Late-onset Krabbe disease presenting as spastic paraplegia - implications of GCase and CTSB/D.
Krabbe disease
cathepsin B
cathepsin D
enzymatic activity
late‐onset
β‐glucocerebrosidase
Journal
Annals of clinical and translational neurology
ISSN: 2328-9503
Titre abrégé: Ann Clin Transl Neurol
Pays: United States
ID NLM: 101623278
Informations de publication
Date de publication:
04 Jun 2024
04 Jun 2024
Historique:
revised:
09
04
2024
received:
18
10
2023
accepted:
12
04
2024
medline:
5
6
2024
pubmed:
5
6
2024
entrez:
5
6
2024
Statut:
aheadofprint
Résumé
Krabbe disease (KD) is a multisystem neurodegenerative disorder with severe disability and premature death, mostly with an infancy/childhood onset. In rare cases of late-onset phenotypes, symptoms are often milder and difficult to diagnose. We here present a translational approach combining diagnostic and biochemical analyses of a male patient with a progressive gait disorder starting at the age of 44 years, with a final diagnosis of late-onset KD (LOKD). Additionally to cerebral MRI, protein structural analyses of the β-galactocerebrosidase protein (GALC) were performed. Moreover, expression, lysosomal localization, and activities of β-glucocerebrosidase (GCase), cathepsin B (CTSB), and cathepsin D (CTSD) were analyzed in leukocytes, fibroblasts, and lysosomes of fibroblasts. Exome sequencing revealed biallelic likely pathogenic variants: GALC exons 11-17: 33 kb deletion; exon 4: missense variant (c.334A>G, p.Thr112Ala). We detected a reduced GALC activity in leukocytes and fibroblasts. While histological KD phenotypes were absent in fibroblasts, they showed a significantly decreased activities of GCase, CTSB, and CTSD in lysosomal fractions, while expression levels were unaffected. The presented LOKD case underlines the age-dependent appearance of a mildly pathogenic GALC variant and its interplay with other lysosomal proteins. As GALC malfunction results in reduced ceramide levels, we assume this to be causative for the here described decrease in CTSB and CTSD activity, potentially leading to diminished GCase activity. Hence, we emphasize the importance of a functional interplay between the lysosomal enzymes GALC, CTSB, CTSD, and GCase, as well as between their substrates, and propose their conjoined contribution in KD pathology.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Interdisciplinary Center for Clinical Research (IZKF) of the University Hospital of the University of Erlangen-Nuremberg
ID : N8
Organisme : Bundesministerium für Bildung und Forschung (BMBF)
ID : 01GM1905B
Organisme : Bundesministerium für Bildung und Forschung (BMBF)
ID : 01GM2205B
Organisme : Bundesministerium für Bildung und Forschung (BMBF)
ID : 01EO2105
Organisme : Deutsche Forschungsgemeinschaft
ID : 270949263/GRK2162
Organisme : Michael J. Fox Foundation for Parkinson's Research
ID : MJFF-022745
Informations de copyright
© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
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