Sjögren–Larsson syndrome: phenotypic variability in two brothers with a neurocutaneous disorder (original) (raw)
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Sjögren-Larsson syndrome: report of monozygote twins and a case with a novel mutation
The Turkish journal of pediatrics
Sjögren-Larsson syndrome is an autosomal recessive neurocutaneous disease caused by mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, a microsomal enzyme that catalyzes the oxidation of medium- and long-chain aliphatic aldehydes fatty acids. We studied three Turkish Sjögren-Larsson syndrome patients with ichthyosis, developmental delay, spastic diplegia, and brain white matter disease. One patient was homozygous for a novel ALDH3A2 mutation in exon 5. The mutation involves the codon 228 (CGC) with the transversion G->A modifying the codon in CAC, leading to the substitution of the original arginine with a histidine (R228H), modifying the stereospecific properties of this region. These results add to the understanding of the genetic basis of Sjögren-Larsson syndrome and will be useful for DNA diagnosis of this disease.
Molecular Genetics and Metabolism, 2007
Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder caused by mutations in the ALDH3A2 gene that encodes fatty aldehyde dehydrogenase (FALDH), an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. Affected patients display ichthyosis, mental retardation and spastic diplegia. More than 70 mutations in ALDH3A2 have been discovered in SLS patients including amino acid substitutions, deletions, insertions and splicing errors. Most mutations are private, but several common mutations reflect founder effects, consanguinity or recurrent mutational events. FALDH oxidizes fatty aldehyde substrates arising from metabolism of fatty alcohols, leukotriene B4, ether glycerolipids and other potential sources such as sphingolipids. The pathogenesis of the cutaneous and neurologic symptoms is thought to result from abnormal lipid accumulation in the membranes of skin and brain; the formation of aldehyde Schiff base adducts with amine-containing lipids or proteins; or defective eicosanoid metabolism. Therapeutic approaches are being developed to target specific metabolic defects associated with FALDH deficiency or to correct the genetic defect by gene transfer.
Case Report: Sjogren-Larsson Syndrome: Two Cases from One Family
Journal of Rehabilitation, 2006
Sjogren–Larsson Syndrome (SLS) is an autosomal recessive disorder characterized by generalized Ichthyosis, mental retardation, spastic diplegia or tetraplegia and epilepsy. This is a rare syndrome that caused by mutation in the ALDH3A2 gene, on chromosome 17p11.2. That encodes fatty aldehyde dehydrogenase (FAIDH), an enzyme that catalyzes the oxidation of medium – long chain aldehydes derived from lipid metabolism. Neuroimaging (MRI) shows retardation of myelination and a mild myelin deficit. Proton Magnetic Resonance Spectroscopy (MRS) shows the peak of lipids that accumulate because of fatty alchohols. We report two cases that they are siblings from relative parents. The Brother is 4 years old and his sister is 3 years old. , The clinical findings are developmental delay, mental retardation, spastic Tetraplegia and refractory seizure. The most important finding in these two siblings was generalized Icthyosis. MRI showed hyper signality in white matter and MRS showed the peak of ac...
Journal of the American Academy of Dermatology, 1996
Background: The Sj6gren-Larsson syndrome is a rare condition characterized by ichthyosis, spasticity, and mental retardation. Patients have deficient activity of the aldehyde portion of the fatty alcohol:nicotirlamide adenine denucleotide (NAD +) oxidoreductase complex. Objective: Our purpose was to describe atypical findings in three siblings with the Sj6gren-Larsson syndrome and implications regarding diagnosis. Methods: Medical histories were taken and physical examinations performed on four siblings and their parents. Analysis of fibroblast fatty alcohol:NAD + oxidoreductase or fatty aldehyde dehydrogenase activity (or of both) was determined in each. Results: Decreased fibroblast fatty alcohol:NAD + oxidoreductase or fatty aldehyde dehydrognase levels (or both) were present in three of four siblings. The fourth sibling and the parents had levels similar to obligate heterozygotes. None of the affected siblings fulfilled the classic criteria for the syndrome. Conclusion: Although all affected siblings had abnormally low activity of the fatty alcohol:NAD + dehydrogenase complex, their clinical findings were variable. This divergence of clinical features in siblings has not been previously reported. We propose that deficient activity of the fatty alcohol:NAD + dehydrogenase complex be considered part of the definition of the Sj6gren-Larsson syndrome that would also include the probable, but not absolute, presence of ichthyosis, mental retardation, and spasticity.
Sj�gren-Larsson syndrome: Seven novel mutations in the fatty aldehyde dehydrogenase gene ALDH3A2
Human Mutation, 2004
Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disease caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase (FALDH), an enzyme involved in lipid metabolism. We performed mutation analysis in probands or fetuses from 13 unrelated SLS families and identified seven novel ALDH3A2 mutations. Two mutations involved an insertion or deletion of a single guanine nucleotide at the same position in exon 9: c.1223delG and c.1223_1224insG. A 66-bp duplication in exon 2 probably arose from unequal crossing over within a mispaired 10-bp sequence that is normally repeated within the exon. Based on RT-PCR of fibroblast RNA, the c.1107+2T>G donor splice-site mutation in intron 7 produced two mRNA transcripts, one skipping exon 7 and the other skipping exons 6-8. Expression of the c.1139G>A mutation in exon 8, which is predicted to cause an amino acid substitution (Ser380Asn) in an evolutionarily conserved region of the FALDH catalytic domain, resulted in a protein with profoundly reduced enzymatic activity. By analyzing single nucleotide polymorphisms within the ALDH3A2 gene, we detected four different haplotypes among the new mutant alleles. These results demonstrate a rich diversity of mutations and haplotype associations in SLS.
Sjögren‐Larsson syndrome: The mild end of the phenotypic spectrum
JIMD Reports
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
Genetics of Sjögren Larsson Syndrome and a Case
2002
Sjögren Larsson syndrome (SLS) is a rare autosomal disorder that is characterised by congenital ichthyosis, spastic diplegia or qudriplegia and mental retardation. It is caused by the deficiency of the enzyme, fatty aldehyde dehydrogenase (FALDH) that is required for the oxidation of fatty alcohol to fatty acid. The metabolism of leukotrine B4 (LTB4) has also been reported to be defective in SLS patients. The gene, ADLH3A2, encoding for FALDH has been localised at 17p11.2 and mutations in it cause SLS. The worldwide frequency of SLS is reported to be less than 1: 100,000 births but rarely a case has been reported from India. This article reviews the genetic factors in SLS and reports a case of SLS from India, with two similarly affected sibs. The management of SLS including genetic counselling and prenatal diagnostic possibilities are also discussed.
Brain, 2001
Sjögren-Larsson syndrome (SLS) is an autosomal recessively inherited neurocutaneous disorder caused by a deficiency of the microsomal enzyme fatty aldehyde dehydrogenase (FALDH). We report the clinical characteristics and the results of molecular studies in 19 SLS patients. Patients 1-17 show the classical triad of severe clinical abnormalities including ichthyosis, mental retardation and spasticity. Most patients were born preterm, and all patients exhibit ocular abnormalities and pruritus. Electro-encephalography shows a slow background activity, without other abnormalities. MRI of the brain shows an arrest of myelination, periventricular signal abnormalities of white matter and mild ventricular enlargement. Cerebral 1 H-MR spectroscopy reveals a characteristic, abnormal lipid peak. The degree of white matter abnormality in the MRIs and the height of the lipid peak in 1 H-MR spectra do not correlate with the
Sjögren-Larsson syndrome : case reports
Pediatric Dermatology, 1991
Sjdgren-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 recentiy was identified and is thought to be responsible for the disorder. We report two sibiings 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 hyperextensibiiity. which has not been reported previously. Both individuals had documented deficient activity of fatty alcohoiiNAD* oxidoreductase.
Sjögren–Larsson syndrome: Novel mutations in the ALDH3A2 gene in a French cohort
Journal of The Neurological Sciences
Sjogren-Larsson syndrome (SLS) is a rare autosomal recessive disorder characterized by ichthyosis, spastic dior 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.