Introduction

Anderson-Fabry disease is an inherited disorder which causes abnormalities in the eyes, skin, heart, peripheral nervous system, brain and kidneys. It is caused by a deficiency of an enzyme known as alpha-galactosidase-A, whose role is to break down fatty materials into smaller components that the body can convert into energy.¹ Anderson-Fabry disease causes a build-up of these fatty materials because the enzyme cannot sufficiently break them down. 

Enzyme replacement therapy is a treatment used to replace a missing or deficient enzyme in people with inherited disorders. This is done via an infusion using genetically modified enzymes from human, animal or plant extracts.²

Understanding Anderson-Fabry disease

Genetic basis and inheritance

Anderson-Fabry disease is inherited through genetics and begins as early as in the foetal stage of life.³ Despite the condition developing this early in life, it is most common to remain asymptomatic for the first few years. Typical presentation of the disease will begin between the ages of 3-10 years-old.⁴ The condition is progressive in nature and may eventually affect all organs in the body with age.⁵

The disease is a recessive inheritance disorder, meaning both parents must carry the mutation to pass it onto the foetus. It is most common for the disease to be hereditary, meaning it has been passed on from parents' genes rather than random genetic mutation. 

Pathophysiology and impact on the body

Anderson-Fabry disease (AFD) causes a buildup of substances called glycosphingolipids inside cells all over the body, and the mechanism of this disease can be explained by the damage that this buildup causes to different structures inside cells.⁶ AFD is considered a multi-systemic disease due to the array of cellular structures affected by this accumulation throughout the body.

The main mechanism derives from the damage to a layer of endothelial cells, which form the inner layer of blood vessels.⁷ The accumulation of compounds within cells leads to cellular dysfunction and activates different pathways, such as inflammatory responses. This catalyses the development of chronic kidney disease, reflecting the beginning of multi-organ involvement. 

Common symptoms and complications

Males are more likely to be affected by AFD, but a less common and more variable form may affect women. As previously mentioned, the onset of symptoms is likely between ages 3-10 but can be earlier or later in life. 

Neurological symptoms

• Burning pain in arms and legs, exacerbated by exercise or temperature change 
• Clouding appearance over the eye caused by a build-up of excess material in the clear layer of the cornea - vision not affected 
• Impaired circulation due to the build-up of fatty materials in blood vessels - increases the risk of heart attack or stroke

Symptoms affecting the skin

• Development of small discoloured bumps, known as angiokeratomas. These occur when capillaries under the skin enlarge or break open
• Lose the ability to sweat 
• Swelling of the lower extremities 

Cardiovascular symptoms

• The development of chest pain, known as angina, in adulthood 
• Increased risk of developing an irregular heartbeat, heart failure and heart attack 

Gastrointestinal symptoms

• Diarrhoea 
• Vomiting 
• Nausea 
• Weight loss 
• Stomach cramps/pain

Other organs and systems

• Renal disease - progressive kidney disease generally presents in the second and third decade of life 
• Lung-associated symptoms may include coughing, wheezing and breathlessness 

Enzyme replacement therapy

Types of enzymes used in enzyme replacement therapy for Anderson-Fabry disease

The first use of enzyme replacement therapy (ERT) in treating AFD was done in 2004 in Korea and it has since become a recognised common treatment pathway for AFD patients.¹⁰ Recombinant human enzyme alpha-galactosidase-a is administered via an intravenous infusion generally once every two weeks. A recombinant enzyme is an enzyme that has been produced using genetic engineering techniques to insert the gene responsible for producing a specific enzyme into a host, such as a human cell so that the host can produce a multiple of the desired enzyme. 

One form of ERT for AFD is produced using cells from Chinese hamster ovarian cells, and this treatment is approved worldwide. Another type of ERT uses human cells and has been approved in many countries; however, the US Food and Drug Administration has not yet approved this technique. 

The aim of ERT for AFD is to alleviate symptoms caused by the build-up of substances due to the enzyme responsible for breaking them down is in low or no supply. By replacing the deficient enzyme alpha-galactosidase-a in the body, these substances can be more efficiently broken down into compounds used for energy and prevent cellular damage from accumulation. The substances that build up as a result of AFD are called globotriaosylceramide (GL-3). 

By reducing the accumulation of GL-3, heart attack and stroke risks are diminished as there are no longer fatty deposits within blood vessel walls. A study found that after 20 weeks of ERT, 20 out of 29 AFD patients had no microvascular deposits of GL-3.¹¹

Other clinical findings after ERT have included a reduction in neuropathic pain amongst patients compared to a placebo group, an improvement in kidney function cardiac function, and an increase in body weight. These findings highlight how ERT effectively minimises the damage to a range of organs caused by the disease. 

Initiation of enzyme replacement therapy

Evidence suggests that the timing of initiating ERT in AFD patients may be critical for the effectiveness of the treatment. Beginning ERT before any organ damage becomes evident will improve the likelihood of ERT significantly reducing the levels of GL-3 accumulation. Although this is known, the exact timing for initiation of treatment remains to be determined, and different presentations of the condition make this challenging in males who are considered to have ‘classic’ AFD. Initiation is recommended when there are clinical signs of kidney, brain or cardiac involvement. If these clinical signs are absent before age 16, treatment is recommended anyway over the age.¹²

Pre-treatment assessments

There is a large array of clinical tests which are recommended for patients presenting with AFD: 

• Medical and family history 
• Vital signs 
• Pain assessment 
• Quality of life assessment 
• Cardiac investigations including an electrocardiogram (ECG) and echocardiogram
• Renal investigations including blood tests for kidney function, ultrasound and urine analysis 
• Neurological testing including an MRI of the brain and reflex testing 
• Full blood tests to check liver function, immune system, electrolytes etc

Once a diagnosis is confirmed, it is important to establish the severity of the disease to assess the need for additional treatments alongside ERT to ensure the most effective outcomes can be seen from the therapy. A scoring system called the Mainz Severity Score Index is a recognised algorithm created specifically to quantify the severity of AFD in individual patients.¹³

Four main areas are considered before a patient qualifies for ERT: pain, renal, cardiovascular, and cerebrovascular disease.¹⁴ Patients with AFD will also likely be sent to a specialist centre to receive treatment. 

Access to enzyme replacement therapy

Despite some research suggesting that the logical approach to initiating ERT for AFD is the earlier, the more effective, many countries have specific criteria regarding the extent of organ damage/involvement required for patients to receive the therapy. The cost of the treatment means that countries must create rigorous qualifying guidelines to make it accessible to the patients who require it the most urgently. 

Given the different structures of healthcare that different countries possess, with some, such as the UK, providing free healthcare and others relying on private medical insurance, there are no international guidelines for the treatment pathway of AFD. 

Patient follow-up

The standard follow-up for patients receiving ERT is every six months, which aims to establish the efficacy of treatment. This is done by comparing current clinical signs and symptoms of the disease prior to beginning therapy. An additional reason for follow-up is to assess the safety of the treatment for individuals. The treatment is reportedly well-tolerated by patients; however, reports of antibody formation against the enzyme infusion have been noted.¹⁵

Antibodies are microorganisms produced by the body’s immune system to fight specific foreign organisms, such as bacteria, entering the body. Because the infused enzyme is foreign to the body, it has triggered the production of antibodies in some patients. However, there is no evidence to suggest that this has affected the clinical efficacy of the treatment.¹⁶

Adverse effects

Possible adverse effects associated with ERT may include.¹⁷

• Cold symptoms 
• Pain
• Gastrointestinal events 
• Hearing impairment 
• Cerebrovascular events (such as transient ischemic attack) 

Summary

Anderson-Fabry disease is a recessive hereditary disease passed onto offspring, occurring most commonly in men. It is caused by a deficiency in the enzyme alpha-galactosidase, which accumulates fatty substances, resulting in cellular damage. This damage can progress throughout life and lead to organ damage in the brain, heart, kidneys, skin and eyes. It is not uncommon for AFD to remain asymptomatic for the first decade of life; however, it is suggested that prompt treatment may improve outcomes.

Enzyme replacement therapy is an effective treatment for AFD, using recombinant enzymes to replace those which are lacking. This is given once every two weeks and will require 6-weekly follow-ups to assess the efficacy of the therapy. Possible side effects have been reported in the past, including cold, pain and gastrointestinal symptoms; however, the benefits gained from replacing the deficient enzymes far outweigh these risks.