Why is Early Diagnosis Important?
Pompe disease is a progressive, neuromuscular disease. While patients may not show symptoms for many years (sometimes even decades), the disease is present and active at birth. Multiple trials have shown that treatment with enzyme replacement therapy (ERT) can significantly alter the natural history of Pompe disease in patients. In short, it saves lives.
However, studies have also shown that a critical component of a successful outcome with ERT is the initiation of treatment before irreversible damage has occurred. In an Editorial titled “Early is better? A new algorithim for early diagnosis in Late Onset Pompe Disease (LOPD),“ Drs. Antonio Toscano and Olimpia Musumeci stated: “In LOPD, the efficacy of ERT has been demonstrated but with less prominent efficacy when compared to the infantile cases. In fact, it has been shown that ERT may improve or stabilize motor performances and respiratory function in at least 2/3 of treated patients. Some studies reported that an early start of therapy may maximize ERT efficacy, suggesting that, in LOPD, an earlier diagnosis has to become the key point in patients’ management” (http://amda-pompe.org/downloads/publications/Early_is_better.pdf).
The importance of early diagnosis is even more critical in Infantile-Onset patients. In fact, in “Very Early Treatment for Infantile-Onset Pompe Disease Contributes to Better Outcomes,” the authors reported “we found that starting ERT even a few days earlier was associated with better biochemical responses and developmental outcomes” (http://amda-pompe.org/downloads/publications/Very_Early_Treatment_for_Infantile-Onset_Pompe_Disease_Contributes_to_Better_Outcomes.pdf). The key to early initiation of treatment is early diagnosis. Without a diagnosis it is impossible to start treatment before irreversible damage has occurred. However, achieving an early diagnosis is complicated by the fact that symptoms of Pompe can occur at any age, and are often difficult to detect at first.
What are the Early Symptoms of Pompe disease?
The first (or early) symptoms of Pompe will often vary from person to person. It is important to remember that not all symptoms may be present, and that the severity and order of the symptoms may vary. Knowing and recognizing the early symptoms of Pompe disease is critical to achieving an early diagnosis.
A. Infantile Onset (Classical Infantile Pompe disease)
- Greatly enlarged heart
- Poor muscle tone - floppy baby
- Difficulty breathing
- Frequent chest infections, and slow to recover from them
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Failure to meet or maintain developmental milestones
Ex: rolling over, sitting up, crawling, and walking - Difficulty sucking, swallowing, or feeding in general
- Enlarged tongue
- Failure to thrive or gain weight
B. Childhood Onset (Late-Onset Pompe disease)
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Difficulty breathing
May be seen in the following ways:
- Heavy breathing during mild/moderate exercise
- Difficulty breathing when laying flat
- Difficulty breathing while sleeping, which may cause morning headaches, nausea, and/or daytime sleepiness - Frequent chest infections, and slow to recover from them
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Failure to meet or maintain developmental milestones
Ex: walking, running, or jumping - Frequent trips and falls (loss of balance)
- Poor performance in sports and other physical activities
- Difficulty with stairs and/or getting off the floor
- Muscle pain and/or fatigue
- Contractures
- Ptosis
- Development of scoliosis (curvature of the spine) and/or lower back pain
- Scapular winging
- Difficulty chewing, swallowing, and/or generally eating because of weakened mouth, tongue, and throat muscles
- Difficulty gaining or maintaining a healthy body weigh
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Higher than normal creatine kinase levels in the blood
Also referred to as CK or CPK - Delayed potty training
C. Adult Onset (Late-Onset Pompe Disease)
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Difficulty breathing
May be seen in the following ways:
- Heavy breathing during mild/moderate exercise
- Difficulty breathing when laying flat
- Difficulty breathing while sleeping, which may cause morning headaches, nausea, and/or daytime sleepiness - Frequent chest infections, and slow to recover from them
- Difficulty climbing stairs, getting up from a chair, or standing up
- Frequent trips and falls (loss of balance)
- Poor performance in sports and other physical activities
- Difficulty with stairs and/or getting off the floor
- Muscle pain and/or fatigue
- Contractures
- Ptosis
- Scapular winging
- Difficulty chewing, swallowing, and/or generally eating because of weakened mouth, tongue, and throat muscles
- Difficulty gaining or maintaining a healthy body weigh
-
Higher than normal creatine kinase levels in the blood
Also referred to as CK or CPK
OTHER SYMPTOMS
- Slightly enlarged liver is sometimes seen in Infantile-Onset Pompe
- In some Late-Onset patients, heart rhythm changes have been observed
“Differential” Diagnosis – Or, what other disease does Pompe share symptoms with?
The first symptoms of Pompe disease can vary greatly from patient to patient, which is one of the reasons it can be so difficult to diagnose. The other reason it can be difficult to diagnose is that Pompe disease shares symptoms with many other diseases.
Infantile-Onset Pompe disease shares symptoms with the following diseases:
- Werdnig-Hoffman disease: poor muscle tone/muscle weakness, feeding difficulties, high CK levels
- Danon disease: heart disease, muscle damage, glycogen accumulation, high CK levels
- Glycogen Storage disease IIIA&IV:poor muscle tone/muscle weakness, enlarged heart, high CK levels, enlarged liver
- Endocardial Fibroelastosis: feeding difficulties, enlarged heart, respiratory difficulties
Late-Onset Pompe disease shares symptoms with the following diseases:
- FSHD (Facioscapulohumeral muscular dystrophy): slowly progressive muscle weakness
- Polymyositis: progressive muscle weakness, difficulty swallowing, high CK levels
- Limb-girdle Muscular Dystrophy: progressive muscle weakness in hips, legs, or shoulders, high CK levels, abnormal walk/gait
- Duchenne-Becker Muscular Dystrophy: progressive muscle weakness, starting in the trunk of the body, respiratory difficulties, difficulty walking, high CK levels
- Glycogen Storage Disease V: High CK levels, difficulty participating in physical activities
If the above diseases are suspected, it is easy to test for Pompe as well. The worst that would happen is that Pompe would be ruled out, but the best outcome would be that an otherwise mis-diagnosed or undiagnosed patient will be diagnosed and can begin treatment.
How to Diagnose Pompe Disease
There are several ways that Pompe disease can be diagnosed. In many cases, after initial diagnosis by one method, confirmation by a second method is required.
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Enzyme Activity Testing is used to evaluate a patient’s GAA enzyme level. GAA is the abbreviation for the enzyme that Pompe patients do not produce in sufficient quantities (i.e. they are deficient in). Pompe patients have enzyme levels that range from <1% to 40%. If an abnormal (i.e. low) level of GAA activity is found, then a confirmatory test using a different sample or one of the methods listed below will be used to confirm a diagnosis of Pompe disease.
- Whole Blood, Dried Blood Spot, and Lymphocyte Testing are all methods by which a patient’s GAA enzyme level can be tested using blood.
- Fibroblasts, which are created from cultured skin biopsies, are another way to measure a patient’s GAA activity. Collecting a skin biopsy is a minimally invasive process that involves removing a very small piece of the patient’s skin.
- Muscle biopsies can also be used to collect samples to test for enzyme activity in patients. - DNA Analysis is another method to diagnose Pompe disease. Through this process, the gene that causes Pompe disease is examined to identify the patient’s mutations. Blood or spit can be used to collect a patient’s DNA for this testing method; however, the spit method is only available in the United States at present.
- Muscle Tissue Pathology, which is obtained by a muscle biopsy, can also be used to diagnose Pompe disease. This is done by a pathologist who examines the tissue to see if there are vacuoles that stain positively for Pompe disease. However, the absence of vacuoles does not rule out Pompe disease.
For country/region specific information on who to contact regarding testing for Pompe disease, please check out the following links:
- Eurogentest - a regularly updated database with plenty of info. Different search options possible
- Orphanet database of Pompe specific labs, mostly EU and Canada
- NCBI database of labs (mostly US), includes plenty of NGS (next generation screening) type test labs so maybe not that relevant
- US resources provided by AMDA (PDF, 260 kB)
How You Can Help
Because Pompe disease is rare, most people have never heard of it. How can you recognize and diagnose a disease if you don’t know if exists? But we can all help to change that! Let’s show the world that “Together We Are Strong” and spread the word about the importance of Early Diagnosis for Pompe and how to recognize its symptoms!
Informational Flyers have been created and translated into multiple languages for the patient community to use. Print some out and share, or share this page and we will get the word out that Early Diagnosis is Key!
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What is Pompe Disease?
Pompe disease, also termed glycogen storage disease type II or acid maltase deficiency is an inherited lysosomal storage disorder with an estimated frequency of 1 in 40,000 births. The disease is characterized by a total or partial deficiency of the enzyme acid α-glucosidase. This enzyme is needed to break down glycogen that is stored within the lysosome, a cytoplasmic organelle involved in cellular recycling and tissue remodeling. Deficiency of acid α-glucosidase leads to accumulation of lysosomal glycogen in virtually all cells of the body, but the effects are most notable in muscle, an organ present in all areas of the body.
Pompe disease is a spectrum disease with classical infantile onset at the severe end of the spectrum and the late onset at the other side of the spectrum. Patients at the severe end of the spectrum typically present with symptoms within the first several months of life. Affected infants have profound and progressive muscle weakness manifested in a 'floppy baby' appearance. Other key manifestations include respiratory insufficiency, enlarged heart, failure to reach developmental milestones, feeding difficulties and an enlarged liver.
There also are “milder” forms of Pompe disease presenting later in life from the age of 1 to the age of 99 with progressive weakness of mainly the skeletal muscles of the trunk and the lower limbs. Patients often have a waddling gait and may have difficulty climbing stairs or rising from a chair. Common respiratory symptoms include shortness of breath, sleep-disordered breathing, and progression to respiratory failure. Other symptoms may include scoliosis, scapular winging, muscle pain, fatigue and frequent falls. If Pompe patients are untreated they will need respiratory support, they become wheelchair dependent, will not be able to lift their arms and it can be fatal. When Pompe disease is suspected, the diagnosis can be confirmed by demonstrating the lack of acid α-glucosidase activity in cells or tissues of the patient. The acid α-glucosidase deficiency in Pompe disease is caused by pathogenic mutations in the gene (DNA) prescribing the mode of synthesis and function of acid α-glucosidase. If the mutations are known, Pompe disease can also be diagnosed by DNA analysis.