Fabry disease is a rare inherited genetic condition that can impact multiple organ systems. Understanding its prevalence, or how often it occurs, is important for recognizing its presence within populations.
Understanding Fabry Disease
Fabry disease is a genetic disorder caused by a deficiency in the alpha-galactosidase A (alpha-Gal A) enzyme. This enzyme normally breaks down a fatty substance called globotriaosylceramide (Gb3) within cells. When alpha-Gal A is absent or not working correctly, Gb3 accumulates in cellular lysosomes. This buildup can lead to cell damage and affect the function of various organs over time.
It is an X-linked inherited disorder, meaning the mutated gene is on the X chromosome. Because males have one X and one Y chromosome, and females have two X chromosomes, the inheritance pattern and symptom severity can differ between sexes. The disease is progressive, with symptoms often starting in childhood or adolescence and worsening with age.
The Global Picture of Fabry Disease Prevalence
Global prevalence estimates for Fabry disease vary widely. The average prevalence at birth worldwide is approximately 1 in 15,000, though some sources suggest it could be higher due to underdiagnosis. Historically, classic Fabry disease incidence was estimated at 1 in 40,000 to 1 in 117,000 males.
However, more recent newborn screening studies indicate higher prevalence rates. For instance, screening in northern Italy found an incidence of 1 in 7,879 newborns, with most having later-onset or unclassified variants. A study in Italy and Taiwan suggests around 50,000 people in the U.S. may have Fabry disease, encompassing both classic and late-onset forms.
Prevalence estimates also vary across different populations and geographical regions. For example, a high incidence of the later-onset form has been reported in Taiwan due to a specific common pathogenic gene variant. The presence of both classical and later-onset forms contributes to the range of prevalence figures.
Due to its X-linked inheritance, prevalence also differs by sex. While classic Fabry disease is often cited with male prevalence rates, females can also be affected, though their symptoms may be milder or present later due to X-inactivation. Older estimates for males in the U.S. are around 3,800, with 7,600 females carrying the gene. Newer estimates suggest approximately 1 in 14,022 males and 1 in 6,978 females in the U.S. carry a pathogenic allele, with many carriers expected to develop symptoms.
Factors Influencing Prevalence Estimates
Accurately determining Fabry disease prevalence is complex due to several factors. Diagnostic challenges contribute significantly, as the disease’s varied and non-specific symptoms can lead to misdiagnosis or delayed diagnosis, sometimes by over 10 years after symptom onset. Fabry disease can affect multiple body systems, causing patients to present to various medical specialists, further complicating recognition.
Increased awareness among healthcare professionals improves diagnosis rates. Historically, many cases remained undiagnosed due to the disease’s rarity and wide spectrum of manifestations. As knowledge of Fabry disease spreads, more individuals unknowingly living with the condition may be identified.
Newborn screening programs have also revealed a higher prevalence than traditional estimates based on clinically diagnosed cases. These screenings, which often measure alpha-Gal A enzyme activity or perform genetic testing, can identify individuals before symptoms appear, including those with atypical or later-onset forms. However, enzyme-based screening may miss a number of affected females, and detecting variants of uncertain significance can also pose challenges.
The detection of atypical or later-onset forms, which can have milder symptoms or manifest in adulthood, further contributes to prevalence variability. These forms were not always captured in older studies that focused primarily on the classical, more severe presentation. The ongoing identification of these cases through expanded screening efforts suggests that the true prevalence of Fabry disease is higher than previously understood.