Sjögren-Larsson syndrome: Inherited defect in the fatty alcohol cycle

Rizzo, William B.; Dammann, A L; Craft, Debra A.; Black, Susan H.; Tilton, Ann; Africk, Diane; Chaves‐Carballo, Enrique; Holmgren, Gösta; Jagell, Sten

doi:10.1016/s0022-3476(89)80070-8

Cited by 57 publications

(43 citation statements)

References 17 publications

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“…0.25 M sucrose using a motor-driven glass-Teflon homogenizer. FALDH was assayed using octadecanal as substrate (3), and FAO activity was determined using [ 3 H]octadecanol as substrate (21). Cell protein was measured according to Lowry et al (22).…”

Section: Cellsmentioning

confidence: 99%

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

Rizzo

Craft

Somer

et al. 2008

Journal of Lipid Research

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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.

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Section: Cellsmentioning

confidence: 99%

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

Rizzo

Craft

Somer

et al. 2008

Journal of Lipid Research

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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%

Section: Introductionmentioning

confidence: 99%

“…6 Therefore, affected patients with impaired fatty alcohol oxidation accumulate long-chain fatty alcohol in their tissues. 3,6 Although the pathogenesis of single abnormalities is yet unclear, fatty alcohol storage is thought to be responsible for the symptoms of the disease. 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.…”

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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“…The etiology of SLS is not known, but deficient alcohol:nicotinamide-adenine dinucleotide oxidoreductase in cultured skin fibroblasts and peripheral blood leukocytes reduced to about 20% of normal has been observed (Rizzo et al, 1989).…”

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Monoaminergic dysfunction in Sjögren-Larsson syndrome

Wester

Bergström

Brun

et al. 1991

Molecular and Chemical Neuropathology

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The anteroposterior distribution of monoamine and monoamine metabolite concentrations was determined in subcortical brain nuclei of two cases of Sjogren-Larsson syndrome (SLS) and was compared to two control cases. The brains were divided into halves and secboned coronally. For biochemical analyses, caudate nucleus, putamen, globus pallidus, substantia nigra, nucleus accumbens, amygdala, and hippocampus were dissected macroscopically. Monoamine and its metabolites were determined by reverse-phase liquid chromatography with electrochemical detection. The other hemisphere was studied neuropathologically.The SLS cases revealed cell loss in substantia nigra and putamen and a widespread white-matter destruction. Biochemically, most pronounced alterations were seen in the dopamine system in putamen with severely reduced concentrations of dopamine (DA; 14% of control values) and the catabolic metabolites 3-methoxytyramine (3-MT; 9% of control values) and homovanillic acid (HVA; 20% of control values). In substantia nigra and the other striatal regions studied, a general decrease of 3-MT and HVA concentrations was observed in the SLS subjects compared to the controls, although the decrease was less pronounced than in putamen. Generally, somewhat reduced *Au th or to whom all correspondence and reprint requests should be addressed. Molecular and chemical Neuropathology 13Vol. 15, 1991 14 Wester et al, noradrenaline and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations were seen in the SLS cases, whereas serotonin and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were increased compared to the controls in most regions studied.These data suggest a specific monoaminergic dysfunction in patients with SLS. The severe decline in the dopaminergic system in putamen suggests that supplementation of dopamine agonists may ameliorate the symptoms of SLS patients.

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Sjögren-Larsson syndrome: Inherited defect in the fatty alcohol cycle

Cited by 57 publications

References 17 publications

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

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

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

Monoaminergic dysfunction in Sjögren-Larsson syndrome

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