What is the incidence of Fabry disease?

Fabry disease is observed in all ethnic, racial and demographic groups.1 Fabry disease is estimated to affect approximately 1 in 40,000 males and approximately 1 in 20,000 females.2,3 An Australian study of lysosomal storage disorders estimated that the prevalence of live births with Fabry disease was 1 per 117,000.4 A systematic review of newborn screening studies indicated that the prevalence of GLA variants in newborns was 0.04% (153/397,271), which equates to an incidence of Fabry disease of 1 per 2597 live births.5 Therefore, data from newborn screening programmes suggest that the incidence of Fabry disease is generally underestimated and may be higher than previously approximated (Figure 1).2,3,6-11

Figure 1.
Incidence of Fabry disease based on newborn screening programmes.6-11

What is the incidence of Fabry disease based on newborn screening programmes?

On the basis of alpha galactosidase A (α-Gal A) deficiency and specific GLA variants, an Italian newborn screening programme (n=37,104 males) estimated that the incidence of Fabry disease was 1 in 3100 males. Based on these data, the ratio of late-onset Fabry disease to classical Fabry disease was predicted to be 11:1. In this Italian study, when only known Fabry disease-causing variants were included and novel variants in the GLA gene were excluded, the incidence of Fabry disease was approximately 1 in 4600 males, with a higher ratio of late-onset to classical Fabry disease (7:1).6 Using dried blood spots from 14,600 asymptomatic newborns in Spain (males, n=7575; females, n=7025), the prevalence of Fabry disease was determined by screening for enzymatic activity of α-Gal A. Since enzymatic testing of α-Gal A cannot be used to make a conclusive diagnosis of Fabry disease in females (see diagnosis of Fabry disease), the estimated prevalence of the disease could only be approximated in males. Based on these data, Fabry disease affected 1 in 7575 males.7 In an additional European newborn screening programme of lysosomal storage disorders, performed in Austria (n=34,736), GLA genetic analysis showed that Fabry disease affected 1 per 3859 births.8 In a Japanese screening programme of 21,170 newborns (males, n=10,827; females, n=10,343), the prevalence of Fabry disease was estimated to be 1 in 7057 live births, based on dried blood spot analysis of α-Gal A enzyme activity and GLA genetic analysis.9 Similarly, a Taiwanese newborn screening programme of 171,977 newborns estimated that the overall frequency of Fabry disease, based on low enzymatic activity of α-Gal A using dried blood spots and GLA genetic analysis, was approximately 1 in 1250 males and 1 in 40,840 females.10 Assessment of enzymatic activity of α-Gal A in a US newborn screening programme of mixed ethnic background (n≈110,000) confirmed a diagnosis of Fabry disease in 1 in 7800 males.11

Does Fabry disease affect male and female patients differently?

Heterozygous females with variants in the GLA gene were historically described as “carriers of the defective gene” who would not develop Fabry disease symptoms. However, the clinical signs and symptoms of Fabry disease do manifest in females, but can be variable.12

Initiated in 2001, the Fabry Registry (sponsored by Sanofi Genzyme) is an ongoing, international, multicentre, observational programme of patients with Fabry disease.13 In 2007, 2236 patients (males, n=1159; females, n=1077) were enrolled in the Fabry Registry, and were primarily from North America and Europe. Male and female patients enrolled in the registry were of a similar mean (standard deviation [SD]) age: 37.3 (14.9) years and 40.5 (17.4) years, respectively. The majority of male (76.6%) and female (84.1%) patients had a family member diagnosed with Fabry disease. The mean (SD) age at first Fabry disease symptoms was younger in males (13.5 [12.1] years) than females (19.9 [15.7] years). The mean (SD) age at diagnosis was also earlier in males compared with females (26.3 [15.5] vs 32.1 [17.6] years), and for the majority of patients, Fabry disease symptoms occurred before a diagnosis was made (males, 67.1%; females, 43.9%). The mean (SD) time from symptom onset to Fabry disease diagnosis was comparable between males and females (14.2 [13.0] vs 15.7 [14.8] years).14

Variants in the GLA gene were reported for 69.6% of male patients (n=788) and 76.4% of female patients (n=806). No significant differences in the frequency of specific GLA variants between male and female patients were reported; however, the R227X (c.679C>T) variant was most commonly reported and was present in 2.3% of patients (n=50). Neuropathic pain was the most commonly reported symptom in both male (63.3%) and female (43.3%) patients with Fabry disease.14

A proportion of male patients presented initially with major cerebrovascular, cardiovascular or renal events. Females were also likely to experience these problems, although there was more variability in the disease manifestations.14

  • For example, 4.2% of female patients experienced a stroke (n=44; mean [SD] age at onset, 43.8 [14.6] years) compared with 6.7% of males (n=76; mean [SD] age at onset, 39.5 [11.7] years).14
  • Cardiovascular involvement was proportional between male (19.3%, n=218) and female (13.9%, n=147) patients with Fabry disease; however, age at onset was typically older for female versus male patients. For example, left ventricular hypertrophy was reported by 18.2% of females and 21.6% of males at a mean (SD) age of 49.8 (12.4) years and 41.6 (10.9) years, respectively.14
  • End-stage renal disease was less common in female patients with Fabry disease compared with males, although mean (SD) age at onset was similar (males, 38.2 [9.8] years; females, 39.2 [13.0] years).14

Data from this study highlight that, similar to male patients, females with Fabry disease have a significant risk of organ involvement and should also be regularly monitored for signs and symptoms of Fabry disease.14


C-ANPROM/INT/FAB/0015; Date of preparation: March 2021