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

Rizzo, William B.; Craft, Debra A.

doi:10.1172/jci115478

Cited by 141 publications

(125 citation statements)

References 19 publications

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“…This enzyme catalyses the oxidation of long chain aldehyde to fatty acids 2,3 . Due to deficiency of this enzyme, there is an accumulation of aldehyde-modified lipids or fatty alcohol in the skin and in the myelin.…”

Section: Discussionmentioning

confidence: 99%

“…SLS is an inborn error of lipid metabolism caused by a deficiency of the microsomal enzyme fatty aldehyde dehyd rogenase (FALDH), a component of the fatty alcohol: NAD + o x i d o reductase enzyme complex. FA L D H deficiency may lead to an accumulation of long-chain fatty alcohols with structural consequences for cellmembrane integrity, which disrupt the barrier function of the skin and the white matter of the brain 3 .…”

mentioning

confidence: 99%

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MRI and ¹H-MRS findings of three patients with Sjögren-Larsson syndrome

Nakayama

Távora

Alvim

et al. 2006

Arq. Neuro-Psiquiatr.

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-Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive neurocutaneous disorder caused by deficiency of the microsomal enzyme fatty aldehyde dehydrogenase. Patients present the classical triad of congenital ichthyosis, mental re t a rdation and spastic di-or tetraplegia. Magnetic resonance imaging (MRI) of the brain usually shows hypomyelination involving the periventricular white matter. Cere b r a l p roton MR spectroscopy ( 1 H-MRS) reveals a characteristic abnormal lipid peak. We re p o rt three cases of SLS from different families with the typical clinical triad. The MRI and 1 H-MRS findings are discussed.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

MRI and ¹H-MRS findings of three patients with Sjögren-Larsson syndrome

Nakayama

Távora

Alvim

et al. 2006

Arq. Neuro-Psiquiatr.

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“…Cultured fibroblasts of patients with SLS were shown to have deficient activity of fatty aldehyde dehydrogenase (FALDH), 5 an enzyme that is necessary for the oxidation of fatty alcohol to fatty acid as a component of the fatty alcohol: NAD + oxidoreductase (FAO) enzyme complex. 6 Therefore, affected patients with impaired fatty alcohol oxidation accumulate long-chain fatty alcohol in their tissues.…”

Section: Introductionmentioning

confidence: 99%

RNA-based mutation screening in German families with Sjögren-Larsson syndrome

et al. 2000

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Sjögren-Larsson syndrome (SLS) is a rare autosomal recessively inherited disorder characterised by mental retardation, spasticity and ichthyosis. SLS patients have a profound deficiency in fatty aldehyde dehydrogenase (FALDH) activity. The human cDNA of FALDH has been shown to map to the SLS locus on chromosome 17p11.2. Here we describe a method based on reverse transcriptase-polymerase chain reaction (RT-PCR) and protein truncation test to identify mutations in the FALDH gene in nine German SLS families. Using this detection system both disease-causing mutations were found in eight of the nine SLS families examined (17/18 chromosomes). Seven different mutations were identified: an exon 2 skipping due to exon 2 splice donor mutation; two different exon 3 splice donor mutations resulting in combined exon 2 and 3 skipping; a 906delT deletion in exon 6; a genomic deletion of about 6 kb including exon 9; a 1277T > G transversion resulting in a Leu426Ter nonsense mutation; and a 1297delGA deletion. Two of the mutations identified, the genomic exon 9 deletion and the 906delT in exon 6 affected five out of seven SLS patients from a small region of Northern Bavaria. Therefore these two mutations accounted for 71% (10/14 chromosomes) of Bavarian SLS alleles and so far have not been described in SLS families from other countries. Our findings do not support our 'historical' hypothesis, that a possible region clustering in Northern Bavaria could be due to the presence of Swedish soldiers during the 30 Years War (1618-1648), but suggest that two mutations causing SLS syndrome originated in Northern Bavaria.

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“…Compared to untransduced or mock-transduced SLS keratinocytes, FALDH-transduced SLS keratinocytes revealed an average of fivefold increase in FALDH activity up to a level of 60-70% of normal keratinocytes ( Figure 2). As some heterozygous carriers of SLS display a partial enzyme deficiency with an activity between 50 and 60% of normal without the manifestation of an altered phenotype, 2,13 this range of activity may result in a clinical benefit for homozygous SLS patients.…”

Section: Resultsmentioning

confidence: 99%

“…2,3 The corresponding gene ALDH3A2 has been linked to chromosome 17p11.2. 4 The full-length cDNA sequence for human FALDH contains an open reading frame of 1455 nucleotides encoding a protein of 485 amino acids (GenBank NM000382).…”

Section: Introductionmentioning

confidence: 99%

Restoration of fatty aldehyde dehydrogenase deficiency in Sjögren–Larsson syndrome

Haug

Braun‐Falco

2006

Gene Ther

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Sjögren-Larsson syndrome (SLS) is an autosomal recessive neurocutaneous disorder caused by mutation in the ALDH3A2 gene that codes for human fatty aldehyde dehydrogenase (FALDH). Sjögren-Larsson syndrome patients lack FALDH, which catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acids. The impaired FALDH activity leads to congenital ichthyosis, mental retardation and spasticity. The current lack of treatment is an impetus to develop gene therapy strategies by introducing functional FALDH into defective cells. We delivered human FALDH into keratinocytes of SLS patients using recombinant adeno-associated virus-2 vectors. Transduction of SLS keratinocytes resulted in an augmentation of FALDH activity comparable to phenotypically normal heterozygous carriers. Toxicity of long-chain aldehydes for FALDH-deficient cells decreased almost to the level of unaffected keratinocytes. Three-dimensional culture of corrected SLS keratinocytes revealed an ameliorated FALDH expression. These studies demonstrate the restoration of FALDH in human SLS cells supporting the concept of gene therapy as a potential future treatment option for SLS.

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

Cited by 141 publications

References 19 publications

MRI and ¹H-MRS findings of three patients with Sjögren-Larsson syndrome

MRI and ¹H-MRS findings of three patients with Sjögren-Larsson syndrome

RNA-based mutation screening in German families with Sjögren-Larsson syndrome

Restoration of fatty aldehyde dehydrogenase deficiency in Sjögren–Larsson syndrome

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