Rare Diseases Report 2022

The paradox of Pompe disease


Until 2006, when a breakthrough therapy first made treatment possible, Pompe disease was a little-known metabolic myopathy fatal to infants. Those with later-onset disease experienced progressive, often severe disability into adulthood.

In this rare autosomal recessive disorder, which occurs in approximately one in 40,000 births worldwide, a deficiency or absence of the enzyme acid alpha-glucosidase causes glycogen to build up in the lysosomes of cells. While many tissues are affected, skeletal and cardiac muscle see the earliest involvement, with muscle hypotonia, cardiomyopathy, and breathing difficulties (mainly due to diaphragm weakness) comprising the hallmark symptoms of the infantile form. Muscle weakness and progressive respiratory failure are prominent in later-onset disease.

Dr. Priya Kishnani

The spectrum of severity and age of onset in Pompe disease is linked to combinations of mutations on the GAA gene, some of which destroy the body’s ability to produce acid alpha-glucosidase whereas others merely hamper it. Less enzyme produced in the body generally corresponds with more severe disease activity.

The most severe end of the disease spectrum, or “classic infantile Pompe disease,” presents at birth and is recognized in early infancy. Until treatment with enzyme replacement therapy (ERT) became available, patients usually died of cardiorespiratory failure within their first year of life. With therapy, patients have survived into their 20s and beyond. Late-onset disease is a far broader category in which patients can present at any time from their first year, including into middle age.

Antonio Toscano, MD, is professor of neurology at the University of Messina, Italy.

Dr. Antonio Toscano

The emergence in 2006 of alglucosidase alfa (Lumizyme, Sanofi Genzyme), an ERT used long-term to improve survival and slow progression in children and adults, resulted in a boom of research interest, a push to timelier diagnosis, and – with patients living longer – a more thorough understanding of the natural history of Pompe disease. In addition to the usual clinical picture of progressive muscle weakness, difficulty breathing, and cardiomyopathy, investigators are seeing nervous system involvement in patients with Pompe disease.

A patient with Pompe, especially one with late-onset disease, may be diagnosed and even managed by his or her neurologist. To learn more, Neurology Reviews talked to two global experts in Pompe disease: Priya Kishnani, MD, of Duke University in Durham, N.C., and Antonio Toscano, MD, of the University of Messina, in Messina, Italy.

Diagnosis: Still room to improve

“Most neurologists will encounter a patient with Pompe disease,” said Dr. Kishnani, who has been working with Pompe for her entire career as a pediatrician and medical geneticist, treating patients of all ages and disease phenotypes.

“In newborns, diagnosis is more straightforward, because you’ve got an enlarged heart,” she said. And thanks to efforts of researchers like Dr. Kishnani and Pompe advocacy groups, Pompe disease is now a part of the RUSP (Recommended Uniform Screening Panel) for newborns; currently 28 U.S. states are screening for Pompe disease.

“The challenge really is for the later-onset cases, which are 80% of all cases,” Dr. Kishnani said.

Previously, muscle biopsies were the first step toward diagnosis. Dried blot spot assays to detect enzyme deficiency have since become the standard, along with other biochemical tests. Confirmation of the diagnosis is through gene sequencing panels to detect GAA mutations.

“Now that there is a treatment for Pompe disease and the availability of blood-based testing, many previously undiagnosed patients with limb girdle weakness are evaluated and the diagnostic odyssey ends,” Dr. Kishnani said. “But there is still a diagnostic delay, and many cases remain undiagnosed.”

Routine blood tests for creatine kinase and for liver enzymes can help point to Pompe disease. But elevated liver enzymes are often misinterpreted. “It’s about the ratios,” Dr. Kishnani said. “ALT is usually much more elevated if it is coming from a liver cause, and AST is usually higher than ALT if it is coming from muscle. But patients often end up getting a liver biopsy due to so-called elevated liver enzymes. As the workup continues, it is often later recognized that the source of the elevated enzymes is muscle involvement, and a referral to the geneticist or neurologist is made. Only then is appropriate testing to confirm a diagnosis initiated.”

Dr. Toscano, a neurologist who specializes in Pompe disease and other myopathies and who has published on tools for diagnosing late-onset Pompe disease,1 said that clinicians should be vigilant when evaluating any patient with limb girdle weakness and elevated creatine kinase (CK) – “especially if the CK is under 2,000,” he said, “because it is very rare that patients with Pompe disease have a more elevated CK than that.”

“Elevated CK, myalgia, and exercise intolerance” should prompt clinicians to suspect Pompe disease in a patient of any age, Dr. Toscano said. “When you come across this, you should be very persistent and get to the end of the story.”

Dr. Toscano noted that the blood spot assay, while an important early step, is not fully diagnostic, “because you can have false positives.” The molecular GAA assay is used to confirm Pompe disease. But detecting pathogenic variants on the GAA gene – of which there are more than 500 – can be more complicated than it sounds. Whereas two mutations are required for Pompe disease, sometimes only one can be detected. Dr. Toscano said he also treated some patients for Pompe with only one known mutation but with unequivocal clinical and biochemical aspects of Pompe disease.

While delays in diagnosis for late-onset Pompe disease remain significant -- between 5 and 6 years on average for older patients, and up to 20 years for those with pediatric onset – both Dr. Kishnani and Dr. Toscano said they perceive them to be improving. With McArdle disease, another inherited glycogen storage disorder that is more common than Pompe disease but for which there is no treatment, “the delay is nearly 12 years,” Dr. Toscano said.


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