Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism

Abstract

Many of the ichthyoses are associated with inherited disorders of lipid metabolism. These disorders have provided unique models to dissect physiologic processes in normal epidermis and the pathophysiology of more common scaling conditions. In most of these disorders, a permeability barrier abnormality "drives" pathophysiology through stimulation of epidermal hyperplasia. Among primary abnormalities of nonpolar lipid metabolism, triglyceride accumulation in neutral lipid storage disease as a result of a lipase mutation provokes a barrier abnormality via lamellar/nonlamellar phase separation within the extracellular matrix of the stratum corneum (SC). Similar mechanisms account for the barrier abnormalities (and subsequent ichthyosis) in inherited disorders of polar lipid metabolism. For example, in recessive X-linked ichthyosis (RXLI), cholesterol sulfate (CSO(4)) accumulation also produces a permeability barrier defect through lamellar/nonlamellar phase separation. However, in RXLI, the desquamation abnormality is in part attributable to the plurifunctional roles of CSO(4) as a regulator of both epidermal differentiation and corneodesmosome degradation. Phase separation also occurs in type II Gaucher disease (GD; from accumulation of glucosylceramides as a result of to beta-glucocerebrosidase deficiency). Finally, failure to assemble both lipids and desquamatory enzymes into nascent epidermal lamellar bodies (LBs) accounts for both the permeability barrier and desquamation abnormalities in Harlequin ichthyosis (HI). The barrier abnormality provokes the clinical phenotype in these disorders not only by stimulating epidermal proliferation, but also by inducing inflammation.

Fig. 1

Proposed pathogenesis of neutral lipid storage disease. LB, lamellar body; PL, phospholipids; SC, stratum corneum; TAG, triacylglyceride; TEWL, transepidermal water loss.

Fig. 2

Potential disruptions in peroxidated lipid pathways in autosomal recessive congenital ichthyosis. CYP4F22, cytochrome P450, family 4, subfamily F, polypeptide 22; FALDH, fatty aldehyde dehydrogenase; PPAR, peroxisome proliferator-activated receptor; 12R-HPETE, 12(R)-hydro-peroxyeicosatetraenoic acid; 12R-LOX, 12R-lipoxygenase.

Fig. 3

How steroid sulfatase (SSase) deficiency leads to recessive X-linked ichthyosis. CE, cornified envelope; CLE, cornified lipid envelope; PKC, protein kinase C; TGM1, transglutaminase 1.

Fig. 4

Consequences of the epidermal cholesterol sulfate cycle for normal skin. Chol, cholesterol; SULT2B1b, cholesterol sulfotransferase.

Fig. 5

Potential pathogenic mechanisms in Gaucher disease. Cer, ceramide; GlcCer, glucocerebroside; GlcCer’ase, glucocerebrosidase.

Fig. 6

Protein delivery to lamellar bodies is dependent upon prior lipid deposition: sites of blockade in harlequin ichthyosis and cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome. ER, endoplasmic reticulum; TGN, trans-Golgi network.