Deficiency Of Fatty Aldehyde Dehydrogenase Research Articles

Discovery of novel diagnostic biomarkers for Sjögren-Larsson syndrome by untargeted lipidomics

AimSjögren-Larsson syndrome (SLS) is a rare neurometabolic disorder that mainly affects brain, eye and skin and is caused by deficiency of fatty aldehyde dehydrogenase. Our recent finding of a profoundly disturbed brain tissue lipidome in SLS prompted us to search for similar biomarkers in plasma as no functional test in blood is available for SLS. Methods and resultsWe performed plasma lipidomics and used a newly developed bioinformatics tool to mine the untargeted part of the SLS plasma and brain lipidome to search for SLS biomarkers. Plasma lipidomics showed disturbed ether lipid metabolism in known lipid classes. Untargeted lipidomics of both plasma and brain (white and grey matter) uncovered two new endogenous lipid classes highly elevated in SLS. The first biomarker group were alkylphosphocholines/ethanolamines containing different lengths of alkyl-chains where some alkylphosphocholines were > 600-fold elevated in SLS plasma. The second group of biomarkers were a set of 5 features of unknown structure. Fragmentation studies suggested that they contain ubiquinol and phosphocholine and one feature was also found as a glucuronide conjugate in plasma. The plasma features were highly distinctive for SLS with levels >100–1000-fold the level in controls, if present at all. We speculate on the origin of the alkylphosphocholines/ethanolamines and the nature of the ubiquinol-containing metabolites. ConclusionsThe metabolites identified in this study represent novel endogenous lipid classes thus far unknown in humans. They represent the first plasma metabolite SLS-biomarkers and may also yield more insight into SLS pathophysiology.

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 infiltrateand 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.

Sjögren-Larsson syndrome: The mild end of the phenotypic spectrum.

Sjögren‐Larsson syndrome (SLS) is a rare inborn error of lipid metabolism. The syndrome is caused by mutations in the ALDH3A2 gene, resulting in a deficiency of fatty aldehyde dehydrogenase. Most patients have a clearly recognizable severe phenotype, with congenital ichthyosis, intellectual disability, and spastic diplegia. In this study, we describe two patients with a remarkably mild phenotype. In both patients, males with actual ages of 45 and 61 years, the diagnosis was only established at an adult age. Their skin had been moderately affected from childhood onward, and both men remained ambulant with mild spasticity of their legs. Cognitive development, as reflected by school performance and professional career, had been unremarkable. Magnetic resonance spectroscopy of the first patient was lacking the characteristic lipid peak. We performed a literature search to identify additional SLS patients with a mild phenotype. We compared the clinical, radiologic, and molecular features of the mildly affected patients with the classical phenotype. We found 10 cases in the literature with a molecular proven diagnosis and a mild phenotype. Neither a genotype‐phenotype correlation nor an alternative explanation for the strikingly mild phenotypes was found. New biochemical techniques to study the underlying metabolic defect in SLS, like lipidomics, may in the future help to unravel the reasons for the exceptionally mild phenotypes. In the meantime, it is important to recognize these mildly affected patients to provide them with appropriate care and genetic counseling, and to increase our insights in the true disease spectrum of SLS.

Sjogren-Larsson Syndrome: Mechanisms and Management.

Sjogren Larsson syndrome (SLS) is a rare autosomal recessive inborn error of lipid metabolism due to mutations in the ALDH3A2 that result in a deficiency of fatty aldehyde dehydrogenase (FALDH). The syndrome has a high prevalence in Sweden where it was first described, but now known to occur worldwide. The classical triad of ichthyosis, mental retardation and spasticity characterizes clinical features. Preterm birth is common. “Glistening white dots” in the retina is a pathognomic clinical feature. Magnetic resonance imaging of the brain demonstrates leukoencephalopathy predominant in the periventricular region. Cerebral MR spectroscopy reveals a characteristic abnormal lipid peak at 1.3ppm and a small peak at 0.9ppm. The primary role of FALDH is oxidation of medium and long-chain aliphatic aldehydes derived from fatty alcohol, phytanic acid, ether glycerolipids and sphingolipids. The diagnosis is based on the typical phenotype, demonstration of the enzyme deficiency and presence of biallelic mutations in the ALDH3A2. The management of SLS largely remains symptomatic currently. However, several potential therapeutic options are being developed, keeping in view of the fundamental metabolic defects or correcting the genetic defect. This review aims to summarize the clinical, genetic and biochemical findings, pathogenetic mechanisms and the current therapeutic options, in SLS.

Understanding fetal factors that contribute to preterm birth: Sjögren-Larsson syndrome as a model.

Preterm birth is the world's leading cause of neonatal death. Unfortunately, the pathophysiology of preterm birth remains poorly understood. Sjögren-Larsson syndrome is a rare, neurometabolic disorder caused by a fatty aldehyde dehydrogenase deficiency. A majority of patients with Sjögren-Larsson syndrome is born preterm. Data of all known Dutch patients with Sjögren-Larsson syndrome and all cases reported in literature were analyzed to learn from preterm birth in context of this rare disease. Exact gestational age was known in 33 Dutch patients; 24 (73%) of them were born preterm, with a median gestational age of 36 weeks. The literature search confirmed our findings: 13 (59%) of 22 cases was born preterm. Preterm birth is a hallmark of Sjögren-Larsson syndrome, presumably caused by the abnormal lipid metabolism of the fetus. At least five additional rare genetic disorders (namely Ehlers-Danlos syndrome, ichthyosis prematurity syndrome, congenital analbuminemia, osteogenesis imperfecta type II and restrictive dermopathy) were found in literature that lead to preterm birth of the affected fetus. These disorders are in fact "experiments of nature" and as such they shed new lights on the mechanisms causing preterm birth.

Shogren Larson disease, a rare disease. Case report from Azerbaijan

Keywords: Diplegia, icthyosis, MRI, Sjogren-Larsson syndrome Introduction: Sjogren–Larsson syndrome (SLS) is a recessively inherited disease with congenital ichthyosis, spastic diplegia or tetraplegia , macular degeneration of retina, specific MRI abnormalities and mental retardation, caused by a deficiency of fatty aldehyde dehydrogenase. This disease can be identified by a triad of medical disorders. The first is ichthyosis, which is a buildup of skin to form a scale-like covering that causes dry skin and other problems. The second identifier is spastic paraplegia which is characterized by leg spasms. The final identifier is mental retardation. Case Report: A 7 year old female child born from a consanguineous marriage presented to our neurology department with complaints of spasticity of low extremities, gait problems and mental retardation. She also complaints of a skin ailment since infancy. On detailed history the child had delay head holding (6 month), sitting without support after 1 year age and walking with support after 2 years old. Stiffness in low limbs started and increased and in our neurological examination we determined increased tone in both lower limbs, brisk deep tendon reflexes, bilateral extensor plantar response suggestive of spastic diplegia. The child had mild mental retardation and not any determined speech abnormalities. Child had a normal head circumference for her age. Eye and limb movements were normal. On the fundus examination there was founded abnormalities consisting of increased macular pigmentation of retina. Skin examination showed ichthyotic lesions affecting all body parts, most presented over trunk and hands and which started few days after the birth. The MRI of brain showed diffuse and symmetrical high signal intensity in bilateral deep periventricular white matter. Ventricles and gray matter of brain, corpus callosum, thalami,brainstem, and cerebellar hemispheres were normal. All this clinical, radiological and opthalmologycal findings were diagnostic as rare disease-Sjogren-Larsson syndrome.

166. Lentiviral Hematopoietic Stem Cell Gene Therapy for Sjögren-Larsson Syndrome

Sjogren-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.

Disorders of phospholipids, sphingolipids and fatty acids biosynthesis: toward a new category of inherited metabolic diseases

We wish to delineate a novel, and rapidly expanding, group of inborn errors of metabolism with neurological/muscular presentations: the defects in phospholipids, sphingolipids and long chain fatty acids biosynthesis. At least 14 disorders have been described so far. Clinical presentations are diverse but can be divided into (1) diseases of the central nervous system; (2) peripheral neuropathies; and (3) muscular/cardiac presentations. (1) Leukodystrophy and/or iron deposits in basal ganglia is a common feature of phospholipase A2 deficiency, fatty acid hydroxylase deficiency, and pantothenate kinase-associated neurodegeneration. Infantile epilepsy has been reported in GM3 synthetase deficiency. Spastic quadriplegia with ichthyosis and intellectual disability are the presenting signs of the elongase 4 deficiency and the Sjogren-Larsson syndrome caused by fatty aldehyde dehydrogenase deficiency. Spastic paraplegia and muscle wasting are also seen in patients with mutations in the neuropathy target esterase gene. (2) Peripheral neuropathy is a prominent feature in PHARC syndrome due to α/β-hydrolase 12 deficiency, and in hereditary sensory autonomic neuropathy type I due to serine palmitoyl-CoA transferase deficiency. (3) Muscular/cardiac presentations include recurrent myoglobinuria in phosphatidate phosphatase 1 (Lipin1) deficiency; cardiomyopathy and multivisceral involvement in Barth syndrome secondary to tafazzin mutations; congenital muscular dystrophy due to choline kinase deficiency, Sengers syndrome due to acylglycerol kinase deficiency and Chanarin Dorfman syndrome due to α/β- hydrolase 5 deficiency. These synthesis defects of complex lipid molecules stand at the frontier between classical inborn errors of metabolism and other genetic diseases involving the metabolism of structural proteins.

The role of fatty aldehyde dehydrogenase in epidermal structure and function

The epidermal water barrier resides in the stratum corneum (SC) and is dependent on a highly organized network of multi-lamellar membranes comprised of a critical lipid composition. The SC membranes are formed from precursor membranes packaged in cytoplasmic lamellar bodies in the stratum granulosum and delivered to the SC by exocytosis. An abnormal lipid composition of the SC membranes often results in a disrupted water barrier and the clinical appearance of ichthyosis. This cutaneous feature is characteristic of Sjögren-Larsson syndrome (SLS), an inborn error of lipid metabolism caused by deficiency of fatty aldehyde dehydrogenase (FALDH). The contribution of FALDH to normal epidermal function has become increasingly evident with the recognition that this enzyme has an essential role in metabolism of several lipids, including fatty aldehydes and alcohols, ether glycerolipids, isoprenoid alcohols and certain lipids that undergo ω-oxidation, such as leukotriene B4 and very long-chain fatty acids. In the absence of FALDH, the skin produces lamellar bodies that are empty, lack their surrounding vesicle membranes or contain granular contents rather then the usual cargo membranes. These defective organelles also have impaired exocytosis, which results in structurally abnormal, deficient multi-lamellar membranes in the SC and a leaky water barrier. Although the exact biochemical mechanism for the cutaneous pathology is still unclear, studies in SLS demonstrate the critical importance of FALDH for normal epidermal structure and function.

Sjögren-Larsson Syndrome: A Study of Clinical Symptoms and Dermatological Treatment in 34 Swedish Patients

Sjögren-Larsson syndrome (SLS) is a recessively inherited disease with congenital ichthyosis, spastic diplegia or tetraplegia and mental retardation, caused by a deficiency of fatty aldehyde dehydrogenase. The aim of this study was to examine all 34 Swedish patients with SLS, emphasizing skin symptoms, dermatological treatment, and neurological symptoms (evaluated in some cases for more than 25 years by one and the same investigator). Structured interviews were conducted with the patients and their close relatives. All patients had generalized ichthyosis. The degree of scaling varied markedly inter-individually from moderate to severe, but there was no obvious change with age. Most patients had pruritus, suffered from hypohidrosis, and had palmo-plantar keratoderma. Nineteen patients (56%) were on oral acitretin and all patients were using some type of topical therapy. Motor disability with spasticity and muscular paresis was most pronounced in the legs and fairly slight in the arms. Twenty patients (59%) were dependent on a wheelchair for mobility. Poor blood circulation in the lower legs and oedematous feet were frequently found in adults. All patients had learning disability, which varied from slight to pronounced and was expressed in their speech disorders. Thirteen patients (38%) were being treated medically for epilepsy and all had photophobia. In conclusion, SLS is a chronic, severely disabling neurocutaneous disease in which optimal dermatological therapy is essential to relieve at least the patient's ichthyosis problem.

Abnormal fatty alcohol metabolism in cultured keratinocytes from patients with Sjögren-Larsson syndrome

Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder characterized by ichthyosis, mental retardation, spasticity, and deficient activity of fatty aldehyde dehydrogenase (FALDH). FALDH is an enzyme component of fatty alcohol:NAD oxidoreductase (FAO), which is necessary for fatty alcohol metabolism. To better understand the biochemical basis for the cutaneous symptoms in this disease, we investigated lipid metabolism in cultured keratinocytes from SLS patients. Enzyme activities of FALDH and FAO in SLS cells were <10% of normal. SLS keratinocytes accumulated 45-fold more fatty alcohol (hexadecanol, octadecanol, and octadecenol) than normal, whereas wax esters and 1-O-alkyl-2,3-diacylglycerols were increased by 5.6-fold and 7.5-fold, respectively. SLS keratinocytes showed a reduced incorporation of radioactive octadecanol into fatty acid (24% of normal) and triglyceride (13% of normal), but incorporation into wax esters and 1-O-alkyl-2,3-diacylglycerol was increased by 2.5-fold and 2.8-fold, respectively. Our results indicate that FALDH deficiency in SLS keratinocytes causes the accumulation and diversion of fatty alcohol into alternative biosynthetic pathways. The striking lipid abnormalities in cultured SLS keratinocytes are distinct from those seen in fibroblasts and may be related to the stratum corneum dysfunction and ichthyosis in SLS.

Sjögren‐Larsson syndrome

Sjögren-Larsson syndrome is a recessively inherited syndrome caused by deficiency of fatty aldehyde dehydrogenase. The most common symptoms and signs are described, especially ichthyosis, spastic diplegia, and severe learning difficulties; but also other less frequent ones. Special investigations include sensory evoked potentials, electromyography, and proton magnetic resonance spectroscopy. Post-mortem examination shows, in particular, an accumulation of lipid substances in specific regions of the brain. The diagnosis depends on the measurement of fatty aldehyde dehydrogenase in cultured fibroblasts from skin biopsies, and by identifying known mutations by allele-specific polymerase chain reaction assay. Prenatal diagnosis is possible by using the same technique. The disorder is located on gene 17, and many mutations have been identified. Most mutations are unique to an affected family, but clinical variations may be due to unknown genetic and environmental factors. The deficiency of the enzyme impairs the oxidation of medium and long chain fatty aldehydes, and this may explain the link between the brain and skin disorders. The treatment of affected children needs input from a number of specialists, and their contributions are discussed.

Bezafibrate induces FALDH in human fibroblasts; implications for Sjögren-Larsson syndrome

Sjögren-Larsson syndrome (SLS) is caused by a deficiency of fatty aldehyde dehydrogenase (FALDH), encoded by the ALDH3A2 gene. In animal studies, the expression of the murine ortholog of FALDH, has been shown to be under the control of peroxisome proliferator-activated receptor α (PPARα). In the present study, we investigated whether the hypolipidemic drug bezafibrate, which is a pan-agonist of all PPAR-isoforms, might induce FALDH activity in human fibroblasts of control subjects and SLS patients that still have some residual FALDH activity. Our results show that FALDH activity was induced 1.4-fold after a 3-day treatment with 800 μM bezafibrate in fibroblasts of control subjects. Interestingly, in fibroblasts of two SLS patients homozygous for the p.R228C substitution, FALDH activity could be induced to 37% of control values by bezafibrate treatment. mRNA analysis in fibroblasts of these patients also revealed a mean 1.8-fold induction of FALDH mRNA after bezafibrate treatment. No induction was observed in fibroblasts of patients with mutations that cause instability of FALDH mRNA or that result in a protein without any residual activity. These data suggest that bezafibrate treatment could be effective in patients with expression of FALDH protein and some residual enzyme activity. Further research is needed to resolve whether patients could benefit from treatment with bezafibrate.

Phenotypic Variability Among Adult Siblings With Sjögren-Larsson Syndrome

Sjögren-Larsson syndrome (SLS) is an early childhood-onset disorder with ichthyosis, mental retardation, spastic paraparesis, macular dystrophy, and leukoencephalopathy caused by the deficiency of fatty aldehyde dehydrogenase due to mutations in the ALDH3A2 gene (the gene that encodes microsomal fatty aldehyde dehydrogenase). Cerebral proton magnetic resonance spectroscopy in those with SLS demonstrates an abnormal white matter peak at 1.3 ppm, consistent with long-chain fatty alcohol accumulation. To define the clinical course and proton magnetic resonance spectroscopic findings of SLS in adults. Case series in a tertiary care center. Six siblings of a consanguineous Arab family with early childhood-onset SLS who carry the 682C-->T mutation in the ALDH3A2 gene were reinvestigated in adulthood. The 6 affected siblings ranged in age from 16 to 36 years. All exhibited the typical clinical and imaging manifestations of SLS, but their severity markedly varied. Neurological involvement was apparently nonprogressive, and its severity showed no correlation with age. Cerebral proton magnetic resonance spectroscopy showed a lipid peak at 1.3 ppm, with decreasing intensity in the older siblings. These observations document significant clinical variability and the nonprogressive neurological course of SLS in adult siblings with the same ALDH3A2 genotype, and demonstrate possible correlation of proton magnetic resonance spectroscopic changes with age, suggesting unknown pathogenic mechanisms to compensate for the responsible biochemical defect in this disease.

A novel assay for the prenatal diagnosis of Sjögren–Larsson syndrome

Sjögren-Larsson syndrome (SLS) is a metabolic disorder characterized by ichthyosis, mental retardation and spastic diplegia or tetraplegia. The biochemical defect has been identified as a deficiency of fatty aldehyde dehydrogenase (FALDH), which is part of an enzyme complex that converts fatty alcohols into fatty acids. Making use of the finding that FALDH is also involved in the degradation of phytol, we set up an enzymatic assay for the prenatal diagnosis of SLS in cultured chorionic villus fibroblasts (CVF) based on a deficiency in the conversion of phytol to phytenic acid. FALDH activity was assessed by incubating fibroblast homogenates with phytol in the presence of NAD+, followed by hexane extraction of the samples and quantification of phytenic acid production by gas chromatography-mass spectrometry (GC-MS). FALDH activity could be detected in cultured CVF cells derived from control fetuses and the activity was found to be markedly deficient in cultured CVF cells derived from an affected SLS fetus. The new assay described in this paper has advantages over previous assays and we conclude that it may well contribute to the prenatal detection of SLS.

Sjögren-Larsson syndrome: clinical and MRI/MRS findings in FALDH-deficient patients.

To determine the spectrum of clinical and MRI/1H MRS features of patients with fatty aldehyde dehydrogenase (FALDH) deficiency. The Sjogren-Larsson syndrome (SLS) was originally defined as a clinical triad consisting of ichthyosis, spastic di- or tetralegia, and mental retardation, with autosomal recessive inheritance. By now, both the deficiency of the enzyme FALDH, and the genetic mutations on chromosome 17 responsible for this deficiency, have been identified. SLS, defined by fibroblast FALDH deficiency, seems to be a much broader syndrome. The clinical findings of 11 FALDH-deficient patients of different ages and one patient with the characteristic SLS-like ichthyosis, but without FALDH deficiency, were evaluated in relation to their cerebral MRI, and to 1H MRS in six patients. The severity of neurologic symptoms showed considerable variation. Fundoscopic perifoveal glistening dots and the characteristic SLS-like ichthyosis were present in all patients. Serial MRI findings showed evidence of retarded myelination and a variable degree of dysmyelination. 1H MRS showed an accumulation of free lipids in the periventricular white matter, even before the stage of visible dysmyelination. The neurologic consequences of FALDH deficiency show considerable variation. The characteristic pattern of ichthyosis and retinal degeneration are seen consistently, yet they are not pathognomonic. MRI and 1H MRS findings suggest an accumulation of long-chain fatty alcohol intermediates, resulting in retarded myelination and dysmyelination.

Genomic Organization and Expression of the Human Fatty Aldehyde Dehydrogenase Gene (FALDH)

Mutations in the fatty aldehyde dehydrogenase (FALDH) gene cause Sjögren-Larsson syndrome (SLS)—a disease characterized by mental retardation, spasticity, and congenital ichthyosis. To facilitate mutation analysis in SLS and to study the pathogenesis of FALDH deficiency, we have determined the structural organization and characterized expression of the FALDH (proposed designation ALDH10) gene. The gene consists of 10 exons spanning about 30.5 kb. A TATA-less promoter is associated with the major transcription initiation site found to be 258 bp upstream of the ATG codon. The GC-rich sequences surrounding the transcription initiation site encompassed regulatory elements that interacted with proteins in HeLa nuclear extracts and were able to promote transcriptionin vitro.FALDH is widely expressed as three transcripts of 2, 3.8, and 4.0 kb, which originate from multiple polyadenylation signals in the 3′ UTR. An alternatively spliced mRNA was detected that contains an extra exon and encodes an enzyme that is likely to have altered membrane-binding properties. The FALDH gene lies only 50–85 kb from ALDH3, an aldehyde dehydrogenase gene that has homologous sequence and intron/exon structure.

Prenatal diagnosis of Sjögren‐Larsson syndrome using enzymatic methods

Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by the presence of congenital ichthyosis, mental retardation, and spasticity. The primary biochemical defect in SLS has recently been identified to be a deficiency of fatty aldehyde dehydrogenase (FALDH), which is a component of fatty alcohol:NAD+ oxidoreductase (FAO). We monitored four pregnancies at risk for SLS by measuring FAO and FALDH in cultured amniocytes or cultured chorionic villus cells. The enzymatic results in one case using amniocytes obtained during the second trimester predicted an affected SLS fetus, which was confirmed at termination of the pregnancy. Another at-risk fetus was predicted to be affected with SLS using cultured chorionic villus cells obtained in the first trimester, and fetal skin fibroblasts confirmed a profound deficiency of FAO and FALDH. Two other fetuses were correctly predicted to be unaffected. These results demonstrate that SLS can be diagnosed prenatally using enzymatic methods.

Sjögren-Larsson syndrome. Deficient activity of the fatty aldehyde dehydrogenase component of fatty alcohol:NAD+ oxidoreductase in cultured fibroblasts.

Sjögren-Larsson syndrome (SLS) is an inherited disorder associated with impaired fatty alcohol oxidation due to deficient activity of fatty alcohol:NAD+ oxidoreductase (FAO). FAO is a complex enzyme which consists of two separate proteins that sequentially catalyze the oxidation of fatty alcohol to fatty aldehyde and fatty acid. To determine which enzymatic component of FAO was deficient in SLS, we assayed fatty aldehyde dehydrogenase (FALDH) and fatty alcohol dehydrogenase in cultured fibroblasts from seven unrelated SLS patients. All SLS cells were selectively deficient in the FALDH component of FAO, and had normal activity of fatty alcohol dehydrogenase. The extent of FALDH deficiency in SLS cells depended on the aliphatic aldehyde used as substrate, ranging from 62% of mean normal activity using propionaldehyde as substrate to 8% of mean normal activity with octadecanal. FALDH activity in obligate SLS heterozygotes was partially decreased to 49 +/- 7% of mean normal activity using octadecanal as substrate. Differential centrifugation studies in fibroblasts indicated that this FALDH enzyme was largely particulate; soluble FALDH activity was normal in SLS cells. Intact SLS fibroblasts oxidized octadecanol to fatty acid at less than 10% of the normal rate, but oxidized free octadecanal normally, suggesting that the FALDH affected in SLS is chiefly involved in the oxidation of fatty alcohol to fatty acid. These results show that the primary enzymatic defect in SLS is the FALDH component of the FAO complex, which leads to deficient oxidation of fatty aldehyde derived from fatty alcohol.