Maechtel, Rebecca and Dobert, Jan-Philipp and Hehr, Ute and Weiss, Alexander and Kettwig, Matthias and Laugwitz, Lucia and Groeschel, Samuel and Schmidt, Manuel and Arnold, Philipp and Regensburger, Martin and Zunke, Friederike (2024) Late-onset Krabbe disease presenting as spastic paraplegia - implications of GCase and CTSB/D. ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY, 11 (7). pp. 1715-1731. ISSN 2328-9503,
Full text not available from this repository. (Request a copy)Abstract
Objective 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).Methods Additionally to cerebral MRI, protein structural analyses of the beta-galactocerebrosidase protein (GALC) were performed. Moreover, expression, lysosomal localization, and activities of beta-glucocerebrosidase (GCase), cathepsin B (CTSB), and cathepsin D (CTSD) were analyzed in leukocytes, fibroblasts, and lysosomes of fibroblasts. Results 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. Interpretation 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GLOBOID-CELL LEUKODYSTROPHY; BETA-GALACTOCEREBROSIDASE; ALPHA-SYNUCLEIN; GALC GENE; LARGE DELETION; ADULT-ONSET; CATHEPSIN-D; PSYCHOSINE; MUTATIONS; TRAFFICKING; cathepsin B; cathepsin D; enzymatic activity; Krabbe disease; late-onset; beta-glucocerebrosidase |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Aug 2025 09:51 |
| Last Modified: | 20 Aug 2025 09:51 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65523 |
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