Gaucher disease (GD) is an inborn error of glycosphingolipid metabolism due to a deficiency of the lysosomal hydrolase, acid β-glucosidase. Neonatal ichthyosis recently was recognized as a phenotypic expression of total acidβ-glucosidase deficiency in a subset of type 2 (infantile-onset neuronopathic) GD patients. A premature infant of mixed Irish-Mexican ancestry presented with progressive encephalopathy, pancytopenia, hepatosplenomegaly, colloidal skin and severe acid β-glucosidase deficiency. Molecular analysis revealed compound heteroallelism for the L444P and E326K mutations which were found to have markedly reduced enzyme activity and stability when expressed in the baculovirus system. Interestingly, the E326K mutation had been previously found in a family (with type 1 GD in 2 siblings) with a second mutation (D140H) in the same allele. Ichthyosiform or colloidal skin changes arise from defects in the production and/or maintenance of the normal stratum corneum. These studies demonstrate that the total or near absence of acid β-glucosidase activity results in a clinically distinct form of type 2 GD characterized by a cutaneous abnormality similar to that in“knockout” GD mice, which had incompetent intercellular lamellar bilayers in the stratum corneum as shown by Holleran and co-workers (J Clin Invest 93:1756-1764; 1994).