# ARSA Variants Associated With Cognitive Decline and Long‐Term Preservation of Motor Function in Metachromatic Leukodystrophy

## TL;DR

This study shows that specific ARSA gene variants in metachromatic leukodystrophy are linked to cognitive decline but not motor loss, with treatment outcomes depending on the variant combination.

## Contribution

Identifies ARSA variants associated with cognitive decline and preserved motor function in MLD, guiding treatment outcome measures.

## Key findings

- ARSA variants c.256C>T, c.257G>A, and c.542T>G are linked to cognitive decline but preserved motor function in MLD.
- Patients with these variants typically retain walking and have less severe MRI scores if treated.
- Treatment outcomes should focus on cognitive function and MRI severity for these patients.

## Abstract

Patients with metachromatic leukodystrophy (MLD) show variable motor and cognitive decline. The ARSA variants c.256C>T, p.(Arg86Trp), c.257G>A, p.(Arg86Gln) and c.542T>G, p.(Ile181Ser) are associated with predominantly cognitive decline. This multinational study analyzed MLD onset type, presenting signs/symptoms, cognitive function, gross motor function, central motor tract involvement, MRI severity score, peripheral neuropathy, and survival of 47 patients (three homozygous for c.256C>T and five, twelve and 27 compound heterozygous for c.256C>T, c.257G>A, or c.542T>G and another ARSA variant, respectively). Eleven underwent hematopoietic stem cell transplantation (HSCT). Onset was late‐juvenile (46.8%) or adult (44.7%) with predominantly cognitive decline (n = 40/41 symptomatic patients). At diagnosis, untreated patients typically retained independent walking (100%), sparing of central motor tracts (87.5%), and absence of demyelinating neuropathy (95.5%), which persisted in follow‐up for most (76.5%, 71.4%, and 64.7%, respectively). Early‐juvenile onset and rapid motor decline occurred only in patients compound heterozygous for c.256C>T and a severe second variant (n = 4), showing central motor tract involvement at diagnosis. One untreated and one treated patient died of disease progression, and another from HSCT complications. All other treated patients retained independent walking, and four of five tested normal cognitive function. Median MRI severity score remained lower in treated (13) than untreated patients (25). The phenotype of c.256C>T carriers depends on the severity of the second ARSA variant. Patients harboring c.257G>A or c.542T>G show late‐juvenile or adult onset with cognitive decline and preserved motor function, usually associated with sparing of central motor tracts. In these patients, cognitive function and MRI severity score should be preferred treatment outcomes.