Mutations in TUBB4A are associated with a spectrum of neurologic disorders categorized as TUBB4A-related leukoencephalopathy. Affected children can present with global developmental delay or normal early development, followed by a variable loss of skills over time. Further research is needed to characterize the factors associated with the divergent developmental trajectories in this rare monogenic disorder because this phenotypic spectrum is not fully explained by genotype alone.

To characterize early psychomotor features, developmental milestones and age of disease onset were collected from medical records (n=54 individuals). Three subcohorts were identified: individuals with the common p.Asp249Asn variant vs all other genotypes with either early (<12 months of age) or late onset of presentation. Individuals with the p.Asp249Asn variant or those with non-p.Asp249Asn genotypes with later disease onset attained key milestones, including head control, sitting, and independent walking. Subjects with early-onset, non-p.Asp249Asn–associated disease were less likely to achieve developmental milestones. Next, we defined the developmental severity as the percentage of milestones attained by age 2 years. The mild form was defined as attaining at least 75% of key developmental milestones. Among cohort categorized as mild, individuals with p.Asp249Asn variant were more likely to lose acquired abilities when compared with non-p.Asp249Asn individuals.

Our results suggest multiple influences on developmental trajectory, including a strong contribution from genotype and age of onset. Further studies are needed to identify additional factors that influence overall outcomes to better counsel families and to design clinical trials with appropriate clinical endpoints.

TUBB4A的突变与被归类为TUBB4A相关的白质脑病的一系列神经系统疾病有关。受影响的儿童可能会出现整体发育迟缓或正常的早期发育，随着时间的推移会出现不同程度的技能丧失。需要进一步的研究来表征与这种罕见的单基因疾病中不同的发育轨迹相关的因素，因为这种表型谱不能仅由基因型完全解释。

为了表征早期精神运动特征，从医疗记录（n = 54 个人）中收集发育里程碑和疾病发病年龄。确定了三个亚群：具有常见 p.Asp249Asn 变体的个体与早期（<12 个月大）或晚期发病的所有其他基因型。具有 p.Asp249Asn 变异体或具有非 p.Asp249Asn 基因型且发病较晚的个体达到了关键里程碑，包括头部控制、坐姿和独立行走。患有早发性、非 p.Asp249Asn 相关疾病的受试者不太可能达到发育里程碑。接下来，我们将发育严重程度定义为 2 岁时达到的里程碑的百分比。轻度形式被定义为达到至少 75% 的关键发育里程碑。在归类为轻度的队列中，

我们的结果表明对发育轨迹有多种影响，包括基因型和发病年龄的重要贡献。需要进一步的研究来确定影响总体结果的其他因素，以便更好地为家庭提供咨询，并设计具有适当临床终点的临床试验。