RARE DISEASE
Sjögren-Larsson syndrome
Sjögren-Larsson syndrome
Sjögren-Larsson syndrome
Synonyms: Fatty acid alcohol oxidoreductase deficiency
Synonyms: Fatty acid alcohol oxidoreductase deficiency
Synonyms: Fatty acid alcohol oxidoreductase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder caused by mutations in ALDH3A2, leading to deficient fatty aldehyde dehydrogenase (FALDH). This results in toxic accumulation of fatty aldehydes/alcohols, manifesting as a triad of congenital ichthyosis, spastic diplegia/quadriplegia, and intellectual disability. Retinal glistening white dots and leukoencephalopathy on MRI are key diagnostic features. Symptomatic management includes emollients, retinoids, physical/speech therapy, and antiepileptics, with experimental therapies targeting aldehyde metabolism in trials [1][2][6][10].
Burden
Chronic, disabling course with wheelchair dependency in ~59% of adults [8][15].
Significant QoL impairment from pruritus, mobility limitations, and lifelong care needs [4][8][17].
Prematurity and associated complications contribute to morbidity; life expectancy varies but can extend into adulthood [6][15].
Therapies
Symptomatic care: Topical keratolytics (urea, lactic acid), oral retinoids (acitretin) [8][14], spasticity management (botulinum toxin, physiotherapy) [6][17], and antiseizure medications [4][6].
Experimental: Aldehyde scavengers (e.g., NS2 in Phase 2 trials) [2][3], zileuton for pruritus [10], and dietary lipid modification (limited efficacy) [2][8].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare skin diseases
Research Papers
49 drug discovery papers about Sjögren-Larsson syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
49 drug discovery papers about Sjögren-Larsson syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-04-01 | Mutation mapping and functional characterization of a missense mutation p.Arg228Cys in ALDH3A2 gene causing Sjögran-Larson syndrome.
BACKGROUND: This study examined a consanguineous family affected by autosomal recessive Sjögren-Larsson syndrome (SLS) that is characterized by congenital ichthyosis, intellectual disabilities, and spastic diplegia. SLS is a rare inborn error of lipid metabolism resulting from mutations in the ALDH3A2 gene, leading to a deficiency in the fatty aldehyde dehydrogenase (FALDH) enzyme. METHODS AND RESULTS: We employed homozygosity-by-descent (HBD) mapping followed by whole-exome sequencing (WES) for mutation identification and conducted protein structure modeling and enzyme assays to determine the functional consequences of the mutation. HBD mapping and WES in a patient with SLS identified a recurrent missense mutation NM_000382:c.C682T: p.(Arg228Cys) in the 5th exon of the ALDH3A2 gene. Protein structural modeling and docking studies indicated significant alterations in the structural and interactional properties of the mutant ALDH3A2. Enzyme analysis of serum extracts revealed reduced ALDH enzyme activity in both affected and carrier individuals. CONCLUSION: This study confirmed the association between diminished ALDH activity and the severity of clinical manifestations, including developmental delay, ichthyosis, spasticity, and cognitive disability. To our knowledge, this is the first report of an ALDH3A2 mutation in a Pakistani family. Our findings reinforce evidence that the NM_000382:c.C682T: p.(Arg228Cys) mutation in ALDH3A2 is causative of SLS, underscoring the importance of genetic counseling and early biochemical diagnosis for families at risk of SLS.
2025-10-06 | Dupilumab Reduces Pruritus in Twins With Sjögren-Larsson Syndrome.
Sjögren-Larsson Syndrome (SLS), now termed ALDH3A2-syndromic epidermal differentiation disorder (sEDD), is a rare genetic disorder marked by thickened skin, spasticity, and intellectual disability. Intractable pruritus is a nearly universal and debilitating feature of SLS that remains poorly managed by current therapies. We describe 4-year-old twin girls with genetically confirmed SLS who showed significant and lasting improvement in itch following treatment with dupilumab, a biologic targeting interleukin-4 receptor signaling. Within 6 months, pruritus severity scores declined markedly, improving sleep and quality of life without adverse effects, supporting further investigation of dupilumab for SLS-associated itch.
2025-09-09 | Genotypic and Phenotypic Characteristics of Turkish Patients with Sjögren-Larsson Syndrome
Introduction: Sjögren-Larsson syndrome (SLS) (OMIM #270200) is an autosomal recessively inherited lipid disorder caused by pathogenic variants in ALDH3A2 gene encoding the fatty aldehyde dehydrogenase (FALDH) enzyme, that catalyzes the oxidation of fatty aldehyde to fatty acid. It is a rare neurocutaneous disorder characterized by the triad of congenital ichthyosis, spasticity, and intellectual disability. The aim of study was to investigate phenotypic and molecular characteristics of Turkish patients with SLS. Methods: Literature search was performed by entering the keywords ALDH3A2, FALDH, SLS in TR index journal list in Turkish and PubMed in English. Turkish patients with SLS reported up to date were retrospectively analyzed. Results: A total of 58 patients from 36 unrelated Turkish families were included in this study. Consanguinity was present in 73% of families. All but three patients younger than 18 months exhibited the triad of ichthyosis, developmental delay, and spastic di-/tetraplegia. Ophthalmological abnormalities were observed in 45% of patients, prematurity in 30%, epilepsy in 28%, and scoliosis in 17%. Additionally, only 2% of patients had peripheral neuropathy. Abnormal findings on brain imaging studies were detected in 84% of patients, all of whom demonstrated white matter involvement, while cerebral atrophy was present in 10%. All families had homozygous mutations, with missense in 45%, nonsense/frameshift/deletion in 35%, and splicing in 20%. Among the 15 distinct variants identified, only three, c.683G>A p.(Arg228His), c.24_25delinsTT p.(Arg9*), and c.1108-1G>C, were found to be recurrent. A review of the literature suggests that the c.24_25delinsTT p.(Arg9*) variant may be specific to the Turkish population, whereas the c.683G>A p.(Arg228His) variant appears to have a broader regional distribution across the Middle East. Conclusion: Although mild and severe phenotypes have been reported, the classical triad plays an important role in the preliminary diagnosis. Phenotypic findings were similar, but genotypic diversity was remarkable, and no clear genotype-phenotype correlation was observed. To make population-specific inferences, it is necessary to generate data from a larger patient cohort with haplotype analysis.
2026-04-01 | Mutation mapping and functional characterization of a missense mutation p.Arg228Cys in ALDH3A2 gene causing Sjögran-Larson syndrome.
BACKGROUND: This study examined a consanguineous family affected by autosomal recessive Sjögren-Larsson syndrome (SLS) that is characterized by congenital ichthyosis, intellectual disabilities, and spastic diplegia. SLS is a rare inborn error of lipid metabolism resulting from mutations in the ALDH3A2 gene, leading to a deficiency in the fatty aldehyde dehydrogenase (FALDH) enzyme. METHODS AND RESULTS: We employed homozygosity-by-descent (HBD) mapping followed by whole-exome sequencing (WES) for mutation identification and conducted protein structure modeling and enzyme assays to determine the functional consequences of the mutation. HBD mapping and WES in a patient with SLS identified a recurrent missense mutation NM_000382:c.C682T: p.(Arg228Cys) in the 5th exon of the ALDH3A2 gene. Protein structural modeling and docking studies indicated significant alterations in the structural and interactional properties of the mutant ALDH3A2. Enzyme analysis of serum extracts revealed reduced ALDH enzyme activity in both affected and carrier individuals. CONCLUSION: This study confirmed the association between diminished ALDH activity and the severity of clinical manifestations, including developmental delay, ichthyosis, spasticity, and cognitive disability. To our knowledge, this is the first report of an ALDH3A2 mutation in a Pakistani family. Our findings reinforce evidence that the NM_000382:c.C682T: p.(Arg228Cys) mutation in ALDH3A2 is causative of SLS, underscoring the importance of genetic counseling and early biochemical diagnosis for families at risk of SLS.
2025-10-06 | Dupilumab Reduces Pruritus in Twins With Sjögren-Larsson Syndrome.
Sjögren-Larsson Syndrome (SLS), now termed ALDH3A2-syndromic epidermal differentiation disorder (sEDD), is a rare genetic disorder marked by thickened skin, spasticity, and intellectual disability. Intractable pruritus is a nearly universal and debilitating feature of SLS that remains poorly managed by current therapies. We describe 4-year-old twin girls with genetically confirmed SLS who showed significant and lasting improvement in itch following treatment with dupilumab, a biologic targeting interleukin-4 receptor signaling. Within 6 months, pruritus severity scores declined markedly, improving sleep and quality of life without adverse effects, supporting further investigation of dupilumab for SLS-associated itch.
2025-09-09 | Genotypic and Phenotypic Characteristics of Turkish Patients with Sjögren-Larsson Syndrome
Introduction: Sjögren-Larsson syndrome (SLS) (OMIM #270200) is an autosomal recessively inherited lipid disorder caused by pathogenic variants in ALDH3A2 gene encoding the fatty aldehyde dehydrogenase (FALDH) enzyme, that catalyzes the oxidation of fatty aldehyde to fatty acid. It is a rare neurocutaneous disorder characterized by the triad of congenital ichthyosis, spasticity, and intellectual disability. The aim of study was to investigate phenotypic and molecular characteristics of Turkish patients with SLS. Methods: Literature search was performed by entering the keywords ALDH3A2, FALDH, SLS in TR index journal list in Turkish and PubMed in English. Turkish patients with SLS reported up to date were retrospectively analyzed. Results: A total of 58 patients from 36 unrelated Turkish families were included in this study. Consanguinity was present in 73% of families. All but three patients younger than 18 months exhibited the triad of ichthyosis, developmental delay, and spastic di-/tetraplegia. Ophthalmological abnormalities were observed in 45% of patients, prematurity in 30%, epilepsy in 28%, and scoliosis in 17%. Additionally, only 2% of patients had peripheral neuropathy. Abnormal findings on brain imaging studies were detected in 84% of patients, all of whom demonstrated white matter involvement, while cerebral atrophy was present in 10%. All families had homozygous mutations, with missense in 45%, nonsense/frameshift/deletion in 35%, and splicing in 20%. Among the 15 distinct variants identified, only three, c.683G>A p.(Arg228His), c.24_25delinsTT p.(Arg9*), and c.1108-1G>C, were found to be recurrent. A review of the literature suggests that the c.24_25delinsTT p.(Arg9*) variant may be specific to the Turkish population, whereas the c.683G>A p.(Arg228His) variant appears to have a broader regional distribution across the Middle East. Conclusion: Although mild and severe phenotypes have been reported, the classical triad plays an important role in the preliminary diagnosis. Phenotypic findings were similar, but genotypic diversity was remarkable, and no clear genotype-phenotype correlation was observed. To make population-specific inferences, it is necessary to generate data from a larger patient cohort with haplotype analysis.
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0 orphan drug designations.
0 orphan drug designations.
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