Overview

Pompe disease, also known as acid maltase deficiency or glycogen storage disease type II, is a rare, inherited genetic disorder caused by the buildup of glycogen in the body's cells. This accumulation results from a deficiency of the enzyme acid alpha-glucosidase (GAA), which is necessary for breaking down glycogen into glucose. There are two types of Pompe disease, infantile-onset Pompe disease and late-onset Pompe disease. There are also varying degrees of severity, with infantile-onset Pompe disease presenting as the most aggressive form. Early treatment and diagnosis can help improve the patient's response to treatment. Standard treatments include enzyme replacement therapy (ERT) and supportive treatment depending on the patient. Pompe disease is a progressive disorder, which has no cure. However, there are ongoing clinical trials for treatments for Pompe disease, these advancements offer hope for decreasing the progression of the disease, and improving quality of life for patients.^1,2 

Understanding Pompe disease

What causes Pompe disease?

Pompe disease is an inherited genetic disorder. It is caused by a mutation in the GAA (acid alpha-glucosidase) gene. This gene codes for an enzyme which breaks down a complex sugar called glycogen in the body. The mutation means that this enzyme is either partially or completely absent, causing glycogen to build up in the body’s cells. The process of glycogen degradation occurs in lysosomes. Lysosomes contain enzymes that break down biological polymers which can either be recycled or used as energy sources.³

Pompe disease occurs due to autosomal recessive inheritance of the mutated GAA gene. One gene contains two chromosomes. For an individual to have Pompe disease, both chromosomes must contain the mutation. Therefore for this to be passed to offspring both parents must be carriers. Other ways to inherit Pompe disease include when one parent has Pompe disease and the other parent is a carrier, meaning  the offspring has a 50% chance of inheriting the disease. If one parent has Pompe disease and the other parent does not and is also not a carrier, then alloffspring will become carriers.¹

What are the types of Pompe disease?^1,3

There are two types of Pompe disease:

Infantile-onset

Classic early/infantile-onset Pompe disease is the most severe form. Symptoms usually present within the first months of life. Symptoms progress rapidly with patients developing cardiomegaly (enlarged heart), hepatomegaly (enlarged liver), muscle weakness, floppiness, breathing difficulties and problems with weight gain. Due to these complications most infants die before their first birthday.Infantile variant Pompe disease usually presents within the first year of life, however, the symptoms are less severe and disease progression is slower.

Late-onset

Late-onset (juvenile/adult) Pompe disease occurs a little later in life, begining in the first decade of childhood or in adults. Patients will either have no GAA enzyme or some production of the enzyme. Patients typically do not experience cardiomyopathy, however, they do suffer from slow progressive muscle weakness which may lead to respiratory failure and ultimately death.

Pathophysiology of Pompe disease

Pompe disease is caused by a mutation in the GAA gene which codes for an enzyme required to break down glycogen in lysosomes. Normally, glycogen breakdown into glucose via the GAA emzyme occurs to provide energy to cells. A dysfunctional or absent enzyme means that glycogen becomes accumulated in the lysosomes of the cell. This can cause lysosomes to rupture. Glycogen begins to build up in the cytoplasm of the cells, particularly affecting cardiac and skeletal muscles. This leads to symptoms such as muscle weakness, respiratory problems, and cardiomyopathy. 

Muscle damage is worsened due to secondary events that take place due to glycogen accumulation. Impaired Autophagy (self-destruction of cells/ components within cells) , defective calcium haemostasis, oxidative stress, and mitochondrial defects all contribute to muscle weakness and muscle atrophy.⁴

The extent of muscle damage varies between patients. The earlier the disease presents, the more severe the symptoms are. The lower limbs are typically more affected than the upper limbs. The spinal muscles are usually affected, this may lead to scoliosis in patients around puberty.⁵

Diagnosis of Pompe disease

Pompe disease is usually difficult to diagnose as many physicians are unfamiliar with the disease. A clinical evaluation is conducted and a detailed patient and family history is taken. Enzyme assays and genetic testing are also amongst the tests conducted.

Which diagnostic tests are conducted for Pompe disease?

Enzyme assays

Enzyme assays can be conducted to assess GAA presence. This can be done on either a blood spot, muscle biopsy, leukocytes (white blood cells), or fibroblasts (type of cell that makes up the connective tissue). Testing using skin fibroblasts is considered better than using other samples as it is highly sensitive and can differentiate between infantile-onset and late-onset Pompe disease.^4,5,6

Genetic tests

Genetic tests are generally conducted to confirm the diagnosis of Pompe disease. This analyses the GAA gene and aims to detect mutations. Genetic testing also proves useful in determining whether a person is a carrier and can aid in providing genetic counselling.^4,5,6

Heart and respiratory function tests

Heart and respiratory function tests include electrocardiography (ECG) and echocardiography to assess the heart.  Maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC), and vital capacity (VC) are measured to assess respiratory function.^4,5,6

Muscle biopsies

Muscle biopsies help to provide a definitive diagnosis of Pompe disease. Tests usually show glycogen accumulation in the cells. It can prove useful when tests such as the enzymatic assay are inconclusive.^4,5,6

Newborn screening

Newborn screening may be conducted on individuals suspected to have Pompe disease. It aims to provide an early diagnosis, thus timely treatment, which may help to prolong and increase quality of life.^4,5,6

Differential diagnosis of Pompe disease

Diseases that have a similar clinical presentation to Pompe disease should be ruled out before making a definitive diagnosis. These conditions may include:⁴

• Werdnig-Hoffman disease
• Danon disease
• Glycogenoses types III, IV, V and VI
• Nemaline myopathy
• Myofibrillar myopathy
• Mitochondrial myopathies
• Limb-girdle muscle dystrophy
• Duchenne muscular dystrophy
• Becker muscular dystrophy
• Facioscapulohumeral muscular dystrophy (FSHD)
• Scapuloperoneal syndromes
• Rigid spine syndrome
• Myasthenia gravis
• Polymyositis
• Fibromyalgia
• Chronic fatigue syndrome

Treatment options for Pompe disease

Enzyme replacement therapy (ERT)

Standard treatment for patients with Pompe disease includes enzyme replacement therapy. This involves compensating for the missing or malfunctioning enzyme, through intravenous infusion of recombinant human acid alpha-glucosidase (rhGAA). This treatment is called Myozyme or Lumizyme, andhas shown to increase the life expectancy of patients, however some symptoms remain.^5,6

Patients with late-onset Pompe disease may also undergo ERT. This involves treatment with Nexviazyme. Patients aged one and older may use this type of treatment. If patients' current therapy is not as effective, they may undertake combination therapy of cipa glucosidase alfa-atga (Pombiliti) and miglustat (Opfolda).^5,6

Studies have shown that ERT works to improve cardiac and respiratory symptoms as well as reducing glycogen build up in cells. However this treatment has its limitations as although it is initially effective, over the years patients may experience hearing loss, problems with speech, cognitive impairment, and GI and respiratory dysfunction.^5,6

Supportive therapies

Patients will need supportive treatments to help mitigate their symptoms. Patients are required to have regular assessments due to the progressive nature of the disease. Patients may require respiratory support which includes therapy to help strengthen respiratory muscles, or even mechanical ventilation during periods throughout the day or during infections. Patients may need physiotherapy to help improve their movement, as well as occupational therapy to help them adjust to aid such as walkers or wheelchairs. Patients may also require orthopaedic support. In more severe cases such as contractures or spinal abnormalities, surgery may be necessary.⁵

Patients may also require help with their speech and hearing problems. A dietician may also be involved in the patient's treatment plan due to difficulties chewing and swallowing food. Some patients, particularly children, may require a feeding tube for nutritional support.⁵

Emerging therapies

Gene therapy is an exciting new avenue for treatment of Pompe disease. This is done by introducing a transgene, which is a gene that is artificially integrated into the genome. This would then produce the GAA enzyme. This would remove the need for regular ERT therapy.⁶

Another experimental therapy involves pharmacological chaperones. This form of therapy may aid in mitigating the complications that may occur during ERT therapy. Chaperone therapy works by small molecules binding to the defective GAA molecule to stabilise it.⁴

Summary

Pompe disease is a rare, progressive genetic disorder. Early diagnosis and treatment is key in improving patient outcomes and prolonging prognosis. The disease causes muscle weakness and atrophy leading to respiratory, cardiac, and musculoskeletal damage. Various diagnostic tests like enzyme assays and genetic tests can be conducted to confirm Pompe disease. Patients have treatment plans with ERT at the centre. Other treatments are supportive to help improve the patients symptoms. Gene therapy and pharmacological chaperones are exciting new experimental therapies, which involve producing and repairing the defective or missing enzyme. This could potentially improve the quality of life and prognosis of patients with Pompe disease.