A common GLA mutation is highly associated with the development of Fabry disease in both men and women, and even women with no typical disease symptoms show signs of heart damage, a Finish study suggests.
These findings highlight the importance of cardiac evaluations in women carrying GLA mutations, regardless of evident disease symptoms.
The study, “Natural course of Fabry disease with the p. Arg227Ter (p.R227*) mutation in Finland: Fast study,” was published in the journal Molecular Genetics & Genomic Medicine.
Since men only have one X chromosome, those who inherit a mutated GLA gene will develop the disease and present more severe symptoms. In women — who have two X chromosomes — a healthy GLA gene copy can compensate for the mutated copy to a certain extent.
This compensation process, called X‐chromosome inactivation, varies significantly among women carrying GLA mutations, resulting in considerably different disease types, severity, and age of onset, or no signs of disease at all (in this case, women are called asymptomatic carriers).
Both men and women can develop the two main types of Fabry disease: type 1 (classical and more severe form) and type 2 (late-onset form), which is usually milder and leads to heart and kidney problems between the ages of 30 and 70.
Researchers evaluated the natural course of Fabry disease in 14 people carrying a common Fabry disease-causing mutation in the GLA gene — c.679C>T — and living in western Finland. The c.679C>T mutation is the most common cause of classic Fabry disease in Finland, and one of the most common disease-causing mutations in the world.
This study — called the Fabry follow‐up single mutation study in Finland (FAST) — aimed to better understand the link between the c.679C>T mutation and disease symptoms, and to assess the effects of enzyme replacement therapy (ERT) in both men and women for up to five years.
These results concern the first part of the study, before patients initiated ERT.
The team collected the patients’ data from medical records and the Fabry Registry (NCT00196742), a worldwide, multicenter, observational study to understand the variability, progression, and natural history of Fabry disease and assess the effects of Fabrazyme (agalsidase beta) — an ERT— in both men and women for up to 15 years.
Participants comprised four men and 10 women, whose mean age at diagnosis was 46, varying from 15 to 36 years old among men, and 25 to 80 among women. All patients belonged to two different families who shared a common 19th century ancestor.
Researchers noted that this link between patients provided more strength to their study, since it minimized other influencing factors, including environmental and cultural factors.
Results of the last follow-up visit before starting ERT showed that six people (43%) had cardiac hypertrophy (enlargement and thickening of the heart muscles), four (29%) showed elevated high blood pressure, three people (21%) presented a history of stroke, and three (21%) had irregularly fast heart rate, with two of them having a pacemaker.
Five out of nine patients (55%) also showed scarring on the heart muscle, and one had abnormally high levels of protein in the urine (proteinuria). None showed signs of severe kidney dysfunction.
All four men had classic Fabry disease, with multiple organ involvement. Those older than 30 (three out of four) had at least one of these symptoms: cardiac hypertrophy, history of stroke, or proteinuria.
The severity of Fabry disease in women varied from late-onset disease with heart involvement to severe classic disease. No one was completely asymptomatic. However, besides heart involvement considered significant in some cases, several women showed no typical Fabry symptoms.
“Females can be easily misclassified as asymptomatic mutation carriers and withdraw from regular follow‐up and therapy,” the researchers wrote, adding that regular follow-up is crucial for the determination of the “the right time to begin ERT when there is evidence of early damage in critical organs, such as the heart, brain, or kidneys.”
The team also emphasized that heart involvement should be effectively assessed in these women before considering them asymptomatic.
Future studies are required to determine whether these results can be generalized to other patients carrying this mutation, and to identify other mutations associated with milder late-onset forms of the disease.
“In addition, the role of X‐chromosome inactivation in Fabry disease severity is still unanswered and should be further investigated,” the researchers concluded.