Defective transglutaminase 1 (TGM1) is a causative factor in some cases of lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE) despite large differences in the phenotype between these conditions. ...Defective transglutaminase 1 (TGM1) is a causative factor in some cases of lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE) despite large differences in the phenotype between these conditions. In some of these indi viduals, defective cornified envelopes (CEs) have been reported by light or elec tron microscopic examination in epidermal scale, nail and/or hair. These finding s suggest that assessment of such defects could have a diagnostic utility in dis tinguishing TGM1-deficient versus non-deficient cases of autosomal recessive i chthyosis (ARI) . Present work (a) examines the integrity of CEs in epidermal sc ale and appendages in a case of TGM1-deficient CIE, (b) assesses the utility of hair/nail versus scale analysis in the diagnosis of TGM1 deficiency in vivo and (c)-helps characterize the consequences of the V518M mutation in TGM1, about w hich conflicting reports have appeared. To this end, epidermal scale or callus, nail and hair samples from a patient with TGM1-deficient CIE, his asymptomatic family members and control subjects were extracted vigorously in sodium dodecyl sulfate and dithiothreitol and examined by light (phase contrast) and electronmi croscopy. Both epidermal scale and nail from the index case lacked the prominent cell borders that were visible by phase contrast microscopy after detergent ext raction of control samples. (By contrast, abundant envelope structures were visi ble in extracted epidermal scale from patients with ichthyosis vulgaris, loricri n keratoderma and epidermolytic hyperkeratosis.) Electronmicroscopy confirmed th e paucity of intact CEs, and revealed further that hair cuticle cells from the s ame subject also lacked the marginal bands that are visible in control hair samp les. Such aberrations were evident neither in the samples from asymptomatic rela tives of the index case nor in the hair-cuticle cells of numerous normal indivi duals, evidence that this defect is not a common polymorphism. These studies ext end our prior work on TGM1-deficient LI展开更多
Neutral lipid storage disease with ichthyosis (NLSDI; Chanarin-Dorfman syndrome) is an ichthyosiform syndrome, often associated with mutations in a lipid hydrolase, CGI-58. The presence of oil red O-positive, neutral ...Neutral lipid storage disease with ichthyosis (NLSDI; Chanarin-Dorfman syndrome) is an ichthyosiform syndrome, often associated with mutations in a lipid hydrolase, CGI-58. The presence of oil red O-positive, neutral lipid droplets in tissue biopsies, and/or in leukocytes on blood smears, coupled with a constellation of multisystem abnormalities and a pruritic ichthyosiform erythroderma, are together diagnostic of NLSDI. We investigated the pathogenesis of the ichthyosiform erythroderma in patients from three unrelated kindreds with a clinical diagnosis of NLSDI. Basal permeability barrier function and stratum corneum (SC) integrity were abnormal, but barrier recovery rates were faster than normal, as in atopic dermatitis. The basal barrier abnormality was linked to the secretion of lipid micro-inclusions, first segregated within lamellar bodies (LB), which then form a non-lamellar phase within the SC interstices, shown by combined ruthenium tetroxide post-fixation and lipid-retaining resin-white embedding. With colloidal lanthanum nitrate perfusion, excess water/solute movement was restricted to the SC interstices, and further localized to non-lamellar domains. Phase separation of excess stored lipid provides a unifying pathogenic mechanism not only for NLSDI, but also in several other inherited ichthyosiform disorders of lipid metabolism, such as recessive X-linked ichthyosis and type 2 Gaucher’s disease.展开更多
文摘Defective transglutaminase 1 (TGM1) is a causative factor in some cases of lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE) despite large differences in the phenotype between these conditions. In some of these indi viduals, defective cornified envelopes (CEs) have been reported by light or elec tron microscopic examination in epidermal scale, nail and/or hair. These finding s suggest that assessment of such defects could have a diagnostic utility in dis tinguishing TGM1-deficient versus non-deficient cases of autosomal recessive i chthyosis (ARI) . Present work (a) examines the integrity of CEs in epidermal sc ale and appendages in a case of TGM1-deficient CIE, (b) assesses the utility of hair/nail versus scale analysis in the diagnosis of TGM1 deficiency in vivo and (c)-helps characterize the consequences of the V518M mutation in TGM1, about w hich conflicting reports have appeared. To this end, epidermal scale or callus, nail and hair samples from a patient with TGM1-deficient CIE, his asymptomatic family members and control subjects were extracted vigorously in sodium dodecyl sulfate and dithiothreitol and examined by light (phase contrast) and electronmi croscopy. Both epidermal scale and nail from the index case lacked the prominent cell borders that were visible by phase contrast microscopy after detergent ext raction of control samples. (By contrast, abundant envelope structures were visi ble in extracted epidermal scale from patients with ichthyosis vulgaris, loricri n keratoderma and epidermolytic hyperkeratosis.) Electronmicroscopy confirmed th e paucity of intact CEs, and revealed further that hair cuticle cells from the s ame subject also lacked the marginal bands that are visible in control hair samp les. Such aberrations were evident neither in the samples from asymptomatic rela tives of the index case nor in the hair-cuticle cells of numerous normal indivi duals, evidence that this defect is not a common polymorphism. These studies ext end our prior work on TGM1-deficient LI
文摘Neutral lipid storage disease with ichthyosis (NLSDI; Chanarin-Dorfman syndrome) is an ichthyosiform syndrome, often associated with mutations in a lipid hydrolase, CGI-58. The presence of oil red O-positive, neutral lipid droplets in tissue biopsies, and/or in leukocytes on blood smears, coupled with a constellation of multisystem abnormalities and a pruritic ichthyosiform erythroderma, are together diagnostic of NLSDI. We investigated the pathogenesis of the ichthyosiform erythroderma in patients from three unrelated kindreds with a clinical diagnosis of NLSDI. Basal permeability barrier function and stratum corneum (SC) integrity were abnormal, but barrier recovery rates were faster than normal, as in atopic dermatitis. The basal barrier abnormality was linked to the secretion of lipid micro-inclusions, first segregated within lamellar bodies (LB), which then form a non-lamellar phase within the SC interstices, shown by combined ruthenium tetroxide post-fixation and lipid-retaining resin-white embedding. With colloidal lanthanum nitrate perfusion, excess water/solute movement was restricted to the SC interstices, and further localized to non-lamellar domains. Phase separation of excess stored lipid provides a unifying pathogenic mechanism not only for NLSDI, but also in several other inherited ichthyosiform disorders of lipid metabolism, such as recessive X-linked ichthyosis and type 2 Gaucher’s disease.
