Abstract
Metachromatic leukodystrophy (MLD) is a progressive demyelinating disorder resulting from the toxic accumulation of sulfatides. The stereotyped neurodegeneration of MLD is well understood, and cases are categorized into subtypes by age at neurologic onset: late infantile (LI), juvenile (J), and adult. The systemic burden of disease, such as gallbladder involvement, however, is less well characterized. It is important to understand the longitudinal trajectory of gallbladder complications in MLD and its relationship with neurologic progression as this has the potential to identify cases of active disease before neurologic onset. Additionally, as newborn screening is established in MLD, it will inform clinical care during the presymptomatic period. To address this knowledge gap, we leveraged a retrospective natural history study of MLD and published cases in the medical literature. Medical records from subjects consented to a natural history study were used to collect information of disease course, including gallbladder abnormality. Neurologic function was retrospectively assessed using the gross motor function classification scale (GMFC-MLD). Additionally, a comprehensive review identified published cases of MLD with subject-level information around gallbladder disease. Data was summarized using descriptive statistics, Fisher's exact test for significance, and survival analysis with log rank test. The natural history cohort includes 40 subjects with gallbladder reports (imaging or pathology). The first gallbladder evaluation occurred after neurologic onset in 35/40 cases. Gallbladder abnormalities were noted in 36 subjects, often within the initial evaluation (97.2 %). There was no difference in the time to first gallbladder abnormality (log rank: p = 0.4170) and risk of polyps or higher (log rank: p = 0.6414) between the LI- and non-LI subtypes. The level of gallbladder involvement does not correlate with GMFC-MLD score (Fisher's exact: p = 0.321). A review of the literature identified 87 additional cases of MLD with mention of gallbladder status across 40 published studies. Gallbladder involvement was noted in 74 cases and occurred at similar rates across subtypes (X(2) = 4.68, p = 0.7925). Overall, the study showed a high prevalence of gallbladder complications in MLD. Gallbladder abnormalities were commonly found at first evaluation, even in pre- or early symptomatic disease. Since gallbladder disease has the potential to progress to malignancy, this supports the integration of regular gallbladder monitoring as clinical care and its potential as a predictive biomarker supporting disease onset.