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  • Writer's pictureThe Rare360 Editorial Team

Unveiling Pompe Disease: A Rare Genetic Disorder with Profound Impact



Pompe Disease, a rare genetic disorder, is characterized by an abnormal build-up of a complex sugar molecule, called glycogen, inside of cells.


Glycogen serves as a form of energy storage in our bodies. It is mainly stored in the liver and the muscles, where it can be converted to glucose when needed. Glycogen helps regulate glucose levels in the blood and provides fuel for our body’s cells.


In muscle cells, glycogen also helps provide energy to muscle tissue. Muscles need a lot of fuel to help our body move, especially during exercise, but taking it from the blood would cause problems for the rest of the body. So, muscles store glycogen for their own use [1].


When there is an abnormal buildup of glycogen inside cells, it can lead to glycogen storage diseases (GSDs). GSDs are a group of inherited metabolic disorders that affect the body’s ability to break down glycogen and convert it to glucose [2].


Pompe disease is a type of GSD [3]. It is also known as Type II GSD (or GSDII) [4]. Pompe disease is an autosomal recessive neuromuscular disorder that affects people of all ages. It causes progressive weakness in the heart and skeletal muscles. Pompe disease is caused by mutations in the GAA gene, which provides instructions for making an enzyme called acid alpha-glucosidase (GAA). This enzyme is responsible for breaking down glycogen [5].


In people living with Pompe disease, mutations in the GAA gene lead to a deficiency or complete absence of the GAA enzyme. Without enough GAA enzyme, glycogen builds up in cells, causing damage to various organs and tissues. Other common names for Pompe disease are:

  • Acid maltase deficiency disease (AMD)

  • Alpha-1,4-glucosidase deficiency

  • Deficiency of alpha-glucosidase

  • GAA deficiency

  • Glycogen storage disease type II (GSD II)

  • Glycogenosis type II

Types of Pompe Disease

The extent of the GAA enzyme deficiency determines the severity of the disease and the age at which symptoms begin to present. As a result, there are three types of Pompe disease:


Classic Infantile Onset Type

The ‘classic infantile’ form of Pompe disease usually presents within the first three months after birth. Infants with this type of Pompe disease typically experience poor muscle tone (also known as hypotonia), muscle weakness (also known as myopathy), enlarged liver (also known as hepatomegaly), respiratory issues, and heart defects (i.e. hypertrophic cardiomyopathy). These children often also have trouble gaining body weight, breathing issues, and delayed developmental milestones. A large majority of these children experience cardio-respiratory failure within the first 2 years of life, which if left untreated, can lead to the child experiencing a heart attack.


Common Symptoms for Classic Infantile Pompe disease:

o Weak muscles

o Poor muscle tone

o Enlarged liver

o Trouble gaining weight

o Breathing issues

o Feeding problems

o Problems with hearing


Non-Classic Infantile Onset Type

The non-classic form of infantile-onset Pompe disease is characterized by delayed motor skills and progressive muscle weakness, which often leads to serious breathing problems. Children diagnosed with this type of Pompe disease often develop an abnormally large heart (also known as cardiomegaly). Children with classic infantile-onset Pompe disease rarely live past 1 year of age [6]. Without treatment, children with classic infantile-onset Pompe disease usually die within the first two years. However, treatment may slow the progression of symptoms [7].


Common Symptoms for Non-classic Infatile Pompe disease:

o Delayed motor skills (such as rolling over and sitting)

o Muscles weakness

o Breathing issues

o Abnormally large heart


Late-Onset Type

The late-onset type of Pompe disease may not become apparent until later in childhood, adolescence, or adulthood. Most individuals with late-onset Pompe disease experience progressive muscle weakness, especially in the legs and the trunk, including the muscles that control breathing. As the disorder progresses, breathing problems can lead to respiratory failure. Common Symptoms for Late-Onset Pompe disease:

o Enlarged heart

o Increasing difficulty in walking

o Muscle pain

o Frequent lung infections and breathing problems

o Headaches in the morning

o Fatigue

o Significant weight loss

o Difficulty hearing

o Higher levels of creatine kinase (CK)


Prevalence data for Pompe disease is limited and appears to vary by geographical region. In the United States, it is estimated that 1 in 40,000 people have one of the types of Pompe disease. The prevalence in the Netherlands is estimated to be 1 in 138,000 people. In China and Taiwan, the incidence appears to be estimated to be as high as 1 in 14,000 people. Even though prevalence data is limited, there is a global Pompe disease registry. The Pompe Registry is a global, multicenter, international, longitudinal, observational, and voluntary program for patients with Pompe disease. It is designed to track the disease’s natural history and impact on the lives of patients, both treated and not [8], [9], [10].

Diagnosing Pompe Disease

Being a rare genetic condition, diagnosing Pompe disease can be tricky. Additionally, the signs and symptoms of Pompe disease are very similar to other conditions and can present differently for each person living with condition, making it often very difficult to get the correct diagnosis on time.


Here are some tests that can help diagnose Pompe disease:

Genetic Testing

Genetic testing plays a vital role in unravelling the mysteries of Pompe disease. The primary objective of genetic testing is to pinpoint specific mutations in the GAA gene. This process typically involves analysing a sample of blood or saliva. Various advanced technologies are employed, some targeting known disease-causing mutations, while others delve into the entire sequence of the GAA gene.


As Pompe disease is hereditary, it's crucial to identify family members who may carry GAA mutations. This information can then be used to empower family members to make informed decisions about their own family planning journey.


For expecting parents with a high risk of having a child with Pompe disease, prenatal testing is available. This specialized form of genetic testing can be performed during pregnancy, providing crucial insights into the health of the developing baby.


Newborn Screening

Soon after a baby is born in the United States, they undergo a comprehensive newborn screening panel, which involves a simple blood draw using a heel stick. This procedure allows healthcare professionals to assess the baby's health and detect if the baby may have any of the conditions included in the state’s newborn screening program.


At least 20 states, including New York, Massachusetts, and California, have now incorporated screening for Pompe disease into their newborn screening programs. This proactive approach empowers healthcare providers to identify potential signs of Pompe disease at an early stage, enabling timely intervention and treatment.


The significance of newborn screening for Pompe disease cannot be overstated. By detecting this rare genetic disorder in its earliest stages, healthcare professionals can swiftly initiate appropriate therapeutic measures. The growing inclusion of Pompe disease in newborn screening programs is a testament to the dedication of healthcare professionals, researchers, and advocacy-based organizations.


Enzyme Activity Tests

Understanding the activity of enzymes is key to diagnosing the various forms of Pompe disease. The acid alpha-glucosidase enzyme plays a vital role in breaking down glycogen in the body. Testing the activity level of this enzyme provides valuable insights into the presence, type and severity of Pompe disease. The enzyme activity can vary depending on the disease type and holds essential diagnostic clues.


In individuals with infantile-onset Pompe disease, enzyme activity is typically less than 1% of normal. In contrast, those with late-onset disease may exhibit enzyme activity levels up to 40% of normal.


Traditionally, enzyme activity tests were conducted using cells obtained from a muscle or skin biopsy. However, advancements in medical technology have paved the way a less invasive testing method. In recent years, blood samples have become the preferred choice for enzyme activity tests, making the process simpler and more accessible.


Enzyme activity tests stand as a cornerstone in the diagnostic journey, guiding healthcare providers towards accurate diagnoses, tailored treatments, and improved quality of life for individuals and their families.


Other Tests

An image featuring a table with two columns: one listing test names, and the other outlining their respective purposes. These tests play a crucial role in the diagnostic journey of the patient with pompe disease

Treatment Options

Living with Pompe disease presents unique challenges, but there are treatment options available to extend and improve the lives of individuals living with this condition. While there is no permanent cure, advancements in medical science have paved the way for interventions that can make a profound difference. Let's explore some of the treatment options currently available for Pompe disease as of 2023:


Enzyme Replacement Therapy (ERT)

In the late 1990s, a groundbreaking breakthrough emerged in the form of enzyme replacement therapy (ERT) for Pompe disease. The first human clinical trials, conducted in the Netherlands and the United States, laid the foundation for a transformative treatment approach.


The pioneers of this therapy, sponsored by Genzyme Corporation, administered regular intravenous infusions of a synthetic enzyme called alglucosidase alfa to patients with Pompe disease. This man-made enzyme serves as a substitute for the faulty enzyme in the body, tackling the underlying cause of the condition. In 2006, the U.S. Food and Drug Administration (FDA) granted approval for this treatment, marking a significant milestone in the battle against Pompe disease.


Enzyme replacement therapy has shown remarkable efficacy in improving the outcomes of individuals with Pompe disease. By infusing the missing enzyme into the body, ERT addresses the enzyme deficiency and helps manage the disease's progression. Infants, children, and adults with Pompe disease have experienced longer life expectancy and a reduction in associated complications.


Supportive Therapies

While enzyme replacement therapy (ERT) takes center stage in slowing the progression of Pompe disease, a comprehensive treatment approach encompasses supportive therapies that empower people living with this condition to maximize their daily functionality. Below are some of the key supportive therapies for individuals with Pompe disease:


Physical Therapy: Reclaiming Mobility and Strength

Physical therapy can help enhance muscle strength, reducing contractures, and preserving mobility for individuals living with Pompe disease. Through targeted exercises and stretching routines, a physical therapist guides patients in improving their overall muscle function. The therapist can provide valuable insights on managing day-to-day symptoms, fall prevention strategies, and recommendations for mobility aids or adaptive equipment.


Speech Therapy: Empowering Effective Communication

Pompe disease can impact facial muscles and respiratory function, affecting speech clarity and intelligibility. Speech therapy becomes crucial in enhancing communication skills and helping individuals overcome speech challenges. Therapists work on improving verbal abilities and exploring alternative communication strategies. Additionally, speech therapy can address swallowing difficulties, promoting safer and more efficient swallowing techniques.


Respiratory Therapy: Breathing New Life

Respiratory weaknesses due to Pompe disease can result in breathing difficulties. Respiratory therapy focuses on strengthening the muscles involved in respiration through targeted exercises. These exercises not only enhance breathing capacity but also assist patients in learning techniques to clear respiratory secretions. By optimizing respiratory function, patients can experience improved breathing and enhanced quality of life.


Occupational Therapy: Nurturing Everyday Independence

Occupational therapy aims to empower individuals with Pompe disease to navigate daily life challenges with greater ease. Occupational therapists collaborate with patients to develop personalized strategies and adaptations. This may involve the use of supportive devices like walkers, hand exercises to maintain dexterity, and finding innovative ways to accomplish daily activities that may have become more challenging. By fostering independence, occupational therapy empowers patients to engage in meaningful tasks and reclaim control over their lives.


Expanding Treatment Horizons: Emerging Therapies for Pompe Disease

As our understanding of Pompe disease deepens, researchers are diligently exploring new avenues to provide enhanced treatment options for patients. In addition to current therapies, several experimental approaches hold promise in addressing the complex nature of the disease. Let's delve into these novel treatments and supportive devices that are shaping the future of Pompe disease management:


Experimental Therapies

a) ERT plus Enzyme Stabilizer: Amicus Therapeutics is spearheading the development of AT-GAA, a two-part therapy combining cipaglucosidase alfa (a modified GAA enzyme) and miglustat (an enzyme stabilizer). Phase 3 trials demonstrated superior outcomes compared to Lumizyme, improving walking ability and preserving lung function in adults with late-onset Pompe disease. The therapy is currently approved in the United Kingdom.


b) Gene Therapy: Gene therapy aims to deliver a functional copy of the GAA gene to cells, enabling them to produce a healthy GAA enzyme. Multiple experimental gene therapies are being investigated, including AT845, rAAV1-CMV-GAA, rAAV9-DES-hGAA, ACT-101, and SPK-3006. These innovative approaches hold potential for addressing the root cause of Pompe disease.


c) Substrate Reduction Therapy: This experimental strategy seeks to reduce the toxic buildup of glycogen by blocking its production within cells. MZE001 by Maze Therapeutics and ABX1100 by Aro Biotherapeutics are notable substrate reduction therapies currently undergoing clinical testing, offering hope for slowing disease progression.


d) Chaperone Therapy: Chaperone therapy utilizes small molecules known as chaperones to assist the proper folding of dysfunctional GAA enzymes, restoring their normal activity. Although not effective for all patients, it holds promise for individuals with specific mutations amenable to chaperone therapy. Researchers are exploring chaperone therapy both as an independent approach and in conjunction with ERT to augment enzyme functionality.


e) Stimulation of Lysosomal Exocytosis: Lysosomes, responsible for breaking down complex molecules, accumulate glycogen in Pompe disease due to enzyme deficiency. Researchers are investigating the stimulation of lysosomal exocytosis, a process that allows lysosomes to release their contents outside the cell. Preclinical studies are exploring the potential of this strategy to alleviate glycogen accumulation.


Supportive Devices and Additional Treatments


a) Nutritional Support: Following a dietician's plan is crucial to meet nutritional needs, with a focus on a high-protein, low-carbohydrate diet. Nutritional supplements may also be recommended. In cases where swallowing difficulties arise, the use of a feeding tube ensures adequate nutrition for infants and individuals.


b) Management of Osteoporosis: Many Pompe patients develop weakened bones, leading to osteoporosis. Supplements containing calcium, vitamin D, and bisphosphonates are commonly prescribed to support bone health.


c) Assistive Devices: Canes, walkers, wheelchairs, and orthopedic devices such as leg braces play a pivotal role in enhancing mobility and preventing further complications. These supportive devices enable individuals with walking difficulties to maintain independence and improve their quality of life.


As research advances, the landscape of Pompe disease treatment continues to evolve. These experimental therapies and supportive interventions hold promise in expanding treatment options and empowering patients to lead more fulfilling lives.


Pompe disease can affect many parts of your body. So, treatment may also include care from a team of specialists, including:

  • Metabolic specialists

  • Neurologists

  • Cardiologists

  • Pulmonologists

  • Orthopaedists

  • Physical, occupational, and speech therapists

Pompe Disease Support Organizations and Resources

Following is a list of some Pompe disease support groups or resources globally that may connect you with other families affected by the disease:

References


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