Neurological Manifestations

Central nervous system involvement is less prominent in Fabry disease than in many of the other lysosomal storage disorders. However, peripheral neurological abnormalities are common.1-3 Proton magnetic resonance spectroscopy demonstrates diffuse central neuronal involvement in cortical and subcortical locations.4

Cerebrovascular abnormalities

Recent literature has documented many cerebrovascular abnormalities associated with Fabry disease, including early stroke, thromboses, transient ischemic attacks, hemiparesis, vertigo/dizziness, diplopia, seizures, labyrinthine disorders, cerebral hemorrhage, dysarthria, nystagmus, nausea/vomiting, head pain, hemiataxia, dementia, and ataxia of gait.3, 5-6

Accumulation of GL-3 in vascular endothelium

 Electron micrograph image shows deficiency of cellular accumulation of the substrate GL-3 in the the renal endothelium of a Fabry patient.

Electron micrograph showing the vascular endothelium of a small vessel from a patient with Fabry disease. Progressive accumulation of substrate leads to ischemia and eventual vessel infarction. Used with permission from R.J. Desnick, MD, Phd.

Stroke incidence

Ischemic strokes were noted in one retrospective study in 8 of 33 patients (24%).7 An MRI study quantified cerebral vasculopathy in 50 Fabry disease patients ranging in age from 6 to 63 (mean age, 33). The youngest patient with a detectable cerebral lesion was 27 years old, and the mean age at which the first MRI lesion was detected was 43 years old for white matter lesions, and 41 years old for gray matter lesions. The presence of cerebral lesions correlated with neurologic symptoms in only 38% of patients. Disease burden increased with age; all patients older than 54 had cerebrovascular involvement.8

Causes of stroke

Thrombosis of small arteries thickened by the vascular accumulation of GL-3 lipids makes Fabry disease patients vulnerable to early ischemic stroke.3,9 Thrombus formation may also be enhanced in Fabry disease due to adhesion of neutrophils and monocytes to endothelial cell walls.10 Hypertension associated with renal dysfunction may also increase the risk for hemorrhagic stroke.7

Peripheral nerve damage

Degeneration of small myelinated and unmyelinated fibers has been documented, and may be related to both the pain and hypohidrosis associated with Fabry disease.2-3 Loss of small peripheral sensory neurons in the dorsal root ganglia2 and small fiber dysfunction11 may be related to pain and temperature sensitivity.

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References:

1. Morgan SH, P Rudge, SJ Smith, et al. The neurological complications of Anderson-Fabry disease (α-galactosidase A deficiency)--investigation of symptomatic and presymptomatic patients. Q J Med. 1990;75:491-507.

2. Ohnishi A, PJ Dyck. Loss of small peripheral sensory neurons in Fabry disease. Arch Neurol. 1974;31:6.

3. Desnick RJ, YA Ioannou, CM Eng. α-galactosidase A deficiency: Fabry disease. In: The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw Hill, 2001: 3733-3774.

4. Tedeschi G, S Bonavita, TK Banerjee, A Virta, R Schiffmann. Diffuse central neuronal involvement in Fabry disease: a proton MRS imaging study. Neurology. 1999;52:1663-1667.

5. Mitsias P, SR Levine. Cerebrovascular complications of Fabry's disease. Ann Neurol. 1996;40:8-17.

6. Mendez MF, TM Stanley, NM Medel, Z Li, DT Tedesco. The vascular dementia of Fabry's disease. Dement Geriatr Cogn Disord. 1997;8:252-257.

7. Grewal RP. Stroke in Fabry's disease. J Neurol. 1994;241:153-156.

8. Crutchfield KE, NJ Patronas, JM Dambrosia, et al. Quantitative analysis of cerebral vasculopathy in patients with Fabry disease. Neurology. 1998;50:1746-1749.

9. Grewal RP, SK McLatchey. Cerebrovascular manifestations in a female carrier of Fabry's disease. Acta Neurol Belg. 1992;92:36-40.

10. DeGraba T, S Azhar, F Dignat-George, et al. Profile of endothelial and leukocyte activation in Fabry patients. Ann Neurol. 2000;47:229-233.

11. Hilz MJ, B Stemper, EH Kolodny. Lower limb cold exposure induces pain and prolonged small fiber dysfunction in Fabry patients. Pain. 2000;84:361-365.