This study, involving the largest cohort of females heterozygous for Fabry disease, confirms the findings of MacDermot et al4
and Whybra et al7
that the majority of females who are heterozygous for disease causing mutations in the α‐galactosidase A gene report clinical features of Fabry disease. Indeed, in the present study severe manifestations of disease were common, with 77% of women reporting neurological involvement, 59% cardiac involvement, and 40% renal involvement. Although the onset of symptoms was not as early as is typically observed in males, the majority of signs and symptoms assessed had developed by the third and fourth decades of life; however, there was considerable variation between individuals. This study demonstrates the considerable delay between onset of symptoms and diagnosis in this group of women. In an earlier analysis of the FOS database, Mehta and co‐workers12
reported a similar prevalence of symptoms and a wide range of disease expression in female patients. One possible explanation for this variation is skewed X chromosome inactivation.22
Early in embryonic development one of the two X chromosomes in each somatic cell becomes inactivated, which results in patchy and variable expression of the defective gene. This may impact upon the degree of disease expression observed. Two groups have shown an association between patterns of X inactivation in peripheral blood leukocytes and clinical severity of Fabry disease.23,24
In a recent review, Dobyns et al
suggest that most X linked conditions are neither dominant nor recessive.25
In view of the high prevalence of symptoms in female patients, we suggest that the X linked inheritance of Fabry disease should no longer be regarded as recessive and that the term “carrier” should be avoided, if possible, as it may give the false impression to a patient or relative, ignorant of the terminology of medical genetics, that females are asymptomatic or only mildly affected.
It is worth commenting on the fact that the severity of disease was not related to plasma or leukocyte activity of α‐galactosidase A. This serves to reinforce the point that the measurement of α‐galactosidase A activity in plasma or leukocytes is of no diagnostic or prognostic value in females and should not be used to determine treatment options. The enzyme deficiency is intracellular and occurs only in cells where the X chromosome carrying the wild type allele is inactivated. Activity of the enzyme in plasma or leukocytes may not reflect the situation within the lysosome of relevant cell types in Fabry disease.
It is also noteworthy that proteinuria was not associated with a more rapid decline in GFR in these women; in fact, the reverse was the case. This finding should prompt further study into the prognostic relevance of proteinuria in Fabry disease.
One potential source of bias of data in FOS relates to the possibility that the more severely affected female patients, who attend their physicians on a more frequent basis and who are either on ERT or are immediate candidates for this treatment, are more likely to be registered in the database. However, a secular trend apparent in FOS is that as the relative number of women registered in FOS has approached the number of male patients and as more mildly affected and asymptomatic women have been recruited, the average reported severity of the condition has lessened. The prevalence of features of Fabry disease in women enrolled in FOS should not be interpreted as being the same as the prevalence in all females heterozygous for disease causing mutations. Nevertheless, this is a rare condition, and we report on 303 women, a number equal to that of males registered in the database. The prevalence of disease manifestations in this study is similar to the prevalence of features as reported by MacDermot and co‐workers,4
who in their study, attempted to trace all known obligate heterozygous females in the UK. One way to examine potential bias would be to compare disease severity in index cases and individuals diagnosed through pedigree analysis. FOS permits only an approximate estimate of index cases according to whether the diagnosis was made by a clinician or through an affected family member. Using this method, we found no significant difference between the number of affected organ systems between index cases and those identified by pedigree.
Assessment of the severity of disease revealed that cardiac and renal involvement increased progressively with age. Using the relationship between age and disease parameters as a tool to examine the natural history of a disease has potential disadvantages. Survivor bias (based on the early death of more severely affected patients) may dilute the apparent rate of progression of the disease and perhaps even give rise to a false impression of improvement over time.26
Selection bias, as a result of the recruitment of young, mildly affected females through pedigree analysis, and older severely affected index cases, may also give a false impression of disease progression. We examined our data for such bias (data not shown), and although older women were more likely to be index cases, their disease severity did not differ significantly from the severity of those identified by pedigree analysis. Despite these disadvantages, this approach allows the early reporting of results from large numbers of individuals, which is important in rare diseases such as Fabry disease.
It has previously been established that the MSSI is a useful tool for assessing the severity of Fabry disease. This disease specific severity score has the advantage of summarising the diverse aspects of disease expression and of concentrating on those aspects of health most relevant to Fabry disease. In the present study, a modification of this index, the FOS‐MSSI, was used and results showed that the score obtained correlated positively with age and the number of affected organ systems. The score was also found to correlate inversely with HRQoL, indicating that increasingly severe disease is associated with a poorer quality of life. This suggests that the modified score is a suitable index for assessing the severity of Fabry disease in women enrolled in FOS.
Although longitudinal data are limited, the data available from FOS are consistent with the hypothesis that Fabry disease in women is progressive. Interestingly, data available on the female relations of women enrolled in FOS show that the mean age at death was approximately 50 years.
In conclusion, females with Fabry disease show evidence of deterioration of HRQoL, renal function, and cardiac size with advancing age. FOS is a useful tool to evaluate the phenotype and natural history of this orphan disorder, and the information gathered will serve as a baseline against which to evaluate the effects of enzyme replacement or other new treatments. Change in the rate of decline of quality of life parameters, severity score indices, renal function, and left ventricular mass should be considered as measures of outcome of enzyme replacement therapy. The progressive nature of the condition mandates thorough and repeated clinical assessment of affected female heterozygotes.