Purpose

TUBA1A and TUBB2B tubulinopathies are rare neurodevelopmental disorders characterized by cortical and extracortical malformations and heterogenic phenotypes. There is a need for quantitative clinical endpoints that will be beneficial for future diagnostic and therapeutic trials.

Methods

Quantitative natural history modeling of individuals with TUBA1A and TUBB2B tubulinopathies from clinical reports and database entries of DECIPHER and ClinVar. Main outcome measures were age at disease onset, survival, and diagnostic delay. Phenotypical, neuroradiological, and histopathological features were descriptively illustrated.

Results

Mean age at disease onset was 4 (TUBA1A) and 6 months (TUBB2B), respectively. Mortality was equally estimated with 7% at 3.2 (TUBA1A) and 8.0 years (TUBB2B). Diagnostic delay was significantly higher in TUBB2B (12.3 years) compared with TUBA1A tubulinopathy (4.2 years). We delineated the isotype-dependent clinical, neuroradiological, and histopathological phenotype of affected individuals and present brain malformations associated with epilepsy and an unfavorable course of disease.

Conclusion

The natural history of tubulinopathies is defined by the genotype and associated brain malformations. Defined data on estimated survival, diagnostic delay, and disease characteristics of TUBA1A and TUBB2B tubulinopathy will help to raise disease awareness and encourage future clinical trials to optimize genetic testing, family counseling, and supportive care.

中文翻译：

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TUBA1A 和 TUBB2B 微管蛋白病自然史的横断面定量分析

目的

TUBA1A和TUBB2B 微管蛋白病是罕见的神经发育障碍，其特征是皮质和皮质外畸形和异源表型。需要有利于未来诊断和治疗试验的定量临床终点。

方法

来自临床报告和 DECIPHER 和 ClinVar 数据库条目的 TUBA1A 和 TUBB2B 肾小管病变个体的定量自然史模型。主要结局指标是发病年龄、生存率和诊断延迟。描述性地说明了表型、神经放射学和组织病理学特征。

结果

发病时的平均年龄分别为 4 ( TUBA1A ) 和 6 个月( TUBB2B ) 。在 3.2 岁 ( TUBA1A ) 和 8.0 岁 ( TUBB2B )时死亡率同样估计为 7% 。TUBB2B（12.3 年）的诊断延迟显着高于TUBA1A 肾小管病变（4.2 年）。我们描述了受累个体的同种型依赖性临床、神经放射学和组织病理学表型，并存在与癫痫和不利病程相关的脑畸形。

结论

微管病变的自然史由基因型和相关的脑畸形定义。关于TUBA1A和TUBB2B肾小管病变的估计生存期、诊断延迟和疾病特征的明确数据将有助于提高疾病意识并鼓励未来的临床试验以优化基因检测、家庭咨询和支持性护理。