Pathogenetic Considerations

The basic defect in FD is deficient activity of a-galac-tosidase A, the lysosomal enzyme responsible for the hydrolysis of terminal a-galactosyl residues from gly-colipids and glycoproteins. The gene encoding for the enzyme is GALA and is localized on the long arm of the X chromosome (Xq22.11). Different mutations have been identified. In male patients with classical FD (classical hemizygotes) there is no detectable enzyme activity and either no detectable enzyme protein or normal or decreased amounts of enzyme protein. In the latter case, presumably, the enzyme is altered and kinetically defective. In mild, atypical hemizygotes, some residual enzyme activity is found. Females have a variable clinical phenotype related to random X inactivation.

Glycosphingolipids are important constituents of plasma cell membranes and of some intracellular membranes including lysosomal membranes. Deficiency of a-galactosidase A leads to progressive accumulation of neutral glycosphingolipids with terminal a-galactosyl residues in lysosomes. The highest increase is found in globotriaosylceramide and digalac-tosylceramide. FD hemizygotes and heterozygotes who have blood group B or AB also accumulate B and Bj glycosphingolipids, which are normal human ery-throcyte antigens. Another neutral glycosphingolipid that can accumulate in FD is the Pj blood group antigen.

There are several factors that may contribute to the phenotypic expression. First of all, there is the type of mutation. The blood group may also have an effect on the severity of the disease. It has often been reported that patients with blood group types B and BA are more severely affected than patients with blood group types O and A. This can be due to the fact that patients with blood groups B and BA accumulate the erythrocyte antigens B and B1. In female heterozygotes, the phenotype is also influenced by the pattern of X chromosome inactivation.

The pattern of glycosphingolipid accumulation in FD differs from that in other glycosphingolipidoses. There is a very special cellular and tissue distribution of accumulated glycosphingolipids with particular involvement of vascular endothelium, smooth muscles, and neurons. Within the nervous system the pattern of involved neurons is also very special. A number of explanations have been given for this distribution of neuronal storage. Site-specific differences in globotriaosylceramide metabolism have been proposed. Absorption of high levels of globotriaosylce-ramide from blood has been suggested as the source of glycosphingolipids in cells, as concentrations of this substance are much elevated in the blood of patients with FD. Anatomical location in areas of reduced blood-brain barrier could potentially pro mote neuronal absorption from blood, but not all involved neuronal groups are in such areas. Absorption of globotriaosylceramide from the CSF into adjacent neurons could be a possible mechanism. Many of the involved neuronal groups are located adjacent to the CSF. There is, however, selective sparing of neighboring neuronal groups similarly exposed to CSF. Selective uptake and transfer of globotriaosylceramide by neurons could play a role.

Although structural compromise to the cerebral, renal, and cardiac arterial vasculature is believed to play a major role in the ischemic events in FD,there is also evidence for increased endothelium-mediated vascular reactivity and hyperdynamic cerebral circulation. Patients with FD have been found to have increased cerebral blood flow velocities. It is presently unclear how the disturbance in regulation of the vascular tone contributes to the ischemic incidents. The white matter involvement in FD is of hypoxic-is-chemic origin, related to small vessel disease, and not demyelinating in nature.

The correlation of neurological complaints and lipid storage is hampered by the presence of a combination of neuronal storage, angiopathic infarcts in nervous tissue, and deposition of glycosphingolipids in end-organs such as the sweat glands in the skin. The episodic limb pain typical of FD has been ascribed to dorsal root ganglia neuropathy, peripheral small-fiber neuropathy, involvement of substantia gelatinosa neurons, and peripheral nerve ischemia due to involvement of the vasa nervorum. Autonomic dysfunction could arise from involvement of the autonomic nervous system at either central or peripheral level, but anhidrosis could also be explained by dysfunction of sweat glands. The episodic fever may be related to lesions of the hypothalamus and to the inability to sweat. The clinical correlate of the cerebral neuronal glycosphingolipid deposition is unclear. Psychosis,personality changes, and dementia have been described in FD but are not prominent phenomena. Seizures are rare. Apparently the accumulation of glycosphingolipids in neurons is a problem of lesser importance than their accumulation in endothelial cells,producing occlusive angiopathy and cerebral infarction.

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