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.
2025-09-09 | 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.
2025-06-06 | Biosynthesis of fatty aldehydes and alcohols in the eye and their role in meibogenesis.
Fatty alcohols (FAlc) and aldehydes (FAld) are essential intermediates/precursors in the biosynthesis of lipids. However, elevated FAld levels were shown to be geno- and cytotoxic, thus requiring conversion into less toxic FAlc and fatty acids (FA). An increase in FAlc and FAld in tissues of patients with Sjögren-Larsson syndrome was reported before and repeatedly linked to inactivation of ALDH3A2, which oxidizes FAld in FA. Recently, we hypothesized that another group of enzymes, namely SDR16C5/SDR16C6 (EC 1.1.1.105), could control the balance between FA, FAlc, and FAld via a separate mechanism. In this study, we assessed the in vivo biosynthesis of FAlc and FAld in mammals using Meibomian glands (MG) of wild-type (WT) and Sdr16c5/Sdr16c6-null (Hom) mice as models. Lipids were extracted from MG of experimental animals and analyzed using LC/MS. Because of high reactivity and instability of FAld, the compounds were initially converted to stable, sodium borohydride-reduced 3-aminopyridine conjugates, while FAlc were analyzed as N-alkyl pyridinium ions. A wide range of saturated and unsaturated FAld, FAlc, and FA ranging from C3 to C28 and longer were found in MG of mice of both genotypes. Our experiments revealed a multifold upregulation of almost all detected straight chain, but not branched, FAlc in MG lipidomes of Hom mice, which implied a previously unknown ability of SDR16C5/SDR16C6 to oxidize a wide range of FAlc in FAld in vivo. We have concluded that SDR16C5/SDR16C6 plays a central, and selective, role in FA/FAlc/FAld metabolism in vivo and proposed a generalized mechanism of these reactions.
2024-10-01 | Sjogren–Larsson Syndrome: A Familial Disease Afflicting Three Siblings Born of a Nonconsanguinous Marriage
Abstract Sjogren-Larsson syndrome (SLS) is an autosomal recessive ichthyotic syndrome characterized by a triad of congenital ichthyosis, mental retardation, and diplegia or tetraplegia. It occurs due to the defect in the gene responsible for encoding the enzyme fatty aldehyde dehydrogenase. Accumulating these abnormal aldehyde lipids in the skin and brain leads to clinical symptoms. This case report presents three siblings, born of a nonconsanguineous marriage, with a unique and rare manifestation of SLS. The siblings, aged 7, 5, and 3 years, respectively, exhibited pruritic dry, scaly rashes since infancy, along with abnormal gait and mental retardation. Genetic examination confirmed a homozygous mutation of the ALDH3A2 gene, leading to the diagnosis of SLS. Treatment involving capsule acitretin and a multidisciplinary approach resulted in a significant reduction in dryness and scaling. The case underscores the importance of early SLS diagnosis to mitigate morbidity and improve the quality of life for affected individuals.
2024-10-01 | SJÖGREN-LARSSON SYNDROME ASSOCIATED WITH MYELODYSPLASTIC SYNDROME: A CASE REPORT
Introduction: The Sjögren-Larsson Syndrome (SSL) is a rare autoimmune disease that causes glandular inflammation, normally in salivary and lacrimal glands. It can be classified as primary, when it is isolated, or secondary, when it is concomitant with other syndromes. Several studies correlate immune diseases with bone-marrow neoplasias, between them, the Myelodysplastic neoplasms (MDS). MDS is a heterogeneous group of hematologic diseases characterized by cytopenias in one or more hematologic lineages. Also, immunological disorders and chronic immunological stimulation are shown to be a trigger to ineffective hematopoiesis in patients with genetic predisposition. This report aims to describe MDS diagnosis in a patient with a rare immune disease and to demonstrate the complications associated with this condition. Case report: A 76-year-old woman, diagnosed with secondary SSL and autoimmune hemolytic anemia (AHAI), mastectomized, returned to a follow-up declaring fatigue and indisposition. The hematologic perfil showed: direct coombs positive, reticulocytes 8.0%, hemoglobin 7.7 g/dL, leukocytes 1280, platelets 318,000, homogeneous nuclear ANA 1/640, hypergammaglobulinemia, anti-SSA 240.0 and Schirmer positive. She was submitted to multiple treatments with antihistamines and immunosuppressants, but had infectious complications and hospital admissions. In 2023, it was indicated a splenectomy due to refractory disease and she started to be followed up by a hematologist, who suggested treatment with rituximab (500 mg in two sections with intervals of 14 days) as an alternative to active AHAI secondary to SSL. The treatment showed a good clinical result with the hemoglobin increased to 10,6 g/dL. However, at the end of 2023, the patient was unable to undergo a new pulse therapy of mabthera due to changes in the follow-up examinations of previously treated breast adenocarcinoma. A new biopsy showed multiple adenopathy attributed to the SSL itself. In 2024, a new bone marrow aspirate was taken which showed dyserythropoiesis, dysgranulopoiesis, 2% blasts and, in the cytogenetics test, 47,XX,+14[4]/46,XX[16]. In this context, the patient was diagnosed with MDS with a low percentage of blasts (MDS-LB). Discussion: The immunological dysregulation and hyperactivation of T and B lymphocytes will destroy self-antigens present in the epithelium of the exocrine glands, characterizing SSL, and in the erythrocytes, as in AHAI, leading to the release of hemoglobin into the plasma and dysfunction in gas transport. Studies show that autoimmune manifestations can lead to secondary diseases in bone marrow and MDS is one of them. Recently, studies linked UBA1 somatic mutations as the recurrent cause of clinically complex diagnoses with overlapping hematologic features. This new disease entity is known as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. VEXAS syndrome is frequently associated with hematological disorders, around 30-50% of these patients have concurrent MDS. Interestingly, the 14 trisomy finding has been associated with hematologic neoplasias and MDS overlap syndromes. In addition, it is crucial to confirm UBA1 mutation to VEXAS-associated diagnoses in this context of inflammatory clinical presentation. The correct diagnosis of MDS overlap syndromes is essential because their prognosis differs from isolated disorders and may require specific treatments due to unique molecular vulnerabilities.
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.
2025-09-09 | 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.
2025-06-06 | Biosynthesis of fatty aldehydes and alcohols in the eye and their role in meibogenesis.
Fatty alcohols (FAlc) and aldehydes (FAld) are essential intermediates/precursors in the biosynthesis of lipids. However, elevated FAld levels were shown to be geno- and cytotoxic, thus requiring conversion into less toxic FAlc and fatty acids (FA). An increase in FAlc and FAld in tissues of patients with Sjögren-Larsson syndrome was reported before and repeatedly linked to inactivation of ALDH3A2, which oxidizes FAld in FA. Recently, we hypothesized that another group of enzymes, namely SDR16C5/SDR16C6 (EC 1.1.1.105), could control the balance between FA, FAlc, and FAld via a separate mechanism. In this study, we assessed the in vivo biosynthesis of FAlc and FAld in mammals using Meibomian glands (MG) of wild-type (WT) and Sdr16c5/Sdr16c6-null (Hom) mice as models. Lipids were extracted from MG of experimental animals and analyzed using LC/MS. Because of high reactivity and instability of FAld, the compounds were initially converted to stable, sodium borohydride-reduced 3-aminopyridine conjugates, while FAlc were analyzed as N-alkyl pyridinium ions. A wide range of saturated and unsaturated FAld, FAlc, and FA ranging from C3 to C28 and longer were found in MG of mice of both genotypes. Our experiments revealed a multifold upregulation of almost all detected straight chain, but not branched, FAlc in MG lipidomes of Hom mice, which implied a previously unknown ability of SDR16C5/SDR16C6 to oxidize a wide range of FAlc in FAld in vivo. We have concluded that SDR16C5/SDR16C6 plays a central, and selective, role in FA/FAlc/FAld metabolism in vivo and proposed a generalized mechanism of these reactions.
2024-10-01 | Sjogren–Larsson Syndrome: A Familial Disease Afflicting Three Siblings Born of a Nonconsanguinous Marriage
Abstract Sjogren-Larsson syndrome (SLS) is an autosomal recessive ichthyotic syndrome characterized by a triad of congenital ichthyosis, mental retardation, and diplegia or tetraplegia. It occurs due to the defect in the gene responsible for encoding the enzyme fatty aldehyde dehydrogenase. Accumulating these abnormal aldehyde lipids in the skin and brain leads to clinical symptoms. This case report presents three siblings, born of a nonconsanguineous marriage, with a unique and rare manifestation of SLS. The siblings, aged 7, 5, and 3 years, respectively, exhibited pruritic dry, scaly rashes since infancy, along with abnormal gait and mental retardation. Genetic examination confirmed a homozygous mutation of the ALDH3A2 gene, leading to the diagnosis of SLS. Treatment involving capsule acitretin and a multidisciplinary approach resulted in a significant reduction in dryness and scaling. The case underscores the importance of early SLS diagnosis to mitigate morbidity and improve the quality of life for affected individuals.
2024-10-01 | SJÖGREN-LARSSON SYNDROME ASSOCIATED WITH MYELODYSPLASTIC SYNDROME: A CASE REPORT
Introduction: The Sjögren-Larsson Syndrome (SSL) is a rare autoimmune disease that causes glandular inflammation, normally in salivary and lacrimal glands. It can be classified as primary, when it is isolated, or secondary, when it is concomitant with other syndromes. Several studies correlate immune diseases with bone-marrow neoplasias, between them, the Myelodysplastic neoplasms (MDS). MDS is a heterogeneous group of hematologic diseases characterized by cytopenias in one or more hematologic lineages. Also, immunological disorders and chronic immunological stimulation are shown to be a trigger to ineffective hematopoiesis in patients with genetic predisposition. This report aims to describe MDS diagnosis in a patient with a rare immune disease and to demonstrate the complications associated with this condition. Case report: A 76-year-old woman, diagnosed with secondary SSL and autoimmune hemolytic anemia (AHAI), mastectomized, returned to a follow-up declaring fatigue and indisposition. The hematologic perfil showed: direct coombs positive, reticulocytes 8.0%, hemoglobin 7.7 g/dL, leukocytes 1280, platelets 318,000, homogeneous nuclear ANA 1/640, hypergammaglobulinemia, anti-SSA 240.0 and Schirmer positive. She was submitted to multiple treatments with antihistamines and immunosuppressants, but had infectious complications and hospital admissions. In 2023, it was indicated a splenectomy due to refractory disease and she started to be followed up by a hematologist, who suggested treatment with rituximab (500 mg in two sections with intervals of 14 days) as an alternative to active AHAI secondary to SSL. The treatment showed a good clinical result with the hemoglobin increased to 10,6 g/dL. However, at the end of 2023, the patient was unable to undergo a new pulse therapy of mabthera due to changes in the follow-up examinations of previously treated breast adenocarcinoma. A new biopsy showed multiple adenopathy attributed to the SSL itself. In 2024, a new bone marrow aspirate was taken which showed dyserythropoiesis, dysgranulopoiesis, 2% blasts and, in the cytogenetics test, 47,XX,+14[4]/46,XX[16]. In this context, the patient was diagnosed with MDS with a low percentage of blasts (MDS-LB). Discussion: The immunological dysregulation and hyperactivation of T and B lymphocytes will destroy self-antigens present in the epithelium of the exocrine glands, characterizing SSL, and in the erythrocytes, as in AHAI, leading to the release of hemoglobin into the plasma and dysfunction in gas transport. Studies show that autoimmune manifestations can lead to secondary diseases in bone marrow and MDS is one of them. Recently, studies linked UBA1 somatic mutations as the recurrent cause of clinically complex diagnoses with overlapping hematologic features. This new disease entity is known as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. VEXAS syndrome is frequently associated with hematological disorders, around 30-50% of these patients have concurrent MDS. Interestingly, the 14 trisomy finding has been associated with hematologic neoplasias and MDS overlap syndromes. In addition, it is crucial to confirm UBA1 mutation to VEXAS-associated diagnoses in this context of inflammatory clinical presentation. The correct diagnosis of MDS overlap syndromes is essential because their prognosis differs from isolated disorders and may require specific treatments due to unique molecular vulnerabilities.
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