Salla Disease

Mendelian MONDO:0011449 Pathograph 23 Free Sialic Acid Storage Disease Lysosomal Storage Disease

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1
Inheritance
6
Pathophys.
14
Phenotypes
23
Pathograph
1
Genes
2
Medical Actions
1
Subtypes
2
Differentials
1
Datasets
1
Trials
1
References
2
Deep Research
👪

Inheritance

1
Autosomal Recessive
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.
Show evidence (1 reference)
PMID:37727271 PARTIAL In Vitro
"Free sialic acid storage disorders (FSASDs) result from pathogenic variations in the SLC17A5 gene, which encodes the lysosomal transmembrane protein sialin."
Study of patient-derived fibroblasts and mouse models demonstrates biallelic SLC17A5 mutations and identifies founder variants.
◆

Subtypes

1
Intermediate-Severe Salla Disease
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.
Show evidence (2 references)
PMID:37713976 SUPPORT Human Clinical
"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."
Longitudinal study characterizes clinical course of intermediate-severe Salla disease as distinct from classic form with progressive regression.
PMID:28662915 SUPPORT Human Clinical
"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..."
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.
⚙

Pathophysiology

6
SLC17A5 Gene Mutation
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.
SLC17A5 hgnc:10933
Downstream
Loss of Sialin Protein Function Pathogenic SLC17A5 variants impair the encoded lysosomal sialic acid exporter sialin.
Show evidence (2 references)
PMID:37727271 PARTIAL In Vitro
"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)"
Study of patient-derived cells confirms c.115C>T as founder variant and demonstrates pathogenicity through CRISPR approaches.
PMID:20301643 SUPPORT Human Clinical
"The diagnosis of FSASD is established in a proband by identification of biallelic pathogenic variants in SLC17A5 by molecular genetic testing."
GeneReviews directly links biallelic pathogenic SLC17A5 variants to FSASD diagnosis.
Loss of Sialin Protein Function
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.
Sialic acid transport GO:0015739 ↓ DECREASED
sialic acid transmembrane transporter activity GO:0015136 ↓ DECREASED
Downstream
Lysosomal Free Sialic Acid Accumulation Loss of sialin transporter activity prevents lysosomal export of free sialic acid.
Show evidence (3 references)
DOI:10.1126/sciadv.ade8346 PARTIAL In Vitro
"Malfunction of the sialic acid transporter caused by various genetic mutations in the SLC17A5 gene encoding Sialin leads to a spectrum of neurodegenerative conditions called free sialic acid storage disorders."
2023 Science Advances cryo-EM structure and functional assays support the role of SLC17A5/sialin transporter malfunction in FSASD.
PMID:39742826 SUPPORT In Vitro
"Functional studies, including SLC17A5 knockout cells and transient transfections of mutated SLC17A5 demonstrated pathogenicity of the identified variants."
2025 study demonstrates pathogenicity of SLC17A5 variants including tissue-specific mosaic mutations causing atypical FSASD presentations.
PMID:37727271 SUPPORT In Vitro
"Loss or deficiency of sialin impairs FSA transport out of the lysosome, leading to cellular dysfunction and neurological impairment"
Patient-cell and model study directly links sialin deficiency to impaired lysosomal free sialic acid export and cellular dysfunction.
Lysosomal Free Sialic Acid Accumulation
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.
Downstream
Glycosphingolipid Metabolic Dysregulation Lysosomal free sialic acid storage is associated with altered neural-cell glycosphingolipid composition and catabolic enzyme activity.
Neuronal Dysfunction and Neurodegeneration Lysosomal storage and cellular dysfunction contribute to progressive neurological impairment.
Free Sialic Acid Lysosomal Neu5Ac storage is measured clinically as elevated free sialic acid.
Show evidence (2 references)
PMID:40529477 SUPPORT Human Clinical
"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)."
Diagnostic study demonstrates profound accumulation of free sialic acid in FSASD patients, confirming primary biochemical defect.
PMID:39257666 PARTIAL In Vitro
"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..."
2024 soft X-ray spectromicroscopy study demonstrates cellular vacuolation and lysosomal dysfunction in Salla disease fibroblasts.
Glycosphingolipid Metabolic Dysregulation
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.
Oligodendrocyte CL:0000128 Neuron CL:0000540 Astrocyte CL:0000127
Glycosphingolipid metabolic process GO:0006687 Myelination GO:0042552
Downstream
Oligodendroglial Dysfunction and Hypomyelination Altered neural glycosphingolipid metabolism contributes to selective vulnerability of myelinating glia and white matter pathology.
Neuronal Dysfunction and Neurodegeneration GSL dysregulation in patient-derived neural cells is a plausible contributor to neuronal dysfunction.
Show evidence (2 references)
PMID:39991440 SUPPORT Human Clinical
"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."
Study of CSF and plasma in FSASD patients demonstrates dysregulated GSL metabolism with elevated gangliosides, supporting alterations in pathogenesis.
DOI:10.1038/s41598-025-12682-4 SUPPORT In Vitro
"Transcriptomic analyses uncovered differential expression of genes involved in GSL catabolism, including those encoding glycohydrolases."
Patient-derived iPSC neural-cell study supports secondary GSL catabolic dysregulation in FSASD neural cells.
Oligodendroglial Dysfunction and Hypomyelination
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.
Oligodendrocyte CL:0000128
Myelination GO:0042552 CNS myelination GO:0022010
Downstream
White Matter Hypomyelination Impaired oligodendroglial myelination produces cerebral white matter hypomyelination.
Corpus Callosum Hypoplasia Hypomyelinating white matter disease is associated with thinning of the corpus callosum.
Cerebellar Atrophy CNS white matter and neurodegenerative involvement includes cerebellar atrophy.
Show evidence (2 references)
DOI:10.1038/s41598-025-12682-4 SUPPORT In Vitro
"While the involvement of oligodendroglia in FSASD pathogenesis is established, the roles of other neural cell types remain elusive."
iPSC disease modeling confirms oligodendroglial involvement and differential cell-type vulnerability in FSASD.
PMID:33862140 SUPPORT Human Clinical
"Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features."
FSASD review directly links the disease to central hypomyelination and associated neuroimaging abnormalities.
Neuronal Dysfunction and Neurodegeneration
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.
Neuron CL:0000540
Glycosphingolipid metabolic process GO:0006687
Downstream
Intellectual Disability Progressive neurodegenerative involvement produces cognitive impairment and intellectual disability.
Developmental Delay Early neuronal dysfunction delays psychomotor and global developmental milestones.
Hypotonia Neurodegenerative motor-system involvement produces muscular hypotonia.
Ataxia Cerebellar and broader neurologic involvement produces ataxia.
Nystagmus Neurologic involvement in Salla disease includes ocular motor abnormalities.
Spasticity Slowly progressive neurologic deterioration causes spasticity.
Athetosis Progressive neurologic deterioration in Salla disease includes athetotic movements.
Seizure Progressive neurologic involvement can include epileptic seizures.
Psychotic Disorder Progressive CNS disease can include adolescent and adult psychiatric manifestations.
Sleep Disturbance CNS involvement is associated with sleep disorders in Salla disease cohorts.
Aggressive Behavior CNS involvement is associated with behavioral dysregulation including aggression or restlessness.
Show evidence (2 references)
PMID:37713976 PARTIAL Human Clinical
"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."
Longitudinal study documents progressive neurodegeneration from infancy through adolescence in intermediate-severe Salla disease.
PMID:33862140 SUPPORT Human Clinical
"Clinical features of FSASD include coarse facial features, organomegaly, and progressive neurodegenerative symptoms with cognitive impairment, cerebellar ataxia and muscular hypotonia."
FSASD review supports progressive neurodegenerative involvement with cognitive and motor manifestations.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Salla Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

14
Eye 1
Nystagmus Nystagmus HP:0000639
Show evidence (1 reference)
PMID:35796883 SUPPORT Human Clinical
"Salla disease (SD) is a rare lysosomal storage disorder characterised by intellectual disability ataxia, athetosis, nystagmus, and central nervous system demyelination."
Salla disease cohort review lists nystagmus among characteristic neurological features.
Musculoskeletal 2
Hypotonia Hypotonia HP:0001252
Show evidence (1 reference)
PMID:33862140 SUPPORT Human Clinical
"Clinical features of FSASD include coarse facial features, organomegaly, and progressive neurodegenerative symptoms with cognitive impairment, cerebellar ataxia and muscular hypotonia."
Review lists muscular hypotonia among FSASD neurodegenerative clinical features.
Spasticity Spasticity HP:0001257
Show evidence (1 reference)
PMID:20301643 SUPPORT Human Clinical
"Less severe FSASD (historically called Salla disease) is characterized by normal appearance and absence of neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delays, spasticity, athetosis, and epileptic seizures."
GeneReviews lists spasticity among features of less severe FSASD historically called Salla disease.
Nervous System 10
Intellectual Disability Intellectual disability HP:0001249
Show evidence (1 reference)
PMID:33862140 SUPPORT Human Clinical
"Clinical features of FSASD include coarse facial features, organomegaly, and progressive neurodegenerative symptoms with cognitive impairment, cerebellar ataxia and muscular hypotonia."
Review identifies cognitive impairment among FSASD neurodegenerative clinical features, supporting intellectual disability in Salla disease spectrum.
Developmental Delay Global developmental delay HP:0001263
Show evidence (1 reference)
PMID:37713976 SUPPORT Human Clinical
"Disease onset occurred within the first six months of life in both patients. Early childhood development was delayed"
Longitudinal study confirms disease onset in early infancy with delayed developmental milestones.
Ataxia Ataxia HP:0001251
Show evidence (1 reference)
PMID:35796883 SUPPORT Human Clinical
"Salla disease (SD) is a rare lysosomal storage disorder characterised by intellectual disability ataxia, athetosis, nystagmus, and central nervous system demyelination."
Salla disease cohort review lists ataxia among characteristic neurological features.
Seizure Seizure HP:0001250
Show evidence (1 reference)
PMID:20301643 SUPPORT Human Clinical
"Less severe FSASD (historically called Salla disease) is characterized by normal appearance and absence of neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delays, spasticity, athetosis, and epileptic seizures."
GeneReviews lists epileptic seizures among characteristic neurologic features of less severe FSASD historically called Salla disease.
Corpus Callosum Hypoplasia Hypoplasia of the corpus callosum HP:0002079
Show evidence (1 reference)
PMID:33862140 SUPPORT Human Clinical
"Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features."
Review identifies thinning of the corpus callosum as a prominent FSASD neuroimaging feature.
White Matter Hypomyelination Cerebral hypomyelination HP:0006808
Show evidence (1 reference)
PMID:33862140 SUPPORT Human Clinical
"Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features."
Review identifies central hypomyelination as a prominent disease feature.
Cerebellar Atrophy Cerebellar atrophy HP:0001272
Show evidence (1 reference)
PMID:33862140 SUPPORT Human Clinical
"Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features."
Review identifies cerebellar atrophy as a prominent FSASD disease feature.
Psychotic Disorder Psychosis HP:0000709
Show evidence (1 reference)
PMID:35796883 SUPPORT Human Clinical
"Psychiatric symptoms were frequently associated with SD (10/24, 42%), and two patients were described as developing psychosis as adolescents."
Systematic review of 24 Salla disease patients identified psychosis as a previously unreported psychiatric manifestation, occurring in 2 of the 24 patients during adolescence.
Sleep Disturbance Sleep disturbance HP:0002360
Show evidence (1 reference)
PMID:35796883 SUPPORT Human Clinical
"Other psychiatric factors associated with SD were sleeping disorders (8/24, 32%)"
Systematic cohort analysis of 24 Salla disease patients found sleep disorders in 32% of the population, making it a common neuropsychiatric comorbidity.
Aggressive Behavior Aggressive behavior HP:0000718
Show evidence (1 reference)
PMID:35796883 SUPPORT Human Clinical
"aggressive behaviour disorders or restlessness (6/24, 25%)"
Cohort study of 24 Salla disease patients identified aggressive behavior and restlessness in 25% of individuals, demonstrating frequent behavioral manifestations.
Other 1
Athetosis Athetosis HP:0002305
Show evidence (2 references)
PMID:20301643 SUPPORT Human Clinical
"Less severe FSASD (historically called Salla disease) is characterized by normal appearance and absence of neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delays, spasticity, athetosis, and epileptic seizures."
GeneReviews lists athetosis among characteristic neurologic features of less severe FSASD historically called Salla disease.
PMID:26171070 SUPPORT Human Clinical
"Ataxia was prominent in childhood, but it was replaced by athetotic movements during the teens."
Longitudinal Finnish cohort data support age-related emergence of athetotic movements in Salla disease.
🧬

Genetic Associations

1
SLC17A5 (Causative)
Gene: SLC17A5 hgnc:10933 relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:37727271 PARTIAL In Vitro
"Free sialic acid storage disorders (FSASDs) result from pathogenic variations in the SLC17A5 gene, which encodes the lysosomal transmembrane protein sialin."
Studies of patient-derived cells demonstrate SLC17A5 biallelic mutations as causative for FSASD including Salla disease.
PMID:34667062 SUPPORT Human Clinical
"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."
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.
💊

Medical Actions

2
Supportive Care
Action: supportive care MAXO:0000950
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.
Show evidence (1 reference)
PMID:37727271 PARTIAL In Vitro
"There are currently no therapies for FSASDs."
Standard treatment remains supportive pending development of specific disease-modifying therapies.
Base Editing Gene Therapy (Investigational)
Action: gene therapy MAXO:0001001
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.
Mechanism Target:
RESTORES SLC17A5 Gene Mutation — Adenine base editing is designed to correct the SLC17A5 c.115C>T founder variant.
Show evidence (1 reference)
PMID:37727271 SUPPORT In Vitro
"ABE treatment of either homozygous or compound heterozygous SLC17A5 c.115C>T human dermal fibroblasts demonstrated significant FSA reduction, supporting amelioration of disease pathology."
Base editing approach successfully corrects the founder variant and reduces sialic acid accumulation in patient-derived cells and animal models.
🔬

Biochemical Markers

1
Free Sialic Acid (Elevated)
Context: Elevated free Neu5Ac in leukocytes, urine, or fibroblasts is the diagnostic biochemical signature of impaired lysosomal sialic acid export.
Pathograph Readouts
Readout Of Lysosomal Free Sialic Acid Accumulation Positive Diagnostic
Higher free Neu5Ac reports the lysosomal free sialic acid storage burden caused by impaired sialin export.
Show evidence (1 reference)
PMID:40529477 SUPPORT Human Clinical
"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)."
Leukocyte free Neu5Ac elevations directly support free sialic acid as a diagnostic readout of the storage node.
Show evidence (3 references)
PMID:40529477 SUPPORT Human Clinical
"Individuals with FSASD exhibited significantly higher levels of free Neu5Ac compared to their unaffected biological parents (36-fold)"
Free sialic acid accumulation is the pathognomonic biochemical feature and a diagnostic biomarker in FSASD.
PMID:24993898 SUPPORT Human Clinical
"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"
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.
PMID:29875421 SUPPORT Human Clinical
"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..."
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.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Salla Disease:

Infantile Free Sialic Acid Storage Disorder Not Yet Curated MONDO:0010027
Overlapping Features 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.
Show evidence (1 reference)
PMID:37713976 SUPPORT Human Clinical
"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."
Clinical spectrum of FSASD demonstrates infantile form as most severe.
Niemann-Pick Disease Type C MONDO:0009757
Overlapping Features Lysosomal storage disorder with overlapping neurological manifestations including developmental delay, hypotonia, ataxia, and white matter abnormalities on MRI.
Show evidence (1 reference)
PMID:40529477 PARTIAL Human Clinical
"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)"
Diagnostic study demonstrates distinct biochemical profile in FSASD vs other lysosomal storage disorders including NPC.
📊

Related Datasets

1
Lysosomal free sialic acid storage disorder iPSC-derived neural cells display altered glycosphingolipid metabolism PMID:40804080
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.
human BULK RNA SEQ RNA sequencing (Illumina)
Neuron CL:0000540 Astrocyte CL:0000127
Conditions: Free Sialic Acid Storage Disorder
Findings
Dysregulated glycosphingolipid metabolism in FSASD patient-derived neural cells with elevated glycohydrolase activities
"Mature astrocytes derived from FSASD patients show pronounced alterations in GSL catabolism genes and significantly elevated lysosomal glycohydrolase enzyme activities"
PMID:40804080
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.
🔬

Clinical Trials

1
NCT03047369 RECRUITING
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.
Show evidence (1 reference)
clinicaltrials:NCT03047369 PARTIAL
"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."
MDBP is an active biorepository network that includes Salla disease as a condition of interest for myelin disorder research.
{ }

Source YAML

click to show 
name: Salla Disease
creation_date: '2026-02-05T21:04:11Z'
updated_date: '2026-05-30T05:21:52Z'
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
references:
- reference: PMID:20301643
  title: "Free Sialic Acid Storage Disorder."
  tags:
  - GeneReviews
  findings: []
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
  percentage: Rare; enriched in Finnish disease heritage
  notes: >
    Salla disease is classically associated with the Finnish disease heritage,
    consistent with geographic enrichment in Finland.
  evidence:
  - reference: PMID:26171070
    reference_title: "A 13-year follow-up of Finnish patients with Salla disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SD belongs to the Finnish disease heritage, and it is caused by mutations in the SLC17A5 gene."
    explanation: Longitudinal Finnish cohort paper directly supports the Finnish-disease-heritage association for Salla disease.
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.
  - reference: PMID:20301643
    reference_title: Free Sialic Acid Storage Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of FSASD is established in a proband by identification of biallelic pathogenic variants in SLC17A5 by molecular genetic testing."
    explanation: GeneReviews directly links biallelic pathogenic SLC17A5 variants to FSASD diagnosis.
  downstream:
  - target: Loss of Sialin Protein Function
    causal_link_type: DIRECT
    description: Pathogenic SLC17A5 variants impair the encoded lysosomal sialic acid exporter sialin.
    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: "Free sialic acid storage disorders (FSASDs) result from pathogenic variations in the SLC17A5 gene, which encodes the lysosomal transmembrane protein sialin."
      explanation: The abstract links pathogenic SLC17A5 variation to the encoded lysosomal sialin transporter.
- 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.
  molecular_functions:
  - preferred_term: sialic acid transmembrane transporter activity
    term:
      id: GO:0015136
      label: sialic acid transmembrane transporter activity
    modifier: DECREASED
  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: "Malfunction of the sialic acid transporter caused by various genetic mutations in the SLC17A5 gene encoding Sialin leads to a spectrum of neurodegenerative conditions called free sialic acid storage disorders."
    explanation: 2023 Science Advances cryo-EM structure and functional assays support the role of SLC17A5/sialin transporter malfunction in FSASD.
  - 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.
  - reference: PMID:37727271
    reference_title: "Base editing corrects the common Salla disease SLC17A5 c.115C>T variant."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Loss or deficiency of sialin impairs FSA transport out of the lysosome, leading to cellular dysfunction and neurological impairment"
    explanation: Patient-cell and model study directly links sialin deficiency to impaired lysosomal free sialic acid export and cellular dysfunction.
  downstream:
  - target: Lysosomal Free Sialic Acid Accumulation
    causal_link_type: DIRECT
    description: Loss of sialin transporter activity prevents lysosomal export of free sialic acid.
    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: "Loss or deficiency of sialin impairs FSA transport out of the lysosome, leading to cellular dysfunction and neurological impairment"
      explanation: Patient-cell and model evidence directly links sialin loss to impaired lysosomal free sialic acid export.
- 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.
  chemical_entities:
  - preferred_term: N-acetylneuraminic acid
    modifier: INCREASED
    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), 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.
  downstream:
  - target: Glycosphingolipid Metabolic Dysregulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Lysosomal free sialic acid storage is associated with altered neural-cell glycosphingolipid composition and catabolic enzyme activity.
    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: "These results reveal dysregulated GSL metabolism and suggest the potential of gangliosides as biomarkers."
      explanation: Human plasma and CSF profiling supports secondary glycosphingolipid dysregulation in lysosomal free sialic acid storage disorder.
  - target: Neuronal Dysfunction and Neurodegeneration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Lysosomal storage and cellular dysfunction contribute to progressive neurological impairment.
    evidence:
    - reference: PMID:20301643
      reference_title: Free Sialic Acid Storage Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Free sialic acid storage disorder (FSASD) is a spectrum of neurodegenerative phenotypes resulting from increased lysosomal storage of free sialic acid."
      explanation: GeneReviews directly connects increased lysosomal free sialic acid storage to the neurodegenerative phenotype spectrum.
  - target: Free Sialic Acid
    causal_link_type: DIRECT
    description: Lysosomal Neu5Ac storage is measured clinically as elevated free sialic 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), LSD-negative subjects (22-fold), and individuals with other LSDs (49-fold)."
      explanation: Leukocyte measurements in affected individuals support elevated free Neu5Ac as the direct biochemical manifestation of FSASD storage.
- 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.
  - reference: DOI:10.1038/s41598-025-12682-4
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transcriptomic analyses uncovered differential expression of genes involved in GSL catabolism, including those encoding glycohydrolases."
    explanation: Patient-derived iPSC neural-cell study supports secondary GSL catabolic dysregulation in FSASD neural cells.
  downstream:
  - target: Oligodendroglial Dysfunction and Hypomyelination
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Altered neural glycosphingolipid metabolism contributes to selective vulnerability of myelinating glia and white matter pathology.
    evidence:
    - reference: DOI:10.1038/s41598-025-12682-4
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "While the involvement of oligodendroglia in FSASD pathogenesis is established, the roles of other neural cell types remain elusive."
      explanation: Patient-derived iPSC neural-cell modeling supports oligodendroglial involvement downstream of FSASD neural metabolic dysregulation.
  - target: Neuronal Dysfunction and Neurodegeneration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: GSL dysregulation in patient-derived neural cells is a plausible contributor to neuronal dysfunction.
    evidence:
    - reference: DOI:10.1038/s41598-025-12682-4
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "Collectively, these data may help refine our understanding of neural cell phenotypes and potential contributors to selective vulnerability in FSASD."
      explanation: The neural-cell study ties altered glycosphingolipid metabolism to cell-type vulnerability in FSASD.
- 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: IN_VITRO
    snippet: "While the involvement of 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.
  - reference: PMID:33862140
    reference_title: "Free sialic acid storage disorder: Progress and promise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features."
    explanation: FSASD review directly links the disease to central hypomyelination and associated neuroimaging abnormalities.
  downstream:
  - target: White Matter Hypomyelination
    causal_link_type: DIRECT
    description: Impaired oligodendroglial myelination produces cerebral white matter hypomyelination.
    evidence:
    - reference: PMID:33862140
      reference_title: "Free sialic acid storage disorder: Progress and promise."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features."
      explanation: FSASD clinical review identifies central hypomyelination as a prominent disease feature.
  - target: Corpus Callosum Hypoplasia
    causal_link_type: DIRECT
    description: Hypomyelinating white matter disease is associated with thinning of the corpus callosum.
    evidence:
    - reference: PMID:33862140
      reference_title: "Free sialic acid storage disorder: Progress and promise."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features."
      explanation: FSASD clinical review links central hypomyelination with corpus callosum thinning.
  - target: Cerebellar Atrophy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: CNS white matter and neurodegenerative involvement includes cerebellar atrophy.
    evidence:
    - reference: PMID:33862140
      reference_title: "Free sialic acid storage disorder: Progress and promise."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features."
      explanation: FSASD clinical review lists cerebellar atrophy with the central hypomyelination phenotype.
- 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.
  - reference: PMID:33862140
    reference_title: "Free sialic acid storage disorder: Progress and promise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features of FSASD include coarse facial features, organomegaly, and progressive neurodegenerative symptoms with cognitive impairment, cerebellar ataxia and muscular hypotonia."
    explanation: FSASD review supports progressive neurodegenerative involvement with cognitive and motor manifestations.
  downstream:
  - target: Intellectual Disability
    causal_link_type: DIRECT
    description: Progressive neurodegenerative involvement produces cognitive impairment and intellectual disability.
    evidence:
    - reference: PMID:33862140
      reference_title: "Free sialic acid storage disorder: Progress and promise."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical features of FSASD include coarse facial features, organomegaly, and progressive neurodegenerative symptoms with cognitive impairment, cerebellar ataxia and muscular hypotonia."
      explanation: FSASD review links progressive neurodegeneration to cognitive impairment.
  - target: Developmental Delay
    causal_link_type: DIRECT
    description: Early neuronal dysfunction delays psychomotor and global developmental milestones.
    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 clinical data support early developmental delay in Salla disease.
  - target: Hypotonia
    causal_link_type: DIRECT
    description: Neurodegenerative motor-system involvement produces muscular hypotonia.
    evidence:
    - reference: PMID:33862140
      reference_title: "Free sialic acid storage disorder: Progress and promise."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical features of FSASD include coarse facial features, organomegaly, and progressive neurodegenerative symptoms with cognitive impairment, cerebellar ataxia and muscular hypotonia."
      explanation: FSASD review includes muscular hypotonia among progressive neurodegenerative manifestations.
  - target: Ataxia
    causal_link_type: DIRECT
    description: Cerebellar and broader neurologic involvement produces ataxia.
    evidence:
    - reference: PMID:33862140
      reference_title: "Free sialic acid storage disorder: Progress and promise."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical features of FSASD include coarse facial features, organomegaly, and progressive neurodegenerative symptoms with cognitive impairment, cerebellar ataxia and muscular hypotonia."
      explanation: FSASD review includes cerebellar ataxia among progressive neurodegenerative manifestations.
  - target: Nystagmus
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Neurologic involvement in Salla disease includes ocular motor abnormalities.
    evidence:
    - reference: PMID:35796883
      reference_title: "Psychiatric symptoms in Salla disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Salla disease (SD) is a rare lysosomal storage disorder characterised by intellectual disability ataxia, athetosis, nystagmus, and central nervous system demyelination."
      explanation: Salla disease cohort review lists nystagmus in the neurologic phenotype.
  - target: Spasticity
    causal_link_type: DIRECT
    description: Slowly progressive neurologic deterioration causes spasticity.
    evidence:
    - reference: PMID:20301643
      reference_title: Free Sialic Acid Storage Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Less severe FSASD (historically called Salla disease) is characterized by normal appearance and absence of neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delays, spasticity, athetosis, and epileptic seizures."
      explanation: GeneReviews links slowly progressive neurologic deterioration in Salla disease to spasticity.
  - target: Athetosis
    causal_link_type: DIRECT
    description: Progressive neurologic deterioration in Salla disease includes athetotic movements.
    evidence:
    - reference: PMID:20301643
      reference_title: Free Sialic Acid Storage Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Less severe FSASD (historically called Salla disease) is characterized by normal appearance and absence of neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delays, spasticity, athetosis, and epileptic seizures."
      explanation: GeneReviews links slowly progressive neurologic deterioration in Salla disease to athetosis.
  - target: Seizure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Progressive neurologic involvement can include epileptic seizures.
    evidence:
    - reference: PMID:20301643
      reference_title: Free Sialic Acid Storage Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Less severe FSASD (historically called Salla disease) is characterized by normal appearance and absence of neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delays, spasticity, athetosis, and epileptic seizures."
      explanation: GeneReviews links slowly progressive neurologic deterioration in Salla disease to epileptic seizures.
  - target: Psychotic Disorder
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Progressive CNS disease can include adolescent and adult psychiatric manifestations.
    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: Salla disease cohort review supports psychosis as an adolescent psychiatric manifestation.
  - target: Sleep Disturbance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: CNS involvement is associated with sleep disorders in Salla disease cohorts.
    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: Salla disease cohort review reports sleeping disorders in affected individuals.
  - target: Aggressive Behavior
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: CNS involvement is associated with behavioral dysregulation including aggression or restlessness.
    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: Salla disease cohort review reports aggressive behavior disorders or restlessness in affected individuals.
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:33862140
    reference_title: "Free sialic acid storage disorder: Progress and promise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features of FSASD include coarse facial features, organomegaly, and progressive neurodegenerative symptoms with cognitive impairment, cerebellar ataxia and muscular hypotonia."
    explanation: Review identifies cognitive impairment among FSASD neurodegenerative clinical features, supporting intellectual disability in Salla disease spectrum.
- 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: 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:33862140
    reference_title: "Free sialic acid storage disorder: Progress and promise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features of FSASD include coarse facial features, organomegaly, and progressive neurodegenerative symptoms with cognitive impairment, cerebellar ataxia and muscular hypotonia."
    explanation: Review lists muscular hypotonia among FSASD neurodegenerative clinical features.
- 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: PMID:35796883
    reference_title: "Psychiatric symptoms in Salla disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Salla disease (SD) is a rare lysosomal storage disorder characterised by intellectual disability ataxia, athetosis, nystagmus, and central nervous system demyelination."
    explanation: Salla disease cohort review lists ataxia among characteristic neurological features.
- name: Nystagmus
  description: Involuntary eye movements.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:35796883
    reference_title: "Psychiatric symptoms in Salla disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Salla disease (SD) is a rare lysosomal storage disorder characterised by intellectual disability ataxia, athetosis, nystagmus, and central nervous system demyelination."
    explanation: Salla disease cohort review lists nystagmus among characteristic neurological features.
- name: Spasticity
  description: Increased muscle tone and stiffness in limbs.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:20301643
    reference_title: Free Sialic Acid Storage Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Less severe FSASD (historically called Salla disease) is characterized by normal appearance and absence of neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delays, spasticity, athetosis, and epileptic seizures."
    explanation: GeneReviews lists spasticity among features of less severe FSASD historically called Salla disease.
- name: Athetosis
  description: Slow involuntary writhing movements that can emerge as Salla disease progresses, including replacement of childhood ataxia by athetotic movements during adolescence.
  phenotype_term:
    preferred_term: Athetosis
    term:
      id: HP:0002305
      label: Athetosis
  evidence:
  - reference: PMID:20301643
    reference_title: Free Sialic Acid Storage Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Less severe FSASD (historically called Salla disease) is characterized by normal appearance and absence of neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delays, spasticity, athetosis, and epileptic seizures."
    explanation: GeneReviews lists athetosis among characteristic neurologic features of less severe FSASD historically called Salla disease.
  - reference: PMID:26171070
    reference_title: "A 13-year follow-up of Finnish patients with Salla disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ataxia was prominent in childhood, but it was replaced by athetotic movements during the teens."
    explanation: Longitudinal Finnish cohort data support age-related emergence of athetotic movements in Salla disease.
- name: Seizure
  description: Epileptic seizures can occur as part of the slowly progressive neurologic deterioration in Salla disease.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:20301643
    reference_title: Free Sialic Acid Storage Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Less severe FSASD (historically called Salla disease) is characterized by normal appearance and absence of neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delays, spasticity, athetosis, and epileptic seizures."
    explanation: GeneReviews lists epileptic seizures among characteristic neurologic features of less severe FSASD historically called Salla disease.
- 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: PMID:33862140
    reference_title: "Free sialic acid storage disorder: Progress and promise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features."
    explanation: Review identifies thinning of the corpus callosum as a prominent FSASD neuroimaging feature.
- 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: PMID:33862140
    reference_title: "Free sialic acid storage disorder: Progress and promise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features."
    explanation: Review identifies central hypomyelination as a prominent disease feature.
- 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: PMID:33862140
    reference_title: "Free sialic acid storage disorder: Progress and promise."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features."
    explanation: Review identifies cerebellar atrophy as a prominent FSASD disease feature.
- 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
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  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
  context: Elevated free Neu5Ac in leukocytes, urine, or fibroblasts is the diagnostic biochemical signature of impaired lysosomal sialic acid export.
  biomarker_term:
    preferred_term: N-acetylneuraminic acid
    term:
      id: CHEBI:17012
      label: N-acetylneuraminic acid
  readouts:
  - target: Lysosomal Free Sialic Acid Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Higher free Neu5Ac reports the lysosomal free sialic acid storage burden caused by impaired sialin export.
    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: Leukocyte free Neu5Ac elevations directly support free sialic acid as a diagnostic readout of the storage node.
  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.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  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.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: gene therapy
  target_mechanisms:
  - target: SLC17A5 Gene Mutation
    treatment_effect: RESTORES
    description: Adenine base editing is designed to correct the SLC17A5 c.115C>T founder variant.
  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.
📚

References & Deep Research

References

1
PMID:20301643
Free Sialic Acid Storage Disorder.
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Salla Disease
  • Category: Mendelian
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 39

Key Pathophysiology Nodes

  • SLC17A5 Gene Mutation
  • Loss of Sialin Protein Function
  • Lysosomal Free Sialic Acid Accumulation
  • Glycosphingolipid Metabolic Dysregulation
  • Oligodendroglial Dysfunction and Hypomyelination
  • Neuronal Dysfunction and Neurodegeneration
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1002/9781119697312.ch21
  • DOI:10.1038/s41598-025-12682-4
  • DOI:10.1126/sciadv.ade8346
  • DOI:10.3233/trd-160005
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 18 citations 2026-02-05T14:40:48.860892

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

  1. (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.

  2. (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.

  3. (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.

  4. (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.

  5. (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.

  6. (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.

  7. (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.

  8. (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.