Introduction

Fucosidosis is a rare, inherited neurodegenerative disorder, where the body cannot break down a particular sugar, called fucose.¹ In fucosidosis, a genetic mutation in the DNA means the body doesn’t produce enough fucosidase.¹ Fucosidase is the enzyme that breaks down and digests fucose. Fucosidase cannot be broken down without fucosidase, so it builds up in the body, leading to fucosidosis. 

Treating fucosidosis is extremely important, as the build-up of fucose in the body can lead to various complications. Treatments for fucosidosis are limited, and they generally involve targeting and managing the specific symptoms of the condition. As science and genetic conditions advance with more innovations and technologies, so more chances of treatments are being developed for conditions like fucosidosis. 

Hematopoietic stem cell transplantation (HSCT) is being used to treat genetic conditions, including fucosidosis. Stem cells are early, immature cells, that still have the potential to develop into many different types of mature cells in the body. In HSCT, healthy stem cells can be given to patients with fucosidosis, and the stem cells can help the body to develop the fucosidase enzyme.⁹ This can then reduce the abnormal level of fucose in the body, so relieving the symptoms of fucosidosis. 

Understanding fucosidosis

What is fucosidosis?

Fucosidosis develops when the body is not able to produce enough fucosidase. Fucosidase is a type of protein, called an enzyme, that helps break down a particular sugar that we get from our diet, called fucose.¹ In fucosidosis, fucose cannot be broken down, so its level increases in the body from the normal range, leading to various complications.¹

In fucosidosis, the fucosidase enzyme deficiency is due to a genetic mutation in the FUCA1 gene.¹ The condition can be inherited from parents, following an autosomal recessive pattern- this means that two copies of the faulty gene must be inherited for the condition to develop, one from each parent. If only one faulty copy is inherited, fucosidosis will not develop.¹ 

Signs and symptoms of fucosidosis

Fucosidosis is a neurodegenerative disorder, meaning that, over time, nerve cells in the brain and spinal cord lose function and die, leading to damage to the nervous system. As it is a progressive disease, the symptoms, and complications tend to advance and get worsen over a long time. 

Many of the symptoms of fucosidosis affect the brain and the nervous system, including:

• Intellectual disability
• Delay in the development of motor skills
• Abnormal skeletal development
• Seizures
• Spasticity (abnormal muscle tightness with prolonged contraction)¹

Fucosidosis can also affect various other organs and systems in the body, including the skin, liver, and respiratory tract. 

Skin

Angiokeratomas are commonly found on the skin of patients with fucosidosis.² Tiny blood vessels break through the skin, forming small raised lesions on the skin that can be red/purple. These lesions are benign (non-cancerous) and tend to develop around the lower abdomen and thighs. 

Liver and spleen

In some cases of fucosidosis, the liver and spleen can be abnormally enlarged. 

Respiratory tract

Recurrent respiratory tract infections are most common in patients with fucosidosis- up to 78% of patients with fucosidosis experience respiratory tract infections, often every 1-2 months.²

Other signs and symptoms

Other signs and symptoms of fucosidosis include:

• Heart murmurs and problems with the valves in the heart²
• Abnormally large heart⁴
• Coarse facial features
  • Some patients with milder fucosidosis may have a normal facial appearance, but others, especially those with more severe disease, may have coarse facial features. This can include having prominent eyebrows³; a wider nose³; thickened lips³; large, low-set ears⁴; and a small skull⁴
• Various eye conditions
  • Patients with fucosidosis can experience a variety of eye conditions- these can range from mild abnormalities to more significant visual impairment.⁴ The blood vessels on the white of the eye (the cornea) can sometimes be more prominent in people with fucosidosis⁴

Patients with fucosidosis often don’t grow and gain weight as they should- this is known as ‘failure to thrive.⁷ 

Progression and prognosis

The prognosis for patients with fucosidosis varies from individual to individual and depends on the type and severity of the condition. 

Type 1 fucosidosis is much more severe as patients are often diagnosed within the first year of life, and they tend to deteriorate much faster as the condition progresses at a quicker rate. Patients with type 1 fucosidosis tend to live 5-10 years of age,⁷ until they die due to cachexia, a condition characterised by significant weight loss and muscle wastage.⁵ 

Type 2 fucosidosis is the milder form of the condition.⁶ Patients with type 2 fucosidosis are usually diagnosed later, and the condition progresses at a slower rate than in type 1; therefore, many people with type 2 fucosidosis might reach adulthood.⁶ 

Hematopoietic stem cell transplantation (HSCT)

Hematopoietic stem cell transplantation (HSCT) is mostly used to treat genetic conditions like fucosidosis, despite the stage of the disease In HSCT, defective and damaged blood cells are killed, and then stem cells from a healthy donor are administered to the patient through an IV.⁹ Stem cells are immature cells, produced by the bone marrow, that can turn into different specialist cell types in the body.⁹ Haematopoietic stem cell transplants are also known as bone marrow transplants. 

After a stem cell transplant, the stem cells can turn into different types of blood cells. Some types of blood cells can produce particular enzymes. In genetic disorders, these blood cells can be used to produce more enzymes, therefore correcting enzyme deficiencies and replacing defective cells with healthy, functioning ones.¹⁰ This is how hematopoietic stem cell transplantation would work in fucosidosis. 

How will HSCT work in fucosidosis?

After being administered to the patient, the stem cells can differentiate and develop into many different types of blood cells.⁹ In genetic conditions, the stem cells usually develop into macrophages, a type of white blood cell. Macrophages are responsible for detecting and destroying harmful bacteria in the blood, as well as communicating with other cells and regulating inflammation. They can also produce lysosomes, which are sac-like structures inside cells that release special enzymes. One of the enzymes that lysosomes can release is fucosidase, the enzyme that is not produced correctly in fucosidosis. 

After the transplant, these healthy donor stem cells can develop into mature macrophages, which produce lysosomes and release enzymes, including fucosidase.¹⁰ Therefore, these patients now have higher numbers of functioning fucosidase enzymes, and there is no longer a deficiency of fucosidase in the body.¹⁰ These enzymes can digest and break down fucose, stopping the build-up of fucose and helping relieve the symptoms of fucosidosis. 

Hematopoietic stem cell transplantation can help to relieve symptoms, slow progression and improve outcomes in fucosidosis, but researchers are yet to determine the long-term results for patients who undergo the procedure.⁸ Many reports suggest that enzyme activity, including fucosidase, is increased after a bone marrow transplant; but, we still do not know how safe and effective the procedure is for treating fucosidosis in the long-term.⁵

Challenges and considerations

There are various risks associated with hematopoietic stem cell transplants that must be considered before the procedure can go ahead. 

Graft versus host disease

Graft versus host disease (GvHD) is one of the major risks of stem cell transplants.

Graft versus host disease happens when the healthy donor stem cells recognise the recipient’s cells as foreign and begin to attack and kill them. The severity can range from fairly mild to life-threatening, and it tends to develop in the first few years after receiving a bone marrow transplant.¹¹

Common symptoms of GVHD include: nausea and diarrhoea; dry, flaky skin; shortness of breath; joint pain; jaundice (yellowing of the eyes and skin); and an itchy rash.¹¹ 

Chemotherapy

Before they receive the stem cell transplant, patients must have chemotherapy to destroy and kill the diseased blood cells. This chemotherapy comes with several risks, including:

• Infections
  • As chemotherapy weakens and destroys the immune system, patients are vulnerable to infections whilst receiving stem cell transplants¹¹ 
• Iron deficiency anaemia
  • Chemotherapy kills the red blood cells inside the body- this can lead to iron deficiency anaemia, causing extreme tiredness and fatigue¹¹
• Bleeding and bruising
  • Bleeding and bruising are often side effects of chemotherapy- this happens when there are not enough small cell fragments in the blood, called platelets.¹¹ Platelets are responsible for helping the blood to clot; therefore, not having enough platelets increases the risk of excessive bleeding and bruising

Long-term effects

Stem cell transplants can also have long-term side effects that can develop months to years after receiving a transplant. 

These side effects can include:

• Increased risk of certain types of cancer
• Infertility (due to the chemotherapy before the transplant)
• Osteoporosis (thinning of the bones)
• Underactive thyroid (hypothyroidism)

Summary

Fucosidosis, a rare, progressive neurodegenerative condition, has significant impacts on the patients who live with the condition, and their families. Currently, treatments for fucosidosis are limited, and the outcomes for patients are determined mostly by how severe their condition is. 

Hematopoietic stem cell transplantation is being used increasingly as a treatment for fucosidosis, as it can help to increase the amount of fucosidase enzymes in the body and relieve some of the symptoms of the condition. However, not everyone is a suitable candidate for a stem cell transplant, as the treatment works best when the condition is in its very early stages. With more research into this very rare condition, further developments can help improve the treatments and outcomes for patients with fucosidosis.