Investigating the Utility of Leukocyte Sialic Acid Measurements in Lysosomal Free Sialic Acid Storage Disorder
ABSTRACT Lysosomal free sialic acid storage disorder (FSASD) is a rare, multisystem neurodegenerative disease caused by biallelic pathogenic variants in SLC17A5, encoding sialin. FSASD is characterized by aberrant accumulation of unconjugated “free” sialic acid (Neu5Ac) within lysosomes. Depending o...
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Wiley
2025-07-01
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| Series: | JIMD Reports |
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| Online Access: | https://doi.org/10.1002/jmd2.70029 |
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| author | Marya S. Sabir Laura Pollard Lynne Wolfe David R. Adams Carla Ciccone Petcharat Leoyklang Frances M. Platt Marjan Huizing William A. Gahl May Christine V. Malicdan |
| author_facet | Marya S. Sabir Laura Pollard Lynne Wolfe David R. Adams Carla Ciccone Petcharat Leoyklang Frances M. Platt Marjan Huizing William A. Gahl May Christine V. Malicdan |
| author_sort | Marya S. Sabir |
| collection | DOAJ |
| description | ABSTRACT Lysosomal free sialic acid storage disorder (FSASD) is a rare, multisystem neurodegenerative disease caused by biallelic pathogenic variants in SLC17A5, encoding sialin. FSASD is characterized by aberrant accumulation of unconjugated “free” sialic acid (Neu5Ac) within lysosomes. Depending on the specific genetic variants, affected individuals may present with either a rapidly fatal disease or progressive neurodegeneration. While skin fibroblasts have traditionally been used for diagnosis and research, the use of leukocytes in FSASD remains underexplored. This study examined Neu5Ac levels in leukocytes from three individuals with FSASD carrying distinct SLC17A5 variants. The levels in affected individuals were compared to three different groups: (1) the unaffected biological parents of each case; (2) subjects for whom 14 distinct lysosomal storage disorders (LSDs) were excluded based on enzyme analysis (n = 11); and (3) participants with a confirmed LSD diagnosis, as determined by enzyme analysis (n = 9). Individuals with FSASD exhibited significantly higher levels of free Neu5Ac compared to their unaffected biological parents (36‐fold), LSD‐negative subjects (22‐fold), and individuals with other LSDs (49‐fold). Although total Neu5Ac levels showed a non‐significant trend toward an increase in FSASD (1.3‐fold), this was primarily due to elevated free Neu5Ac, as bound Neu5Ac was slightly decreased in the leukocytes of FSASD cases relative to their unaffected parents. Overall, these findings highlight leukocytes as a valuable, minimally invasive cellular model for FSASD, offering an alternative, reliable diagnostic tool and a potential platform for monitoring therapeutic responses in future intervention trials. |
| format | Article |
| id | doaj-art-869e228cf74e40dbbc6b0063e4d6d2cd |
| institution | DOAJ |
| issn | 2192-8312 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | JIMD Reports |
| spelling | doaj-art-869e228cf74e40dbbc6b0063e4d6d2cd2025-08-20T03:08:40ZengWileyJIMD Reports2192-83122025-07-01664n/an/a10.1002/jmd2.70029Investigating the Utility of Leukocyte Sialic Acid Measurements in Lysosomal Free Sialic Acid Storage DisorderMarya S. Sabir0Laura Pollard1Lynne Wolfe2David R. Adams3Carla Ciccone4Petcharat Leoyklang5Frances M. Platt6Marjan Huizing7William A. Gahl8May Christine V. Malicdan9NIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health Bethesda Maryland USABiochemical Genetics Laboratory Greenwood Genetic Center Greenwood South Carolina USANIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health Bethesda Maryland USANIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health Bethesda Maryland USAHuman Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health Bethesda Maryland USAHuman Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health Bethesda Maryland USADepartment of Pharmacology University of Oxford Oxford UKHuman Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health Bethesda Maryland USANIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health Bethesda Maryland USANIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health Bethesda Maryland USAABSTRACT Lysosomal free sialic acid storage disorder (FSASD) is a rare, multisystem neurodegenerative disease caused by biallelic pathogenic variants in SLC17A5, encoding sialin. FSASD is characterized by aberrant accumulation of unconjugated “free” sialic acid (Neu5Ac) within lysosomes. Depending on the specific genetic variants, affected individuals may present with either a rapidly fatal disease or progressive neurodegeneration. While skin fibroblasts have traditionally been used for diagnosis and research, the use of leukocytes in FSASD remains underexplored. This study examined Neu5Ac levels in leukocytes from three individuals with FSASD carrying distinct SLC17A5 variants. The levels in affected individuals were compared to three different groups: (1) the unaffected biological parents of each case; (2) subjects for whom 14 distinct lysosomal storage disorders (LSDs) were excluded based on enzyme analysis (n = 11); and (3) participants with a confirmed LSD diagnosis, as determined by enzyme analysis (n = 9). Individuals with FSASD exhibited significantly higher levels of free Neu5Ac compared to their unaffected biological parents (36‐fold), LSD‐negative subjects (22‐fold), and individuals with other LSDs (49‐fold). Although total Neu5Ac levels showed a non‐significant trend toward an increase in FSASD (1.3‐fold), this was primarily due to elevated free Neu5Ac, as bound Neu5Ac was slightly decreased in the leukocytes of FSASD cases relative to their unaffected parents. Overall, these findings highlight leukocytes as a valuable, minimally invasive cellular model for FSASD, offering an alternative, reliable diagnostic tool and a potential platform for monitoring therapeutic responses in future intervention trials.https://doi.org/10.1002/jmd2.70029leukocyteslysosomal storage disordersSalla diseasesialic acidsialinSLC17A5 |
| spellingShingle | Marya S. Sabir Laura Pollard Lynne Wolfe David R. Adams Carla Ciccone Petcharat Leoyklang Frances M. Platt Marjan Huizing William A. Gahl May Christine V. Malicdan Investigating the Utility of Leukocyte Sialic Acid Measurements in Lysosomal Free Sialic Acid Storage Disorder JIMD Reports leukocytes lysosomal storage disorders Salla disease sialic acid sialin SLC17A5 |
| title | Investigating the Utility of Leukocyte Sialic Acid Measurements in Lysosomal Free Sialic Acid Storage Disorder |
| title_full | Investigating the Utility of Leukocyte Sialic Acid Measurements in Lysosomal Free Sialic Acid Storage Disorder |
| title_fullStr | Investigating the Utility of Leukocyte Sialic Acid Measurements in Lysosomal Free Sialic Acid Storage Disorder |
| title_full_unstemmed | Investigating the Utility of Leukocyte Sialic Acid Measurements in Lysosomal Free Sialic Acid Storage Disorder |
| title_short | Investigating the Utility of Leukocyte Sialic Acid Measurements in Lysosomal Free Sialic Acid Storage Disorder |
| title_sort | investigating the utility of leukocyte sialic acid measurements in lysosomal free sialic acid storage disorder |
| topic | leukocytes lysosomal storage disorders Salla disease sialic acid sialin SLC17A5 |
| url | https://doi.org/10.1002/jmd2.70029 |
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