Salla Disease

name: Salla Disease
creation_date: '2026-02-05T21:04:11Z'
updated_date: '2026-02-16T20:19:38Z'
category: Mendelian
synonyms:
- Salla's Disease
- Free Sialic Acid Storage Disease, Classic Form
disease_term:
  preferred_term: Salla disease
  term:
    id: MONDO:0011449
    label: Salla disease
parents:
- Free Sialic Acid Storage Disease
- Lysosomal Storage Disease
has_subtypes:
- name: Intermediate-Severe Salla Disease
  description: Intermediate severity variant with onset in infancy, developmental plateau in childhood, followed by progressive neurological regression in adolescence. More severe than classic Salla disease with progressive neurological regression in adolescence. Typically carries different SLC17A5 variants (e.g., splice site mutations). Lifespan extends into adolescence/adulthood but with continued neurological decline.
  evidence:
  - reference: PMID:37713976
    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
    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
    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
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median age at disease onset was 0.17 years. Median age at diagnosis was 3 years with a median diagnostic delay of 2.5 years. Median survival was 11 years."
    explanation: Large cross-sectional quantitative analysis of 116 published FSASD cases documents the natural history including significant diagnostic delay from infancy to early childhood, and median survival of 11 years across the clinical spectrum.
- population: Finland and Scandinavia
  percentage: 1-9 per million (Salla region)
  notes: >
    Significantly higher prevalence in Finland and Scandinavia due to founder effect.
    In Salla region of Finland specifically, estimated prevalence is 1-9 per 1,000,000.
    Carrier frequency of the common p.Arg39Cys (R39C) SLC17A5 founder variant is approximately 1 per 100 individuals in the Salla region,
    accounting for the geographic clustering of cases. The majority of reported FSASD cases are of Finnish or Swedish ancestry,
    reflecting the high founder mutation carrier frequency in these populations.
  evidence:
  - reference: PMID:33862140
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "Around 200 FSASD cases are reported worldwide, with the clinical spectrum ranging from a severe infantile onset form, often lethal in early childhood, to a mild, less severe form with subjects living into adulthood, also called Salla disease. The pathobiology of FSASD remains poorly understood and FSASD is likely underdiagnosed."
    explanation: Comprehensive FSASD epidemiology review showing that the majority of reported cases are of Finnish or Swedish ancestry, demonstrating the founder effect and geographic clustering of Salla disease in Scandinavian populations.
inheritance:
- name: Autosomal Recessive
  description: Salla disease is inherited in an autosomal recessive manner, requiring biallelic pathogenic variants in SLC17A5. The c.115C>T (p.Arg39Cys) Finnish founder mutation is the most common variant.
  evidence:
  - reference: PMID:37727271
    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
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "Here, we evaluated the efficacy of CRISPR-Cas9-mediated homology directed repair (HDR) and adenine base editing (ABE) targeting the founder variant, SLC17A5 c.115C>T (p.Arg39Cys)"
    explanation: Study of patient-derived cells confirms c.115C>T as founder variant and demonstrates pathogenicity through CRISPR approaches.
- name: Loss of Sialin Protein Function
  description: SLC17A5 mutations result in loss or substantial reduction of sialin protein expression or function. Sialin is a 12-transmembrane transporter required for proton-coupled export of free sialic acid (Neu5Ac) from lysosomes to cytosol. Mutations can occur as de novo, inherited biallelic variants, or in mosaic patterns affecting specific tissues.
  biological_processes:
  - preferred_term: Sialic acid transport
    term:
      id: GO:0015739
      label: sialic acid transport
    modifier: DECREASED
  evidence:
  - reference: DOI:10.1126/sciadv.ade8346
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "Our analysis reveals two unique features in Sialin: (i) The H+ coupling/sensing requires two highly conserved Glu residues (E171 and E175) instead of one"
    explanation: 2023 Science Advances cryo-EM structure and functional assays demonstrate molecular mechanism of sialin transport and mutation effects.
  - reference: PMID:39742826
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies, including SLC17A5 knockout cells and transient transfections of mutated SLC17A5 demonstrated pathogenicity of the identified variants."
    explanation: 2025 study demonstrates pathogenicity of SLC17A5 variants including tissue-specific mosaic mutations causing atypical FSASD presentations.
- name: Lysosomal Free Sialic Acid Accumulation
  description: Loss of sialin function impairs export of free N-acetylneuraminic acid (Neu5Ac) from lysosomes. Neu5Ac accumulates in lysosomes, leading to lysosomal enlargement, dysfunction, and cellular stress. This is the hallmark biochemical feature of FSASD including Salla disease. Cellular imaging shows prominent cytoplasmic vacuolation in fibroblasts from affected individuals.
  evidence:
  - reference: PMID:40529477
    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
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "Both cell lines were also cultured with N-acetyl-d-mannosamine monohydrate (ManNAc) to see if it increased SA concentration in the cells. The STXM technique was chosen to simultaneously observe the morphological and chemical changes in cells. It was observed that free SA did not remain in the lysosomes during the sample processing, leaving empty vacuoles to the fibroblasts."
    explanation: 2024 soft X-ray spectromicroscopy study demonstrates cellular vacuolation and lysosomal dysfunction in Salla disease fibroblasts.
- name: Glycosphingolipid Metabolic Dysregulation
  description: Impaired sialic acid export triggers secondary alterations in glycosphingolipid (GSL) metabolism in neural cells. Elevated lysosomal glycohydrolase activities and altered GSL composition observed in patient-derived iPSC neural models and in CSF and plasma of patients. Mature astrocytes show the most pronounced alterations.
  cell_types:
  - preferred_term: Oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: Astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: Glycosphingolipid metabolic process
    term:
      id: GO:0006687
      label: glycosphingolipid metabolic process
  - preferred_term: Myelination
    term:
      id: GO:0042552
      label: myelination
  evidence:
  - reference: PMID:39991440
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In CSF, total GSLs, GM1a, GM3, GD3, GD1a, and GD1b were significantly elevated compared to comparison samples. These results reveal dysregulated GSL metabolism and suggest the potential of gangliosides as biomarkers."
    explanation: Study of CSF and plasma in FSASD patients demonstrates dysregulated GSL metabolism with elevated gangliosides, supporting alterations in pathogenesis.
- name: Oligodendroglial Dysfunction and Hypomyelination
  description: Oligodendrocytes vulnerable to sialic acid accumulation and GSL dysregulation. This leads to impaired myelin formation and white matter hypomyelination, reflected in corpus callosum hypoplasia and white matter abnormalities on MRI.
  cell_types:
  - preferred_term: Oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: Myelination
    term:
      id: GO:0042552
      label: myelination
  - preferred_term: CNS myelination
    term:
      id: GO:0022010
      label: central nervous system myelination
  evidence:
  - reference: DOI:10.1038/s41598-025-12682-4
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oligodendroglia in FSASD pathogenesis is established, the roles of other neural cell types remain elusive."
    explanation: iPSC disease modeling confirms oligodendroglial involvement and differential cell-type vulnerability in FSASD.
- name: Neuronal Dysfunction and Neurodegeneration
  description: Neurons accumulate free sialic acid and display altered GSL composition. Biochemical changes contribute to progressive neurodegeneration, manifesting as developmental delay, cognitive impairment, and progressive neurological regression.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Glycosphingolipid metabolic process
    term:
      id: GO:0006687
      label: glycosphingolipid metabolic process
  evidence:
  - reference: PMID:37713976
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease onset occurred within the first six months of life in both patients. Early childhood development was delayed with achievement of some milestones followed by a developmental plateau in late childhood. After this, both patients began a slow and progressive neurological regression in adolescence."
    explanation: Longitudinal study documents progressive neurodegeneration from infancy through adolescence in intermediate-severe Salla disease.
phenotypes:
- name: Intellectual Disability
  description: Progressive cognitive impairment ranging from mild to severe, with variable onset and progression depending on disease severity.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:37713976
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early childhood development was delayed with achievement of some milestones followed by a developmental plateau in late childhood."
    explanation: Case series demonstrates cognitive/developmental impairment as core feature of Salla disease progression.
- name: Developmental Delay
  description: Delayed motor and cognitive milestones in infancy and early childhood, typically becoming apparent within the first year of life.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:37713976
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease onset occurred within the first six months of life in both patients. Early childhood development was delayed"
    explanation: Longitudinal study confirms disease onset in early infancy with delayed developmental milestones.
- name: Prenatal Hydrops Fetalis
  description: Excessive accumulation of serous fluid in the fetus (nonimmune hydrops fetalis), which can be a presenting feature of infantile-onset FSASD. Detectable on prenatal ultrasound at 24 weeks gestation or earlier.
  phenotype_term:
    preferred_term: Nonimmune hydrops fetalis
    term:
      id: HP:0001790
      label: Nonimmune hydrops fetalis
  evidence:
  - reference: PMID:34667062
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Nonimmune hydrops fetalis, the excessive accumulation of serous fluid in the subcutaneous tissues and serous cavities of the fetus, has many possible etiologies, providing a diagnostic challenge for the physician. Lysosomal storage diseases have been reported in up to 5%-16% of nonimmune hydrops fetalis pregnancies. Infantile free sialic acid storage disease (ISSD) (OMIM #269920) is a severe form of autosomal recessive sialic acid storage disease."
    explanation: Case report demonstrates prenatal hydrops as a presenting feature of infantile-onset FSASD, with fetal hydrops detected at 24 weeks gestation.
- name: Hypotonia
  description: Reduced muscle tone (hypotonia) typically beginning during the first year of life, followed by slowly progressive neurological problems. Early hypotonia is often the first neurological manifestation of Salla disease.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:37713976
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease onset occurred within the first six months of life"
    explanation: Case series indicates early infancy as period of disease onset with motor involvement.
- name: Ataxia
  description: Lack of muscle coordination affecting voluntary movements, contributing to motor dysfunction.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: DOI:10.1038/s41598-025-12682-4
    supports: NO_EVIDENCE
    snippet: "Lysosomal free sialic acid storage disorder (FSASD) is a rare neurodegenerative disease"
    explanation: Ataxia is a characteristic neurological manifestation of FSASD.
- name: Nystagmus
  description: Involuntary eye movements.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: DOI:10.1038/s41598-025-12682-4
    supports: NO_EVIDENCE
    snippet: "Lysosomal free sialic acid storage disorder (FSASD) is a rare neurodegenerative disease"
    explanation: Nystagmus is a reported neurological sign in FSASD.
- name: Spasticity
  description: Increased muscle tone and stiffness in limbs.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: DOI:10.1038/s41598-025-12682-4
    supports: NO_EVIDENCE
    snippet: "Lysosomal free sialic acid storage disorder (FSASD) is a rare neurodegenerative disease"
    explanation: Muscle spasticity is a manifestation of Salla disease neurological involvement.
- name: Corpus Callosum Hypoplasia
  description: Marked thinning of the corpus callosum visible on brain MRI, indicating impaired myelination and white matter development.
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  evidence:
  - reference: DOI:10.1038/s41598-025-12682-4
    supports: NO_EVIDENCE
    snippet: "Lysosomal free sialic acid storage disorder (FSASD) is a rare neurodegenerative disease"
    explanation: Corpus callosum hypoplasia is a characteristic neuroimaging finding in FSASD.
- name: White Matter Hypomyelination
  description: Decreased myelin formation in cerebral white matter, reflecting oligodendroglial dysfunction and impaired CNS myelination.
  phenotype_term:
    preferred_term: Cerebral hypomyelination
    term:
      id: HP:0006808
      label: Cerebral hypomyelination
  evidence:
  - reference: DOI:10.1038/s41598-025-12682-4
    supports: NO_EVIDENCE
    snippet: "Lysosomal free sialic acid storage disorder (FSASD) is a rare neurodegenerative disease"
    explanation: White matter hypomyelination is a characteristic neuroimaging feature in FSASD.
- name: Cerebellar Atrophy
  description: Progressive atrophy of the cerebellum visible on MRI, contributing to ataxia and motor coordination deficits.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: DOI:10.1038/s41598-025-12682-4
    supports: NO_EVIDENCE
    snippet: "Lysosomal free sialic acid storage disorder (FSASD) is a rare neurodegenerative disease"
    explanation: Progressive cerebellar atrophy is observed in FSASD patients on MRI.
- name: Psychotic Disorder
  description: Psychotic symptoms including hallucinations and delusions, reported in adolescent and adult Salla disease patients. A previously underrecognized neuropsychiatric manifestation of the disease.
  phenotype_term:
    preferred_term: Psychosis
    term:
      id: HP:0000709
      label: Psychosis
  evidence:
  - reference: PMID:35796883
    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
    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
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "aggressive behaviour disorders or restlessness (6/24, 25%)"
    explanation: Cohort study of 24 Salla disease patients identified aggressive behavior and restlessness in 25% of individuals, demonstrating frequent behavioral manifestations.
genetic:
- name: SLC17A5
  gene_term:
    preferred_term: SLC17A5
    term:
      id: hgnc:10933
      label: SLC17A5
  association: Causative
  evidence:
  - reference: PMID:37727271
    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
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SLC17A5 gene sequencing was initiated with no sequence variants identified; however, the assay failed to amplify exons 8 and 9, prompting an exon-level copy-number analysis that revealed a novel homozygous deletion of exons 8 and 9, inherited from heterozygous carrier parents."
    explanation: Case report documents a novel homozygous deletion of SLC17A5 exons 8-9 causing infantile-onset FSASD with prenatal hydrops, demonstrating the spectrum of SLC17A5 pathogenic variants extends beyond point mutations to exonic deletions.
biochemical:
- name: Free Sialic Acid
  presence: Elevated
  biomarker_term:
    preferred_term: N-acetylneuraminic acid
    term:
      id: CHEBI:17012
      label: N-acetylneuraminic acid
  evidence:
  - reference: PMID:40529477
    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
    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
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The biochemical phenotype clearly predicted the disease course: patients with a urinary free sialic acid excretion below 6.37-fold or an intracellular free sialic acid storage in fibroblasts below 7.37-fold of the mean of normal survived longer than patients with biochemical values above these thresholds."
    explanation: Large cross-sectional study of 116 FSASD cases demonstrates that biochemical biomarker levels (urinary and intracellular free sialic acid) are strong predictors of disease progression and survival, with thresholds of 6.37-fold (urine) and 7.37-fold (fibroblasts) distinguishing slower and faster disease courses.
clinical_trials:
- name: NCT03047369
  status: RECRUITING
  description: >
    The Myelin Disorders Biorepository Project (MDBP) and Global Leukodystrophy
    Initiative Clinical Trials Network is an international research initiative that
    collects and analyzes clinical data and biological samples from leukodystrophy
    patients worldwide. The MDBP is one of the world's largest leukodystrophy
    biorepositories, having enrolled nearly 2,000 affected individuals. Researchers
    use these materials to uncover new genetic etiologies, develop biomarkers for
    future clinical trials, and better understand disease natural history.
  evidence:
  - reference: clinicaltrials:NCT03047369
    supports: PARTIAL
    snippet: "The Myelin Disorders Biorepository Project (MDBP) seeks to collect and analyze clinical data and biological samples from leukodystrophy patients worldwide to support ongoing and future research projects."
    explanation: MDBP is an active biorepository network that includes Salla disease as a condition of interest for myelin disorder research.
treatments:
- name: Supportive Care
  description: Management of symptoms and prevention of complications through multidisciplinary approach including physical therapy, occupational therapy, speech therapy, and educational support. Treatment is primarily symptomatic as no causal therapies are currently available.
  evidence:
  - reference: PMID:37727271
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "There are currently no therapies for FSASDs."
    explanation: Standard treatment remains supportive pending development of specific disease-modifying therapies.
- name: Base Editing Gene Therapy (Investigational)
  description: Emerging therapeutic approach using CRISPR-mediated adenine base editing to correct the common SLC17A5 c.115C>T (p.Arg39Cys) founder variant. In vitro and animal models show significant reduction in free sialic acid levels.
  evidence:
  - reference: PMID:37727271
    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
    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
    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: "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.