Macular crystalline inclusions in Sjögren-Larsson syndrome are dynamic structures that undergo remodeling.

BACKGROUND: Sjögren-Larsson syndrome (SLS) is a rare genetic neurocutaneous disease caused by mutations in ALDH3A2 that results in deficiency of fatty aldehyde dehydrogenase and accumulation of fatty aldehydes and alcohols. The disease is associated with ichthyosis, spasticity, and intellectual disability. Patients exhibit a characteristic retinopathy with macular crystalline inclusions that first appear in early childhood and increase with age. Once formed, the inclusions are thought to be inert and irreversible. We sought to document how the crystalline inclusions change over time. MATERIALS AND METHODS: Serial retinal photographs of 4 SLS subjects (9-23 years old) were taken over a period of 1-3 years. Images were compared by visual inspection and analyzed using ImageJ/Fiji software to observe changes. RESULTS: Visual inspection of retinal photographs of SLS subjects taken over time demonstrated distinctive changes in crystalline inclusions. New inclusions were formed and some established inclusions regressed. These changes were conveniently demonstrated with software-based photographic image analysis. CONCLUSIONS: We conclude that macular inclusions in SLS are not simply inert deposits, but are dynamic structures that form over time and are subject to remodeling. This conclusion provides new insight into the interplay between the metabolic defect and retinal pathology in SLS, and raises the potential for new therapeutic approaches to reverse some aspects of the maculopathy.

Disruption of the Sjögren-Larsson Syndrome Gene Aldh3a2 in Mice Increases Keratinocyte Growth and Retards Skin Barrier Recovery.

The fatty aldehyde dehydrogenase (FALDH) ALDH3A2 is the causative gene of Sjögren Larsson syndrome (SLS). To date, the molecular mechanism underlying the symptoms characterizing SLS has been poorly understood. Using Aldh3a2(-/-) mice, we found here that Aldh3a2 was the major FALDH active in undifferentiated keratinocytes. Long-chain base metabolism was greatly impaired in Aldh3a2(-/-) keratinocytes. Phenotypically, the intercellular spaces were widened in the basal layer of the Aldh3a2(-/-) epidermis due to hyperproliferation of keratinocytes. Furthermore, oxidative stress-induced genes were up-regulated in Aldh3a2(-/-) keratinocytes. Upon keratinocyte differentiation, the activity of another FALDH, Aldh3b2, surpassed that of Aldh3a2 As a result, Aldh3a2(-/-) mice were indistinguishable from wild-type mice in terms of their whole epidermis FALDH activity, and their skin barrier function was uncompromised under normal conditions. However, perturbation of the stratum corneum caused increased transepidermal water loss and delayed barrier recovery in Aldh3a2(-/-) mice. In conclusion, Aldh3a2(-/-) mice replicated some aspects of SLS symptoms, especially at the basal layer of the epidermis. Our results suggest that hyperproliferation of keratinocytes via oxidative stress responses may partly contribute to the ichthyosis symptoms of SLS.

The Sjögren-Larsson syndrome gene encodes a hexadecenal dehydrogenase of the sphingosine 1-phosphate degradation pathway.

Sphingosine 1-phosphate (S1P) functions not only as a bioactive lipid molecule, but also as an important intermediate of the sole sphingolipid-to-glycerolipid metabolic pathway. However, the precise reactions and the enzymes involved in this pathway remain unresolved. We report here that yeast HFD1 and the Sjögren-Larsson syndrome (SLS)-causative mammalian gene ALDH3A2 are responsible for conversion of the S1P degradation product hexadecenal to hexadecenoic acid. The absence of ALDH3A2 in CHO-K1 mutant cells caused abnormal metabolism of S1P/hexadecenal to ether-linked glycerolipids. Moreover, we demonstrate that yeast Faa1 and Faa4 and mammalian ACSL family members are acyl-CoA synthetases involved in the sphingolipid-to-glycerolipid metabolic pathway and that hexadecenoic acid accumulates in Δfaa1 Δfaa4 mutant cells. These results unveil the entire S1P metabolic pathway: S1P is metabolized to glycerolipids via hexadecenal, hexadecenoic acid, hexadecenoyl-CoA, and palmitoyl-CoA. From our results we propose a possibility that accumulation of the S1P metabolite hexadecenal contributes to the pathogenesis of SLS.

Sjögren-Larsson syndrome: phenotypic variability in two brothers with a neurocutaneous disorder.

Sjögren-Larsson syndrome (SLS) is a rare autosomal recessively inherited neurocutaneous disorder caused by mutations in the ALDH3A2 gene that encodes fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. It is characterized by an unusual combination of cutaneous and neurologic signs and symptoms. The authors describe two brothers of consanguineous parents with SLS, one of whom was born from a dizygotic twin pregnancy (with an apparently normal sister), and they focus on the variability of the clinical findings of the syndrome even among siblings and twins.

[Sjögren's syndrome: clinical and therapeutic features. A review of the literature]. / La sindrome di Sjgren: aspetti clinici e terapeutici. Revisione della letteratura.

UNLABELLED: Sjögren' Syndrome (SS), also named Sicca Syndrome, is a complex disease, characterized by a series of clinical symptoms and signs chiefly represented by xerostomia, xerophthalmia and connectival diseases. The pathogenetic mechanisms consist of an autoimmune process leading to salivary and lacrimal glands progressive destruction. There is a primary form with salivary and lacrimal glands compromission only and a second form in which xerostomia and/or xerophthalmia are associated with connectival diseases like rheumatoid arthritis, systemic lupus erythematosus and scleroderma. The diagnosis of SS is rather difficult and it is based on various world-wide established and accepted criteria: the labial minor salivary glands biopsy and the research of specific seric autoantibodies are the basic elements. From the therapeutic point of view, various types of immunomodulant treatments based on cyclosporine, corticosteroids, methotrexate or alpha-interferon have been proposed with different RESULTS: Cholinergic drugs, like pilocarpine and cevimeline, are also used in order to stimulate the gland functionality.

Microsomal fatty aldehyde dehydrogenase catalyzes the oxidation of aliphatic aldehyde derived from ether glycerolipid catabolism: implications for Sjögren-Larsson syndrome.

The enzyme that catalyzes the oxidation of fatty aldehyde derived from ether glycerolipid catabolism has not been identified. To determine whether microsomal fatty aldehyde dehydrogenase (FALDH) is responsible, we investigated the metabolism of 1-O-[9, 10-(3)H-octadecyl]-glycerol ([(3)H]OG) in FALDH-deficient cultured cells from patients with Sjögren-Larsson syndrome (SLS) and in mutant Chinese hamster ovary (CHO) cells. Intact fibroblasts from SLS patients incubated with [(3)H]OG showed a selective deficiency (38+/-7% of normal) in the incorporation of radioactivity into fatty acid, but no decrease in incorporation of radioactivity into fatty alcohol, total lipids and phosphatidylethanolamine (PE). Consistent with fatty aldehyde accumulation, incorporation of radioactivity into N-alkyl-phosphatidylethanolamine, which is derived from Schiff base formation of free aldehyde with PE, was 4-fold higher in SLS fibroblasts compared to normal controls. Similar results were seen with SLS keratinocytes, whereas FALDH-deficient CHO cells showed a more profound reduction in radioactive fatty acid to 12+/-2% of normal. These results implicate FALDH in the oxidation of ether-derived fatty aldehyde in human and rodent cells. Metabolism of ether glycerolipids is a previously unrecognized source of fatty aldehyde that may contribute to the pathogenesis of SLS.