Local and global cerebral blood flow and glucose utilization in the α-galactosidase A knockout mouse model of Fabry disease.

Fabry disease is an X-linked lysosomal disorder characterized by deficient α-galactosidase A activity and intracellular accumulations of glycosphingolipids, mainly globotriaosylceramide (Gb3). Clinically, patients occasionally present CNS dysfunction. To examine the pathophysiology underlying brain dysfunction, we examined glucose utilization (CMR[sub glc]) and cerebral blood flow (CBF) globally and locally in 18 brain structures in the α-galactosidase A gene knockout mouse. Global CMR[sub glc] was statistically significantly reduced by 22% in Fabry mice (p < 0.01). All 18 structures showed decreases in local CMR[sub glc] ranging from 14% to 33%. The decreases in all structures of the diencephalon, caudate-putamen, brain stem, and cerebellar cortex were statistically significant (p < 0.05). Global cerebral blood flow (CBF) and local CBF measured in the same 18 structures were lower in Fabry mice than in control mice, but none statistically significantly. Histological examination of brain revealed no cerebral infarcts but abundant Gb3 deposits in the walls of the cerebral vessels with neuronal deposits localized to the medulla oblongata. These results indicate an impairment in cerebral energy metabolism in the Fabry mice, but one not necessarily due to circulatory insufficiency. [ABSTRACT FROM AUTHOR]