Two-step process successfully diagnoses over 700 Pompe patients
Biochemical and genetic testing strategy used to screen 30K suspected cases
A two-step process used to screen thousands of people with suspected Pompe disease led to diagnoses of the rare genetic condition in more than 700 individuals across 50-plus nations, a new retrospective study reports.
The researchers used both biochemical and genetic testing to analyze more than 30,000 blood-spot samples collected from suspected Pompe patients.
“We were able to identify patients with [Pompe disease] at a very early stage,” the scientists wrote, concluding “our two-step approach … is recommendable for the identification of [Pompe disease] patients.”
According to the researchers, the study’s results also suggest that certain patterns of disease-causing mutations seem to be more common in people with specific types of Pompe disease.
The team noted that the “cases were multiracial because they were from 57 countries, so they can be considered very representative without ethnical biases.”
The study, “Biochemical and Genetic Testing of GAA in Over 30.000 Symptomatic Patients Suspected to Be Affected With Pompe Disease,” was published in the journal Human Mutation. The work was funded by Sanofi Genzyme, the maker of Nexviazyme (avalglucosidase alfa) and Lumizyme (alglucosidase alfa). These two enzyme replacement therapies (ERTs) are widely approved as treatments for Pompe disease.
Two-step process used for screening blood spot samples from 57 countries
Pompe disease is caused by mutations in the GAA gene, which provides instructions to make the enzyme acid alpha-glucosidase. The resulting low or no working enzyme in Pompe leads to a toxic buildup of a sugar molecule called glycogen that damages cells, especially muscle cells.
Because Pompe is a rare disease, it often is difficult for those with the genetic condition to get a correct diagnosis. The estimated incidence, or number of new cases, of Pompe disease varies widely by location and ethnic group. In the U.S., Pompe affects approximately 1 in every 40,000 people, though the rate is higher among African Americans, at about 1 in every 14,000 individuals.
Now, a team of scientists from Austria and the Netherlands used a two-step process to test for Pompe in blood samples from 30,836 people. All of these samples came from individuals with symptoms that led to a suspicion of possible Pompe disease.
In the first part of the test, the activity of the alpha-glucosidase enzyme was measured. Then, if enzyme activity was found to be lower than normal, the GAA gene was sequenced.
“To our knowledge, this is one of the largest studies with more than 30,000 symptomatic cases suspicious for [Pompe disease] from 57 countries,” the researchers wrote.
Ultimately, 723 people were diagnosed with Pompe disease. Across these patients, the scientists identified a total of 283 unique GAA mutations; most of them had been reported before, but slightly more than a third were novel.
Researchers note diagnosis delays can ‘negatively affect treatment outcomes’Â Â
All people inherit two copies of the GAA enzyme — one from each biological parent. Pompe disease only develops if both copies of the gene carry a mutation. As such, people with Pompe can either be homozygous, meaning both copies carry the exact same mutation, or compound heterozygous, meaning both copies are mutated but the specific mutation is different in each copy.
Further, Pompe can be broadly divided into infantile-onset disease, or IOPD, and late-onset disease, known as LOPD. In IOPD, symptoms appear in infancy, while in LOPD manifestations of the disease don’t appear until after the first year of life.
In additional analyses, the researchers looked for associations between specific GAA mutation types and Pompe disease type.
The team found that 85.6% of patients with IOPD carried homozygous mutations. By contrast, about three-quarters of LOPD patients (76.9%) had compound heterozygous mutations.
The combined enzyme activity and genetic testing from [the blood spot] cards can reliably identify [Pompe disease] and significantly accelerate diagnosis.
Individuals with IOPD also more frequently had nonsense mutations — a type of mutation in which, essentially, an erroneous stop signal is placed in the middle of the gene. The effect is sort of like having a period in the middle of a sentence, and it typically prevents any functional enzyme from being made.
The LOPD patients, meanwhile, more frequently had missense mutations. These are changes in the genetic sequence that result in different amino acids, which function as building blocks, being encoded.
Still, the researchers noted that a correlation between genetic profile, or genotype, and observable clinical status, or phenotype, could not be established, though exceptions were identified. One was the c.896T>C/p.L299P mutation, found exclusively in homozygous early-onset cases.
Overall, according to the researchers, “the combined enzyme activity and genetic testing from [the blood spot] cards can reliably identify [Pompe disease] and significantly accelerate diagnosis.”
The team stressed the importance of identifying Pompe patients at an early stage, noting it “can be decisive for ERT because any delay can negatively affect treatment outcomes.”
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