Fabry Disease in Women

As an X-linked genetic disorder, Fabry disease was first thought to affect only males, and females were generally considered to be asymptomatic carriers. With a prevalence of only 1 in 117,000 live births,1 [Australian inference population] clinical data about Fabry disease have been slow to accumulate.

However, research suggests that most females who carry the altered gene do develop symptoms.2-3 Of 303 women in the Fabry Outcome Survey, 77% experienced neurological symptoms such as pain, and 59% had cardiac manifestations such as left ventricular hypertrophy and palpitations.2 In a retrospective analysis of 44 female carriers, neurological, cardiopulmonary, and renal system manifestations of Fabry disease were present far above predicted rates.4

X-inactivation in females

The variable expression of symptoms in females is thought to be influenced by X-inactivation, a phenomenon in which one of two haploid sets of X-linked genes in each cell is inactivated and has no phenotypic expression.

Analysis has shown that X-inactivation is an important factor in determining the severity and clinical involvement in heterozygous females, and that there is a statistically significant difference between symptom severity scores of patients with balanced and skewed X-inactivation patterns.5 In a study of 38 affected females, X-inactivation appeared in statistically skewed, non-random patterns in the majority (27/38) females studied.6 The pattern of inactivation may differ from one organ to another, so that a female patient may experience severe symptoms in some organs, while remaining symptom-free in others.

Manifestations in females

Clinical manifestations in women with the altered α-galactosidase A (α-GAL) gene are increasingly being reported. Recent studies found that females with the altered α-GAL gene are usually, and often severely, affected in specific organs despite blood α-GAL enzyme levels within the normal range.7-8 Specific Fabry disease manifestations in women include:

  • Cardiac events: Reported similarly in men and women. Fabry Registry data reported cardiac events in 23% of both males and females enrolled in the Fabry Registry. These events occurred at median ages of 42 (males) and 48 (females).9
  • Cerebrovascular events: May be more likely in women. A European outcomes database reported cerebrovascular events in 27% of 165 females and 12% of 201 males.10
  • Renal manifestations: Reported to occur less frequently in females, {Fabry Registry} but when present, can progress to end-stage renal disease.10
  • Neurological manifestations: Most commonly reported signs and symptoms in both males and females. In a study of baseline characteristics, 43% of females reported neuropathic pain.11

Learn more about the Fabry Registry 

Confirming diagnosis in females

While blood tests to measure α-galactosidase A (α-GAL) activity are used to diagnose Fabry disease in males, these enzyme assays have limitations in the diagnosis of females. In one study using dried whole blood spots to measure α-GAL activity, 8 of 21 females with documented Fabry disease had false negative results.12

Learn about diagnosing Fabry disease 

Blood α-GAL activity in symptomatic females can be normal, likely due to skewed X-inactivation.10

For this reason, genetic analysis must be conducted in the event of a negative enzyme assays result. Genomic DNA and total RNA can be extracted from peripheral blood leukocytes or cultured skin fibroblasts. All α-GAL coding regions and adjacent intronic regions can then be sequenced.

References:

1. Meikle PJ, JJ Hopwood, AE Clague, WF Carey. Prevalence of lysosomal storage disorders. Jama. 1999;281:249-254.

2. Deegan PB, AF Baehner, MA Barba Romero, et al. Natural history of Fabry disease in females in the Fabry Outcome Survey. J Med Genet. 2006;43:347-352.

3. MacDermot KD, A Holmes, AH Miners. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet. 2001;38:769-775

4. Wang RY, A Lelis, J Mirocha, WR Wilcox. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med. 2007;9:34-45.

5. Dobrovolny R, L Dvorakova, J Ledvinova, et al. Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the α-galactosidase A gene in the Czech and Slovak population. J Mol Med. 2005;83:647-654.

6. Sharp A, D Robinson, P Jacobs. Age- and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genet. 2000;107:343-349.

7. Whybra C, K Wendrich, M Ries, A Gal, M Beck. Clinical manifestation in female Fabry disease patients. Contrib Nephrol. 2001245-250.

8. Gupta S, Ries M, Kotsopoulos S, Schiffmann R. The relationship of vascular glycolipid storage to clinical manifestations of Fabry disease: A cross-sectional study of a large cohort of clinically affected heterozygous women. Medicine 2005;84:261-268.

9. Genzyme Fabry Registry data on file (Accessed January 3, 2018).

10. Mehta A, R Ricci, U Widmer, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest. 2004;34:236-242.

11. Wilcox WR, Oliveira JP, Hopkin RJ, et al. Females with Fabry disease frequently have major organ involvement: Lessons from the Fabry Registry. Mol Genet Metab 2008;93:112-28.

12. Linthorst GE, AC Vedder, JM Aerts, CE Hollak. Screening for Fabry disease using whole blood spots fails to identify one-third of female carriers. Clin Chim Acta. 2005;353:201-203.