Autosomal Recessive Lamellar Ichthyosis Research Articles

Genetic Mutations Responsible for Lamellar Ichthyosis

Our understanding of the pathogenesis of the autosomal recessive disease lamellar ichthyosis has been hampered by the lack of clear biochemical markers

Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis

We recently mapped the disease locus for severe autosomal recessive lamellar ichthyosis (LI) to chromosome 14q11 and showed complete linkage with TGM1, the gene encoding transglutaminase 1. We have now identified point mutations in TGM1 in two of the multiplex LI families used in the linkage study. Each nucleotide change causes a non-conservative amino acid substitution of histidine for one of two adjacent arginine residues in exon 3 of the gene (Arg141His, Arg142His). Within the transglutaminase family, these arginines are invariant within a conserved region, distant from the catalytic site of the enzyme. We hypothesize that these mutations adversely affect formation of crosslinks essential in production of cornified cell envelopes and a normal stratum corneum layer of the skin.

Autosomal recessive lamellar ichthyosis: identification of a new mutation in transglutaminase 1 and evidence for genetic heterogeneity.

Autosomal recessive lamellar ichthyosis (ARLI) belongs to the group of congenital disorders of cornification. It is characterized by a severe and generalized ichthyosis, and other variable cutaneous signs. The human transglutaminase 1 (TGM1) gene was recently found to be the disease-causing gene. Linkage analysis in 23 families (of which 13 were consanguineous) showed that for 10 of them, the disease was linked to the TGM1 gene. A new deleterious mutation introducing a stop codon in the TGM1 reading frame was found. Nevertheless, for the 13 other ARLI families, TGM1 was found to be unlinked to the disease. The present data show that ARLI is genetically heterogeneous and confirm that TGM1 is one of the responsible genes.

Epidermal transglutaminase in the ichthyoses.

Membrane-bound transglutaminase (TGm) is responsible for the cross-linking of proteins to form the cornified envelope. Since abnormalities have been reported in the envelope in certain ichthyoses, we have carried out a survey of TGm concentrations in scales from these disorders. Surprisingly, a striking and specific increase in enzyme activity was found in patients with non-erythrodermic autosomal recessive lamellar ichthyosis. It is not clear how this increase is related to the underlying recessive mutation.

Elastase-inhibiting activity in scaling skin disorders.

Elastase inhibiting activity (EIA) has been observed in normal skin as a response to surface trauma, immediately following the intra-epidermal accumulation of polymorphonuclear leukocytes (PMN). In order to elucidate the relation between EIA and inflammation, the inhibiting activity was assessed in skin samples of scaling dermatoses (a) without significant inflammation: erythrodermic autosomal recessive lamellar ichthyosis (EARLI), non-erythrodermic autosomal recessive lamellar ichthyosis (NEARLI), X-linked recessive ichthyosis (XLRI) and X-linked dominant chondrodysplasia punctata (XLD-CDP); (b) with predominantly mononuclear cell infiltration: atopic dermatitis; (c) with mixed infiltration of PMN and mononuclear cells: psoriasis and Netherton syndrome. All skin disorders investigated showed an increased EIA as compared with normal skin. Scales from psoriatic lesions, EARLI and Netherton syndrome showed a statistically significant increase in EIA above that observed in other monogenic disorders of keratinization NEARLI, XLRI XLD-CDP and above atopic dermatitis. EIA proved to be an indicator for abnormal keratinization with a marked expression when a mixed infiltrate is present in the skin.

Elastase-inhibiting activity in scaling skin disorders.

Elastase inhibiting activity (EIA) has been observed in normal skin as a response to surface trauma, immediately following the intra-epidermal accumulation of polymorphonuclear leukocytes (PMN). In order to elucidate the relation between EIA and inflammation, the inhibiting activity was assessed in skin samples of scaling dermatoses (a) without significant inflammation: erythrodermic autosomal recessive lamellar ichthyosis (EARLI), non-erythrodermic autosomal recessive lamellar ichthyosis (NEARLI), X-linked recessive ichthyosis (XLRI) and X-linked dominant chondrodysplasia punctata (XLD-CDP); (b) with predominantly mononuclear cell infiltration: atopic dermatitis; (c) with mixed infiltration of PMN and mononuclear cells: psoriasis and Netherton syndrome. All skin disorders investigated showed an increased EIA as compared with normal skin. Scales from psoriatic lesions, EARLI and Netherton syndrome showed a statistically significant increase in EIA above that observed in other monogenic disorders of keratinization NEARLI, XLRI XLD-CDP and above atopic dermatitis. EIA proved to be an indicator for abnormal keratinization with a marked expression when a mixed infiltrate is present in the skin.

Autosomal dominant lamellar ichthyosis exhibits an abnormal scale lipid pattern

Autosomal dominant lamellar ichthyosis (ADLI) is a recently recognized genetic skin disorder. Clinically and histologically, it cannot be distinguished with certainty from the more frequent autosomal recessive lamellar ichthyosis (ARLI), which in itself may still be heterogeneous. By ultrastructural examination of ADLI a prominent transforming zone between the stratum granulosum and stratum corneum and lipid inclusions in the stratum corneum have been observed. Using sequential high-performance thin-layer chromatography, we studied the plantar scale lipid pattern of two patients, mother and daughter, affected with ADLI. We found a distinctive alteration in the relative composition of the scale lipid pattern characterized by excessive amounts of free fatty acids, triglycerides, elevated n-alkanes, reduced free sterols and decreased total ceramides. This scale lipid profile clearly differs from that of the erythrodermic and non-erythematous variants of ARLI and confirms that this disorder is a distinct entity of the heterogeneous group of lamellar ichthyoses.

Retinoids in disorders of keratinization: their use in adults.

Hereditary disorders of keratinization may be a considerable handicap. Oral treatment with retinoids has been shown to be effective in many of these diseases. In the group of ichthyoses, the best results can be obtained in the various types of nonbullous congenital ichthyosis (erythrodermic autosomal recessive lamellar ichthyosis, nonerythrodermic autosomal recessive lamellar ichthyosis, autosomal dominant lamellar ichthyosis). It should be borne in mind, however, that retinoid therapy alone cannot lead to a complete response of these forms of ichthyosis and that this treatment cannot replace an appropriate topical treatment. During continuous treatment with etretinate a reduction of the dosis to 0.5 mg/kg is often necessary. Etretinate treatment of bullous congenital ichthyosiform erythroderma is more difficult, and it is advisable to begin with a low dosis of 0.25-0.5 mg/kg. The epidermolytic form of palmoplantar keratoderma is in our opinion no indication for retinoid treatment which seems to result inevitably in large erosions. Good or excellent results have been seen in other forms of palmoplantar keratoderma including mal de Meleda, Papillon-Lefèvre syndrome, erythrokeratodermia variabilis, verrucous epidermal nevi, Darier disease and pityriasis rubra pilaris. In patients with Darier disease it is wise to begin with a relatively low dosage of 0.5 mg/kg and to adjust the dosage to the further course of the disease. The same is true for the ichthyosis seen in the Netherton syndrome, which may be either a diffuse hyperkeratosis or ichthyosis linearis circumflexa. In view of the fact that any inherited keratinization disorder requires long-term treatment, the risk of bone toxicity should be carefully weighed against the benefit of this therapy. The results so far obtained indicate that the effect of etretin is comparable to that of etretinate in the treatment of inherited keratinization disorders. Intermittent therapy should be tried whenever possible. A combination therapy seems reasonable in pityriasis rubra pilaris of the adult type. We have seen good results by combination with PUVA treatment. Autosomal dominant ichthyosis vulgaris and X-linked recessive ichthyosis are inappropriate to treat with oral retinoid therapy because these diseases are too mild. Papillomatous epidermal nevi should also be excluded because they do not respond to the drug. Hailey-Hailey disease may even be worsened by this treatment. According to our experience, oral retinoid therapy has no effect in monilethrix.