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:
categories:
Small molecules
small molecules
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.
2021-10-12 | Impaired Skin Barrier Function Due to Reduced ω-O-Acylceramide Levels in a Mouse Model of Sjögren-Larsson Syndrome.
Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder whose causative gene encodes the fatty aldehyde dehydrogenase ALDH3A2. To date, the detailed molecular mechanism of the skin pathology of SLS has remained largely unclear. We generated double-knockout (DKO) mice for Aldh3a2 and its homolog Aldh3b2 (a pseudogene in humans). These mice showed hyperkeratosis and reduced fatty aldehyde dehydrogenase activity and skin barrier function. The levels of ω-O-acylceramides (acylceramides), which are specialized ceramides essential for skin barrier function, in the epidermis of DKO mice were about 60% of those in wild-type mice. In the DKO mice, levels of acylceramide precursors (ω-hydroxy ceramides and triglycerides) were increased, suggesting that the final step of acylceramide production was inhibited. A decrease in acylceramide levels was also observed in human immortalized keratinocytes lacking ALDH3A2. Differentiated keratinocytes prepared from the DKO mice exhibited impaired long-chain base metabolism. Based on these results, we propose that the long-chain-base-derived fatty aldehydes that accumulate in DKO mice and SLS patients attack and inhibit the enzyme involved in the final step of acylceramide production. Our findings provide insight into the pathogenesis of the skin symptoms of SLS, i.e., decreased acylceramide production, and its molecular mechanism.
2021-02-04 | Comprehensive in silico screening and molecular dynamics studies of missense mutations in Sjogren-Larsson syndrome associated with the ALDH3A2 gene.
Sjögren-Larsson syndrome (SLS) is an autoimmune disorder inherited in an autosomal recessive pattern. To date, 80 missense mutations have been identified in association with the Aldehyde Dehydrogenase 3 Family Member A2 (ALDH3A2) gene causing SLS. Disruption of the function of ALDH3A2 leads to excessive accumulation of fat in the cells, which interferes with the normal function of protective membranes or materials that are necessary for the body to function normally. We retrieved 54 missense mutations in the ALDH3A2 from the OMIM, UniProt, dbSNP, and HGMD databases that are known to cause SLS. These mutations were examined with various in silico stability tools, which predicted that the mutations p.S308N and p.R423H that are located at the protein-protein interaction domains are the most destabilizing. Furthermore, to determine the atomistic-level differences within the protein-protein interactions owing to mutations, we performed macromolecular simulation (MMS) using GROMACS to validate the motion patterns and dynamic behavior of the biological system. We found that both mutations (p.S380N and p.R423H) had significant effects on the protein-protein interaction and disrupted the dimeric interactions. The computational pipeline provided in this study helps to elucidate the potential structural and functional differences between the ALDH3A2 native and mutant homodimeric proteins, and will pave the way for drug discovery against specific targets in the SLS patients.
2020-12-05 | Nuclear receptor NHR-49 promotes peroxisome proliferation to compensate for aldehyde dehydrogenase deficiency inC. elegans
Abstract The intracellular level of fatty aldehydes is tightly regulated to minimize the formation of toxic aldehyde adducts of cellular components. Accordingly, deficiency of a fatty aldehyde dehydrogenase FALDH causes the neurologic disorder Sjögren-Larsson syndrome (SLS) in humans. However, cellular responses to unresolved, elevated fatty aldehyde levels are poorly understood. Based on lipidomic and imaging analysis, we report that the loss of endoplasmic reticulum-, mitochondria- and peroxisomes-associated ALH-4, the C. elegans FALDH ortholog, increases fatty aldehyde levels and reduces fat storage. ALH-4 deficiency in the intestine, cell-nonautonomously induces NHR-49/NHR-79-dependent hypodermal peroxisome proliferation. This is accompanied by the upregulation of catalases and fatty acid catabolic enzymes, as indicated by RNA sequencing. Such a response is required to counteract ALH-4 deficiency since alh-4; nhr-49 double mutant animals are not viable. Our work reveals unexpected inter-tissue communication of fatty aldehyde levels, and suggests pharmacological modulation of peroxisome proliferation as a therapeutic strategy for SLS.
gene therapies
2022-07-05 | Sjogren- Larsson Syndrome with Type-1 Distal Renal Tubular Acidosis in Siblings
Sjogren-Larsson syndrome (SLS) is a rare autosomal recessive lipid metabolic disorder caused because of the defect in fatty alcohol oxidation resulting from fatty aldehyde dehydrogenase (FALDH3A2) deficiency. Sjogren-Larsson syndrome is constituted by the trio of generalised spastic paralysis, intellectual impairment, & ichthyosis. The inability of hydrogen ions secretion from the distal tubule characterises dRTA (distal (Type 1) renal tubular acidosis). The dRTA aetiology is diverse, but it can be acquired or inherited. We report siblings who presented with congenital ichthyotic hyperkeratosis, spastic diplegia and severe learning disabilities, which were suggestive of SLS. Distal renal tubular acidosis diagnosis was done on the basis of severe serum hypokalaemia, urine electrolytes showing high potassium levels, metabolic acidosis with a positive anion gap, high pH of urine, Urinary & Blood PCO2 difference (UB PCO2) on the lower side, (FeHCO3%) showing mild bicarbonaturia (<5%), medullary nephrocalcinosis, Hypercalciuria as well as the omission of other differential diagnosis. Management in SLS was supportive. The child demonstrated symptomatic improvement after starting standard therapy for SLS & distal renal tubular acidosis. To conclude, distal renal tubular acidosis ailment in children can be controlled with a good long-term prognosis, but precise diagnosis as well as management are critical. Early detection can assist the physician in implementing appropriate supportive care as well as possible curative gene therapy. Keywords: Ichthyosis, spastic diplegia, Intellectual disability, Distal Renal Tubular Acidosis, Hypokalaemia
2022-03-31 | Novel ALDH3A2 mutations in structural and functional domains of FALDH causing diverse clinical phenotypes in Sjögren-Larsson syndrome patients.
Mutations in ALDH3A2 cause Sjögren-Larsson syndrome (SLS), a neuro-ichthyotic condition due to the deficiency of fatty aldehyde dehydrogenase (FALDH). We screened for novel mutations causing SLS among Indian ethnicity, characterized the identified mutations in silico and in vitro, and retrospectively evaluated their role in phenotypic heterogeneity. Interestingly, asymmetric distribution of nonclassical traits was observed in our cases. Nerve conduction studies suggested intrinsic-minus-claw hands in two siblings, a novel neurological phenotype to SLS. Genetic testing revealed five novel homozygous ALDH3A2 mutations in six cases: Case-1-NM_000382.2:c.50C>A, NP_000373.1:p.(Ser17Ter); Case-2-NM_000382.2:c.199G>T, NP_000373.1:p.(Glu67Ter); Case-3-NM_000382.2:c.1208G>A, NP_000373.1:p.(Gly403Asp); Case-4-NM_000382.2:c.1325C>T, NP_000373.1:p.(Pro442Leu); Case-5 and -6 NM_000382.2:c.1349G>A, NP_000373.1:p.(Trp450Ter). The mutations identified were predicted to be pathogenic and disrupt the functional domains of the FALDH. p.(Pro442Leu) at the C-terminal α-helix, might impair the substrate gating process. Mammalian expression studies with exon-9 mutants confirmed the profound reduction in the enzyme activity. Diminished aldehyde-oxidizing activity was observed with cases-2 and 3. Cases-2 and 3 showed epidermal hyperplasia with mild intracellular edema, spongiosis, hypergranulosis, and perivascular-interstitial lymphocytic infiltrate and a leaky eosinophilic epidermis. The presence of keratin-containing milia-like lipid vacuoles implies defective lamellar secretion with p.(Gly403Asp). This study improves our understanding of the clinical and mutational diversity in SLS, which might help to fast-track diagnostic and therapeutic interventions of this debilitating disorder.
2019-01-01 | A case report: Sjogren Larsson Syndrome
Sjogren-Larsson Syndrome (SLS) is an autosomal recessive disorder with 100% penetrance. It has a characteristic set of clinical features, ichthyosis, spastic diplegia, and severe learning difficulties. To educate the patients about the treatment of dry skin and proper counseling regarding the genetic basis of disease are needed. The recent discoveries of the responsible biochemical abnormalities have explained the underlying links between the neurological and the dermatological manifestations. Its early diagnosis can help the physician to institute proper supportive treatment and possible curative gene therapy. Hence, ichthyosis cases must be investigated thoroughly. We report a case of 19-year-old Indian male patient with clinical features favoring the rare disease, Sjogren-Larsson syndrome (SLS).
2016-05-01 | 166. Lentiviral Hematopoietic Stem Cell Gene Therapy for Sjögren-Larsson Syndrome
Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder characterized by scaling skin (ichthyosis), mental retardation, and spasticity. SLS is caused by mutations in the ALDH3A2 gene, which encodes fatty aldehyde dehydrogenase (FALDH), an enzyme that is involved in the oxidation of fatty aldehyde and fatty alcohol. In SLS, FALDH deficiency and impaired fatty aldehyde oxidation results in lipid accumulation, which is responsible for the symptoms. Spurred by previous hematopoietic stem cell gene therapy trials for multi-systemic diseases, such as Adrenoleukodystrophy (ALD), Metachromatic leukodystrophy (MLD), and Cystinosis, we investigated the plausibility of hematopoietic stem cell gene transfer to correct FALDH deficiency and alleviate the phenotype in SLS. We designed the hematopoietic stem cell gene therapy using a lentiviral vector containing human ALDH3A2 cDNA based on our previous MND-WASP (Wiskott-Aldrich syndrome protein) vector design. The lentiviral vector contains the normal human ALDH3A2 coding sequence which was derived from PCR products using human mobilized peripheral blood CD34+ cDNA. The vector was tested for FALDH protein expression in transfected human HEK293T cells by western blot and the enzyme activity was confirmed using HPLC-MS/UV. A transplantation experiment was performed using the Aldh3a2-/- KO mouse model, where the lineage negative BM cells from CD45.1 Aldh3a2-/- KO mice (C57BL/6 background) were sorted and transduced with a lentiviral vector followed by transplantation into lethally irradiated CD45.2 Aldh3a2-/- KO mice (C57BL/6 background). These mice are being monitored for cell engraftment, vector copy numbers, and any phenotypic changes. An initial analysis for the grafts showed 56% transduction in the MND(a synthetic promoter that contains the U3 region of a modified MoMuLV LTR with myeloproliferative sarcoma virus enhancer)-GFP group and 31% transduction in the MND-ALDH3A2 group based on the CFU-C data. Flow cytometric analysis of peripheral blood on these mice at 6 and 12 post- transplant week showed 32% transduction in MND-GFP group. Further analysis including vector copy numbers and end point analysis for various tissues including liver, spleen, and brain are underway. This work provides the foundation for moving forward with potential lentiviral hematopoietic stem cell gene therapy for non-hematological disorders.
2010-02-12 | Fatty aldehyde dehydrogenase is up-regulated by polyunsaturated fatty acid via peroxisome proliferator-activated receptor alpha and suppresses polyunsaturated fatty acid-induced endoplasmic reticulum stress.
Fatty aldehyde dehydrogenase (FALDH; also known as ALDH3A2 or ALDH10) oxidizes medium- or long-chain aliphatic aldehydes. FALDH deficiency in humans is known to be the cause of Sjögren-Larsson syndrome, in which individuals display neurological symptoms and cutaneous abnormality. FALDH-V, a splice isoform of FALDH, is localized in the peroxisome and contributes to the oxidization of pristanal, an intermediate of the alpha-oxidation pathway. FALDH-N, another splice isoform of FALDH, is induced by peroxisomal proliferator-activated receptor alpha ligands, although its activation mechanism has not been clarified. In the present study, we show that transcriptional activation of FALDH is directly regulated by peroxisomal proliferator-activated receptor alpha through a direct repeat-1 site located in the FALDH promoter. In addition, FALDH is efficiently induced by linoleic acid in rat hepatoma Fao cells through transcriptional activation by peroxisomal proliferator-activated receptor alpha. Furthermore, ectopic expression of endoplasmic reticulum-localizing FALDH-N, but not peroxisome-localizing FALDH-V, suppresses endoplasmic reticulum stress caused by linoleic acid in HEK293 cells. These results suggest the autocatalytic nature of the FALDH-N system against endoplasmic reticulum stress that is induced by polyunsaturated fatty acid; polyunsaturated fatty acid binds to peroxisomal proliferator-activated receptor alpha to activate the expression of FALDH-N, which then detoxifies polyunsaturated fatty acid-derived fatty aldehydes and protects cells from endoplasmic reticulum stress.
antibodies
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.
proteins
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.
small molecules
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.
2021-10-12 | Impaired Skin Barrier Function Due to Reduced ω-O-Acylceramide Levels in a Mouse Model of Sjögren-Larsson Syndrome.
Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder whose causative gene encodes the fatty aldehyde dehydrogenase ALDH3A2. To date, the detailed molecular mechanism of the skin pathology of SLS has remained largely unclear. We generated double-knockout (DKO) mice for Aldh3a2 and its homolog Aldh3b2 (a pseudogene in humans). These mice showed hyperkeratosis and reduced fatty aldehyde dehydrogenase activity and skin barrier function. The levels of ω-O-acylceramides (acylceramides), which are specialized ceramides essential for skin barrier function, in the epidermis of DKO mice were about 60% of those in wild-type mice. In the DKO mice, levels of acylceramide precursors (ω-hydroxy ceramides and triglycerides) were increased, suggesting that the final step of acylceramide production was inhibited. A decrease in acylceramide levels was also observed in human immortalized keratinocytes lacking ALDH3A2. Differentiated keratinocytes prepared from the DKO mice exhibited impaired long-chain base metabolism. Based on these results, we propose that the long-chain-base-derived fatty aldehydes that accumulate in DKO mice and SLS patients attack and inhibit the enzyme involved in the final step of acylceramide production. Our findings provide insight into the pathogenesis of the skin symptoms of SLS, i.e., decreased acylceramide production, and its molecular mechanism.
2021-02-04 | Comprehensive in silico screening and molecular dynamics studies of missense mutations in Sjogren-Larsson syndrome associated with the ALDH3A2 gene.
Sjögren-Larsson syndrome (SLS) is an autoimmune disorder inherited in an autosomal recessive pattern. To date, 80 missense mutations have been identified in association with the Aldehyde Dehydrogenase 3 Family Member A2 (ALDH3A2) gene causing SLS. Disruption of the function of ALDH3A2 leads to excessive accumulation of fat in the cells, which interferes with the normal function of protective membranes or materials that are necessary for the body to function normally. We retrieved 54 missense mutations in the ALDH3A2 from the OMIM, UniProt, dbSNP, and HGMD databases that are known to cause SLS. These mutations were examined with various in silico stability tools, which predicted that the mutations p.S308N and p.R423H that are located at the protein-protein interaction domains are the most destabilizing. Furthermore, to determine the atomistic-level differences within the protein-protein interactions owing to mutations, we performed macromolecular simulation (MMS) using GROMACS to validate the motion patterns and dynamic behavior of the biological system. We found that both mutations (p.S380N and p.R423H) had significant effects on the protein-protein interaction and disrupted the dimeric interactions. The computational pipeline provided in this study helps to elucidate the potential structural and functional differences between the ALDH3A2 native and mutant homodimeric proteins, and will pave the way for drug discovery against specific targets in the SLS patients.
2020-12-05 | Nuclear receptor NHR-49 promotes peroxisome proliferation to compensate for aldehyde dehydrogenase deficiency inC. elegans
Abstract The intracellular level of fatty aldehydes is tightly regulated to minimize the formation of toxic aldehyde adducts of cellular components. Accordingly, deficiency of a fatty aldehyde dehydrogenase FALDH causes the neurologic disorder Sjögren-Larsson syndrome (SLS) in humans. However, cellular responses to unresolved, elevated fatty aldehyde levels are poorly understood. Based on lipidomic and imaging analysis, we report that the loss of endoplasmic reticulum-, mitochondria- and peroxisomes-associated ALH-4, the C. elegans FALDH ortholog, increases fatty aldehyde levels and reduces fat storage. ALH-4 deficiency in the intestine, cell-nonautonomously induces NHR-49/NHR-79-dependent hypodermal peroxisome proliferation. This is accompanied by the upregulation of catalases and fatty acid catabolic enzymes, as indicated by RNA sequencing. Such a response is required to counteract ALH-4 deficiency since alh-4; nhr-49 double mutant animals are not viable. Our work reveals unexpected inter-tissue communication of fatty aldehyde levels, and suggests pharmacological modulation of peroxisome proliferation as a therapeutic strategy for SLS.
gene therapies
2022-07-05 | Sjogren- Larsson Syndrome with Type-1 Distal Renal Tubular Acidosis in Siblings
Sjogren-Larsson syndrome (SLS) is a rare autosomal recessive lipid metabolic disorder caused because of the defect in fatty alcohol oxidation resulting from fatty aldehyde dehydrogenase (FALDH3A2) deficiency. Sjogren-Larsson syndrome is constituted by the trio of generalised spastic paralysis, intellectual impairment, & ichthyosis. The inability of hydrogen ions secretion from the distal tubule characterises dRTA (distal (Type 1) renal tubular acidosis). The dRTA aetiology is diverse, but it can be acquired or inherited. We report siblings who presented with congenital ichthyotic hyperkeratosis, spastic diplegia and severe learning disabilities, which were suggestive of SLS. Distal renal tubular acidosis diagnosis was done on the basis of severe serum hypokalaemia, urine electrolytes showing high potassium levels, metabolic acidosis with a positive anion gap, high pH of urine, Urinary & Blood PCO2 difference (UB PCO2) on the lower side, (FeHCO3%) showing mild bicarbonaturia (<5%), medullary nephrocalcinosis, Hypercalciuria as well as the omission of other differential diagnosis. Management in SLS was supportive. The child demonstrated symptomatic improvement after starting standard therapy for SLS & distal renal tubular acidosis. To conclude, distal renal tubular acidosis ailment in children can be controlled with a good long-term prognosis, but precise diagnosis as well as management are critical. Early detection can assist the physician in implementing appropriate supportive care as well as possible curative gene therapy. Keywords: Ichthyosis, spastic diplegia, Intellectual disability, Distal Renal Tubular Acidosis, Hypokalaemia
2022-03-31 | Novel ALDH3A2 mutations in structural and functional domains of FALDH causing diverse clinical phenotypes in Sjögren-Larsson syndrome patients.
Mutations in ALDH3A2 cause Sjögren-Larsson syndrome (SLS), a neuro-ichthyotic condition due to the deficiency of fatty aldehyde dehydrogenase (FALDH). We screened for novel mutations causing SLS among Indian ethnicity, characterized the identified mutations in silico and in vitro, and retrospectively evaluated their role in phenotypic heterogeneity. Interestingly, asymmetric distribution of nonclassical traits was observed in our cases. Nerve conduction studies suggested intrinsic-minus-claw hands in two siblings, a novel neurological phenotype to SLS. Genetic testing revealed five novel homozygous ALDH3A2 mutations in six cases: Case-1-NM_000382.2:c.50C>A, NP_000373.1:p.(Ser17Ter); Case-2-NM_000382.2:c.199G>T, NP_000373.1:p.(Glu67Ter); Case-3-NM_000382.2:c.1208G>A, NP_000373.1:p.(Gly403Asp); Case-4-NM_000382.2:c.1325C>T, NP_000373.1:p.(Pro442Leu); Case-5 and -6 NM_000382.2:c.1349G>A, NP_000373.1:p.(Trp450Ter). The mutations identified were predicted to be pathogenic and disrupt the functional domains of the FALDH. p.(Pro442Leu) at the C-terminal α-helix, might impair the substrate gating process. Mammalian expression studies with exon-9 mutants confirmed the profound reduction in the enzyme activity. Diminished aldehyde-oxidizing activity was observed with cases-2 and 3. Cases-2 and 3 showed epidermal hyperplasia with mild intracellular edema, spongiosis, hypergranulosis, and perivascular-interstitial lymphocytic infiltrate and a leaky eosinophilic epidermis. The presence of keratin-containing milia-like lipid vacuoles implies defective lamellar secretion with p.(Gly403Asp). This study improves our understanding of the clinical and mutational diversity in SLS, which might help to fast-track diagnostic and therapeutic interventions of this debilitating disorder.
2019-01-01 | A case report: Sjogren Larsson Syndrome
Sjogren-Larsson Syndrome (SLS) is an autosomal recessive disorder with 100% penetrance. It has a characteristic set of clinical features, ichthyosis, spastic diplegia, and severe learning difficulties. To educate the patients about the treatment of dry skin and proper counseling regarding the genetic basis of disease are needed. The recent discoveries of the responsible biochemical abnormalities have explained the underlying links between the neurological and the dermatological manifestations. Its early diagnosis can help the physician to institute proper supportive treatment and possible curative gene therapy. Hence, ichthyosis cases must be investigated thoroughly. We report a case of 19-year-old Indian male patient with clinical features favoring the rare disease, Sjogren-Larsson syndrome (SLS).
2016-05-01 | 166. Lentiviral Hematopoietic Stem Cell Gene Therapy for Sjögren-Larsson Syndrome
Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder characterized by scaling skin (ichthyosis), mental retardation, and spasticity. SLS is caused by mutations in the ALDH3A2 gene, which encodes fatty aldehyde dehydrogenase (FALDH), an enzyme that is involved in the oxidation of fatty aldehyde and fatty alcohol. In SLS, FALDH deficiency and impaired fatty aldehyde oxidation results in lipid accumulation, which is responsible for the symptoms. Spurred by previous hematopoietic stem cell gene therapy trials for multi-systemic diseases, such as Adrenoleukodystrophy (ALD), Metachromatic leukodystrophy (MLD), and Cystinosis, we investigated the plausibility of hematopoietic stem cell gene transfer to correct FALDH deficiency and alleviate the phenotype in SLS. We designed the hematopoietic stem cell gene therapy using a lentiviral vector containing human ALDH3A2 cDNA based on our previous MND-WASP (Wiskott-Aldrich syndrome protein) vector design. The lentiviral vector contains the normal human ALDH3A2 coding sequence which was derived from PCR products using human mobilized peripheral blood CD34+ cDNA. The vector was tested for FALDH protein expression in transfected human HEK293T cells by western blot and the enzyme activity was confirmed using HPLC-MS/UV. A transplantation experiment was performed using the Aldh3a2-/- KO mouse model, where the lineage negative BM cells from CD45.1 Aldh3a2-/- KO mice (C57BL/6 background) were sorted and transduced with a lentiviral vector followed by transplantation into lethally irradiated CD45.2 Aldh3a2-/- KO mice (C57BL/6 background). These mice are being monitored for cell engraftment, vector copy numbers, and any phenotypic changes. An initial analysis for the grafts showed 56% transduction in the MND(a synthetic promoter that contains the U3 region of a modified MoMuLV LTR with myeloproliferative sarcoma virus enhancer)-GFP group and 31% transduction in the MND-ALDH3A2 group based on the CFU-C data. Flow cytometric analysis of peripheral blood on these mice at 6 and 12 post- transplant week showed 32% transduction in MND-GFP group. Further analysis including vector copy numbers and end point analysis for various tissues including liver, spleen, and brain are underway. This work provides the foundation for moving forward with potential lentiviral hematopoietic stem cell gene therapy for non-hematological disorders.
2010-02-12 | Fatty aldehyde dehydrogenase is up-regulated by polyunsaturated fatty acid via peroxisome proliferator-activated receptor alpha and suppresses polyunsaturated fatty acid-induced endoplasmic reticulum stress.
Fatty aldehyde dehydrogenase (FALDH; also known as ALDH3A2 or ALDH10) oxidizes medium- or long-chain aliphatic aldehydes. FALDH deficiency in humans is known to be the cause of Sjögren-Larsson syndrome, in which individuals display neurological symptoms and cutaneous abnormality. FALDH-V, a splice isoform of FALDH, is localized in the peroxisome and contributes to the oxidization of pristanal, an intermediate of the alpha-oxidation pathway. FALDH-N, another splice isoform of FALDH, is induced by peroxisomal proliferator-activated receptor alpha ligands, although its activation mechanism has not been clarified. In the present study, we show that transcriptional activation of FALDH is directly regulated by peroxisomal proliferator-activated receptor alpha through a direct repeat-1 site located in the FALDH promoter. In addition, FALDH is efficiently induced by linoleic acid in rat hepatoma Fao cells through transcriptional activation by peroxisomal proliferator-activated receptor alpha. Furthermore, ectopic expression of endoplasmic reticulum-localizing FALDH-N, but not peroxisome-localizing FALDH-V, suppresses endoplasmic reticulum stress caused by linoleic acid in HEK293 cells. These results suggest the autocatalytic nature of the FALDH-N system against endoplasmic reticulum stress that is induced by polyunsaturated fatty acid; polyunsaturated fatty acid binds to peroxisomal proliferator-activated receptor alpha to activate the expression of FALDH-N, which then detoxifies polyunsaturated fatty acid-derived fatty aldehydes and protects cells from endoplasmic reticulum stress.
antibodies
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.
proteins
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.
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