Clinical, biochemical and molecular genetic characteristics of 19 patients with the Sjogren-Larsson syndrome

Abstract

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 severity of the neurological signs. The clinical presentation and the clinical course is strikingly similar in these patients. Patient 18 shows a mild phenotype that essentially contains the same, but less severe, clinical features. Patient 19 exhibits the typical, but very mild, dermatological and ocular abnormalities, without any clinical neurological involvement. The diagnosis of SLS was confirmed by demonstration of the enzyme defect in cultured skin fibroblasts. Furthermore, as might be predicted from the essential role of FALDH in leucotriene B(4) (LTB(4)) metabolism, elevated urinary concentrations of LTB(4) and 20-OH-LTB(4) were found in all patients studied. Molecular studies of the FALDH gene revealed eight different mutations, including three new ones: a large 26-base pair deletion (21-46del), a missense mutation (80C-->T) and an insertion mutation (487-488insA). The vast majority of SLS patients seem to be severely affected independent of their genotype.

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

“…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.…”

“…Willemsen et al 2 re p o rted a clinical, biochemical and molecular characteristics of 19 patients with SLS who presented periventricular white matter abnormalities on MRI and abnormal lipid peak on 1 H -M R S studies. Miyanomae et al 7 described a SLS case whose MRI showed high signal on T2-weighted and low signal on T1-weighted images at the peritrigonal are a s .…”

“…However, t h e re are only a few re p o rts on brain proton magnetic resonance spectroscopy ( 1 H-MRS), with typical findings of abnormal high peak in spectral curve, between 0.8 and 1.6 ppm, corresponding to the range of lipids. It is also re p o rted a nonspecific diminished peak of N-Acetyl Aspartate (NAA) at the periventricular white matter 1,2,7 .…”

Characterization of the human ω‐oxidation pathway for ω‐hydroxy‐very‐long‐chain fatty acids

“…Primary human fibroblast cell lines were obtained from normal control subjects and patients with Sjögren-Larsson syndrome (SLS). In each patient, the diagnosis was established using clinical, biochemical, and molecular methods, which included demonstration of deficient fatty aldehyde dehydrogenase (FALDH) activity and the identification of mutations in the ALDH3A2 gene (25). Cells were harvested with trypsin and washed twice with PBS and once with 0.9% NaCl.…”

Novel and recurrent ALDH3A2 mutations in Italian patients with Sjögren–Larsson syndrome

“…A number of mutations involving the ALDH3A2 gene have been reported in SLS patients (De Laurenzi et al 1996;Rizzo 2007;Rizzo and Carney 2005;Sillen et al 1998;Willemsen et al 2001a). Here we describe diseasecausing mutations in two Italian patients.…”