Prenatal diagnosis of Sjögren‐Larsson syndrome using enzymatic methods

Rizzo, William B.; Craft, Debra A.; Kelson, Todd L.; Bonnefont, Jean‐Paul; Saudubray, J. M.; Schulman, Joseph D.; Black, Susan H.; Tabsh, Khalil; DiRocco, M.; Gardner, R. J. M.

doi:10.1002/pd.1970140711

Cited by 31 publications

(18 citation statements)

References 16 publications

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“…Using this method we were able to identify truncated RT-PCR products of reduced size in the index patients P1, P2, P3, P4 and P5 ( Figure 1: Lanes 1, 6,8,10). Since in all four cases no full length FALDH product was observed, we speculated that they could be homozygous for the particular deletion.…”

Section: Three Different Exon Deletions Identified By Rt-pcr Analysesmentioning

confidence: 99%

“…3 Prior to the identification of the SLS gene, enzymatic activity testing was necessary for diagnosis of SLS patients, carrier detection 7 and prenatal diagnosis. 8 The SLS gene was assigned to chromosome 17p11.2 by linkage analysis 9,10 and the FALDH gene was mapped to the same locus using yeast artificial chromosomes. 11 The gene consists of 10 exons spanning about 30.5 kb 12,13 and the coding region encompasses 1458 bp.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Three Different Exon Deletions Identified By Rt-pcr Analysesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2000

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“…DNA-based diagnosis by screening for common mutations in select populations or sequencing the entire gene is possible. Prenatal diagnosis of SLS using enzymatic [75] or DNA methods [76] can be performed on amniocytes or chorionic villus cells.…”

Section: Diagnosis and Therapeutic Approachesmentioning

confidence: 99%

Sjögren–Larsson syndrome: Molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency

Rizzo

2007

Molecular Genetics and Metabolism

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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.

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“…However, complete enzyme deficiency and partial enzyme deficiency have both been reported in SLS patients [2, 19, 20]. In the case of complete enzyme deficiency, FALDH activity tends to be less than 10% that of normal.…”

Section: Discussionmentioning

confidence: 99%

Incomplete Sjögren-Larsson Syndrome in Two Japanese Siblings

et al. 1999

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Sjögren-Larsson syndrome (SLS) is a rare, autosomal recessive disorder characterized by ichthyosis, spastic diplegia and mental retardation. Biochemical studies have pinpointed the pathogenesis resulting in the deficiency of the fatty aldehyde dehydrogenase (FALDH) component of the fatty alcohol NAD⁺ oxidoreductase complex. Histochemical analysis revealed a reduction in alcohol dehydrogenase (AD) activity in the skin. SLS patients have been categorized biochemically into two groups: complete and incomplete reduction according to the degree of FALDH deficiency. Our patients demonstrated incomplete clinical features, including a 1/3 reduction in FALDH activity, and decreased AD activity in the ichthyotic lesion. The phenotypical differences between our cases and classic SLS are probably due to the partial FALDH deficiency.

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Prenatal diagnosis of Sjögren‐Larsson syndrome using enzymatic methods

Cited by 31 publications

References 16 publications

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

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

Sjögren–Larsson syndrome: Molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency

Incomplete Sjögren-Larsson Syndrome in Two Japanese Siblings

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