Journal Article

DZNE-2025-00915

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png ARSA Variants Associated With Cognitive Decline and Long-Term Preservation of Motor Function in Metachromatic Leukodystrophy.

Beerepoot, S. ; Schoenmakers, D. H. ; Fumagalli, F. ; Groeschel, S. ; Schöls, L.DZNE* ; Schiffmann, R. ; Wong, S. ; Boespflug-Tanguy, O. ; Sevin, C. ; Nadjar, Y. ; Bley, A. ; Mochel, F. ; Horn, M. A. ; Baldoli, C. ; Locatelli, S. ; Hengel, H. ; Laugwitz, L. ; Hollak, C. E. M. ; Gieselmann, V. ; van der Knaap, M. S. ; Wolf, N. I.

2025
Wiley Hoboken, NJ

This record in other databases:  

Please use a persistent id in citations: doi:10.1002/jimd.70072

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.

Keyword(s): Humans (MeSH) ; Leukodystrophy, Metachromatic: genetics (MeSH) ; Male (MeSH) ; Female (MeSH) ; Adult (MeSH) ; Cognitive Dysfunction: genetics (MeSH) ; Adolescent (MeSH) ; Cerebroside-Sulfatase: genetics (MeSH) ; Young Adult (MeSH) ; Child (MeSH) ; Middle Aged (MeSH) ; Magnetic Resonance Imaging (MeSH) ; Child, Preschool (MeSH) ; Hematopoietic Stem Cell Transplantation (MeSH) ; Mutation (MeSH) ; ARSA gene ; arylsulfatase A ; genetic association studies ; hematopoietic stem cell transplantation ; metachromatic leukodystrophy ; Cerebroside-Sulfatase

---

Contributing Institute(s):

1. Clinical Neurogenetics (AG Schöls)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

---

Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF < 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---