Glucosylsphingosine accumulation in mice and patients with type 2 Gaucher disease begins early in gestation

Gaucher disease, the most common of the sphingolipidoses, results from the inherited deficiency of the enzyme glucocerebrosidase (EC 3.2.1.45). Althou gh type 2 (acute neuronopathic) Gaucher disease is associated with rapidly progressive and fatal neurologic deterioration, the pathophysiologic mechan isms leading to the neurologic symptoms and early demise remain uncharacter ized. While the pathology encountered in Gaucher disease has been attribute d to glucocerebroside storage, glucosylsphingosine (Glc-sph), a cytotoxic c ompound, also accumulates in the tissues. Elevations of brain Glc-sph have been reported in patients with types 2 and 3 Gaucher disease. In this study , Glc-sph levels were measured using HPLC in tissues from mice with type 2 Gaucher disease created with a null glucocerebrosidase allele. Compared wit h unaffected littermates, homozygous mice with type 2 Gaucher disease had a pproximately a 100-fold elevation of Glc-sph in brain, as well as elevated levels in other tissues. This accumulation was detected in utero by E 13 an d increased progressively throughout gestation. Similarly, elevated Glc-sph levels were seen in human fetuses with type 2 Gaucher disease, indicating that therapy initiated after birth may be too late to prevent the sequaelae of progressive neurologic damage that begins early in gestation. These fin dings suggest that the accumulation of Glc-sph may be responsible for the r apid demise of mice with type 2 Gaucher disease and the devastating clinica l course seen in patients with type 2 Gaucher disease.