Study Suggests Improved Screening Strategies for Fabry Disease


Early diagnosis of Fabry disease is essential and that since symptoms depend on the type of disease and sex and age of the patient, a high-risk screening system should account for the age of the target population, the researchers said.

A recent study suggested improved strategies to screen for Fabry disease, based on the authors’ own screening methods in Japan as well as a literature review.

Writing in Diagnostics, the researchers said early diagnosis of Fabry disease is essential and that since manifestations depend on the type of disease and sex and age of the patient, a high-risk screening system should account for the age of the target population.

Fabry disease is an X-linked inherited disorder caused by mutations in the GLA gene, which encodes the lysosomal enzyme α-galactosidase A (α-Gal A).

The classical type of Fabry disease affects males early in life; symptoms include limb pain, acroparesthesia, sweating disorders, angiokeratoma, and/or gastrointestinal symptoms.

In the late-onset type, patients develop kidney, heart, and cerebrovascular disorders.

Since Fabry is an X-linked inheritance, some females can develop these manifestations, and heterozygous female patients develop symptoms similar to those of the classical type, suggesting inactivation.

On the other hand, the types of presentations often seen in older people with Fabry disease—renal, cardiac, and central neurological symptoms—are not specific for Fabry disease and the frequency is not as high, even in pediatric patients with a higher risk of Fabry disease.

Treatment includes enzyme replacement therapy; it slows renal deterioration, alleviates the progression of cardiomyopathy, and prevents illness and death. Another therapy, migalastat, is cleared for patients with certain GLA variants.

Existing newborn screening suggests that the prevalence of Fabry disease in Japan suggests that prevalence may be higher than expected.

In children and adolescents, the observed peripheral neurological manifestations are specific to Fabry disease, raising the likelihood of a diagnosis.

Methods for high-risk screening include measuring α-Gal A enzyme activity in the blood; measuring Gb3 level in urine or blood and/or Lyso-Gb3 level in the blood; and GLA gene sequencing. However, the authors cautioned, some females with polymorphisms that do not cause disease may have false-positive results; they should be screened using GLA gene sequencing but noted that all variants can be detected.

In the researchers’ own work, they followed up on a previous study and screened individuals with disease-related manifestations who did not receive screening as a newborn.

Using the same methods as used in newborn screening, they screened 18,135 individuals throughout Japan with at least 1 of the following 5 risk factors: renal manifestations, cardiac manifestations, central neurological system involvement, or peripheral neurological manifestations.

In individuals with a family history of the disease, some of their relatives within the third degree of kinship had already been diagnosed. Individuals who screened positive according to α-Gal A activity in dried blood spots underwent GLA sequencing.

Twenty-eight individuals (0.4%, 28/8823) with renal symptoms, 29 (0.9%, 29/4057) with cardiac involvement, and 5 (0.2%, 5/3075) with central neurological manifestations were diagnosed.

Fabry disease was mostly found in those with peripheral neurological manifestations (4.4%, 30/894), which is known to be a key signal for early detection of FD. Family history of the disease was observed in 128 of 715 (23.4%) individuals.

While high-risk screening by GLA sequencing carries cost and ethical issues, the authors said, a better system to definitively diagnose Fabry disease is needed.


Sawada T, Kido J, Sugawara K, Nakamura K. High-risk screening for Fabry disease: A nationwide study in Japan and literature review. Diagnostics. Published online September 27, 2021. doi: 0.3390/diagnostics11101779

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