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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\u2009years, with a final diagnosis of late\u2010onset KD (LOKD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Additionally to cerebral MRI, protein structural analyses of the \u03b2\u2010galactocerebrosidase protein (GALC) were performed. Moreover, expression, lysosomal localization, and activities of \u03b2\u2010glucocerebrosidase (GCase), cathepsin B (CTSB), and cathepsin D (CTSD) were analyzed in leukocytes, fibroblasts, and lysosomes of fibroblasts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Exome sequencing revealed biallelic likely pathogenic variants:\n                      <jats:italic>GALC<\/jats:italic>\n                      exons 11\u201317: 33\u2009kb deletion; exon 4: missense variant (c.334A&gt;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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      The presented LOKD case underlines the age\u2010dependent appearance of a mildly pathogenic\n                      <jats:italic>GALC<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.52078","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:45:50Z","timestamp":1717548350000},"page":"1715-1731","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Late\u2010onset Krabbe disease presenting as spastic paraplegia \u2013 implications of\n                    <scp>GCase<\/scp>\n                    and\n                    <scp>CTSB<\/scp>\n                    \/D"],"prefix":"10.1002","volume":"11","author":[{"given":"Rebecca","family":"M\u00e4chtel","sequence":"first","affiliation":[{"name":"Department of Molecular Neurology University Hospital Erlangen, 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