In this study, we characterize the natural course of metachromatic leukodystrophy (MLD), explore intra/inter group differences, and identify biomarkers to monitor disease progression. This is a longitudinal observational study. Genotype and characteristics at disease onset were recorded. Time-to-event analyses were performed to assess time to major disease-related milestones in different subgroups. Longitudinal trajectories of nerve conduction velocities (NCV), brain MRI score, and brainstem auditory evoked responses (BAERs) were described. We recruited 22 late-infantile, 14 early-juvenile, 5 late-juvenile, and 4 adult MLD patients. Thirty-four were prospectively evaluated (median FU time 43 months). In late-infantile patients, the attainment of independent walking was associated with a later age at dysphagia. In early-juvenile, the presence of isolated cognitive impairment at onset was not a favorable prognostic factor. Late-infantile and early-juvenile subjects showed similar rapid loss of ambulation and onset of seizures, but late-infantile displayed earlier loss of trunk control, dysphagia, and death. We found significant differences in all major disease-related milestones (except death) between early-juvenile and late-juvenile patients. Late-juvenile and adult patients both presented with a predominant cognitive impairment, mild/no peripheral neuropathy, lower brain MRI score at plateau compared to LI/EJ, and later cerebellar involvement. NCV and BAER were consistently severely abnormal in late-infantile but not in older subjects, in whom both NCV and BAER were variably affected, with no deterioration over time in some cases. This study clarifies intra/inter group differences between MLD subtypes and provides additional indications regarding reliable clinical and instrumental tools to monitor disease progression and to serve as areference to evaluate the efficacy of future therapeutic interventions inthe different MLD variants.

中文翻译：

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异染性脑白质营养不良：45 名患者的单中心纵向研究

在这项研究中，我们描述了异染性脑白质营养不良 (MLD) 的自然过程，探索组内/组间差异，并确定生物标志物以监测疾病进展。这是一项纵向观察研究。记录疾病发作时的基因型和特征。进行事件发生时间分析以评估不同亚组中主要疾病相关里程碑的时间。描述了神经传导速度 (NCV)、脑 MRI 评分和脑干听觉诱发反应 (BAER) 的纵向轨迹。我们招募了 22 名晚期婴儿、14 名早期青少年、5 名晚期青少年和 4 名成人 MLD 患者。34 人进行了前瞻性评估（中位 FU 时间 43 个月）。在晚期婴儿患者中，获得独立行走与吞咽困难的年龄较大有关。在少年时期，发病时存在孤立的认知障碍并不是一个有利的预后因素。晚期婴儿和早期青少年受试者表现出相似的快速行走丧失和癫痫发作，但晚期婴儿表现出较早失去躯干控制、吞咽困难和死亡。我们发现早期青少年和晚期青少年患者在所有主要疾病相关里程碑（死亡除外）方面存在显着差异。晚期青少年和成年患者均表现出主要的认知障碍、轻度/无周围神经病变、与 LI/EJ 相比在平台期的脑 MRI 评分较低，以及后来的小脑受累。NCV 和 BAER 在晚期婴儿中始终存在严重异常，但在老年受试者中则没有，其中 NCV 和 BAER 均受到不同程度的影响，在某些情况下随着时间的推移没有恶化。