Siblings have same gene mutations, but different symptoms: Report

Case highlights question of when to start treatment in asymptomatic patients

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A child jumps rope while two children play with hula-hoops while toys and stars surround them.

Three siblings with Pompe disease caused by the same mutations were described in a recent report.

Despite all having the same disease-causing mutations, the clinical presentation of the three children differed dramatically — one began showing symptoms in infancy, while another had not shown clinical abnormalities at the age of 10 years.

The study, “Treatment Dilemma in Children with Late-Onset Pompe Disease,” was published in Genes.

Pompe disease is caused by mutations in the GAA gene, leading to reduced function or absence of the enzyme acid alpha-glucosidase. The current standard treatment for Pompe disease is enzyme replacement therapy (ERT), which involves administering a working version of this enzyme.

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Researchers in Italy described the case of a 7-month-old boy who was diagnosed with nonclassic infantile-onset Pompe disease. The infant had been brought to the emergency room at the age of 3 months due to unusually low muscle tone around the neck and trunk.

A battery of diagnostic tests were performed, leading to a suspicion of Pompe disease. A dry blood spot test of GAA enzyme activity resulted in values slightly lower than the minimum reference level. Blood tests showed a slight increase in the muscle damage marker creatine phosphokinase, the tissue damage marker lactate dehydrogenase, and the liver enzymes aspartate aminotransferase and alanine transaminase.

Genetic testing revealed mutations in both copies of the GAA gene, confirming the diagnosis. Specifically, the copy of GAA inherited from the baby’s father was found to harbor a mutation called c.2284G>A, which has been described before, though its association with disease is not fully understood. The mutation inherited from the baby’s mother, called c.1994G>A, has not been reported before, though analyses suggested it is likely disease-causing.

Analysis of siblings shows same two mutations

The baby’s two older siblings were an 8-year-old sister and a 10-year-old brother. After the baby was diagnosed, both siblings also underwent genetic testing and clinical evaluations. Results showed that all three children harbored the same two mutations.

The 8-year-old didn’t report any symptoms of Pompe other than a slight tendency to tire out in recent months, and her only sign of muscle weakness on clinical examination was difficulty in whistling and blowing. MRI scans of her legs indicated some small areas where fat was replacing muscle tissue, which is suggestive of the type of muscle damage that usually occurs in Pompe disease.

Meanwhile, the 10-year-old did not show any signs or symptoms of Pompe disease and MRI scans of his muscles were normal.

The 8-year-old has been started on ERT, and the infant was expected to also start treatment soon by the time of study conclusion. The 10-year-old is undergoing regular monitoring, including yearly MRI scans of his muscles.

This case highlights a current challenge for the treatment of Pompe disease: as diagnostics have improved, and particularly as many places have implemented newborn screening programs, an increasing number of children are being diagnosed with late-onset Pompe disease before they show any signs or symptoms. As illustrated here, even knowing the exact mutations a person has may not be enough to predict when symptoms will actually appear.

It is not clear when is best to start treatment for such children — while it is generally recommended to start ERT as early as possible, giving ERT before it’s needed is expensive and burdensome for patients who have to go in for regular infusions. ERT also comes with the risk of side effects, and the body’s immune system can react against the therapy, reducing its effectiveness.

“The dilemma is when to start ERT, considering its important benefits in terms of muscle but also its very high cost, risk of side effects, and long-term immunogenicity,” the researchers wrote.

Current European guidelines suggest monitoring asymptomatic late-onset Pompe cases with minimal MRI findings, whereas other guidelines consider starting ERT in asymptomatic patients with subtle Pompe signs. The researchers suggested that, as was the case for the 8-year-old here, muscle MRI could be a useful tool for detecting Pompe-related muscle damage, even before the affected person starts to notice symptoms.

“Muscle MRI can be considered a potential useful biomarker not only for diagnosis and follow-up but also to define when to start therapy,” the team wrote.