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Stroke in Fabry Disease
Fabry disease (FD), also known as angiokeratoma corporis diffusum , is an X-linked lysosomal storage disorder caused by deficiency of α-galactosidase A (α-gal). This defect causes the accumulation of glycosphingolipids in cells, including endothelial and vascular smooth muscle cells of small arterioles. These vessels become dysfunctional and undergo progressive stenosis resulting in ischemia and end-organ damage. Stroke constitutes one of the most devastating complications of FD.
Epidemiology
The prevalence of FD in the general population ranges from 1 in 117,000 to 1 in 476,000; in males, the range increases to 1 in 40,000 to 1 in 60,000 . FD can have a subclinical course and remain unrecognized, suggesting that population studies may underestimate the true prevalence of this disease. Data from newborn screening programs seem to support this hypothesis ( Table 108.1 ). A study performed in Italy (n = 37,104) showed that the frequency of FD in males may be as high as 1 in 3100 .
Table 108.1
Rate of Fabry Disease Obtained in Newborn Screening Studies
| Population | N | Rate a |
|---|---|---|
| Austria | 34,736 | 1 in 3859 |
| Italy | 37,104 | 1 in 3100 |
| Japan | 21,170 | 1 in 3014 |
| Taiwan | 110,027 | 1 in 1512 |
| United States b | 47,701 | 1 in 2355 |
a Diagnosis based on enzyme activity and confirmed by genetic analysis.
b Rates based on statewide newborn screening program performed in the state of Missouri.
The frequency of FD in stroke patients is significantly higher than in the general population. In an early German study that included 721 adults aged 18–55 years with cryptogenic stroke, a biologically significant mutation in the GAL gene was found in 4.9% of men and 2.4% of women . Based on these findings, it was hypothesized that FD was responsible for up to 1.2% of the strokes of unknown origin in young patients. Later studies done in other cohorts reported an incidence of FD in patients with cryptogenic stroke of 0–2.3% in men and 0–2.6% in women . The Stroke in Young Fabry Patients (SIFAP-1) study was the largest initiative designed to prospectively investigate the incidence of FD in young stroke patients. Definite FD occurred in 0.5% of the 5023 patients (median age 46 years) and probable FD in 0.4%. About 74% of the qualifying events were related to brain ischemia and 20% were recurrent events. Silent strokes were observed in 20% of the patients who had first-ever strokes. The mean number of silent lesions was significantly higher in FD than in non-FD patients (1.7 ± 2.2 versus 1.0 ± 2.2; P = 0.025) .
Pathophysiology
FD is caused by a mutation in the GAL gene, which is located in the long arm of the X-chromosome. De novo mutations occur so that the absence of a family history consistent with FD does not preclude the diagnosis. To date, more than 600 mutations have been described. The deficiency in α-gal leads to the accumulation of glycosphingolipids, particularly globotriaosylceramide (Gb3) and its deacylated derivative, lyso-globotriaosylceramide (lyso-Gb3). These molecules are stored in the cells of most organs, including the heart (cardiomyocytes and valvular cells), kidney (tubular and glomerular cells), neurons, and vascular cells (endothelial and smooth muscle cells).
The first manifestations become evident early in life. Depending on the residual enzyme activity, however, late presentations might occur. During embryogenesis, one copy of the X-chromosome in females undergoes irreversible inactivation or lyonization. Thus, females are mosaics of cell populations with different wild-type/mutated X-chromosome ratios and α-gal activities. The process of lyonization is genetically and epigenetically regulated and both random and skewed patterns of X-chromosome inactivation have been described in FD . Heterozygous females with random X-chromosome inactivation have delayed manifestation of symptoms. In comparison, organ-specific skewed X-chromosome inactivation results in tissue-specific α-gal deficiency and, consequently, pleomorphic presentations. The occurrence of genotype–phenotype correlations has been posited. As such, genetic mutations resulting in renal or cardiac variants of FD have been described. It is posited that carriers of the mutation S126G and A143T may be particularly susceptible to stroke . Familial studies show that phenotypic heterogeneity exists within family members carrying the same mutation, suggesting the importance of environmental or acquired factors .
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