目的:异染性脑白质营养不良(MLD)是一种罕见的神经退行性疾病。新兴疗法在症状前阶段最有效,因此定义这个窗口是至关重要的。我们假设早期发育延迟可能先于发育高原。随着症状前筛查平台和变革性疗法的出现,定义神经系统疾病的发病至关重要。
方法:从受MLD影响的个体的医疗记录中获取发育里程碑的得失的具体年龄。里程碑获取的特征是:在目标上(与标准数据集相比,在90百分位数的年龄限制之前获得2个标准偏差),延迟(在第90百分位数加上2个标准偏差后获得),或高原(从未获得的技能)。回归被定义为技能丧失的年龄。LI-MLD定义为2.5岁之前的发病年龄。
结果:在整个国际队列中,纳入351名受试者(n=194个LI-MLD亚组)。LI-MLD队列的中位年龄为1.4岁(第25-75%的年龄:1.0-1.5)。在LI-MLD队列中,75/194(39%)在MLD临床表现之前有发育延迟(或平台期)。在至少1.5年随访的LI-MLD队列中(n=187),73名(39.0%)受试者从未实现独立行走。在LI-MLD+延迟子队列中,从首次错过里程碑目标到MLD下降的中位时间为0.60年(从延迟到发病的最大距离:1.9年).
结论:在受LI-MLD影响的儿童中,早期发育延迟先于消退,比以前认识到的更早定义神经功能障碍的发作。在诊断之前使用现实世界数据显示出与典型发展的早期偏差。密切监测症状前个体的早期发育迟缓可能有助于早期诊断,对治疗决策具有重要影响。
OBJECTIVE: Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease.
METHODS: The specific ages of gain and loss of developmental milestones were captured from the medical records of individuals affected by MLD. Milestone acquisition was characterized as: on target (obtained before the age limit of 90th percentile plus 2 standard deviations compared to a normative dataset), delayed (obtained after 90th percentile plus 2 standard deviations), or plateau (skills never gained). Regression was defined as the age at which skills were lost. LI-MLD was defined by age at onset before 2.5 years.
RESULTS: Across an international cohort, 351 subjects were included (n = 194 LI-MLD subcohort). The median age at presentation of the LI-MLD cohort was 1.4 years (25th-75th %ile: 1.0-1.5). Within the LI-MLD cohort, 75/194 (39%) had developmental delay (or plateau) prior to MLD clinical presentation. Among the LI-MLD cohort with a minimum of 1.5 years of follow-up (n = 187), 73 (39.0%) subjects never attained independent ambulation. Within LI-MLD + delay subcohort, the median time between first missed milestone target to MLD decline was 0.60 years (maximum distance from delay to onset: 1.9 years).
CONCLUSIONS: Early developmental delay precedes regression in a subset of children affected by LI-MLD, defining the onset of neurologic dysfunction earlier than previously appreciated. The use of realworld data prior to diagnosis revealed an early deviation from typical development. Close monitoring for early developmental delay in presymptomatic individuals may help in earlier diagnosis with important consequences for treatment decisions.