Gaucher disease, the inherited deficiency of the lysosomal enzyme β-glucocerebrosidase (E.C. GCase), is commonly divided into three subtypes based upon the presence and progression of neurological manifestations. Neurodegeneration in type 2 Gaucher disease is rapidly progressive and refractory to treatment.1, 2
Therefore, early differentiation of type 2 infants from more treatable infants affected with type 1 and 3 Gaucher disease is imperative. Beta-glucocerebrosidase plays an essential role in maintaining epidermal permeability function, including water homeostasis, by regulating the balance of ceramides to glucosylceramides in the stratum corneum of the skin.3, 4
A transgenic knock-out mouse model of Gaucher disease led to the appreciation of a distinct Gaucher phenotype, consisting of neonates presenting at or shortly after birth, with rapidly progressing fulminant disease, often associated with ichthyotic skin and/or hydrops fetalis.5, 6
The initial studies of human epidermal lipid content and cutaneous ultrastructure in all three types of Gaucher disease identified unique epidermal abnormalities specific only to type 2 disease. 5, 7
These alterations were consistently present, regardless of whether ichthyosis was clinically evident.8, 9
Electron microscopic examination of the skin from three patients with type 2 Gaucher disease showed immature, incompletely processed arrays of loosely-packed lamellar-body derived membranes, as compared to the fully-processed, orderly lamellar bilayers that typify normal skin. Notably, skin from patients with type 1 and type 3 Gaucher disease had a normal lamellar bilayer pattern, presumably preserved because of residual β-glucocerebrosidase activity.
These unique ultrastructural characteristics identified in patients with type 2 Gaucher disease were identical to the earlier epidermal ultrastructure findings in skin from type 2 (null-allele) Gaucher disease mice with a complete absence of epidermal β-glucocerebrosidase activity.6
These mice display dry, peeling skin and die in the first day of life, a clinical course resembling severely-affected human neonates with type 2 Gaucher disease.5
They also exhibit severely impaired barrier function, with markedly impaired transepidermal water loss and increased permeability.7
Their skin ultrastructure reveals immature, partially-processed lamellar bilayers, similar to that subsequently observed in type 2 Gaucher disease patients. In contrast, the ultrastructure of skin from heterozygous knock-out mice with residual β-glucocerebrosidase activity, as well as patients with type 1 and 3 Gaucher disease, showed orderly, normal lamellar membranes.7, 9
The relationship between the extent of residual enzyme activity and the structure and formation of epidermis was further demonstrated in topical inhibitor studies, which showed that abnormalities appear only when enzyme activity is less than 10 percent.7
In addition, lipid analyses showed structural changes corresponding to the altered stratum corneum glucosylceramide:ceramide ratio. Stratum corneum from type 2 Gaucher disease infants had increased levels of glucosylceramides and decreased ceramides, whereas patients with type 1 and 3 Gaucher disease had a lipid distribution showing a predominance of ceramides, comparable to that of normal individuals.7
These lipid abnormalities were identical to those observed in stratum corneum from the null-allele Gaucher mouse model, and in inhibitor-treated C57bl/6 normal mice.10, 11
The similar findings in patients and knock-out and pharmacological murine models of Gaucher disease, suggested that the unique epidermal ultrastructure in patients with type 2 Gaucher disease is related directly to reduced β-glucocerebrosidase activity and could provide a valuable prognostic tool to distinguish type 2 from the more treatable type 1 and 3 disease.9
More recently, several additional case reports have confirmed skin involvement in type 2 Gaucher disease,8, 12, 13
and the ultrastructural features in type 2 Gaucher disease have been characterized in more detail in comparison to other ichthyotic presentations.14
The lamellar membranes display an immature appearance, which is attributed to both persistence of glucosylceramides, and the failure to generate ceramides in the extracellular spaces of the stratum corneum. Because glucosylceramides are relatively non-polar glycosphingolipids, they form an electron-dense, non-lamellar phase that is interspersed within the partially processed lamellar membranes. Although a similar electron-dense non-lamellar phase feature occurs in recessive X-linked ichthyosis, it is interspersed among otherwise “mature” lamellar bilayers,14
and sufficient ceramides are generated in Niemann-Pick disease, types A and B, to generate mature lamellar bilayers.15, 16
Thus, in an appropriate clinical context, these features, coupled with normal-appearing lamellar body contents and a normal progression of corneodesmosome degradation, are characteristic of type 2 Gaucher disease.
We now present skin ultrastructural findings from a greatly expanded cohort of 22 patients with Gaucher disease in an effort to re-examine the prognostic utility of this method in distinguishing type 2 disease, and to determine whether the ultrastructural findings correlated with particular genotypes or patient phenotypes.