Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy.

Autor: Adang LA; The Children's Hospital of Philadelphia, Neurology, Philadelphia, PA, USA. Electronic address: adangl@chop.edu., Groeschel S; University Children's Hospital, Hoppe-Seyler-Str.1, Tuebingen, DE 72070, USA. Electronic address: samuel.groeschel@med.uni-tuebingen.de., Grzyb C; University of Pittsburgh, Department of Pediatrics, 4401 Penn Avenue, Pittsburgh, PA 15224, USA. Electronic address: cgrzyb@pennstatehealth.psu.edu., D'Aiello R; The Children's Hospital of Philadelphia, Neurology, Philadelphia, PA, USA. Electronic address: daielloiir@chop.edu., Gavazzi F; The Children's Hospital of Philadelphia, Neurology, Philadelphia, PA, USA. Electronic address: gavazzif@chop.edu., Sherbini O; The Children's Hospital of Philadelphia, Neurology, Philadelphia, PA, USA. Electronic address: serbinio@chop.edu., Bronner N; The Children's Hospital of Philadelphia, Neurology, Philadelphia, PA, USA; Uniformed Services University of Health Sciences, Bethesda, MD, USA., Patel A; The Children's Hospital of Philadelphia, Neurology, Philadelphia, PA, USA; Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA., Vincent A; The Children's Hospital of Philadelphia, Neurology, Philadelphia, PA, USA. Electronic address: vincenta@chop.edu., Sevagamoorthy A; The Children's Hospital of Philadelphia, Neurology, Philadelphia, PA, USA. Electronic address: sevagamooa@chop.edu., Mutua S; The Children's Hospital of Philadelphia, Neurology, Philadelphia, PA, USA. Electronic address: mutuas@chop.edu., Muirhead K; The Children's Hospital of Philadelphia, Neurology, Philadelphia, PA, USA., Schmidt J; The Children's Hospital of Philadelphia, Neurology, Philadelphia, PA, USA. Electronic address: schmidtj1@chop.edu., Pizzino A; The Children's Hospital of Philadelphia, Neurology, Philadelphia, PA, USA. Electronic address: pizzinoa@chop.edu., Yu E; The Children's Hospital of Philadelphia, Neurology, Philadelphia, PA, USA. Electronic address: Yue2@chop.edu., Jin D; University of Minnesota, Minneapolis, MN, USA. Electronic address: zhuxx003@umn.edu., Eichler F; Massachusetts General Hospital, Boston, MA, USA. Electronic address: feichler@partners.org., Fraser JL; Children's National Medical Center, Washington, DC 20010-2978, USA. Electronic address: JFraser@childrensnational.org., Emrick L; Baylor College of Medicine, Houston, TX 77030-3411, USA. Electronic address: emrick@bcm.edu., Van Haren K; Stanford University, Neurology, Stanford, CA, USA. Electronic address: kvh@stanford.edu., Boulanger JM; Charles-LeMoyne Hospital, Greenfield Park, QC, Canada. Electronic address: jean-martin.boulanger.med@ssss.gouv.qc.ca., Ruzhnikov M; Stanford University, Neurology, Stanford, CA, USA. Electronic address: ruzhnikov@stanford.edu., Sylvain M; Université Laval, Division of Pediatric Neurology, Centre Mère-Enfant Soleil, Quebec, QC, Canada., Nguyen CÉ; Centre Hospitalier Universitaire Sainte-Justine, Department of Neurosciences and Pediatrics, Division of Pediatric Neurology, Montreal, QC, Canada. Electronic address: cam-tu.emilie.nguyen.hsj@ssss.gouv.qc.ca., Potic A; University of Belgrade Faculty of Medicine, Department of Neurology, Clinic for Child Neurology and Psychiatry, Beograd, Republic of Serbia., Keller S; Children's Healthcare of Atlanta Scottish Rite Hospital, Atlanta, GA, USA. Electronic address: stephanie.keller@choa.org., Fatemi A; Kennedy Krieger Institute and Department of Neurology, Johns Hopkins University, Baltimore, MD, USA. Electronic address: fatemi@kennedykrieger.org., Uebergang E; Royal Children's Hospital, Murdoch Children's Research Institute and University of Melbourne, Department of Paediatrics, Melbourne, VIC, Australia. Electronic address: eloise.uebergang@mcri.edu.au., Poe M; University of Pittsburgh, Department of Pediatrics, 4401 Penn Avenue, Pittsburgh, PA 15224, USA. Electronic address: michele.poe@chp.edu., Yazdani PA; Research Institute of the McGill University Health Centre, Montreal, QC, Canada. Electronic address: pouneh.amir-yazdani.1@ulaval.ca., Bernat J; University of Iowa Hospitals and Clinics, Iowa City, IA, USA. Electronic address: john-bernat@uiowa.edu., Lindstrom K; BioMarin Pharmaceutical Inc, Novato, CA, USA; Phoenix Children's Hospital, Phoenix, AZ, USA., Bonkowsky JL; University of Utah School of Medicine, Division of Pediatric Neurology, Department of Pediatrics, 295 Chipeta Way, Williams Building, Salt Lake City, UT 84108, USA. Electronic address: joshua.bonkowsky@hsc.utah.edu., Bernard G; Montreal Children's Hospital, McGill University Health Center, Departments of Pediatrics, Neurology and Neurosurgery, 2300 Tupper, Room A-506, Montreal, QC H3H 1P3, Canada. Electronic address: genevieve.bernard@mcgill.ca., Stutterd CA; Royal Children's Hospital, Murdoch Children's Research Institute and University of Melbourne, Department of Paediatrics, Melbourne, VIC, Australia. Electronic address: chloe.stutterd@vcgs.org.au., Orchard P; University of Minnesota, Minneapolis, MN, USA. Electronic address: orcha001@umn.edu., Gupta AO; University of Minnesota, Minneapolis, MN, USA. Electronic address: gupta461@umn.edu., Ljungberg M; Copenhagen University Hospital, Centre Inherited Metabolic Disease, Department of Pediatrics and Adolescent Medicine, Kobenhavn, Denmark. Electronic address: merete.ljungberg@regionh.dk., Groenborg S; Copenhagen University Hospital, Centre Inherited Metabolic Disease, Department of Pediatrics and Adolescent Medicine, Kobenhavn, Denmark. Electronic address: sabine.groenborg@regionh.dk., Zambon A; San Raffaele Scientific Institute, Division of Neuroscience, Milan, Italy. Electronic address: zambon.alberto@hsr.it., Locatelli S; San Raffaele Hospital, Paediatric Immunohematology and Unit of Neurology, Milano, Lombardia, Italy. Electronic address: locatelli.sara@hsr.it., Fumagalli F; Ospedale San Raffaele, Via Olgettina 60, Milano 20132, Italy. Electronic address: fumagalli.francesca@hsr.it., Elguen S; University Children's Hospital, Hoppe-Seyler-Str.1, Tuebingen, DE 72070, USA. Electronic address: Saskia.Elguen@med.uni-tuebingen.de., Kehrer C; University Children's Hospital, Hoppe-Seyler-Str.1, Tuebingen, DE 72070, USA. Electronic address: christiane.kehrer@med.uni-tuebingen.de., Krägeloh-Mann I; University Children's Hospital, Hoppe-Seyler-Str.1, Tuebingen, DE 72070, USA. Electronic address: ingeborg.kraegeloh-mann@med.uni-tuebingen.de., Shults J; The Children's Hospital of Philadelphia, Philadelphia, PA, USA. Electronic address: shultsj@chop.edu., Vanderver A; The Children's Hospital of Philadelphia, Neurology, Philadelphia, PA, USA. Electronic address: vandervera@chop.edu., Escolar ML; University of Pittsburgh, Department of Pediatrics, 4401 Penn Avenue, Pittsburgh, PA 15224, USA. Electronic address: mle26@pitt.edu.
Jazyk: angličtina
Zdroj: Molecular genetics and metabolism [Mol Genet Metab] 2024 Aug; Vol. 142 (4), pp. 108521. Date of Electronic Publication: 2024 Jun 29.
DOI: 10.1016/j.ymgme.2024.108521
Abstrakt: Objective: Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease.
Methods: The specific ages of gain and loss of developmental milestones were captured from the medical records of individuals affected by MLD. Milestone acquisition was characterized as: on target (obtained before the age limit of 90th percentile plus 2 standard deviations compared to a normative dataset), delayed (obtained after 90th percentile plus 2 standard deviations), or plateau (skills never gained). Regression was defined as the age at which skills were lost. LI-MLD was defined by age at onset before 2.5 years.
Results: Across an international cohort, 351 subjects were included (n = 194 LI-MLD subcohort). The median age at presentation of the LI-MLD cohort was 1.4 years (25th-75th %ile: 1.0-1.5). Within the LI-MLD cohort, 75/194 (39%) had developmental delay (or plateau) prior to MLD clinical presentation. Among the LI-MLD cohort with a minimum of 1.5 years of follow-up (n = 187), 73 (39.0%) subjects never attained independent ambulation. Within LI-MLD + delay subcohort, the median time between first missed milestone target to MLD decline was 0.60 years (maximum distance from delay to onset: 1.9 years).
Interpretation: Early developmental delay precedes regression in a subset of children affected by LI-MLD, defining the onset of neurologic dysfunction earlier than previously appreciated. The use of realworld data prior to diagnosis revealed an early deviation from typical development. Close monitoring for early developmental delay in presymptomatic individuals may help in earlier diagnosis with important consequences for treatment decisions.
Competing Interests: Declaration of competing interest Dr. Adang is an advisor to Takeda Pharmaceuticals (enzyme replacement study for MLD), Orchard Therapeutics (gene therapy development for MLD), and is a site sub-investigator for the Takeda trial (enzyme replacement study); Dr. Gröschel is an advisor Takeda and Orchard Therapeutics; Dr. Bonkowsky is a site principal investigator for the Takeda trial; Dr. Bernard is a site principal investigator for the Takeda trial; Dr. Weller Grønborg is a consultant to Orchard Therapeutics; Dr. Orchard is a consultant to Orchard Therapeutics. Dr. Krägeloh-Mann is an advisor to Takeda, Orchard Therapeutics; Dr. Vanderver is an advisor to Takeda, Passagebio, Orchard; and is site PI Takeda trial; Dr. Escolar is an advisor to Takeda, Janssen; she is employed by Forge Biologics; Dr. Fumagalli is the license holder of OTL-200, I Orchard Therapeutics trial, advisor Orchard, Takeda, funding Telethon Foundation, GSK, Orchard. Dr. Eichler, Dr. Fatemi, Dr. Gavazzi, Dr. Sevagamoorthy, Ms. Mutua, Ms. Muirhead, Ms. Schmidt, Ms. Pizzino, Ms. Yu, Ms. Jin, Mr. Vincent, Ms. Grzyb, Mr. D'Aiello, Mr. Sherbini, Mr. Bronner, Mr. Patel, Dr. Fraser, Dr. Emrick, Dr. Van Haren, Dr. Ruzhnikov, Dr. Keller, Ms. Uebergang, Ms. Poe, Dr. Yazdani, Dr. Bernat, Dr. Lindstrom, Dr. Stutterd, Dr. Gupta, Dr. Boulanger, Dr. Sylvain, Dr. Nguyen, Dr. Potic, Dr. Ljungberg, Dr. Zambon, Ms. Locatelli, Ms. Elgün, Dr. Kehrer, and Dr. Shults have no relevant disclosures.
(Copyright © 2024. Published by Elsevier Inc.)
Databáze: MEDLINE
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