National Screening Leads to More Fabry Diagnoses in Czech Republic

Enlarged heart, a late-onset symptom, is often misdiagnosed as heart condition

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Implementing nationwide screening programs for Fabry disease in people with a heart condition called hypertrophic cardiomyopathy (HCM) may help improve diagnosis of the disease, a study in Czech Republic shows.

In the country, the program led to the diagnosis of Fabry in four men and two women among the 589 HCM patients screened.

These findings also highlight the importance of screening both sexes, the researchers noted, as the disease shows milder symptoms in women, who are more difficult to diagnose, than in men.

The program and its results were described in a study, “Nationwide screening of Fabry disease in patients with hypertrophic cardiomyopathy in Czech Republic,” published in ESC Heart Failure.

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‘Sequencing First’ Strategy Aims to Speed Diagnosis

Fabry disease is caused by mutations on the GLA gene, which is located on the X chromosome and provides instructions for making the alpha-galactosidase A (Gal A) enzyme. The lack of a working Gal A enzyme leads to a toxic buildup of fatty molecules such as Gb3 (globotriaosylceramide) and lyso-Gb3 in the body’s tissues.

As males have only one X chromosome (inherited from the mother), those who have the mutated gene will develop the disease. In females — who have two X chromosomes, one from the mother and one from the father — the presence of a healthy gene copy can compensate for the mutated copy to a certain extent.

While symptoms of classic Fabry start to show up in childhood, people with the rarer late-onset form of the disease do not typically experience any noticeable symptoms until later in adulthood.

One of the most common manifestations of late-onset Fabry is heart problems that typically start with enlargement of heart muscles. Clinically, this enlargement can appear similar to HCM — a more common heart disease characterized by an enlarged heart.

Prior research has shown that a small but significant proportion of people being evaluated for HCM at cardiology clinics actually have late-onset Fabry that is not yet diagnosed.

Early diagnosis important to slow down disease progression

“Early identification of affected patients … is of utmost importance as available specific treatment with enzyme replacement therapy and small molecular chaperone [Galafold (migalastat)] may slow down the disease progression and leads to some functional and structural improvements,” the researchers wrote.

In the study, a team of researchers in Czech Republic (also known as Czechia) conducted a nationwide program to screen HCM patients for possible Fabry. A novelty of this screening program, which involved 16 of the 17 cardiology specialty centers in the country, was that it included female patients, the researchers noted.

From 2017 to 2018, a total of 589 HCM patients were screened. The average age was 58.4 years and 66.2% were male. All provided a sample of blood, collected as a dry blood spot.

Samples from male patients were tested for Gal A activity, while those from female patients were tested to measure the activity of Gal A and levels of lyso-Gb3.

This was based on the fact that female Fabry patients may show Gal A activity within normal ranges. As such, also measuring lyso-Gb3 levels could theoretically reduce the risk of a false-negative test.

Blood test results identified 17 patients with signs of possible Fabry disease: 11 men and three women with lower-than-normal Gal A activity, and three other women with normal Gal A activity but elevated lyso-Gb3. These patients were referred for additional confirmatory and genetic testing.

Two of the three women with low Gal A activity also had high lyso-Gb3 levels, while these levels were normal in the other.

Genetic testing ultimately confirmed a diagnosis of Fabry in the two women who had both low Gal A activity and high lyso-Gb3, whereas the other female patient tested negative. Among the 11 men suspected to have Fabry, four were ultimately diagnosed via genetic testing.

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‘Sequencing First’ Strategy Aims to Speed Diagnosis

Classic Fabry disease diagnosed in one woman carrying novel mutation

Further analysis and clinical evaluation after the screening indicated that one of the diagnosed women had the classic form of Fabry.

The 53-year-old woman had evidence of systemic manifestation affecting the skin, kidneys, and nervous system as well as the heart, but symptoms “were overlooked by cardiology routine follow-up,” the researchers wrote.

She carried a previously unknown mutation, p.L294*, but lab and clinical data strongly suggested it was the cause of her disease.

The other woman diagnosed with Fabry (as well as all four men) carried a mutation called p.N215S, which is a well-established cause of late-onset Fabry. While most female Fabry patients have only one mutated copy of the GLA gene, this woman carried the p.N215S mutation on both copies. This explained why she exhibited “a disease severity and biomarker levels similar to male patients,” the team wrote.

These findings “support recommendation for routine screening in all adult HCM patient” for Fabry, the researchers wrote.

“Despite the successful detection of [disease-causing] mutations in women, we cannot exclude that a small proportion of females with late-onset variants may be missed due to low lyso-Gb3 values and [Gal A] activity above threshold limits,” they added.

Therefore, and “because many HCM patients undergo a complex search of [heart-related] genes responsible for the disease anyway, GLA gene should be included in the diagnostic panel,” the team concluded.