Mutation Causing Late-onset Fabry Mainly Affects Heart and Males, Researchers Find

A specific mutation in the GLA gene is associated with late-onset Fabry disease, and primarily affects the heart with more severe symptoms in males, according to researchers who received information from an international Fabry disease registry. 

Cardiac problems in people carrying this mutation may become as severe or even more severe than in classic Fabry disease patients, particularly in men.

The study, “Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry Registry study,” published in the journal Molecular Genetics and Metabolism, is the largest study so far characterizing the clinical traits of Fabry patients with this type of mutation.

Fabry disease is caused by genetic mutations affecting the GLA gene, which provides instructions for making an enzyme called alpha-galactosidase A, or α-Gal A. This results in insufficient activity of α-Gal A, which leads to the accumulation of a type of fat known as globotriaosylceramide (Gb3).

The onset of Fabry disease symptoms typically starts in childhood, often with life-threatening complications developing with age. In atypical, milder forms of the disease, patients may not develop symptoms until later in life, and symptoms may affect only one organ, particularly the heart or the kidney.

This atypical late-onset Fabry disease has been associated with specific mutations in the GLA gene that lead to decreased amounts of functional alpha-galactosidase A enzyme.

The p.N215S mutation is the most common type of GLA variant linked to late-onset Fabry with heart involvement in Western countries.

Even though researchers has established a link between this mutation and the late-onset cardiac variant, there is still little data about which disease traits characterize patients who carry this particular genetic variant.

In this study, researchers expanded the clinical data available for patients with the p.N215S mutation by evaluating disease symptoms and outcomes compared to those with classic Fabry disease.

The team analyzed 125 patients with p.N215S (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742), a worldwide multi-center, observational program.

Data from 401 patients (237 females, 164 males) carrying mutations linked with classic Fabry disease were also analyzed for comparison.

The analysis has the advantage of separating males from females, who generally present a milder form of the disease.

The study analyzed patients’ natural history — before initiation of enzyme replacement therapy — including heart and kidney exams and the first reported severe clinical events.

Most men with the p.N215S phenotype — atypical Fabry — had abnormal heart measurements, including thickness between ventricles and thickness of the left ventricle wall (chambers of the heart that collect and pump blood), which progressed to severely abnormal values in older patients ages 65 to 75.

But researchers found that the severity of both heart irregularities was similar in men with classic Fabry disease, as well.

In general, women had less frequent heart disorders, and when they did, their symptoms were milder even at advanced ages. A similar trend was observed in women with classic Fabry disease.

Kidney involvement seemed to affect a minority of p.N215S males who had slightly abnormal estimated glomerular filtration rates (which measures kidney function), particularly older patients. 

Overall, kidney disease was seen in 17% of men and 3% of women with the pN215S mutation.

The first severe clinical events reported in p.N215S males (32%) occurred at a mean age of 52.4 years, approximately 14 years later compared to classic Fabry male patients (33%).

These mainly included heart problems (males 31%, females 8%), with kidney and cerebrovascular events, including stroke, considered rare.

Generally, women experienced severe events less frequently than males, with very few patients with atypical p.N215S presenting them (9%) compared to women with classic Fabry disease (20%).

Heart disorders occurred at younger ages in classic Fabry males but were less frequent compared with male p.N215S patients (21% vs. 31%).

Comparively, classic Fabry females had more frequent heart problems than p.N215S females (15% vs. 8%), but both developed heart symptoms at around age 50.

In general, male p.N215S patients started to have heart problems much earlier than females, many in the fourth decade of their life. Female p.N215S patients had fewer heart problems, and they began in the sixth decade of their life.

No deaths were reported during natural history follow-up in the p.N215S patients as first severe clinical events, whereas three classic patients died.

Of note, among p.N215S patients, enzyme replacement therapy was more frequent in men (76%) than women (21%).

These findings confirm p.N215S as a mutation causing late-onset Fabry with severe clinical manifestations essentially limited to the heart until adulthood, especially in males.

“Once abnormalities have been observed in patients with the Fabry p.N215S genotype, early diagnosis and close monitoring of cardiac status is important because Fabry-specific therapeutic intervention and treatment of cardiovascular risk factors may be indicated, as well as cascade family screening for early diagnosis of family members,” researchers wrote.