition of TDP1(H493R) appears to be useful in containment the progression of the disease. A library of compounds was synthesized starting from dehydroabietylamine including heterocyclic pharmacophore groups in the core. To obtain the desired products, the starting dehydroabietylamine was introduced sequentially in reaction with isothiocyanate and ethyl bromoacetate. Different classes of heterocyclic derivatives-2-iminothiazolidin-4-ons and 2-thioxoimidazolidin-4-ones-were obtained depending on the addition order of reagents. 2-Iminothiazolidin-4-thiones were obtained from 2-iminothiazolidin-4-ones under the action of the Lawesson's reagent. Effective TDP1 inhibitors were found among the obtained compounds that work in submicromolar concentrations. The inhibitor of TDP1(H493R) was also detected.

2020-01-01·Bioorganic & Medicinal Chemistry

Identification of novel inhibitors for the tyrosyl-DNA-phosphodiesterase 1 (Tdp1) mutant SCAN1 using virtual screening

Article

作者: Zakharenko, A L ; Zakharova, O D ; Volcho, K P ; Reynisson, J ; Mamontova, E M ; Salakhutdinov, N F ; Dyrkheeva, N S ; Lavrik, O I ; Arabshahi, H J

Spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1) is a debilitating neurological disease that is caused by the mutation the Tyrosyl-DNA phosphodiesterase 1 (TDP1) DNA repair enzyme. The crucial His493 in TDP1's binding site is replaced with an arginine amino acid residue rendering the enzyme dysfunctional. A virtual screen was performed against the homology model of SCAN1 and seventeen compounds were identified and tested in a novel SCAN1 specific biochemical assay. Six compounds showed activity with IC₅₀ values between 3.5 and 25.1 µM. The most active ligand 5 (3.5 µM) is a dicoumarin followed by a close structural analogue 6 at 6.0 µM. A less potent series of β-carbolines (14 and 15) was found with potency in the mid-teens. According to molecular modelling an excellent fit for the active ligands into the binding pocket is predicted. To the best of our knowledge, data on inhibitors of the mutant form of TDP1 has not been reported previously. The virtual hits were also tested for wild type TDP1 activity and all six SCAN1 inhibitors are potent for the former, e.g., ligand 5 has a measured IC₅₀ at 99 nM. In the last decade, TDP1 is considered as a promising target for adjuvant therapy against cancer in combination with Topoisomerase 1 poisons. The active ligands are mostly non-toxic to cancer cell lines A-549, T98G and MCF-7 as well as the immortalized WI-38 human fetal lung cells. Furthermore, ligands 5 and 7, show promising synergy in conjunction with topotecan, a clinically used topoisomerase 1 anticancer drug. The active ligands 5, 7, 14 and 15 have a good balance of the physicochemical properties required for oral bioavailability making the excellent candidates for further development.

分析

对领域进行一次全面的分析。

或

查看完整样例数据

Eureka LS:

全新生物医药AI Agent 覆盖科研全链路，让突破性发现快人一步

立即开始免费试用!

智慧芽新药情报库是智慧芽专为生命科学人士构建的基于AI的创新药情报平台，助您全方位提升您的研发与决策效率。

立即开始数据试用!

智慧芽新药库数据也通过智慧芽数据服务平台，以API或者数据包形式对外开放，助您更加充分利用智慧芽新药情报信息。