Phenotypic Variability Among Adult Siblings With Sjögren-Larsson Syndrome

Lossos, Alexander; Khoury, Moona; Rizzo, William B.; Gomori, John M.; Banin, Eyal; Zlotogorski, Abraham; Jaber, S.; Abramsky, Oded; Argov, Zohar; Rosenmann, Hanna

doi:10.1001/archneur.63.2.278

Cited by 29 publications

(34 citation statements)

References 6 publications

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“…The Swedish patients who carry an identical ALDH3A2 allele seem to have a limited spectrum of phenotypic variation [2,7]. Nevertheless, significant variation in neurologic disease has been reported in a large Arab family with 6 affected siblings [30]. Among 9 Brazilian patients homozygous for c. 1108-1G>C, there were some differences in the presence of pruritus, retinal glistening white dots and photophobia [29].…”

Section: Aldh3a2 Mutations and Sequence Variations In Slsmentioning

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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Section: Aldh3a2 Mutations and Sequence Variations In Slsmentioning

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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142

159

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“…15 Most mutations are unique to each affected family 6 and clinical variations, even among siblings, may be due to unknown genetic or environmental factors. 20 The possibility of genetic heterogeneity is not excluded 21 and missence mutations comprise the largest class of the many mutations. 22,23 Biochemistry The exact pathogenesis is uncertain, but the deficiency of fatty aldehyde dehydrogenase in this syndrome impairs the process which catalyzes the oxidation of medium-and longchain fatty aldehydes.…”

Section: Diagnosismentioning

confidence: 99%

Sjögren‐Larsson syndrome

Gordon¹

2007

Develop Med Child Neuro

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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.

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“…They also demonstrated that the spectral abnormalities emerged during the first years after birth and then stabilized. Lossos et al [124] investigated 6 patients with early childhood onset SL aged 16-36 years. There was considerable phenotype variability with a decrease in the lipid peak with age.…”

Section: Sjogren -Larsson Syndromementioning

confidence: 99%

Nuclear Magnetic Resonance Spectroscopy and Genetic Disorders

Ra¹

2008

CMC

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Nuclear magnetic resonance spectroscopy has been exploited to study the metabolic characteristics (phenotype) of genetic disorders by taking advantage of some unique characteristics of the technique. The first application, metabolic profiling for diagnosis and therapeutic monitoring in vitro, demonstrates the exceptional diversity of metabolites detected by NMR, and has resulted in new interest in significant metabolites largely ignored previously because other techniques do not detect them, e.g. betaine and creatine. Moreover, previously 'unknown' genetic disorders have been detected and characterised The same NMR technique can be effectively exploited for metabolic profiling of mutation models in yeast and mice, leading to a prominent role in the development of large scale metabolomic profiling to link genomic information with phenotype. The second application, magnetic resonance spectroscopy (MRS), exploits the unique possibility of studying human metabolism in vivo, which permits intracellular rather than extracellular metabolic profiling. When it is possible to detect the precise diagnostic metabolites in vivo, investigators have been able to link clinical status with cellular biochemistry, sometimes questioning the clinical value of extracellular (plasma) metabolite measurements. Thus, claims have been made that brain phenylalanine concentrations match more closely the clinical status of patients with phenylketonuria. These studies in vivo have also led to new diagnoses e.g. the disorders of creatine synthesis and transport, highlighting a new category of brain syndromes. Future applications of NMR are cautiously considered as they are critically dependent on continued improvement in resolution and sensitivity in turn generated by developments in magnet design and higher fields.

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Phenotypic Variability Among Adult Siblings With Sjögren-Larsson Syndrome

Cited by 29 publications

References 6 publications

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

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

Sjögren‐Larsson syndrome

Nuclear Magnetic Resonance Spectroscopy and Genetic Disorders

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