Genetic testing of 331 family members of Russian patients with Fabry disease led to the detection of 165 undiagnosed cases, a study reports.
Family genetic testing has also been shown to be more effective than other screening programs in identifying Fabry cases.
“Family genetic testing was significantly more effective (49.8%) than screening programs in newborns or patients with end-stage renal disease. [kidney] disease, unexplained left ventricular hypertrophy [thickening of the heart wall], or stroke, which are expensive and often have a diagnostic yield of less than 1%. … Genetic testing of all at-risk family members (including males and females) should be encouraged,” the researchers wrote.
The study, “Benefits of family screening for rare diseases: genetic testing reveals 165 new cases of Fabry disease among at-risk family members of 83 indexed patients,” was published in Genoa.
Fabry disease is a rare genetic disorder caused by mutations in the GLA gene, which codes for the enzyme alpha-galactosidase A (Gal A) which breaks down fatty molecules, mainly globotriaosylceramide (Gb3 or Gl-3). Abnormal Gal A proteins lead to toxic accumulation of Gb3 in several organs, especially the heart, kidneys and nervous system, causing irreversible damage.
Treatment with long-term enzyme replacement therapy and small molecule pharmacological chaperones can effectively reduce symptoms and slow organ damage if started early. However, Fabry disease is often diagnosed late because symptoms may be nonspecific and clinicians may not be sufficiently aware of the disease.
Programs that screened patients with end-stage renal disease undergoing dialysis or kidney transplantation or those with unexplained left ventricular hypertrophy are expensive and typically identify only up to 0.9% of cases. Russian researchers have studied the possibility and effectiveness of genetically testing families of patients diagnosed with Fabry to increase detection rates and facilitate early treatment.
The study and its results
They analyzed data from 83 patients (72 men and 11 women) with Fabry disease registered at a Russian reference center for lysosomal storage diseases. Although most patients showed signs of the disease in early childhood or adolescence, they were not diagnosed until after a median of 21 years, when they developed advanced disease affecting the kidneys, heart or brain. All patients provided information about their family, allowing researchers to identify and genetically screen other family members.
The researchers identified 659 potentially affected family members and tested 331 of them. Fabry disease was diagnosed in 165 family members, 30 of whom were under 18 years old. A total of 107 had symptoms and, after diagnosis, 42 started enzyme replacement therapy.
Unlike other studies where cost is a barrier to family genetic testing, the researchers note that cost is not an issue in Russia because all tests are provided free of charge to patients and medical institutions. However, they confirm that knowledge of Fabry disease among physicians is low, leading to most cases being missed despite patients showing symptoms since childhood.
“It should be noted that almost 20% of patients newly diagnosed with Fabry disease in this study were under the age of 18,” the researchers wrote, adding that “[s]Fabry disease awareness strategies among pediatricians are particularly important.
“Genetic testing using cascade genotyping in families of index patients identified by presentation of symptoms or by a screening program may significantly increase the number of patients diagnosed with Fabry disease and may thus facilitate diagnosis and treatment before that irreversible organic damage is present,” they concluded.
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