Genetic test uncovers LOPD hidden by decades of autoimmune disease
Pompe overlooked in man due to symptoms that resembled dermatomyositis
Late-onset Pompe disease (LOPD), a rare, inherited muscle disorder, was finally diagnosed in a 52-year-old man in Austria after decades of misdiagnosis, a case study shows.
The condition had long been hidden by overlapping symptoms of dermatomyositis, an autoimmune disorder. Only after treatment for the autoimmune disease failed to fully resolve his muscle weakness did doctors pursue genetic testing, leading to the correct diagnosis of dermatomyositis and LOPD.
Enzyme replacement therapy (ERT), along with low-dose corticosteroids, stabilized his muscle and lung function and led to a small but clinically meaningful improvement in walking ability.
The importance of genetic testing
The team said the case highlights the importance of careful diagnostic workup in neuromuscular disease and genetic testing when treatment results are atypical.
The case report, “Dermatomyositis masking late onset Pompe disease in a patient with proximal muscle weakness,” was published in the Journal of Neuromuscular Diseases by a team of researchers in Austria.
Pompe disease is caused by mutations in the GAA gene that result in a deficiency of the enzyme acid alpha-glucosidase (GAA). Without enough GAA, the complex sugar glycogen builds up within muscles, gradually impairing their function.
LOPD usually appears after the first year of life and causes progressive weakness of the hip, thigh, and trunk muscles, sometimes accompanied by breathing problems. Because LOPD symptoms develop gradually and resemble those of other neuromuscular conditions, the disease is often overlooked or diagnosed late.
Dermatomyositis is an autoimmune condition marked by muscle inflammation and distinctive skin features, often leading to rapid progression of weakness in muscles closest to the body’s core (shoulders, hips, and thighs).
In the report, the researchers detailed the case of a man who had experienced progressive muscle weakness for more than two decades before receiving a diagnosis of LOPD.
At age 29, he had mildly elevated levels of creatine kinase (CK), an enzyme released when muscle tissue is damaged. Over the following years, he developed gradually worsening muscle weakness and wasting in his upper thighs and hips.
Doctors noticed a waddling gait when the man was 52, as well as muscle wasting on his thighs. He also showed mild weakness in his hip and knee muscles.
His performance on the 6-minute walk test (6MWT), which measures the distance a person can walk in six minutes, was about 91% of the expected distance for his age and sex, indicating a mild reduction in endurance, while lung function remained normal.
Doctor suspected dermatomyositis, which was confirmed by blood tests that detected characteristic self-reactive antibodies.
Atypical response triggers LOPD diagnosis
The man began treatment with corticosteroids, followed by the immunosuppressant methotrexate. Although his CK levels dropped significantly at first, this effect was temporary, and his muscle weakness showed no clinical improvement.
The man’s slow progression of muscle weakness and his non-response to therapy were atypical for dermatomyositis and suggested another condition.
Genetic analysis identified two mutations in the GAA gene (c.842G>A and c.1544T>C) that were initially classified as of uncertain significance, meaning it was unclear whether these could lead to disease-causing changes in the resulting enzyme. Initial enzyme testing also showed normal GAA activity.
However, additional testing on dried blood samples and skin cells confirmed low GAA activity, allowing the mutations to be reclassified as likely disease-causing, and the man to be diagnosed with LOPD.
MRI scans showed signs of both dermatomyositis (patchy inflammation) and LOPD (fat replacement) in his thigh muscles. The researchers suggested Pompe disease may have existed first, slowly damaging the muscles over time, and that chronic muscle degeneration might have triggered the autoimmune disease, leading to secondary dermatomyositis.
The man was started on Nexviazyme (avalglucosidase alfa), an ERT, while continuing low-dose corticosteroids to control inflammation. After about a year, his muscle strength and lung function remained stable. The distance he covered on the 6MWT improved, reaching 97% of the expected value, a gain considered clinically significant.
“In cases with inflammatory [muscle diseases], sub-optimal treatment responses should lead to a re-consideration of the working hypothesis, possibly resulting in genetic testing,” the researchers concluded.
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