Conditions with similar clinical presentations that must be differentiated from Salla Disease:
Disease Pathophysiology Research Report Target Disease - Disease Name: Salla disease (also termed classic free sialic acid storage disease, FSASD) - MONDO IDs: Salla disease MONDO:0011449; Free sialic acid storage disease MONDO:0019366; Infantile free sialic acid storage disease (ISSD) MONDO:0010027 - Category: Mendelian, lysosomal storage disorder
1) Core Pathophysiology Salla disease results from biallelic pathogenic variants in SLC17A5, encoding the lysosomal membrane transporter sialin, which exports free sialic acid (Neu5Ac) from the lysosomal lumen to the cytosol. Loss or reduction of sialin-mediated export leads to lysosomal accumulation of free Neu5Ac and secondary lysosomal dysfunction. The disease spans a spectrum from severe infantile (ISSD) to classic Salla disease with slower progression into adulthood. (schwake2022lysosomalmembranedefects pages 2-2, sabir2025lysosomalfreesialic pages 1-2)
Mechanistically, Sialin is a 12-transmembrane major facilitator superfamily (MFS) transporter that mediates proton-coupled symport of Neu5Ac. A 3.4 Å cryo-EM structure captured an inward-facing partially open conformation and identified two conserved glutamates (E171 and E175) required for H+ coupling/sensing; alanine/glutamine substitutions at either site reduce transport by ~95%, and double substitution abolishes detectable transport, supporting a dual-Glu H+ coupling mechanism. A cytosolic constriction controlling conformational changes helps enforce gradient-driven transport. (Hu et al., Science Advances, published Jan 2023; URL: https://doi.org/10.1126/sciadv.ade8346) (hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4, hu2023themolecularmechanism pages 1-2)
Consequences for cellular physiology include swollen, numerous lysosomes with trapped free sialic acid and perturbed lysosomal homeostasis. Sialin can transport other acidic sugars (e.g., glucuronic/iduronic acids), implicating broader anion handling at the lysosomal membrane; however, Neu5Ac transport is the canonical defect in Salla disease. (Schwake & Saftig, 2022; URL: https://doi.org/10.1002/9781119697312.ch21) (schwake2022lysosomalmembranedefects pages 2-2)
Neuroglial involvement is prominent. Hypomyelination on MRI, corpus callosum hypoplasia, and progressive cerebellar atrophy indicate oligodendroglial and cerebellar vulnerability. Patient-derived iPSC neural cells (radial glia, cortical neurons, immature and mature astrocytes) display markedly elevated free sialic acid and cell-type-specific disturbances in GSL metabolism, with mature astrocytes showing the largest shifts and increased lysosomal glycohydrolase activities, consistent with widespread lysosomal lipid turnover changes. (Sabir et al., Scientific Reports, Aug 2025; URL: https://doi.org/10.1038/s41598-025-12682-4) (sabir2025lysosomalfreesialic pages 1-2, sabir2025lysosomalfreesialic pages 2-3, sabir2025lysosomalfreesialic pages 12-13)
2) Key Molecular Players - Gene/Protein: SLC17A5 (HGNC:11079), lysosomal sialic acid/H+ symporter (sialin). Critical residues for mechanism include E171 and E175 (H+ coupling/sensing) and R57 (substrate recognition; pathogenic variants at R57 impair function). (Hu 2023 Science Advances; URL: https://doi.org/10.1126/sciadv.ade8346) (hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4) - Chemical entities: N-acetylneuraminic acid (Neu5Ac) accumulates in lysosomes; broader alterations in glycosphingolipids (gangliosides) are evident in disease models. (sabir2025lysosomalfreesialic pages 1-2, sabir2025lysosomalfreesialic pages 2-3) - Cell types: Oligodendrocytes are implicated by hypomyelination; neurons and astrocytes in iPSC models show elevated free sialic acid and altered GSL metabolism, especially mature astrocytes. (sabir2025lysosomalfreesialic pages 13-14, sabir2025lysosomalfreesialic pages 2-3) - Anatomical locations: Brain—corpus callosum (hypoplasia) and cerebellum (atrophy) are commonly involved on MRI. (sabir2025lysosomalfreesialic pages 1-2)
3) Biological Processes (GO-relevant) - Proton-coupled symport involved in sialic acid transmembrane transport across the lysosomal membrane; dual-Glu (E171/E175) mechanism supports H+ coupling. (hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4) - Lysosomal transport/efflux of small anions (free sialic acid), with downstream lysosomal homeostasis disruption. (schwake2022lysosomalmembranedefects pages 2-2) - Myelination and maintenance of myelin sheaths are impacted, consistent with hypomyelination features. (sabir2025lysosomalfreesialic pages 13-14) - Glycosphingolipid metabolic process and lysosomal lipid catabolism are altered in patient-derived neural cells; glycohydrolase activities are elevated in mature astrocytes. (sabir2025lysosomalfreesialic pages 2-3, sabir2025lysosomalfreesialic pages 12-13)
4) Cellular Components - Sialin resides in the lysosomal membrane; the transporter’s central tunnel and cytosolic constriction mediate inward-facing conformational control of substrate translocation. Pathogenic mutations map to structural regions affecting helix packing, substrate pathway residues, and transporter–lipid interfaces. (hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4, schwake2022lysosomalmembranedefects pages 2-2)
5) Disease Progression - Initiation: Biallelic SLC17A5 pathogenic variants cause reduced/abolished sialic acid export from lysosomes, leading to intralysosomal accumulation of free Neu5Ac. (schwake2022lysosomalmembranedefects pages 2-2) - Cellular cascade: Lysosomal enlargement and dysfunction; secondary perturbations of GSL metabolism and lysosomal glycohydrolase activities, especially in astrocytes; neuronal/oligodendroglial dysfunction with impaired myelination. (sabir2025lysosomalfreesialic pages 2-3, sabir2025lysosomalfreesialic pages 13-14) - Systems-level manifestations: White-matter hypomyelination, corpus callosum hypoplasia, progressive cerebellar atrophy; clinical phenotypes from severe infantile to classic forms. (sabir2025lysosomalfreesialic pages 1-2)
6) Phenotypic Manifestations (selected; HP mapping) - Developmental delay (HP:0001263), spasticity (HP:0001257), athetosis (HP:0002305), seizures (HP:0001250), cognitive impairment (HP:0100543); neuroimaging: hypomyelination (HP:0006809), corpus callosum hypoplasia (HP:0002079), cerebellar atrophy (HP:0001272). These features are aligned with reported clinical spectra across FSASD/Salla disease. (sabir2025lysosomalfreesialic pages 1-2)
Recent Developments and Latest Research (2023–2024 priority) - 2023 mechanistic advance: First high-resolution human Sialin cryo-EM structure with functional assays defining a two-glutamate H+ coupling mechanism (E171, E175), substrate-recognition residue R57, and a cytosolic helix whose stabilization is required for function; mutagenesis quantified strong activity loss (~90–100%) upon disruption. Published Jan 2023, Science Advances; DOI/URL: https://doi.org/10.1126/sciadv.ade8346. (hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4, hu2023themolecularmechanism pages 1-2) - Cellular modeling: iPSC-derived neural cells from FSASD patients (2025) reveal robust increases of free sialic acid across cell types and prominent GSL alterations in mature astrocytes, with increased lysosomal glycohydrolase activities, pinpointing astrocyte involvement and selective vulnerability. Although 2025, these data extend 2023–2024 mechanistic insights into human cell models. URL: https://doi.org/10.1038/s41598-025-12682-4. (sabir2025lysosomalfreesialic pages 2-3, sabir2025lysosomalfreesialic pages 12-13)
Current Applications and Implementations - Structural insights from 2023 enable variant interpretation and mechanistic classification (e.g., residues in proton-coupling network vs. substrate path vs. helix-packing interfaces) that can support pathogenicity assessment for SLC17A5 variants of uncertain significance in clinical genetics workflows. (hu2023themolecularmechanism pages 3-4) - iPSC disease modeling demonstrates quantifiable biochemical endpoints (free sialic acid levels; GSL profiles; lysosomal enzyme activities) that can be used for preclinical screening and mechanistic studies in neural lineages relevant to FSASD. (sabir2025lysosomalfreesialic pages 2-3, sabir2025lysosomalfreesialic pages 12-13)
Expert Opinions and Analysis - Authoritative lysosomal membrane-defect perspective: While the core defect—lysosomal free sialic acid accumulation due to SLC17A5 mutations—is established, the precise links between impaired sialic acid efflux and neurodevelopmental/neurodegenerative outcomes have remained incompletely explained, motivating ongoing mechanistic and cellular modeling studies. (Schwake & Saftig, 2022; URL: https://doi.org/10.1002/9781119697312.ch21) (schwake2022lysosomalmembranedefects pages 2-2) - Structural biophysics experts propose a structure-based mechanism that revises prior single-Glu models to a dual-Glu H+ coupling paradigm, offering clear mechanistic explanations for many mapped pathogenic variants. (Hu 2023; URL: https://doi.org/10.1126/sciadv.ade8346) (hu2023themolecularmechanism pages 1-2, hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4)
Relevant Statistics and Quantitative Data - Transport mutagenesis in human Sialin: E171Q or E175Q reduce transport to ~5% of wild-type, and double mutation eliminates measurable transport; R57A retains ~10% activity; these quantify critical roles in H+ coupling and substrate recognition. (Jan 2023; URL: https://doi.org/10.1126/sciadv.ade8346) (hu2023themolecularmechanism pages 3-4) - iPSC-derived neural cells: Free sialic acid elevations vs. controls—iPSCs 242%, iRGCs 223%, cortical neurons 400%, immature astrocytes 540%, mature astrocytes 830%; neuronal gangliosides (e.g., GM1a) reduced in cortical neurons, with broad GSL shifts most pronounced in mature astrocytes; glycohydrolase activities elevated in mature astrocytes. (Aug 2025; URL: https://doi.org/10.1038/s41598-025-12682-4) (sabir2025lysosomalfreesialic pages 2-3)
Pathophysiology Description (for knowledge base) Salla disease is a lysosomal storage disease due to biallelic SLC17A5 variants impairing the lysosomal transporter sialin, which mediates proton-coupled export of free N-acetylneuraminic acid. A 2023 human cryo-EM structure demonstrates a dual-glutamate (E171/E175) H+ coupling apparatus and identifies substrate and structural residues explaining pathogenic variant classes. Impaired export traps free sialic acid, disturbs lysosomal function, and drives downstream alterations in glycosphingolipid metabolism and lysosomal enzyme activities. Neuroimaging and cell models implicate oligodendrocyte/myelination defects and astrocyte metabolic dysregulation, with clinical expression ranging from severe ISSD to classic Salla disease with hypomyelination, callosal hypoplasia, and cerebellar atrophy. (hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4, schwake2022lysosomalmembranedefects pages 2-2, sabir2025lysosomalfreesialic pages 1-2, sabir2025lysosomalfreesialic pages 2-3)
Gene/Protein Annotations with Ontology Terms - SLC17A5 (HGNC:11079); Function: lysosomal membrane sialic acid:H+ symporter; Processes: sialic acid transport; proton-coupled symport; Localization: lysosomal membrane; Key residues: E171, E175 (H+ coupling), R57 (substrate binding). (hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4)
Phenotype Associations (HP terms) - Developmental delay (HP:0001263); Spasticity (HP:0001257); Athetosis (HP:0002305); Seizures (HP:0001250); Cognitive impairment (HP:0100543); Hypomyelination (HP:0006809); Corpus callosum hypoplasia (HP:0002079); Cerebellar atrophy (HP:0001272). (sabir2025lysosomalfreesialic pages 1-2)
Cell Type Involvement (CL terms) - Oligodendrocyte (CL:0000128) – hypomyelination; Neuron (CL:0000540) – altered GSLs, elevated free sialic acid; Astrocyte (CL:0000127) – pronounced GSL metabolic shifts and increased glycohydrolase activities. (sabir2025lysosomalfreesialic pages 13-14, sabir2025lysosomalfreesialic pages 2-3)
Anatomical Locations (UBERON terms) - Brain (UBERON:0000955); Corpus callosum (UBERON:0002318); Cerebellum (UBERON:0002037). (sabir2025lysosomalfreesialic pages 1-2)
Chemical Entities (CHEBI terms) - N-acetylneuraminic acid (Neu5Ac; CHEBI:25563); Glycosphingolipids/gangliosides (CHEBI:18154). (sabir2025lysosomalfreesialic pages 1-2, sabir2025lysosomalfreesialic pages 2-3)
Biological Processes and Cellular Components (GO) - Proton-coupled symport (GO:0015293); Sialic acid transmembrane transport (term name); Transport/lysosomal efflux (GO:0006810, term family); Myelination (GO:0042552); Glycosphingolipid metabolic process (GO:0006687). Localization: Lysosomal membrane (GO:0005765). (hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4, schwake2022lysosomalmembranedefects pages 2-2, sabir2025lysosomalfreesialic pages 2-3)
Evidence Items with PMIDs/DOIs and URLs - Hu et al. 2023. The molecular mechanism of sialic acid transport mediated by Sialin. Science Advances. DOI: 10.1126/sciadv.ade8346; URL: https://doi.org/10.1126/sciadv.ade8346. Publication date: Jan 2023. (hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4, hu2023themolecularmechanism pages 1-2) - Schwake & Saftig 2022. Lysosomal Membrane Defects. In: Lysosomal Storage Disorders. DOI: 10.1002/9781119697312.ch21; URL: https://doi.org/10.1002/9781119697312.ch21. Publication date: Jul 2022. (schwake2022lysosomalmembranedefects pages 2-2) - Ferreira & Gahl 2017. Lysosomal storage diseases. Translational Science of Rare Diseases. DOI: 10.3233/TRD-160005; URL: https://doi.org/10.3233/trd-160005. Publication date: Sep 2017. (schwake2022lysosomalmembranedefects pages 2-2) - Sabir et al. 2025. Lysosomal free sialic acid storage disorder iPSC-derived neural cells display altered glycosphingolipid metabolism. Scientific Reports. DOI: 10.1038/s41598-025-12682-4; URL: https://doi.org/10.1038/s41598-025-12682-4. Publication date: Aug 2025. (sabir2025lysosomalfreesialic pages 1-2, sabir2025lysosomalfreesialic pages 12-13, sabir2025lysosomalfreesialic pages 2-3)
Ontology-Mapped Annotations Table | Category | Entity (name) | Ontology ID | Role/Note | Evidence (Context ID) | |---|---|---|---|---| | Disease | Salla disease | MONDO:0011449 | Classic (milder) form of free sialic acid storage disease | | | Disease | Free sialic acid storage disease | MONDO:0019366 | Umbrella term for Salla disease / ISSD | | | Disease | Infantile free sialic acid storage disease (ISSD) | MONDO:0010027 | Severe infantile form with early neurodegeneration | | | Gene/Protein | SLC17A5 (Sialin) | HGNC:11079 | Lysosomal sialic acid exporter; H+‑coupled symporter | (hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4) | | Residue | E171 | - | Conserved glutamate required for H+ coupling | (hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4) | | Residue | E175 | - | Conserved glutamate required for H+ coupling | (hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4) | | Residue | R57 | - | Substrate recognition site; pathogenic variants impair function | (hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4) | | Cell type | Oligodendrocyte | CL:0000128 | Implicated in hypomyelination and myelin defects | (sabir2025lysosomalfreesialic pages 13-14) | | Cell type | Neuron | CL:0000540 | Neuronal phenotypes from lysosomal sialic acid accumulation | (sabir2025lysosomalfreesialic pages 2-3) | | Cell type | Astrocyte | CL:0000127 | iPSC data show marked altered GSL metabolism (especially mature astrocytes) | (sabir2025lysosomalfreesialic pages 2-3) | | Anatomical location | Brain | UBERON:0000955 | Primary organ affected; hypomyelination and atrophy reported | (sabir2025lysosomalfreesialic pages 1-2) | | Anatomical location | Corpus callosum | UBERON:0002318 | Hypoplasia commonly observed on MRI | (sabir2025lysosomalfreesialic pages 1-2) | | Anatomical location | Cerebellum | UBERON:0002037 | Progressive cerebellar atrophy reported | (sabir2025lysosomalfreesialic pages 1-2) | | Chemical entity | N-acetylneuraminic acid (Neu5Ac) | CHEBI:25563 | Accumulated free sialic acid within lysosomes | (sabir2025lysosomalfreesialic pages 1-2) | | Chemical entity | Glycosphingolipids (gangliosides) | CHEBI:18154 | Altered composition and metabolism in patient cells/models | (sabir2025lysosomalfreesialic pages 2-3) | | Biological process | Transport (lysosomal efflux) | GO:0006810 | Lysosomal export of free sialic acid mediated by sialin | (hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4) | | Biological process | Proton-coupled symport (H+ cotransport) | GO:0015293 | H+ coupling via E171/E175 required for Neu5Ac translocation | (hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4) | | Biological process | Sialic acid transport (specific) | - | Specific translocation of Neu5Ac across lysosomal membrane | (hu2023themolecularmechanism pages 2-3, hu2023themolecularmechanism pages 3-4) | | Biological process | Myelination | GO:0042552 | Disrupted myelination underlying hypomyelination phenotype | (sabir2025lysosomalfreesialic pages 13-14) | | Biological process | Glycosphingolipid metabolic process | GO:0006687 | Altered GSL metabolism observed in iPSC-derived neural cells | (sabir2025lysosomalfreesialic pages 2-3) | | Cellular component | Lysosome (membrane) | GO:0005765 | Localization of sialin on lysosomal membrane | (schwake2022lysosomalmembranedefects pages 2-2) |
Table: Table mapping key diseases, genes, residues, cell types, anatomical sites, chemicals, biological processes, and cellular components relevant to Salla disease to common ontologies, with primary supporting context citations for mechanistic and cellular evidence.
References
(hu2023themolecularmechanism pages 2-3): Wenxin Hu, Congwu Chi, Kunhua Song, and Hongjin Zheng. The molecular mechanism of sialic acid transport mediated by sialin. Science Advances, Jan 2023. URL: https://doi.org/10.1126/sciadv.ade8346, doi:10.1126/sciadv.ade8346. This article has 25 citations and is from a highest quality peer-reviewed journal.
(hu2023themolecularmechanism pages 3-4): Wenxin Hu, Congwu Chi, Kunhua Song, and Hongjin Zheng. The molecular mechanism of sialic acid transport mediated by sialin. Science Advances, Jan 2023. URL: https://doi.org/10.1126/sciadv.ade8346, doi:10.1126/sciadv.ade8346. This article has 25 citations and is from a highest quality peer-reviewed journal.
(schwake2022lysosomalmembranedefects pages 2-2): Michael Schwake and Paul Saftig. Lysosomal membrane defects. Lysosomal Storage Disorders, pages 232-240, Jul 2022. URL: https://doi.org/10.1002/9781119697312.ch21, doi:10.1002/9781119697312.ch21. This article has 2 citations.
(hu2023themolecularmechanism pages 1-2): Wenxin Hu, Congwu Chi, Kunhua Song, and Hongjin Zheng. The molecular mechanism of sialic acid transport mediated by sialin. Science Advances, Jan 2023. URL: https://doi.org/10.1126/sciadv.ade8346, doi:10.1126/sciadv.ade8346. This article has 25 citations and is from a highest quality peer-reviewed journal.
(sabir2025lysosomalfreesialic pages 2-3): M. Sabir, V. Jovanovic, Seungmi Ryu, Chaitali Sen, Pinar Ormanoglu, Laura Pollard, Richard Steet, William A. Gahl, M. Huizing, Carlos A. Tristan, Frances M. Platt, and M. Malicdan. Lysosomal free sialic acid storage disorder ipsc-derived neural cells display altered glycosphingolipid metabolism. Scientific Reports, Aug 2025. URL: https://doi.org/10.1038/s41598-025-12682-4, doi:10.1038/s41598-025-12682-4. This article has 2 citations and is from a peer-reviewed journal.
(sabir2025lysosomalfreesialic pages 1-2): M. Sabir, V. Jovanovic, Seungmi Ryu, Chaitali Sen, Pinar Ormanoglu, Laura Pollard, Richard Steet, William A. Gahl, M. Huizing, Carlos A. Tristan, Frances M. Platt, and M. Malicdan. Lysosomal free sialic acid storage disorder ipsc-derived neural cells display altered glycosphingolipid metabolism. Scientific Reports, Aug 2025. URL: https://doi.org/10.1038/s41598-025-12682-4, doi:10.1038/s41598-025-12682-4. This article has 2 citations and is from a peer-reviewed journal.
(sabir2025lysosomalfreesialic pages 12-13): M. Sabir, V. Jovanovic, Seungmi Ryu, Chaitali Sen, Pinar Ormanoglu, Laura Pollard, Richard Steet, William A. Gahl, M. Huizing, Carlos A. Tristan, Frances M. Platt, and M. Malicdan. Lysosomal free sialic acid storage disorder ipsc-derived neural cells display altered glycosphingolipid metabolism. Scientific Reports, Aug 2025. URL: https://doi.org/10.1038/s41598-025-12682-4, doi:10.1038/s41598-025-12682-4. This article has 2 citations and is from a peer-reviewed journal.
(sabir2025lysosomalfreesialic pages 13-14): M. Sabir, V. Jovanovic, Seungmi Ryu, Chaitali Sen, Pinar Ormanoglu, Laura Pollard, Richard Steet, William A. Gahl, M. Huizing, Carlos A. Tristan, Frances M. Platt, and M. Malicdan. Lysosomal free sialic acid storage disorder ipsc-derived neural cells display altered glycosphingolipid metabolism. Scientific Reports, Aug 2025. URL: https://doi.org/10.1038/s41598-025-12682-4, doi:10.1038/s41598-025-12682-4. This article has 2 citations and is from a peer-reviewed journal.
name: Salla Disease
creation_date: '2026-02-05T21:04:11Z'
updated_date: '2026-02-16T20:19:38Z'
category: Mendelian
synonyms:
- Salla's Disease
- Free Sialic Acid Storage Disease, Classic Form
disease_term:
preferred_term: Salla disease
term:
id: MONDO:0011449
label: Salla disease
parents:
- Free Sialic Acid Storage Disease
- Lysosomal Storage Disease
has_subtypes:
- name: Intermediate-Severe Salla Disease
description: Intermediate severity variant with onset in infancy, developmental plateau in childhood, followed by progressive neurological regression in adolescence. More severe than classic Salla disease with progressive neurological regression in adolescence. Typically carries different SLC17A5 variants (e.g., splice site mutations). Lifespan extends into adolescence/adulthood but with continued neurological decline.
evidence:
- reference: PMID:37713976
reference_title: "Longitudinal Characterization of the Clinical Course of Intermediate-Severe Salla Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Disease onset occurred within the first six months of life in both patients. Early childhood development was delayed with achievement of some milestones followed by a developmental plateau in late childhood. After this, both patients began a slow and progressive neurological regression in adolescence."
explanation: Longitudinal study characterizes clinical course of intermediate-severe Salla disease as distinct from classic form with progressive regression.
- reference: PMID:28662915
reference_title: "A New Patient With Intermediate Severe Salla Disease With Hypomyelination: A Literature Review for Salla Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Likely pathogenic variants in SLC17A5 results in allelic disorders of free sialic acid metabolism including (1) infantile free sialic acid storage disease with severe global developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; (2) intermediate severe Salla disease with moderate to severe global developmental delay, hypotonia, and hypomyelination with or without coarse facial features, and (3) Salla disease with normal appearance, mild cognitive dysfunction, and spasticity."
explanation: Comprehensive literature review and case report of intermediate-severe Salla disease identifies hypomyelination, developmental delay, and hypotonia as characteristic features, with compound heterozygous SLC17A5 variants. Demonstrates that normal or marginally elevated urine sialic acid cannot exclude this phenotype.
prevalence:
- population: Global
percentage: Rare
notes: >
Worldwide prevalence estimated at less than 1 per 1,000,000 individuals.
Approximately 200-260 cases of FSASD (including all clinical forms) reported worldwide.
Salla disease (classic mild form) reported in approximately 150 individuals,
predominantly of Finnish and Swedish descent. Likely underdiagnosed given rarity and non-specific clinical presentation.
Diagnostic delay is a significant clinical challenge: median age at disease onset is 0.17 years (approximately 2 months), but median age at diagnosis is 3 years, resulting in a median diagnostic delay of 2.5 years. Median survival across all FSASD phenotypes is 11 years, though this varies substantially based on biochemical severity and clinical phenotype. Patient distribution is panethnic.
evidence:
- reference: PMID:33862140
reference_title: "Free sialic acid storage disorder: Progress and promise."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "Around 200 FSASD cases are reported worldwide, with the clinical spectrum ranging from a severe infantile onset form, often lethal in early childhood, to a mild, less severe form with subjects living into adulthood, also called Salla disease."
explanation: Comprehensive NIH-led consortium review of FSASD epidemiology documents global case numbers and the clinical spectrum with Salla disease as the milder end of the spectrum.
- reference: PMID:29875421
reference_title: "A cross-sectional quantitative analysis of the natural history of free sialic acid storage disease-an ultra-orphan multisystemic lysosomal storage disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Median age at disease onset was 0.17 years. Median age at diagnosis was 3 years with a median diagnostic delay of 2.5 years. Median survival was 11 years."
explanation: Large cross-sectional quantitative analysis of 116 published FSASD cases documents the natural history including significant diagnostic delay from infancy to early childhood, and median survival of 11 years across the clinical spectrum.
- population: Finland and Scandinavia
percentage: 1-9 per million (Salla region)
notes: >
Significantly higher prevalence in Finland and Scandinavia due to founder effect.
In Salla region of Finland specifically, estimated prevalence is 1-9 per 1,000,000.
Carrier frequency of the common p.Arg39Cys (R39C) SLC17A5 founder variant is approximately 1 per 100 individuals in the Salla region,
accounting for the geographic clustering of cases. The majority of reported FSASD cases are of Finnish or Swedish ancestry,
reflecting the high founder mutation carrier frequency in these populations.
evidence:
- reference: PMID:33862140
reference_title: "Free sialic acid storage disorder: Progress and promise."
supports: NO_EVIDENCE
evidence_source: HUMAN_CLINICAL
snippet: "Around 200 FSASD cases are reported worldwide, with the clinical spectrum ranging from a severe infantile onset form, often lethal in early childhood, to a mild, less severe form with subjects living into adulthood, also called Salla disease. The pathobiology of FSASD remains poorly understood and FSASD is likely underdiagnosed."
explanation: Comprehensive FSASD epidemiology review showing that the majority of reported cases are of Finnish or Swedish ancestry, demonstrating the founder effect and geographic clustering of Salla disease in Scandinavian populations.
inheritance:
- name: Autosomal Recessive
description: Salla disease is inherited in an autosomal recessive manner, requiring biallelic pathogenic variants in SLC17A5. The c.115C>T (p.Arg39Cys) Finnish founder mutation is the most common variant.
evidence:
- reference: PMID:37727271
reference_title: "Base editing corrects the common Salla disease SLC17A5 c.115C>T variant."
supports: PARTIAL
evidence_source: IN_VITRO
snippet: "Free sialic acid storage disorders (FSASDs) result from pathogenic variations in the SLC17A5 gene, which encodes the lysosomal transmembrane protein sialin."
explanation: Study of patient-derived fibroblasts and mouse models demonstrates biallelic SLC17A5 mutations and identifies founder variants.
pathophysiology:
- name: SLC17A5 Gene Mutation
description: Biallelic pathogenic variants in SLC17A5 disrupt the coding or regulatory regions necessary for sialin protein function. The c.115C>T (p.Arg39Cys) Finnish founder mutation is the most common variant in Salla disease.
gene:
preferred_term: SLC17A5
term:
id: hgnc:10933
label: SLC17A5
evidence:
- reference: PMID:37727271
reference_title: "Base editing corrects the common Salla disease SLC17A5 c.115C>T variant."
supports: PARTIAL
evidence_source: IN_VITRO
snippet: "Here, we evaluated the efficacy of CRISPR-Cas9-mediated homology directed repair (HDR) and adenine base editing (ABE) targeting the founder variant, SLC17A5 c.115C>T (p.Arg39Cys)"
explanation: Study of patient-derived cells confirms c.115C>T as founder variant and demonstrates pathogenicity through CRISPR approaches.
- name: Loss of Sialin Protein Function
description: SLC17A5 mutations result in loss or substantial reduction of sialin protein expression or function. Sialin is a 12-transmembrane transporter required for proton-coupled export of free sialic acid (Neu5Ac) from lysosomes to cytosol. Mutations can occur as de novo, inherited biallelic variants, or in mosaic patterns affecting specific tissues.
biological_processes:
- preferred_term: Sialic acid transport
term:
id: GO:0015739
label: sialic acid transport
modifier: DECREASED
evidence:
- reference: DOI:10.1126/sciadv.ade8346
supports: PARTIAL
evidence_source: IN_VITRO
snippet: "Our analysis reveals two unique features in Sialin: (i) The H+ coupling/sensing requires two highly conserved Glu residues (E171 and E175) instead of one"
explanation: 2023 Science Advances cryo-EM structure and functional assays demonstrate molecular mechanism of sialin transport and mutation effects.
- reference: PMID:39742826
reference_title: "Atypical free sialic acid storage disorder associated with tissue specific mosaicism of SLC17A5."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Functional studies, including SLC17A5 knockout cells and transient transfections of mutated SLC17A5 demonstrated pathogenicity of the identified variants."
explanation: 2025 study demonstrates pathogenicity of SLC17A5 variants including tissue-specific mosaic mutations causing atypical FSASD presentations.
- name: Lysosomal Free Sialic Acid Accumulation
description: Loss of sialin function impairs export of free N-acetylneuraminic acid (Neu5Ac) from lysosomes. Neu5Ac accumulates in lysosomes, leading to lysosomal enlargement, dysfunction, and cellular stress. This is the hallmark biochemical feature of FSASD including Salla disease. Cellular imaging shows prominent cytoplasmic vacuolation in fibroblasts from affected individuals.
evidence:
- reference: PMID:40529477
reference_title: "Investigating the Utility of Leukocyte Sialic Acid Measurements in Lysosomal Free Sialic Acid Storage Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "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)."
explanation: Diagnostic study demonstrates profound accumulation of free sialic acid in FSASD patients, confirming primary biochemical defect.
- reference: PMID:39257666
reference_title: "Soft X-ray spectromicroscopy of human fibroblasts with impaired sialin function."
supports: PARTIAL
evidence_source: IN_VITRO
snippet: "Both cell lines were also cultured with N-acetyl-d-mannosamine monohydrate (ManNAc) to see if it increased SA concentration in the cells. The STXM technique was chosen to simultaneously observe the morphological and chemical changes in cells. It was observed that free SA did not remain in the lysosomes during the sample processing, leaving empty vacuoles to the fibroblasts."
explanation: 2024 soft X-ray spectromicroscopy study demonstrates cellular vacuolation and lysosomal dysfunction in Salla disease fibroblasts.
- name: Glycosphingolipid Metabolic Dysregulation
description: Impaired sialic acid export triggers secondary alterations in glycosphingolipid (GSL) metabolism in neural cells. Elevated lysosomal glycohydrolase activities and altered GSL composition observed in patient-derived iPSC neural models and in CSF and plasma of patients. Mature astrocytes show the most pronounced alterations.
cell_types:
- preferred_term: Oligodendrocyte
term:
id: CL:0000128
label: oligodendrocyte
- preferred_term: Neuron
term:
id: CL:0000540
label: neuron
- preferred_term: Astrocyte
term:
id: CL:0000127
label: astrocyte
biological_processes:
- preferred_term: Glycosphingolipid metabolic process
term:
id: GO:0006687
label: glycosphingolipid metabolic process
- preferred_term: Myelination
term:
id: GO:0042552
label: myelination
evidence:
- reference: PMID:39991440
reference_title: "Changes in glycosphingolipid levels in plasma and cerebrospinal fluid of individuals with Lysosomal Free Sialic Acid Storage Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In CSF, total GSLs, GM1a, GM3, GD3, GD1a, and GD1b were significantly elevated compared to comparison samples. These results reveal dysregulated GSL metabolism and suggest the potential of gangliosides as biomarkers."
explanation: Study of CSF and plasma in FSASD patients demonstrates dysregulated GSL metabolism with elevated gangliosides, supporting alterations in pathogenesis.
- name: Oligodendroglial Dysfunction and Hypomyelination
description: Oligodendrocytes vulnerable to sialic acid accumulation and GSL dysregulation. This leads to impaired myelin formation and white matter hypomyelination, reflected in corpus callosum hypoplasia and white matter abnormalities on MRI.
cell_types:
- preferred_term: Oligodendrocyte
term:
id: CL:0000128
label: oligodendrocyte
biological_processes:
- preferred_term: Myelination
term:
id: GO:0042552
label: myelination
- preferred_term: CNS myelination
term:
id: GO:0022010
label: central nervous system myelination
evidence:
- reference: DOI:10.1038/s41598-025-12682-4
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Oligodendroglia in FSASD pathogenesis is established, the roles of other neural cell types remain elusive."
explanation: iPSC disease modeling confirms oligodendroglial involvement and differential cell-type vulnerability in FSASD.
- name: Neuronal Dysfunction and Neurodegeneration
description: Neurons accumulate free sialic acid and display altered GSL composition. Biochemical changes contribute to progressive neurodegeneration, manifesting as developmental delay, cognitive impairment, and progressive neurological regression.
cell_types:
- preferred_term: Neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: Glycosphingolipid metabolic process
term:
id: GO:0006687
label: glycosphingolipid metabolic process
evidence:
- reference: PMID:37713976
reference_title: "Longitudinal Characterization of the Clinical Course of Intermediate-Severe Salla Disease."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "Disease onset occurred within the first six months of life in both patients. Early childhood development was delayed with achievement of some milestones followed by a developmental plateau in late childhood. After this, both patients began a slow and progressive neurological regression in adolescence."
explanation: Longitudinal study documents progressive neurodegeneration from infancy through adolescence in intermediate-severe Salla disease.
phenotypes:
- name: Intellectual Disability
description: Progressive cognitive impairment ranging from mild to severe, with variable onset and progression depending on disease severity.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:37713976
reference_title: "Longitudinal Characterization of the Clinical Course of Intermediate-Severe Salla Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Early childhood development was delayed with achievement of some milestones followed by a developmental plateau in late childhood."
explanation: Case series demonstrates cognitive/developmental impairment as core feature of Salla disease progression.
- name: Developmental Delay
description: Delayed motor and cognitive milestones in infancy and early childhood, typically becoming apparent within the first year of life.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:37713976
reference_title: "Longitudinal Characterization of the Clinical Course of Intermediate-Severe Salla Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Disease onset occurred within the first six months of life in both patients. Early childhood development was delayed"
explanation: Longitudinal study confirms disease onset in early infancy with delayed developmental milestones.
- name: Prenatal Hydrops Fetalis
description: Excessive accumulation of serous fluid in the fetus (nonimmune hydrops fetalis), which can be a presenting feature of infantile-onset FSASD. Detectable on prenatal ultrasound at 24 weeks gestation or earlier.
phenotype_term:
preferred_term: Nonimmune hydrops fetalis
term:
id: HP:0001790
label: Nonimmune hydrops fetalis
evidence:
- reference: PMID:34667062
reference_title: "Prenatal hydrops fetalis associated with infantile free sialic acid storage disease due to a novel homozygous deletion in the SLC17A5 gene."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "Nonimmune hydrops fetalis, the excessive accumulation of serous fluid in the subcutaneous tissues and serous cavities of the fetus, has many possible etiologies, providing a diagnostic challenge for the physician. Lysosomal storage diseases have been reported in up to 5%-16% of nonimmune hydrops fetalis pregnancies. Infantile free sialic acid storage disease (ISSD) (OMIM #269920) is a severe form of autosomal recessive sialic acid storage disease."
explanation: Case report demonstrates prenatal hydrops as a presenting feature of infantile-onset FSASD, with fetal hydrops detected at 24 weeks gestation.
- name: Hypotonia
description: Reduced muscle tone (hypotonia) typically beginning during the first year of life, followed by slowly progressive neurological problems. Early hypotonia is often the first neurological manifestation of Salla disease.
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
evidence:
- reference: PMID:37713976
reference_title: "Longitudinal Characterization of the Clinical Course of Intermediate-Severe Salla Disease."
supports: NO_EVIDENCE
evidence_source: HUMAN_CLINICAL
snippet: "Disease onset occurred within the first six months of life"
explanation: Case series indicates early infancy as period of disease onset with motor involvement.
- name: Ataxia
description: Lack of muscle coordination affecting voluntary movements, contributing to motor dysfunction.
phenotype_term:
preferred_term: Ataxia
term:
id: HP:0001251
label: Ataxia
evidence:
- reference: DOI:10.1038/s41598-025-12682-4
supports: NO_EVIDENCE
snippet: "Lysosomal free sialic acid storage disorder (FSASD) is a rare neurodegenerative disease"
explanation: Ataxia is a characteristic neurological manifestation of FSASD.
- name: Nystagmus
description: Involuntary eye movements.
phenotype_term:
preferred_term: Nystagmus
term:
id: HP:0000639
label: Nystagmus
evidence:
- reference: DOI:10.1038/s41598-025-12682-4
supports: NO_EVIDENCE
snippet: "Lysosomal free sialic acid storage disorder (FSASD) is a rare neurodegenerative disease"
explanation: Nystagmus is a reported neurological sign in FSASD.
- name: Spasticity
description: Increased muscle tone and stiffness in limbs.
phenotype_term:
preferred_term: Spasticity
term:
id: HP:0001257
label: Spasticity
evidence:
- reference: DOI:10.1038/s41598-025-12682-4
supports: NO_EVIDENCE
snippet: "Lysosomal free sialic acid storage disorder (FSASD) is a rare neurodegenerative disease"
explanation: Muscle spasticity is a manifestation of Salla disease neurological involvement.
- name: Corpus Callosum Hypoplasia
description: Marked thinning of the corpus callosum visible on brain MRI, indicating impaired myelination and white matter development.
phenotype_term:
preferred_term: Hypoplasia of the corpus callosum
term:
id: HP:0002079
label: Hypoplasia of the corpus callosum
evidence:
- reference: DOI:10.1038/s41598-025-12682-4
supports: NO_EVIDENCE
snippet: "Lysosomal free sialic acid storage disorder (FSASD) is a rare neurodegenerative disease"
explanation: Corpus callosum hypoplasia is a characteristic neuroimaging finding in FSASD.
- name: White Matter Hypomyelination
description: Decreased myelin formation in cerebral white matter, reflecting oligodendroglial dysfunction and impaired CNS myelination.
phenotype_term:
preferred_term: Cerebral hypomyelination
term:
id: HP:0006808
label: Cerebral hypomyelination
evidence:
- reference: DOI:10.1038/s41598-025-12682-4
supports: NO_EVIDENCE
snippet: "Lysosomal free sialic acid storage disorder (FSASD) is a rare neurodegenerative disease"
explanation: White matter hypomyelination is a characteristic neuroimaging feature in FSASD.
- name: Cerebellar Atrophy
description: Progressive atrophy of the cerebellum visible on MRI, contributing to ataxia and motor coordination deficits.
phenotype_term:
preferred_term: Cerebellar atrophy
term:
id: HP:0001272
label: Cerebellar atrophy
evidence:
- reference: DOI:10.1038/s41598-025-12682-4
supports: NO_EVIDENCE
snippet: "Lysosomal free sialic acid storage disorder (FSASD) is a rare neurodegenerative disease"
explanation: Progressive cerebellar atrophy is observed in FSASD patients on MRI.
- name: Psychotic Disorder
description: Psychotic symptoms including hallucinations and delusions, reported in adolescent and adult Salla disease patients. A previously underrecognized neuropsychiatric manifestation of the disease.
phenotype_term:
preferred_term: Psychosis
term:
id: HP:0000709
label: Psychosis
evidence:
- reference: PMID:35796883
reference_title: "Psychiatric symptoms in Salla disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Psychiatric symptoms were frequently associated with SD (10/24, 42%), and two patients were described as developing psychosis as adolescents."
explanation: Systematic review of 24 Salla disease patients identified psychosis as a previously unreported psychiatric manifestation, occurring in 2 of the 24 patients during adolescence.
- name: Sleep Disturbance
description: Sleep disorders including insomnia and other sleep abnormalities, frequently encountered in Salla disease patients.
phenotype_term:
preferred_term: Sleep disturbance
term:
id: HP:0002360
label: Sleep disturbance
evidence:
- reference: PMID:35796883
reference_title: "Psychiatric symptoms in Salla disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Other psychiatric factors associated with SD were sleeping disorders (8/24, 32%)"
explanation: Systematic cohort analysis of 24 Salla disease patients found sleep disorders in 32% of the population, making it a common neuropsychiatric comorbidity.
- name: Aggressive Behavior
description: Behavioral disturbances including aggression, restlessness, and related behavioral disorders occurring in Salla disease patients.
phenotype_term:
preferred_term: Aggressive behavior
term:
id: HP:0000718
label: Aggressive behavior
evidence:
- reference: PMID:35796883
reference_title: "Psychiatric symptoms in Salla disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "aggressive behaviour disorders or restlessness (6/24, 25%)"
explanation: Cohort study of 24 Salla disease patients identified aggressive behavior and restlessness in 25% of individuals, demonstrating frequent behavioral manifestations.
genetic:
- name: SLC17A5
gene_term:
preferred_term: SLC17A5
term:
id: hgnc:10933
label: SLC17A5
association: Causative
evidence:
- reference: PMID:37727271
reference_title: "Base editing corrects the common Salla disease SLC17A5 c.115C>T variant."
supports: PARTIAL
evidence_source: IN_VITRO
snippet: "Free sialic acid storage disorders (FSASDs) result from pathogenic variations in the SLC17A5 gene, which encodes the lysosomal transmembrane protein sialin."
explanation: Studies of patient-derived cells demonstrate SLC17A5 biallelic mutations as causative for FSASD including Salla disease.
- reference: PMID:34667062
reference_title: "Prenatal hydrops fetalis associated with infantile free sialic acid storage disease due to a novel homozygous deletion in the SLC17A5 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SLC17A5 gene sequencing was initiated with no sequence variants identified; however, the assay failed to amplify exons 8 and 9, prompting an exon-level copy-number analysis that revealed a novel homozygous deletion of exons 8 and 9, inherited from heterozygous carrier parents."
explanation: Case report documents a novel homozygous deletion of SLC17A5 exons 8-9 causing infantile-onset FSASD with prenatal hydrops, demonstrating the spectrum of SLC17A5 pathogenic variants extends beyond point mutations to exonic deletions.
biochemical:
- name: Free Sialic Acid
presence: Elevated
biomarker_term:
preferred_term: N-acetylneuraminic acid
term:
id: CHEBI:17012
label: N-acetylneuraminic acid
evidence:
- reference: PMID:40529477
reference_title: "Investigating the Utility of Leukocyte Sialic Acid Measurements in Lysosomal Free Sialic Acid Storage Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Individuals with FSASD exhibited significantly higher levels of free Neu5Ac compared to their unaffected biological parents (36-fold)"
explanation: Free sialic acid accumulation is the pathognomonic biochemical feature and a diagnostic biomarker in FSASD.
- reference: PMID:24993898
reference_title: "The early detection of Salla disease through second-tier tests in newborn screening: how to face incidental findings."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We describe here a 34 months child, practically asymptomatic which presented with high levels of free sialic acid in urine by biochemical detection in second-tier tests newborn screening"
explanation: Newborn screening case report demonstrates early detection of elevated urinary free sialic acid as a diagnostic marker, enabling early identification of asymptomatic FSASD before clinical manifestations.
- reference: PMID:29875421
reference_title: "A cross-sectional quantitative analysis of the natural history of free sialic acid storage disease-an ultra-orphan multisystemic lysosomal storage disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The biochemical phenotype clearly predicted the disease course: patients with a urinary free sialic acid excretion below 6.37-fold or an intracellular free sialic acid storage in fibroblasts below 7.37-fold of the mean of normal survived longer than patients with biochemical values above these thresholds."
explanation: Large cross-sectional study of 116 FSASD cases demonstrates that biochemical biomarker levels (urinary and intracellular free sialic acid) are strong predictors of disease progression and survival, with thresholds of 6.37-fold (urine) and 7.37-fold (fibroblasts) distinguishing slower and faster disease courses.
clinical_trials:
- name: NCT03047369
status: RECRUITING
description: >
The Myelin Disorders Biorepository Project (MDBP) and Global Leukodystrophy
Initiative Clinical Trials Network is an international research initiative that
collects and analyzes clinical data and biological samples from leukodystrophy
patients worldwide. The MDBP is one of the world's largest leukodystrophy
biorepositories, having enrolled nearly 2,000 affected individuals. Researchers
use these materials to uncover new genetic etiologies, develop biomarkers for
future clinical trials, and better understand disease natural history.
evidence:
- reference: clinicaltrials:NCT03047369
supports: PARTIAL
snippet: "The Myelin Disorders Biorepository Project (MDBP) seeks to collect and analyze clinical data and biological samples from leukodystrophy patients worldwide to support ongoing and future research projects."
explanation: MDBP is an active biorepository network that includes Salla disease as a condition of interest for myelin disorder research.
treatments:
- name: Supportive Care
description: Management of symptoms and prevention of complications through multidisciplinary approach including physical therapy, occupational therapy, speech therapy, and educational support. Treatment is primarily symptomatic as no causal therapies are currently available.
evidence:
- reference: PMID:37727271
reference_title: "Base editing corrects the common Salla disease SLC17A5 c.115C>T variant."
supports: PARTIAL
evidence_source: IN_VITRO
snippet: "There are currently no therapies for FSASDs."
explanation: Standard treatment remains supportive pending development of specific disease-modifying therapies.
- name: Base Editing Gene Therapy (Investigational)
description: Emerging therapeutic approach using CRISPR-mediated adenine base editing to correct the common SLC17A5 c.115C>T (p.Arg39Cys) founder variant. In vitro and animal models show significant reduction in free sialic acid levels.
evidence:
- reference: PMID:37727271
reference_title: "Base editing corrects the common Salla disease SLC17A5 c.115C>T variant."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "ABE treatment of either homozygous or compound heterozygous SLC17A5 c.115C>T human dermal fibroblasts demonstrated significant FSA reduction, supporting amelioration of disease pathology."
explanation: Base editing approach successfully corrects the founder variant and reduces sialic acid accumulation in patient-derived cells and animal models.
differential_diagnoses:
- name: Infantile Free Sialic Acid Storage Disorder
disease_term:
preferred_term: Infantile free sialic acid storage disease
term:
id: MONDO:0010027
label: free sialic acid storage disease, infantile form
description: Most severe form of FSASD with earlier onset (typically first weeks to months of life), rapid neurodegeneration, and shortened lifespan. Presents with severe hypotonia and profound developmental impairment, often fatal by early childhood.
notes: Infantile FSASD presents earlier than classic Salla disease (typically first weeks vs first year) with more severe phenotype and faster disease progression. Caused by biallelic SLC17A5 mutations but typically with more deleterious variants. Related to Salla disease within the free sialic acid storage disease spectrum but represents the severe end of the clinical continuum.
evidence:
- reference: PMID:37713976
reference_title: "Longitudinal Characterization of the Clinical Course of Intermediate-Severe Salla Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Biallelic pathogenic variants in SLC17A5 cause three forms of free sialic acid storage disease categorized based on severity from least to most severe: Salla disease, intermediate-severe Salla disease, and infantile free sialic acid storage disease."
explanation: Clinical spectrum of FSASD demonstrates infantile form as most severe.
- name: Niemann-Pick Disease Type C
disease_term:
preferred_term: Niemann-Pick disease type C
term:
id: MONDO:0009757
label: Niemann-Pick disease, type C1
description: Lysosomal storage disorder with overlapping neurological manifestations including developmental delay, hypotonia, ataxia, and white matter abnormalities on MRI.
notes: Can mimic Salla disease clinically but caused by mutations in NPC1/NPC2 genes (not SLC17A5). Characterized by cholesterol accumulation in lysosomes rather than sialic acid. Biochemical testing shows elevated cholesterol instead of elevated free sialic acid. Different enzyme panel on lysosomal storage disease screening.
evidence:
- reference: PMID:40529477
reference_title: "Investigating the Utility of Leukocyte Sialic Acid Measurements in Lysosomal Free Sialic Acid Storage Disorder."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "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)"
explanation: Diagnostic study demonstrates distinct biochemical profile in FSASD vs other lysosomal storage disorders including NPC.
datasets:
- accession: PMID:40804080
title: Lysosomal free sialic acid storage disorder iPSC-derived neural cells display altered glycosphingolipid metabolism
description: >
Transcriptomic analysis of iPSC-derived neural cell types (radial glial cells, astrocytes, neurons)
from FSASD patients and healthy controls. Identifies dysregulated glycosphingolipid metabolism genes,
elevated lysosomal glycohydrolase activities, and differential expression patterns in mature astrocytes.
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: BULK_RNA_SEQ
sample_types:
- preferred_term: Neuron
cell_type_term:
preferred_term: neuron
term:
id: CL:0000540
label: neuron
- preferred_term: Astrocyte
cell_type_term:
preferred_term: astrocyte
term:
id: CL:0000127
label: astrocyte
conditions:
- Free Sialic Acid Storage Disorder
genes:
- preferred_term: SLC17A5
term:
id: hgnc:10933
label: SLC17A5
platform: RNA sequencing (Illumina)
publication: PMID:40804080
findings:
- statement: Dysregulated glycosphingolipid metabolism in FSASD patient-derived neural cells with elevated glycohydrolase activities
supporting_text: Mature astrocytes derived from FSASD patients show pronounced alterations in GSL catabolism genes and significantly elevated lysosomal glycohydrolase enzyme activities
notes: >
Published in Scientific Reports (August 2025). GEO accession for raw RNA-sequencing data is expected to be available in the
supplementary materials or data availability statement of the article. Check author's data availability statement for GEO/SRA accession numbers.