Screening for LOPD may help ID undiagnosed patients

Examining dried blood spots can reduce diagnostic delays, enable earlier treatment

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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While it is not very common, adults with late-onset Pompe disease (LOPD) may go undiagnosed or misdiagnosed, even if they show symptoms or signs suggestive of the disease, a study from Spain has found.

Dried blood spots — a form of sampling where a drop of blood is blotted and dried on filter paper — may help doctors screen for LOPD among patients seen at internal medicine and other clinical departments.

There may exist “a hidden population of LOPD patients in internal medicine departments who might benefit from early diagnosis and concurrent early initiation of potential treatments,” the researchers wrote.

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New GAA mutations linked to infantile-onset disease

The study, “Screening for late-onset Pompe disease in Internal Medicine departments in Spain,” was published in the Orphanet Journal of Rare Diseases.

Pompe disease is caused by mutations in GAA, a gene that provides instructions for making an enzyme that breaks down glycogen, a complex sugar, into a simpler sugar called glucose that cells can use for energy.

GAA mutations result in toxic buildup of glycogen in cells. This affects the muscles particularly, causing a range of symptoms from muscle weakness to difficulty breathing. The disease can manifest in the first year of life (infantile-onset) or later in life (late-onset).

LOPD usually is a milder form of the disease, and its symptoms and signs may overlap with other neuromuscular diseases (for example, muscular dystrophy), “frequently [leading] to a considerable delay in diagnosis and treatment,” the researchers wrote.

Generally, a delayed diagnosis is tied to poorer clinical outcomes, but screening using dried blood spots can help identify undiagnosed patients. The researchers did this to find out how common it is for patients in internal medicine departments to go undiagnosed.

LOPD study design

The study included 322 adults with a clinical suspicion of LOPD from 13 internal medicine departments across Spain. Their median age was 47 years, and nearly two-thirds (63.7%) were men.

The most common reason for suspicion was hyperCKemia, or high levels of creatine kinase in blood, a sign that muscles may be damaged (65.8%). It was followed by polymyositis, a disease that causes muscles to become inflamed and weak (21.7%).

Dried blood spot testing revealed low GAA enzyme activity in 16 (5%) patients. By genetic testing, three (0.9%) patients were found to carry mutations in the GAA gene, but only two (0.6%) were confirmed to have a diagnosis of LOPD.

One patient was 18 years old and presented with polymyositis or other type of muscle disease. His first symptoms appeared when he was 16. Genetic testing revealed c.336-13T>G — a common mutation linked to LOPD — in one copy of the GAA gene; the other copy had a c.1443G>A mutation.

The other patient, a 51-year-old man, had just presented with hyperCKemia, but had no, or few, symptoms. He carried two copies of the c.336-13T>G mutation, which limited enzyme activity to 50% of normal. Imaging scans revealed abnormalities in the muscles of the head, trunk, and lower extremities. 

“These conditions (polymyositis or asymptomatic hyperCKemia) are part of the differential diagnosis of LOPD, together with a number of additional diseases,” the researchers wrote. “Muscle fatigue, clumsiness, difficulty in breathing, and/or elevated muscle enzymes may be suggestive of LOPD.”

Reducing diagnostic delay

In this study, the diagnostic delay was short, ranging from 0 to 2 years. However, “the difficulty in diagnosis usually results in a diagnostic delay, averaging approximately seven years,” the scientists wrote.

“Reducing diagnostic delay is important because it provides the possibility to initiate the only current treatment available (enzyme replacement therapy) earlier,” they added.

The findings of this study show that “it is possible to reach a definitive diagnosis of this type of rare diseases with little or no invasive tests and at a low cost,” the researchers concluded.