Introduction

What is pompe disease?

Pompe disease is a type of glycogen storage disease, or more precisely a genetic condition where a complex sugar called glycogen builds up in your body’s cells.^1,2,3 The condition is caused by recessive mutations to the gene encoding for a digestive enzyme called acid alpha-glucosidase (GAA). GAA normally breaks down complex sugars in your body, but the mutations cause its absence, leading to glycogen accumulation in the lysosome, a membrane-bound cell organelle where the breakdown and digestion of sugars and other molecules from which energy can be metabolised usually occurs.²

The types of pompe disease

Over 300 mutations to the GAA encoding gene were associated with Pompe disease, and the severity and clinical manifestation of the condition varies based on the mutation possessed.² Generally, Pompe disease is differentiated into 2 main categories based on the level of enzyme deficiency² 

Infantile-onset pompe disease (IOPD) 

The “classic” disease type that was originally described by Johannes Pompe in the 1930s.² In this more severe type of the condition, both the cardiac and the skeletal muscles are affected, leading to: 

• The thickening of heart muscle walls, specifically at the left ventricle, which is known as hypertrophic cardiomyopathy
• Disrupted blood flow out of the left ventricle 
• Respiratory problems, leading to progressive loss of unassisted ventilation
• Decreased muscle tone, known as hypotonia and muscle weakness^1,2

This prominent collection of symptoms allows IOPD to be characterised at birth. Unfortunately, the severity of this condition leads to death within the first twelve months of life in most patients, often due to respiratory failure.^1,2 

Late-onset pompe disease (LOPD) 

The late onset variant of Pompe disease was characterised much later, in 1969 by Andrew Engel. LOPD only manifests after 12 months of age, but the age at onset can span from infantile to adult. It is primarily characterised by skeletal muscle problems, but the cardiac tissue is usually unaffected in this milder Pompe Disease form.^1,2 The symptoms progress slowly but ultimately lead to a variety of life-altering symptoms, including:

• Profound muscle weakness and wasting
• Wheelchair dependency or mobility assistance 
• Respiratory failure due to the weakening of the diaphragm muscle¹

It is important to mention, that as the condition progresses, the muscle weakness can cause several other deficits associated with multiple organ systems, including difficulty pronouncing words, swallowing problems, increased bone fragility, scoliosis, sleep apnea, hearing loss, impairments in gastric function, urinary tract and anal sphincter involvement, pain and fatigue, and increased risk of cardiac arrhythmia which makes early diagnosis of LOPD is crucial to avoid their development.

The effects of pompe disease on the musculature

Muscle weakness

Due to the continuous glycogen accumulation from the lack of GAA activity, the lysosomes become full of glycogen and progressively enlarge in the space between muscle fibres called myofibrils. This eventually leads to lysosomal rupture, the accumulation of cytoplasmic glycogen, a noncontractile material, disrupting the contractile machinery of myofibrils and leading to their expansion and displacement.^1,3 The accumulation of undigested metabolites in lysosomes in diseased cells also impairs the activity of an anabolic regulator called mTOR, which would need a functional lysosome to activate. The dysregulation of this molecular pathway adds an additional layer to the causes of muscular abnormalities observed in Pompe disease.¹

The unnatural rearrangement of myofibrils results in progressive muscle weakness and wasting, usually in the form of proximal limb-girdle myopathy in LOPD, meaning the muscle loss is most prominent in the arms and legs. The loss of muscle volume and function leads to a struggle to keep up with everyday tasks, and eventually being confined to wheelchair use. The emergence of the condition must be picked up in the earlier stages for appropriate management. Patients in the early stages usually have a delay in muscular development and have trouble keeping up with their peers with physical activities.^1,2,4

Effects on mobility

While the majority of patients with IOPD unfortunately pass away at an early age, patients with LOPD can experience the different stages of life. However they experience life-altering limitations in their physical abilities. The early signs usually include intolerance to exercise, fatigue, and sometimes milder ventilation problems, which are unfortunately often ignored, or just flagged as unwillingness to exercise.⁵ Eventually, these symptoms become more prominent and will be accompanied by the onset of muscle weakness, mainly affecting muscles of the limbs, with around one-fifth of patients also reporting the presence of pain.^1,4,5 

In more advanced phases, the patients have difficulty not just with performing sports or running, but even walking, or simply getting up after sitting or lying. The leg and spinal cord supporting lower muscles weaken first usually. Foot muscles are usually not affected until the later disease stages. In the upper body, the muscle fibres in the upper back and the shoulders, as well as the neck are affected the most.^1,5 One prominent manifestation of the condition is a so-called “winging scapula”, where the shoulder blades stick out from the back when arms are lifted.⁵

The weakening of the muscles can eventually also lead to scoliosis (curved spine), the numbness of facial muscles, and difficulty swallowing, affecting multiple aspects of life for patients living with Pompe disease.^1,2,5 

Impact on daily activities

The progressive muscle weakness present in LOPD significantly impacts patients' ability to perform routine tasks, extending far beyond mobility issues. Personal care activities such as bathing, dressing, and grooming become increasingly challenging, often requiring adaptive equipment or assistance from caregivers. In the kitchen, patients may struggle with meal preparation, from lifting pots and pans to operating appliances, potentially leading to changes in diet and nutrition, which exacerbates their difficulty in gaining weight. Household chores like cleaning, laundry, and yard work can become overwhelming or impossible. For adult patients who still work, job performance may be affected, requiring workplace accommodations or career changes. Social interactions and leisure activities are also impacted, as patients may find it difficult to participate in hobbies, attend social events, or travel.^1,2 

It is also important to mention that Pompe disease can also affect respiratory abilities, and in most severe cases the abnormal lysosomal function can also have neurological consequences, leading to frequent fatigue and the need for respiratory support as well as to changes in cognitive capacity. The cumulative effect of these challenges can lead to a decreased sense of independence and potentially impact mental health, underlining the importance of comprehensive care that addresses both physical and psychological aspects of living with LOPD.^1,2

Managing the symptoms of pompe disease

As the condition affects multiple organ systems and interferes with several aspects of daily life it is important to consult a healthcare professional after a patient has been diagnosed with Pompe disease. They can advise on how to cope with the lifestyle changes that will arise with the condition and suggest what specialists to visit afterwards (physiotherapist, neurologist, etc.). Dealing with the sudden news of a life-altering disease will also be emotionally challenging for both patients and their families, thus reaching out to a psychologist to help cope with these life changes is also advised.

As for pharmacological symptom management, while there is no current cure for the disease, there are promising therapeutic approaches that can ease symptoms, slow disease progression, and provide a better quality of life for the patients. The most often used approach in Pompe disease is enzyme replacement therapy (ERT), in which they create a genetically engineered synthetic enzyme (recombinant human acid alpha-glucosidase, rhGAA) and give it to patients through IV infusion. The rhGAA enters the diseased cells and breaks down the metabolite build-up in their lysosomes, compensating for the lack of natural GAA.^1,4 The treatment was approved in 2006 and has been the gold standard for treating Pompe disease ever since.

We must mention, that although promising, ERT does have its limitations:

• Clinical trials in infants showed variability in effectiveness, with some showing significant improvement in motor function in a subgroup of patients, while it reduced invasive ventilatory issues and the risk of death by over 90%;⁶ while some trials reported the worsening of ventilatory symptoms in 35%, and death of 60% of patients in their cohort⁷
• The recombinant enzyme cannot cross the blood-brain barrier, making it unable to get into the brain and ease potential neurological symptoms¹
• Multiple studies showed that ERT negatively affected patient’s immune responses, with them developing antibodies against the recombinant enzyme. This effect was especially prominent in infantile cases¹ 

Despite the limitations, ERT still proves to be the most ground-breaking discovery for patients with Pompe disease, as the treatment can significantly reduce the risk of death and promote longevity, successfully eliminate cardiac pathologies regardless of disease severity, and although, with varying success, it can also improve the skeletal muscle symptoms of Pompe disease.^1,6,7

Summary 

Pompe disease is a rare genetic disorder caused by mutations in the GAA gene. The condition is characterised by the harmful accumulation of glycogen in cells and manifests in two primary forms, the severe infantile-onset and the more gradual late-onset variants. Both types lead to progressive muscle weakness, significantly impacting mobility and daily life activities.

The effects of Pompe disease extend beyond simple muscle weakness. Patients face a cascade of challenges, from difficulty with basic personal care to limitations in work and social life. The disease's impact on respiratory function and, in some cases, neurological health, further complicates these challenges. These wide-ranging effects underscore the importance of early diagnosis and comprehensive, multidisciplinary care.

While there is currently no cure for Pompe disease, enzyme replacement therapy (ERT) has emerged as a groundbreaking treatment option. By providing patients with a synthetic version of the missing GAA enzyme, ERT has shown promise in reducing mortality rates, improving cardiac symptoms, and alleviating skeletal muscle weakness to a varying degree. However, the treatment has its limitations, including variable effectiveness and potential immune responses.

Despite these challenges, the discovery of ERT represents a significant step forward in Pompe disease management. It offers hope for improved quality of life and longevity for many patients. As research continues, our understanding of Pompe disease and our ability to treat it effectively will likely continue to advance, potentially leading to even more effective therapeutic approaches in the future.