Pompe Disease

Original Editor - Chelsea Mclene Top Contributors - Nupur Smit Shah, Chelsea Mclene, Janine van Dyk, Kim Jackson, Lucinda hampton, Tarina van der Stockt and Romy Hageman  

Introduction

Glycogen-metabolism, disrupted in Pompe disease

Pompe disease is an inherited genetic disorder known as metabolic myopathy; it is also referred to as glycogen storage disease(type 2). Here there is a deficiency of acid glucosidase(GAA). This leads to the lysosomal accumulation of glycogen in all the cells which causes abnormal myofibrillogenesis in the striated muscles. In normal conditions, GAA is responsible for the acceleration of intralysosomal degradation of glycogen.

It is a rare, progressive, inherited, and often fatal muscular disease - it affects one in 40000 children, but the majority of over 90% of cases is due to late onset adult Pompe disease. It disables the heart and skeletal muscles and is caused by mutations in a gene that makes an enzyme called acid alpha-glucosidase (GAA). It is also an autosomal recessive disorder due to deficiency of a lysosomal enzyme, acid maltase. It affects both males and females.

Causes and Inheritance

Glycogen is a form of sugar that the body stores in cells of the liver and skeletal muscles, and works as a long-term reserve of energy. When the body needs energy, this large molecule is broken down into smaller molecules of a simpler sugar called glucose. Certain proteins are needed for this process. A mutation in the GAA gene can either prevent the production of this enzyme, or create an enzyme that does not work as intended. In either case, glycogen cannot be broken down and builds to toxic levels inside cells, impairing certain organs and systems, particularly the muscles.

Pompe disease is inherited in autosomal recessive disorder which means the disease only develops in people who inherit two faulty copies of the gene, one from each parent. The signs and symptoms are not seen in individuals who have one faulty gene. They are called carriers because they can pass the disease onto their children. When both parents are carriers, child has 50 percent chance of inheriting one mutated gene and also becoming a carrier, and a 25 percent chance of inheriting two healthy genes and neither developing the disease nor being a carrier.

Types

Infantile Onset Pompe disease: Characterized by Cardiomyopathy, respiratory insufficiency, and severe hypotonia.

Late-Onset Pompe disease: This also can be sub-categorise into three groups namely juvenile, childhood or adult onset. Usually begins at any time between one year of age to adulthood. Characterized by fatigue, exercise intolerance, and myalgia. It progresses to severe motor disability and respiratory insufficiency.

Classic infantile-onset

It appears within a few months of birth. Infants experience muscle weakness, poor muscle tone, an enlarged liver, breathing problem, heart defects, fails to gain weight and grow at the expected rate. If untreated, leads to death from heart failure in the first year of life.

Non-classic infantile-onset

It appears at about 1 year of age. It is characterised by delayed motor skills and progressive muscle weakness. The heart may be abnormally large, but affected individuals usually do not experience heart failure. The muscle weakness in this disorder leads to serious breathing problems, and most children live only into early childhood.

Symptoms

Classic Infantile

• Rapidly progressive muscle weakness
• Hypotonia
• Feeding problems
• Macroglossia( abnormally large tongue)
• Infections in the respiratory system
• Problems with hearing
• Enlarged liver
• Failure to gain weight and grow at the expected rate
• Trouble breathing
• Progressive hypertrophic cardiomyopathy

Non-classic Infantile

• Motor skills delayed
• Breathing problems
• Muscles get steadily weaker
• Abnormally large heart

Late-onset type clinical multisystem involvement

Organ invlovement	Clinical Manifestation
Skeletal muscles	Axial muscles as more affected than lower limb Exercise intolerance Scapula winging Myalgia
Respiratory	Sleep apnea Cough Shortness of breath (dyspnea)
CNS	Stroke Intracranial aneurysm Sensorineural deafness Cerebral hemorrhage
Cognitive and Emotional	Mild cognitive impairment Anxiety Depression
CVS	Rhythm disturbances Cardia hypertrophy
Musculoskeletal	Vertebral fractures Bent spine syndrome Scoliosis Kyphosis Hyperlordosis Osteoporosis
Peripheral and Autonomic nervous system	Burning and Paraesthesia

Diagnosis

Laboratory Enzyme testing

Serum Creatine Kinase (CK)

CK activity values (elevated) serves as an important diagnostic marker but should not be a definitive marker as with patients with late onset Pompe disease can have normal CK values.

Additional Enzyme Markers

There are several other enzyme markers that are frequently associated with Pompe disease that is abnormally elevated. They are: aminotransferase (AST), lactate dehydrogenase (LDH) and alanine aminotransferase (ALT). They can provide additional supporting evidence in the diagnostic workup.

Urinary Glucose Tetrasaccharide (Glc4)

With most Pompe patients they have an elevated urinary Glc4 levels with a noteworthy age related correlation where infants shows a higher level compared to adults.

Radiographic Assessment

Image of a chest X-Ray

Chest X Rays reveal a typical characteristic finding of massive cardiomegaly.

Electrocardiographic (ECG) findings

The ECG findings demonstrates specific findings, shortened P-R intervals, increased QT dispersions and abnormally tall QRS complexes this electrical changes corresponds with the the structural changes within the heart muscle that occure due to the glycogen accumulation.

Echocardiographic Assessment

This assessment shows the structural changes. Increased left ventricular wall thickness as well as increased left ventricular mass. In some patients left ventricular outflow tract obstruction may develop which in return can cause significant impact on the the cardiac function and the clinical management.

Pulmonary Function Assessment in Late-Onset Cases

Respiratory muscle and Lung Capacity Test

The evaluation of pulmonary function in LOPD patients entails a comprehensive testing of the respiratory muscle strength. This includes measuring the maximum expiratory pressure and the maximum inspiratory pressure which assess the strength of the muscles involved with breathing. Clinicians also need to the measure both the Vital Capacity and the forced vital capacity both in supine and in an upright position.

Magnetic Resonance Imaging(MRI)

MRI can serve as a diagnostic tool to evaluate both the extent and location of the muscle changes in LOPD patients. It can also play a practical role in guiding invasive procedure to help guide clinicians to the most appropriate site for a muscle biopsy.

Novel Diagnostic Markers.

The most rest research suggest that histological identification of acid phosphatase positive lipofuscin inclusions may serve a new diagnostic marker. Especially in the the use of adult patients where the traditional histological findings may be less reliable.

Definitive Enzymatic Diagnosis

GAA Enzyme Activity Measurement

The definitive diagnosis of Pompe disease is established through demonstration of deficient GAA enzymatic activity. This critical test can be performed using various sample types, including blood, dried blood spots, cultured skin fibroblasts, or muscle biopsy tissue, providing flexibility in diagnostic approaches.

In classic infant-onset Pompe disease (IOPD), GAA enzyme activity is either completely absent or nearly absent, measuring less than 1% of normal activity. In contrast, all other clinical forms of Pompe disease typically maintan measurable levels of remaining enzyme activity, usually up to approximately 30% of normal levels.

Treatment

Pompe disease patients are followed by a multidisciplinary team of specialists, including cardiologists, neurologists, pulmonologists, respiratory therapists, metabolic specialists, dietitians, orthopedists, occupational/speech therapists, geneticists, and genetic counselors. All treatment mentions works best when started early in the disease. To get the most benefit out of the treatment exercise and good nutrition has to go hand in hand.

We are going to look at current treatment options as well as future.

Current Approved treatment

Enzyme replacement therapy (ERT)

• Alglucosidase alfa: This was the first treatment approved in 2006 for Pompe Disease. It works very well for the Infant onset pompe disease, for late onset it usually helps for the the first 2-3 years but often the benefit platue or decline. Some patients do better than others for reasons that arent understood.
• Avalglucosidase alfa: This is newer version that was approved in 2021. This versions works better for getting into the muscle cells where it is needed, also has fever side effects.

Combination Therapy

• Cipaglucosidase alfa plus miglustat: This treatment was approved in 2023 in Europe. It works by using a drug called Miglustat to help stabilise the enzyme so that it can work better and longer. This combination showed improvement in both muscle strength and breathing compared to the other treatment

Experimental therapies

Gene Therapy

• AAV Vector Therapy: This therapy uses modified viruses to bring a healthy copy of the missing gene to the body`s cells. The approach that looks most promising is the liver approach. This turns the liver into a factory to produce the missing enzyme for the while body. This has potential to work with just one or a few treatment compared to the ERT that is lifelong. this approach is still being tested for the right dose and to make sure it is a safe approach.

• Stem cell gene therapy: The approach uses the patients own blood stem cells. The stem cells are taken to a lab and the healthy gene is added. The corrected cells are then put back into the patient where hopefully they grow and produce the missing enzyme. This treatment approach could provide a permanent cure with only a single treatment. Early studies show it can help not only the muscles but the heart and brain as well.

Other promising approaches

• Antisense oligonucleotides (AOs) : They fix errors in how the genes are interpreted. With patients who only has a specific type of mistake this could help. It is still being studied to see if it works in people.

• Substrate reduction therapy: This approach works by stopping the body from making too much glycogen. This can work alongside other treatments to make them work better. Early human studies is just beginning.

• Antioxidant therapy: This approach combines current treatment with antioxidants to reduce cell damage. It works with the idea that oxidative stress makes the disease worse. This approach is still in the early laboratory testing phase.

Physiotherapy Mangement

There is not a specific physiotherapy program to be followed but below are key points to remember when assessing and treating patients.

All of the studies showed that muscle weakness is more proximal than distal and the weakness is symmetrical in nature.

A thorough assessment needs to be done but focus should be place on the hip adductors, lumbar extensors, hip extensors and knee as they are shown to have significant muscle weakness shown in the studies while knee extensors are less affected and the ankle muscle strength is maintained. With the above mentioned muscle weakness the typically waddling gait of the patients can be explained.

Man sitting in a wheelchair

With the progress of the disease patients typically require more assistance by using assistive devices and later on using a wheelchair. Most studies showed significant improvement in locomotion by using a lower limb strength training program even though it may be a temporary improvement.

Balance impairment is also something to note as the relationship between muscle impairments and balance disorders with the risk of falling is linked.With the the muscle strength decreasing the risk of falling increases. There is not a specific balance assessment that is recommended use what is most fitting for your patient.

Due to the nature of the disease respiratory physiotherapy is important. Research showed that an intensive respiratory muscle training program had great benefit in improving the inspiratory and expiatory muscle strength.