Aldh1l2 knockout mouse metabolomics links the loss of the mitochondrial folate enzyme to deregulation of a lipid metabolism observed in rare human disorder.

BACKGROUND: Mitochondrial folate enzyme ALDH1L2 (aldehyde dehydrogenase 1 family member L2) converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 simultaneously producing NADPH. We have recently reported that the lack of the enzyme due to compound heterozygous mutations was associated with neuro-ichthyotic syndrome in a male patient. Here, we address the role of ALDH1L2 in cellular metabolism and highlight the mechanism by which the enzyme regulates lipid oxidation. METHODS: We generated Aldh1l2 knockout (KO) mouse model, characterized its phenotype, tissue histology, and levels of reduced folate pools and applied untargeted metabolomics to determine metabolic changes in the liver, pancreas, and plasma caused by the enzyme loss. We have also used NanoString Mouse Inflammation V2 Code Set to analyze inflammatory gene expression and evaluate the role of ALDH1L2 in the regulation of inflammatory pathways. RESULTS: Both male and female Aldh1l2 KO mice were viable and did not show an apparent phenotype. However, H&E and Oil Red O staining revealed the accumulation of lipid vesicles localized between the central veins and portal triads in the liver of Aldh1l2-/- male mice indicating abnormal lipid metabolism. The metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from ß-oxidation. Specifically, drastically increased plasma acylcarnitine and acylglycine conjugates were indicative of impaired ß-oxidation in the liver. Our metabolomics data further showed that mechanistically, the regulation of lipid metabolism by ALDH1L2 is linked to coenzyme A biosynthesis through the following steps. ALDH1L2 enables sufficient NADPH production in mitochondria to maintain high levels of glutathione, which in turn is required to support high levels of cysteine, the coenzyme A precursor. As the final outcome, the deregulation of lipid metabolism due to ALDH1L2 loss led to decreased ATP levels in mitochondria. CONCLUSIONS: The ALDH1L2 function is important for CoA-dependent pathways including ß-oxidation, TCA cycle, and bile acid biosynthesis. The role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous diseases. On a broader scale, our study links folate metabolism to the regulation of lipid homeostasis and the energy balance in the cell.

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.

Comprehensive Molecular Profiles of Functionally Effective MSC-Derived Extracellular Vesicles in Immunomodulation.

Accumulating evidence indicates that mesenchymal stem/stromal cell-derived extracellular vesicles (MSC-EVs) exhibit immunomodulatory effects by delivering therapeutic RNAs and proteins; however, the molecular mechanism underlying the EV-mediated immunomodulation is not fully understood. In this study, we found that EVs from early-passage MSCs had better immunomodulatory potency than did EVs from late-passage MSCs in T cell receptor (TCR)- or Toll-like receptor 4 (TLR4)-stimulated splenocytes and in mice with ocular Sjögren's syndrome. Moreover, MSC-EVs were more effective when produced from 3D culture of the cells than from the conventional 2D culture. Comparative molecular profiling using proteomics and microRNA sequencing revealed the enriched factors in MSC-EVs that were functionally effective in immunomodulation. Among them, manipulation of transforming growth factor ß1 (TGF-ß1), pentraxin 3 (PTX3), let-7b-5p, or miR-21-5p levels in MSCs significantly affected the immunosuppressive effects of their EVs. Furthermore, there was a strong correlation between the expression levels of TGF-ß1, PTX3, let-7b-5p, or miR-21-5p in MSC-EVs and their suppressive function. Therefore, our comparative strategy identified TGF-ß1, PTX3, let-7b-5p, or miR-21-5p as key molecules mediating the therapeutic effects of MSC-EVs in autoimmune disease. These findings would help understand the molecular mechanism underlying EV-mediated immunomodulation and provide functional biomarkers of EVs for the development of robust EV-based therapies.

Sjögren-Larsson syndrome: a complex metabolic disease with a distinctive ocular phenotype.

Purpose: Sjögren-Larsson Syndrome (SLS) is a rare genetic disorder characterized by a distinctive crystalline maculopathy, congenital ichthyosis, spasticity and intellectual disability. We review the genetic, biochemical and clinical aspects of SLS with a particular focus on the ophthalmologic features of the disease.Methods: Published reports of SLS are combined with clinical experience to provide an overview of this disease.Results: SLS is caused by bi-allelic mutations in ALDH3A2, which codes for fatty aldehyde dehydrogenase, a key enzyme needed for the metabolism of long-chain aliphatic aldehydes and alcohols. SLS patients display perifoveal crystalline inclusions (glistening white dots) that appear in early childhood, vary from sparse to florid and are located in the inner retina. Other findings include retinal thinning, cystic macular degeneration, retinal pigment epithelium atrophy and deficiency of macular pigment. Photophobia is common. Visual evoked potentials are often absent or delayed, whereas electroretinography studies are usually normal. Mild-moderate deficits in visual acuity are common but vision is usually preserved into adulthood. The maculopathy is thought to be due to the accumulation of fatty aldehydes and/or alcohols, which alter membrane function. Defective macular pigment metabolism may also contribute to a unique susceptibility to photo-oxidative damage in the retina.Conclusions: The distinctive retinal phenotype, together with the neurologic and cutaneous symptoms, allows the ophthalmologist to reliably diagnose SLS. Although no effective treatment exists for the ocular symptoms, emerging insight into the pathogenic mechanisms at play in the eye promises to bring effective therapy for SLS in the future.

Síndrome de Sjögren-Larsson: Reporte de caso pediátrico / Sjögren-Larsson syndrome: Pediatric case report

El síndrome de Sjogren-Larsson se caracteriza por retardo mental, ictiosis congènita y diplejía o cuadriplejía espástica. El defecto primario en este síndrome es la mutación del gen ALDH3A2, que codifica la enzima aldehído deshidrogenasa grasa y causa una deficiencia enzimática que produce una acumulación de alcoholes y aldehídos grasos en los tejidos que comprometen la integridad de la membrana celular, cuyos efectos pueden observarse en la piel, los ojos y el sistema nervioso central. El diagnóstico se realiza por medio de la cuantificación de la actividad de la enzima. Se describe el caso de una paciente con signos clínicos patognomónicos del síndrome de Sjogren-Larsson, cuyo diagnóstico se realizó por medio de la cuantificación de la actividad enzimática en un cultivo de fibroblastos. Además, tomando en cuenta el árbol genealógico de la paciente, se realizó el estudio en los padres y un hermano con signos sugestivos del síndrome de Sjogren-Larsson.

Sjogren-Larsson syndrome is characterized by congenital ichthyosis, mental retardation and spastic diplegia or quadriplegia. The primary defect in this syndrome is mutation of ALDH3A2 gen that codes for the fatty aldehyde dehydrogenase. Deficiency of this enzyme causes an accumulation of fatty alcohols and fatty aldehydes, leading to altered cell-membrane integrity. Skin, eyes, and the central nervous system are affected latter. The diagnosis is carried out through the cuantification of the enzyme activity.

Sequence variants in nine different genes underlying rare skin disorders in 10 consanguineous families.

BACKGROUND: Genodermatoses represent genetic anomalies of skin tissues including hair follicles, sebaceous glands, eccrine glands, nails, and teeth. Ten consanguineous families segregating various genodermatosis phenotypes were investigated in the present study. METHODS: Homozygosity mapping, exome, and Sanger sequencing were employed to search for the disease-causing variants in the 10 families. RESULTS: Exome sequencing identified seven homozygous sequence variants in different families, including: c.27delT in FERMT1; c.836delA in ABHD5; c.2453C>T in ERCC5; c.5314C>T in COL7A1; c.1630C>T in ALOXE3; c.502C>T in PPOX; and c.10G>T in ALDH3A2. Sanger sequencing revealed three homozygous variants: c.1718 + 2A>G in FERMT1; c.10459A>T in FLG; and c.92delT in the KRT14 genes as the underlying genetic cause of skin phenotypes. CONCLUSION: This study supports the use of exome sequencing as a powerful, efficient tool for identifying genes that underlie rare monogenic skin disorders.

Inherited ichthyosis: Syndromic forms.

Among diseases that cause ichthyosis as one of the symptoms, there are some diseases that induce abnormalities in organs other than the skin. Of these, diseases with characteristic signs are regarded as syndromes. Although these syndromes are very rare, Netherton syndrome, Sjögren-Larsson syndrome, Conradi-Hünermann-Happle syndrome, Dorfman-Chanarin syndrome, ichthyosis follicularis, atrichia and photophobia (IFAP) syndrome, and Refsum syndrome have been described in texts as representative ones. It is important to know the molecular genetics and pathomechanisms in order to establish an effective therapy and beneficial genetic counseling including a prenatal diagnosis.

Sjögren-Larsson syndrome: novel mutations in the ALDH3A2 gene in a French cohort.

Sjogren-Larsson syndrome (SLS) is a rare autosomal recessive disorder characterized by ichthyosis, spastic di- or tetraplegia and mental retardation due a defect of the fatty aldehyde dehydrogenase (FALDH), related to mutations in the ALDH3A2 gene. In this study, we screened a French cohort of patients with Sjögren-Larsson syndrome (SLS) for mutations in the ALDH3A2 gene. The five unrelated patients with typical SLS all present mutations in this gene. Three novel mutations were identified whereas three other ones were previously described. We also realized functional analyses at the mRNA level for two splice site mutations to study their deleterious consequences. Two of the previously described mutations had already been identified in the same region of Europe, suggesting a putative founder effect. We suggest that, (1) when clinical and MR features are present, direct sequencing of the ALDH3A2 gene in SLS is of particular interest without necessity of a skin biopsy for enzymatic assay in order to propose genetic counsel and (2) identification of mutations already described in the same population with putative founder effects may simplify genetic analysis in this context.

Síndrome Sjögren - Larsson / Sjögren - Larsson syndrome

Relatam-se os casos de dois irmãos consanguíneos com síndrome de Sjögren- Larsson, enfatizando a importância clínica do exame oftalmológico. BPLS, masculino, 11 anos e MBLS, feminino, 10 anos, irmãos de pais não-consanguíneos, apresentando ictiose congênita, diplegia espástica e retardo mental. Ao exame oftalmológico, apresentavam miopia, fotofobia, baixa acuidade visual. A fundoscopia, presença de cristais branco-amarelados em área foveal e parafoveal em ambos os olhos. Aconselhamento genético foi realizado. O manejo foi de suporte. A Síndrome de Sjögren-Larsson é uma rara doença autossômica recessiva em que há 100 por cento de penetrância. Síndrome de Sjögren-Larsson é classicamente caracterizada por ictiose, espasticidade e deficiência mental. A doença é causada por mutações no gene aldeído desidrogenase. As alterações oculares observadas são geralmente bilaterais, cristais branco-amarelados em área retiniana, que aparecem nos dois primeiros anos de vida e que vão aumentando em número com a idade. As anormalidades oculares não têm relação com a severidade da ictiose ou com as anormalidades neurológicas. Acredita-se que as lesões oftalmológicas sejam um sinal patognomônico da síndrome. É necessário enfatizar a importância do diagnóstico precoce e possibilidades de tratamento dietético.

Sjogren - Larsson syndrome is a rare autosomal recessively inherited neurocutaneous disorder which occurs with 100 percent penetrance and is classically characterized by ichthyosis, spasticity and mental handicap. The disease is caused by mutations in the aldehyde dehydrogenase gene. The ocular manifestations are highly characteristic bilateral, glistening yellow-white retinal dots from the age of 1 to 2 years onward. The number of dots increases whit age. The extent of the macular abnormality does not correlate with the severity of the ichthyosis or with the severity of the neurological abnormalities. We report the clinical characteristics and ocular manifestations associated with the Sjögren-Larsson syndrome in two siblings, emphasizing the clinical importance of the ophthalmological examination of the Sjögren-Larsson syndrome. BPLS, a eleven year old boy and MPLS, a ten year old girl from non-consanguinous parents, presenting congenital ichthyosis, spastic diplegia and mental retardation. Miopia, fotofobia, subnormal visual acuity and glistening yellow-white crystalline deposits that were located in the foveal and parafoveal area were found in the ophthalmologic examination.

Sjögren-Larsson syndrome: a case report and literature review.

Sjögren-Larsson syndrome (SLS) is an autosomal recessive neurocutaneous disorder most commonly seen in the Scandinavian population and characterized by congenital ichthyosis, mental retardation, and spastic diplegia or quadriplegia. We report a case of SLS in an 11-month-old girl of Lebanese and Mexican-Syrian ancestry who presented with ichthyosis, developmental delay, and spasticity. Results of an enzymatic assay and genomic DNA testing in cultured skin fibroblasts confirmed a homozygous C237Y mutation. These findings support the rich diversity of mutations associated with this syndrome.

Sjogren-Larsson syndrome.

A 9-year-old boy with classical features of Sjogren-Larsson syndrome was reported. He had had diffuse dry skin with ichthyotic scales since birth. The skin biopsy was compatible with ichthyosis. At the age of two he was unable to walk normally and also had learning problems. Neurological examination revealed spastic paraparesis, macular degeneration and mild mental retardation. MRI of the brain and spinal cord revealed subcortical white matter and corpus callosal lesions as well as focal cerebral atrophy and diffuse spinal cord atrophy.

Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by the presence of congenital ichthyosis, mental retardation, and spastic diplegia or tetraplegia. The ichthyosis is generalized in distribution, and histological features of the skin include hyperkeratosis, papillomatosis, acanthosis, and a mildly thickened granular layer. Electron microscopy shows lamellar membranous inclusions in the granular and cornified cells. SLS patients have impaired fatty alcohol oxidation caused by deficient activity of fatty aldehyde dehydrogenase, a component of the fatty alcohol:NAD+ oxidoreductase complex. This enzymatic defect provides a reliable means for diagnosing SLS patients and unaffected SLS carriers. Prenatal diagnosis of SLS can be accomplished by enzymatic studies of amniocytes and cultured chorionic villi cells, or by histological examination of a fetal skin biopsy. Although still unproven, fatty alcohol accumulation in patients is thought to be responsible for the cutaneous symptoms.

Sjögren-Larsson-like syndrome with bone dysplasia and normal fatty alcohol NAD+ oxidoreductase activity.

We report a boy and girl with a "new" multiple congenital anomalies/mental retardation syndrome which resemblances Sjögren-Larsson syndrome. Both patients had a concordant pattern of anomalies consisting of congenital lamellar ichthyosis with spontaneous improvement, moderate mental retardation, mild pyramidal involvement, telecanthus, flat facies, stubby long bones, and coxa valga. Severe myopia, ventriculoseptal defect, and postaxial polydactyly were present in the girl who had more severe bone involvement with dense, enlarged metaphyses, vertebral dysplasia, and advanced skeletal maturation of the lower limbs. Long-chain fatty alcohol NAD+ oxidoreductase (FAO) and steroid sulfatase were normal.

Sjögren-Larsson syndrome: case reports.

Sjögren-Larsson syndrome (SLS) is a rare, autosomal recessive disorder with worldwide distribution. It consists of ichthyosis, spastic diplegia, and mental retardation. An enzymatic defect in fatty alcohol oxidation recently was identified and is thought to be responsible for the disorder. We report two siblings with SLS. In addition to the typical features of the syndrome, the sister had marked hyperkeratosis of the palms and soles, which is rarely seen to this degree. The brother had joint hyperextensibility, which has not been reported previously. Both individuals had documented deficient activity of fatty alcohol:NAD+ oxidoreductase.