Sjögren-Larsson syndrome: A biochemical rationale for using aldehyde-reactive therapeutic agents.

Sjögren-Larsson syndrome (SLS) is a neurocutaneous disease caused by mutations in ALDH3A2 that result in deficient fatty aldehyde dehydrogenase (FALDH) activity and impaired fatty aldehyde and fatty alcohol oxidation. The pathogenesis of SLS is thought to involve accumulation of long-chain fatty aldehydes and alcohols and/or metabolically-related ether glycerolipids. Fatty aldehydes are particularly toxic molecules that can covalently react with proteins and certain amino-containing lipids such as phosphatidylethanolamine (PE), generating an unusual aldehyde adduct, N-alkyl-PE (NAPE). Using Faldh-deficient Chinese hamster ovary cells (FAA-K1A) as a cellular model for SLS, we investigated the ability of an aldehyde trapping agent, ADX-102 [2-(3-amino-6-chloro-quinolin-2-yl)-propan-2-ol], to mitigate the harmful effects of fatty aldehydes. FAA-K1A cells were protected from octadecanal (C18:0-al) induced cytotoxicity and apoptosis by ADX-102. Metabolism of C18:0-al to fatty alcohol (octadecanol) was also inhibited by ADX-102. FAA-K1A cells accumulated 5-fold more NAPE with C16- and C18-linked N-alkyl chains compared to wild-type cells, but NAPE levels decreased to normal after growth for 4 days with 50 µM ADX-102. Our results suggest that small aldehyde-reactive molecules, such as ADX-102, should be explored as novel therapeutic agents for SLS by preventing aldehyde adduct formation with critical cellular targets and inhibiting fatty aldehyde metabolism to fatty alcohol.

1-O-Alkylglycerol accumulation reveals abnormal ether glycerolipid metabolism in Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) is an inherited metabolic disease characterized by ichthyosis, spasticity, intellectual disability and deficient oxidation and accumulation of of fatty aldehydes and alcohols. We investigated whether excess fatty alcohols in SLS are diverted into biosynthesis of ether glycerolipids (eGLs) by measuring the 1-O-alkylglycerol (AG) backbone of eGLs in stratum corneum, plasma and red blood cells (RBCs). In all tissues, saturated and monounsaturated AGs were detected. In stratum corneum from SLS patients, saturated AGs (C15-C20) were increased 97-fold (range: 86- to 169-fold) compared to controls. AGs were largely (67 ± 9%) derived from neutral esterified eGLs (i.e. alkyl-diacylglyerol) and free non-esterified AGs (28 ± 10%), but very little from plasmalogens (3 ± 5%). Plasma from SLS patients had 2-fold more C18:0-AG (p < 0.005) and 40% less C16:1-AG (p < 0.01) than controls but the total concentration of AGs was not increased, and the AG profile in RBCs from SLS subjects was normal. All AGs were profoundly reduced in plasma and RBCs from patients with Zellweger spectrum disorder, who have impaired eGL (i.e. plasmalogen) synthesis. The striking accumulation of AGs in stratum corneum of SLS patients constitutes a novel lipid biomarker for this disease, and may contribute to the pathogenesis of the ichthyosis. Measurement of AGs is a simple and convenient method to assess global synthesis of eGLs and potentially identify patients with defects in their metabolism.

Aldehyde dehydrogenase 3a2 protects AML cells from oxidative death and the synthetic lethality of ferroptosis inducers.

Metabolic alterations in cancer represent convergent effects of oncogenic mutations. We hypothesized that a metabolism-restricted genetic screen, comparing normal primary mouse hematopoietic cells and their malignant counterparts in an ex vivo system mimicking the bone marrow microenvironment, would define distinctive vulnerabilities in acute myeloid leukemia (AML). Leukemic cells, but not their normal myeloid counterparts, depended on the aldehyde dehydrogenase 3a2 (Aldh3a2) enzyme that oxidizes long-chain aliphatic aldehydes to prevent cellular oxidative damage. Aldehydes are by-products of increased oxidative phosphorylation and nucleotide synthesis in cancer and are generated from lipid peroxides underlying the non-caspase-dependent form of cell death, ferroptosis. Leukemic cell dependence on Aldh3a2 was seen across multiple mouse and human myeloid leukemias. Aldh3a2 inhibition was synthetically lethal with glutathione peroxidase-4 (GPX4) inhibition; GPX4 inhibition is a known trigger of ferroptosis that by itself minimally affects AML cells. Inhibiting Aldh3a2 provides a therapeutic opportunity and a unique synthetic lethality to exploit the distinctive metabolic state of malignant cells.

Novel mutations and a severe neurological phenotype in Sjögren-Larsson syndrome patients from Iran.

Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder characterized by ichthyosis, spasticity and intellectual disability. The disease is caused by mutations in the ALDH3A2 gene that encodes fatty aldehyde dehydrogenase. We describe 7 Iranian SLS patients from 5 unrelated consanguineous families. Sequencing of ALDH3A2 identified 4 novel mutations, including a 26-bp deletion (c.25_50del), small in-frame deletion (c.370_372del; p.G124del), a termination (p.Q35Ter) and a missense mutation (p.Lys211Glu). Bacterial expression of the p.Lys211Glu and p.G124del mutations showed little or no detectable enzyme activity. Three of the patients exhibited an unusual neuro-regressive clinical course associated with seizures, which may reflect the presence of unidentified genetic or environmental modifiers in this consanguineous population. This cohort represents the largest group of Iranian patients with molecularly confirmed SLS and expands the mutational and clinical spectrum of this disease.

Novel mutation in Sjogren-Larsson syndrome is associated with divergent neurologic phenotypes.

Sjögren-Larsson syndrome is an inherited disorder of lipid metabolism caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase, which results in accumulation of fatty aldehydes and alcohols and is characterized by ichthyosis, intellectual disability, and spastic diplegia/quadriplegia. The authors describe 2 unrelated Honduran patients who carried the same novel homozygous nonsense mutation (c.1309A>T, p.K437X) and ALDH3A2 DNA haplotype, but widely differed in disease severity. One patient exhibited spastic quadriplegia with unusual neuroregression, whereas the other patient had the usual static form of spastic diplegia with neurodevelopmental disabilities. Biochemical analyses showed a similar profound deficiency of fatty aldehyde dehydrogenase activity and impaired fatty alcohol metabolism in both patients' cultured fibroblasts. These results indicate that variation in the neurologic phenotype of Sjögren-Larsson syndrome is not strictly determined by the ALDH3A2 mutation or the biochemical defect as expressed in cultured fibroblasts, but by unidentified epigenetic/environmental factors, gene modifiers, or other mechanisms.

Large contiguous gene deletions in Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. More than 70 mutations have been identified in SLS patients, including small deletions or insertions, missense mutations, splicing defects and complex nucleotide changes. We now describe 2 SLS patients whose disease is caused by large contiguous gene deletions of the ALDH3A2 locus on 17p11.2. The deletions were defined using long distance inverse PCR and microarray-based comparative genomic hybridization. A 24-year-old SLS female was homozygous for a 352-kb deletion involving ALDH3A2 and 4 contiguous genes including ALDH3A1, which codes for the major soluble protein in cornea. Although lacking corneal disease, she showed severe symptoms of SLS with uncommon deterioration in oral motor function and loss of ambulation. The other 19-month-old female patient was a compound heterozygote for a 1.44-Mb contiguous gene deletion and a missense mutation (c.407C>T, P136L) in ALDH3A2. These studies suggest that large gene deletions may account for up to 5% of the mutant alleles in SLS. Geneticists should consider the possibility of compound heterozygosity for large deletions in patients with SLS and other inborn errors of metabolism, which has implications for carrier testing and prenatal diagnosis.

Ichthyosis in Sjögren-Larsson syndrome reflects defective barrier function due to abnormal lamellar body structure and secretion.

Sjögren-Larsson syndrome is a genetic disease characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene coding for fatty aldehyde dehydrogenase, an enzyme necessary for oxidation of fatty aldehydes and fatty alcohols. We investigated the cutaneous abnormalities in 9 patients with Sjögren-Larsson syndrome to better understand how the enzymatic deficiency results in epidermal dysfunction. Histochemical staining for aldehyde oxidizing activity was profoundly reduced in the epidermis. Colloidal lanthanum perfusion studies showed abnormal movement of tracer into the extracellular spaces of the stratum corneum consistent with a leaky water barrier. The barrier defect could be attributed to the presence of abnormal lamellar bodies, many with disrupted limiting membranes or lacking lamellar contents. Entombed lamellar bodies were present in the cytoplasm of corneocytes suggesting blockade of lamellar body secretion. At the stratum granulosum-stratum corneum interface, non-lamellar material displaced or replaced secreted lamellar membranes, and in the stratum corneum, the number of lamellar bilayers declined and lamellar membrane organization was disrupted by foci of lamellar/non-lamellar phase separation. These studies demonstrate the presence of a permeability barrier abnormality in Sjögren-Larsson syndrome, which localizes to the stratum corneum interstices and can be attributed to abnormalities in lamellar body formation and secretion.