Symptom-based tool may help ID missed LOPD diagnoses
Diagnosing, treating disease sometimes delayed due to symptom overlap
Combining a symptom-based scoring tool with healthcare provider education may help identify patients who have an increased risk of having a missed diagnosis of late-onset Pompe disease (LOPD), a study in the U.S. shows.
A LOPD diagnosis should be considered in patients with progressive muscle weakness and at least one lab value commonly altered in people with the disease, according to researchers. This may include elevated levels of liver enzymes and creatinine kinase, a marker of tissue damage.
“Identifying at-risk patients is the first step in diagnosing patients early in the disease presentation and allowing them the option of pursuing treatment that could help improve quality of life,” the researchers wrote. The study, “A study to identify individuals at risk to be affected by late-onset Pompe disease who had previously been given a non-specific or tentative diagnosis for their muscle weakness (Pompe PURSUE),” was published in the Orphanet Journal of Rare Diseases.
Pompe disease is caused by mutations in the GAA gene and results in low levels of the acid alpha-glucosidase (GAA) enzyme, which breaks down glycogen, a complex sugar molecule. This allows it to build up to toxic levels within lysosomes, which are cellular compartments where glycogen and other molecules are broken down, particularly in the heart and muscles.
In LOPD, symptoms generally appear after the first year of life and include progressive muscle weakness, particularly in the trunk and pelvic muscles, that may result in respiratory failure and loss of the ability to walk. Diagnosing and treating the disease are sometimes delayed because its symptoms sometimes overlap with other neuromuscular diseases.
Identifying LOPD risk
Here, researchers attempted to identify patients at risk for LOPD using a two-step process that involved electronic medical records. The first step was to collect data automatically based on specific ICD-10 codes, a set of alphanumeric codes used to classify and identify various diseases, related to LOPD. Secondly, a symptom-based scoring tool analyzed the data, including clinical observations, laboratory results, and billing information.
The researchers retrospectively reviewed patients who were given a nonspecific diagnosis at an academic center and a community health system in the U.S. A total of 80,070 adult patients were classified as having an ICD-10 code of interest. Among these, 551 had at least one elevated lab value associated with LOPD, including the liver enzymes aspartate transaminase (AST) and alanine transaminase (ALT), and creatinine kinase.
After excluding for other conditions that could explain the lab findings, 110 patients were classified as at risk of LOPD, according to the symptom-based tool that scored the symptoms as very strong, strong, or moderate indicators of the disease. Among these patients, six had a known LOPD diagnosis, two tested negative for the disease, and 56 were diagnosed with another neuromuscular condition.
The remaining 46 patients were considered at the highest risk of having LOPD. Their most frequent symptoms were elevated liver enzymes (60%), morning headaches (57.3%), injury to the shoulder blade (47.3%), muscle weakness (47.2%), and elevated creatinine kinase (32.7%). Other symptoms included abnormal gait, unspecified muscular dystrophy, or progressive muscle weakness and wasting, frequent falls, and proximal muscle weakness.
Genetic testing for LOPD
The patients were contacted for genetic counseling and three of them accepted genetic testing for GAA mutations. Two had no reduced activity of the GAA enzyme or GAA gene variants, while one showed reduced GAA activity and symptoms that suggested LOPD. The first genetic test didn’t identify disease-causing GAA variants and the patient declined further evaluation.
The reasons for the low acceptance rate of testing in the high-risk population included “COVID exposure concerns, limited mobility or failing health, out of date contact information, and lack of interest,” the researchers said.
Among the healthcare providers given detailed information about LOPD and testing availability, one physician identified a high-risk patient and tested them for LOPD. The woman, 33, had proximal muscle weakness and wasting, elevated creatine kinase, and shortness of breath. She also had childhood onset generalized weakness, asthma, which is a chronic lung disease caused by inflammation of the airways that can make it hard to breathe, a waddling gait, and progressive weakness in her lower extremities since age 31.
Two variants in the GAA gene were identified, leading to a LOPD diagnosis. The patient was referred for further monitoring and treatment.
“This study confirms that a multipart symptom-specific scoring tool is a viable method of identifying patients at-risk for LOPD via retrospective [electronic medical chart] review,” wrote the researchers. “LOPD should be considered when evaluating any patient with progressive muscular weakness and one lab value commonly abnormal in individuals with LOPD.”
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