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@ARTICLE{Beerepoot:280237,
      author       = {Beerepoot, Shanice and Schoenmakers, Daphne H and
                      Fumagalli, Francesca and Groeschel, Samuel and Schöls,
                      Ludger and Schiffmann, Raphael and Wong, Sheila and
                      Boespflug-Tanguy, Odile and Sevin, Caroline and Nadjar, Yann
                      and Bley, Annette and Mochel, Fanny and Horn, Morten A and
                      Baldoli, Cristina and Locatelli, Sara and Hengel, Holger and
                      Laugwitz, Lucia and Hollak, Carla E M and Gieselmann,
                      Volkmar and van der Knaap, Marjo S and Wolf, Nicole I},
      title        = {{ARSA} {V}ariants {A}ssociated {W}ith {C}ognitive {D}ecline
                      and {L}ong-{T}erm {P}reservation of {M}otor {F}unction in
                      {M}etachromatic {L}eukodystrophy.},
      journal      = {Journal of inherited metabolic disease},
      volume       = {48},
      number       = {5},
      issn         = {0141-8955},
      address      = {Hoboken, NJ},
      publisher    = {Wiley},
      reportid     = {DZNE-2025-00915},
      pages        = {e70072},
      year         = {2025},
      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.},
      keywords     = {Humans / Leukodystrophy, Metachromatic: genetics / Male /
                      Female / Adult / Cognitive Dysfunction: genetics /
                      Adolescent / Cerebroside-Sulfatase: genetics / Young Adult /
                      Child / Middle Aged / Magnetic Resonance Imaging / Child,
                      Preschool / Hematopoietic Stem Cell Transplantation /
                      Mutation / ARSA gene (Other) / arylsulfatase A (Other) /
                      genetic association studies (Other) / hematopoietic stem
                      cell transplantation (Other) / metachromatic leukodystrophy
                      (Other) / Cerebroside-Sulfatase (NLM Chemicals)},
      cin          = {AG Schöls},
      ddc          = {610},
      cid          = {I:(DE-2719)5000005},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40751594},
      pmc          = {pmc:PMC12317651},
      doi          = {10.1002/jimd.70072},
      url          = {https://pub.dzne.de/record/280237},
}