Sten Jagell

Sjögren‐Larsson syndrome in Sweden. A clinical, genetic and epidemiological study

Sjögren‐Larsson syndrome (SLS), originally described in Sweden, has been studied in a countrywide survey. A total of 58 SLS patients in 41 families were traced, 35 of them still alive. Thirty patients, 23 alive and seven deceased, have not been reported earlier. The mean incidences per 100,000 in the years 1901–1977 were 0.6 in the whole of Sweden, 10.2 in the county of Västerbotten and 2.7 per 100,000 in the county of Norrbotten. In the above‐mentioned areas, the prevalence figures for SLS on 31st December 1978 were estimated to be 0.4, 8.3 and 2.6 per 100,000 persons, the frequencies of SLS gene carriers 0.5, 2.0 and 1.0%, and the gene frequencies 0.002, 0.010 and 0.005, respectively. Of the 58 identified Swedish SLS patients, 45 were born in a restricted area in the northeast of Sweden.

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

We investigated fatty alcohol metabolism in eight patients with Sjögren-Larsson syndrome, and in nine obligate heterozygotes. Fatty alcohol: nicotinamide-adenine dinucleotide oxidoreductase (FAO) activity was deficient in cultured skin fibroblasts (mean 18% of normal, n = 8) and peripheral blood leukocytes (mean 22% of normal, n = 3) from patients with Sjögren-Larsson syndrome. The palmitoyl coenzyme A-inhibitable component of FAO activity was decreased to 10% and 15% of normal in fibroblasts and leukocytes, respectively, of patients with Sjögren-Larsson syndrome. Most affected patients accumulated long-chain fatty alcohol in plasma, with a greater relative accumulation of octadecanol (mean threefold greater than normal) than hexadecanol (mean twofold greater than normal). Erythrocyte lipid alkyl ether linkages derived from hexadecanol were slightly increased in three of four patients. Fibroblasts and leukocytes from heterozygotes with Sjögren-Larsson syndrome showed mean FAO activities that were intermediate between those seen in homozygotes and in normal control subjects. The heterozygotes had normal fatty alcohol concentrations in plasma. These studies demonstrate FAO deficiency in patients with Sjögren-Larsson syndrome, and suggest that accumulation of fatty alcohol or its metabolic products may be important in the pathogenesis of this disorder.

Ichthyosis in the Sjögren‐Larsson syndrome

The Sjögren‐Larsson syndrome (SLS) is characterized by congenital ichthyosis, spastic dior tetraplegia and mental retardation. The inheritance is autosomal recessive. All 36 patients with SLS alive in Sweden in 1980 were studied with regard to ichthyosis. A slight or moderate generalized hyperkeratosis, less pronounced in the face, was already present at birth. Collodion‐like membranes were never seen. The ichthyosis developed to its full extent during infancy. It was sometimes slight but most often moderate. Three types of hyperkeratosis were observed: dandruff‐like, lamellar and non‐scaly. These types occurred in various combinations. The skin changes were concentrated in the neck, flexures and lower abdomen, in which regions the scales were often dark. The non‐scaly hyperkeratosis produced characteristic and easily visible skin markings. Generalized erythema was rare, especially in adults. The DNA synthesis of the epidermis and the production of a horny layer were increased. Hair and nails were normal, as also was the ability to sweat.

Spectrum of mutations and sequence variants in the FALDH gene in patients with Sjögren-Larsson syndrome.

The gene encoding the human fatty aldehyde dehydrogenase (FALDH) is located on 17p11.2, causing Sjögren‐Larsson syndrome (SLS) when mutated. SLS is an autosomal recessive disorder characterized by a combination of mental retardation, congenital ichthyosis, and spastic di‐ or tetraplegia. We report here on studies of 16 SLS families from Europe and the Middle East, which resulted in identification of 11 different mutations. The spectrum of mutations characterized in the present study are five nucleotide substitutions resulting in amino acid changes, five frameshift mutations introducing a stop codon, and one in‐frame deletion with insertion at the same position. We also observed silent sequence variants in the FALDH gene and a base pair substitution in exon 5 that alters aspartic acid to asparagine, all of which are considered polymorphisms. Hum Mutat 12:377–384, 1998.

A missense mutation in the FALDH gene identified in Sjögren-Larsson syndrome patients originating from the northern part of Sweden

Abstract Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by congenital ichthyosis, spastic di- or tetraplegia, and mental retardation. SLS has been reported to occur in many populations but the highest incidence is in the north of Sweden. The gene causing SLS encodes a fatty aldehyde dehydrogenase (FALDH). In the present study, a point mutation in exon 7 of the FALDH gene was found in SLS patients of northern Swedish origin. The mutation consists of a C-to-T exchange at nucleotide position 943 in the cDNA. As a consequence, a highly conserved proline is replaced by a serine. The mutation was found in 49 out of 58 affected chromosomes and could be the most widely spread SLS mutation in the world.

Lethal and non‐lethal diastrophic dysplasia A study of 14 Swedish cases

A clinical study was performed on 14 patients with diastrophic dysplasia (DD), including three pairs of sibs. Six of these patients, including two pairs of sibs, died shortly after birth of respiratory and circulatory insufficiency. We consider these six patients to represent a special lethal variant of DD. In all infants with the lethal variant of DD the birth weight was lower than in those with the non‐lethal variant. There were also roentgenological differences between these two groups. Overlapping in joints and dislocation of the cervical spine were seen in all the lethal cases. In addition, four of the six patients with lethal DD cases had a congenital heart defect, and none in the non‐lethal group.

Congenital ichthyosis with alopecia, eclabion, ectropion and mental retardation ‐ a new genetic syndrome

A syndrome with severe generalized congenital ichthyosis, alopecia, eclabion, ectropion and mental retardation without neurological symptoms or macular changes in the eyes was seen in two sibs and in two aunts and uncles in an inbred North‐Swedish family. The clinical picture of the patients in the present family strongly deviated from that seen in the Sjögren‐Larsson syndrome found in the same area. This could be a new syndrome with autosomal recessive inheritance.

Dermatoglyphic patterns in the Sjögren-Larsson syndrome

The finger‐ and palm dermal‐ridge patterns of all Swedish cases with the Sjogren‐Larsson syndrome (SLS) were studied. The dermatoglyphic patterns of the SLS material showed variations from the normal material. This indicates an early prenatal pathological influencc on the formation of dermatoglyphics in SLS.

Sjögren‐Larsson syndrome Δ5‐ and Δ6‐fatty acid desaturases in skin fibroblasts

Cultured skin fibroblasts from two patients with Sjögren-Larsson syndrome (SLS) and from a normal control were analyzed for trienoic and tetraenoic fatty acids. In addition, we assayed desaturation of [ l - 14C]linoleic acid in cells from four patients and four controls. There was no significant effect of the disease on the composition of polyunsaturated fatty acids or on the rate of linoleic acid desaturation in fibroblasts. The results indicate the presence of Δ5- and Δ6-fatty acid desaturases in cells from SLS patients.

Zinc and Copper Concentration in Serum of Patients with Congenital Ichthyosis, Spastic Di- or Tetraplegia and Mental Retardation (Sjögren-Larsson Syndrome)

Serum zinc and serum copper were examined in 18 patients with the Sjögren-Larsson syndrome (congenital ichthyosis, spastic di- or tetraplegia and mental retardation), in four patients with congenital ichthyosis and mental retardation, of whom three had alopecia, and in nine healthy controls. No indication of disturbed zinc or copper metabolism in these groups of patients was found.