What Is Fucosidosis?

Fucosidosis is a rare genetic condition that affects many different parts of the body, particularly the brain. It can cause slow growth, skin abnormalities, neurological deterioration, and intellectual disabilities. Fucosidosis is an inherited disorder, so it is passed on from parents to their children.

People with fucosidosis typically have intellectual disabilities and can develop dementia later in life. However, the severity of this disease can vary between individuals. In severe cases, the disease can become apparent during infancy and cause death by late childhood. Researchers used to describe two types of fucosidosis, type I and II, which were based on their symptoms and average age of onset, but they now see these two types as a single condition with symptoms that range in severity. 

What are the symptoms of fucosidosis?

Children with fucosidosis can start to show symptoms as early as infancy. Indeed, in severe cases, symptoms appear in infancy and progress rapidly. However, in milder cases, symptoms may appear in individuals between 18 months to three years of age.¹ The types of symptoms and their severity can vary among individuals but may include:¹

• Coarse facial features, thickened lips and tongue
• Bone deformities
• Speech difficulties 
• Loss of muscle tone, causing ‘floppiness’
• Intellectual disability
• Delays in motor skill development
• Slow growth
• Excessive sweating (hyperhidrosis)
• Abnormal muscle contractions (spasticity)
• Small, red spots on the skin (angiokeratomas)
• Loss of weight and muscle mass (cachexia)

Less common symptoms are:

• Abnormal curvature of the spine
• Enlarged internal organs (visceromegaly)
• Hearing impairment
• Seizures
• Repeated respiratory infections

Causes of fucosidosis

Fucosidosis is caused by mutations or changes in the FUCA1 gene, which is responsible for encoding an enzyme called alpha-L-fucosidase.¹ Alpha-L-fucosidase is involved in the breakdown of complex sugars that are attached to protein and fat molecules. These mutations reduce (or completely eliminate) the activity of the alpha-L-fucosidase enzyme and lead to a build-up of complex sugars in your cells, causing them to malfunction. Brain cells are particularly sensitive to this build-up and will often die in response.

Lysosomal storage diseases 

Fucosidosis is a lysosomal storage disease, meaning that it primarily affects lysosomes - cellular structures full of enzymes needed to break large molecules down into smaller pieces.² For example, the enzymes in lysosomes are responsible for breaking down molecules like fats and sugars. People with lysosomal storage disorders don’t have enough of one of these enzymes for proper cell function or lack the enzyme completely. Individuals with fucosidosis do not have enough alpha-L-fucosidase enzyme to break down compounds containing a sugar called fucose. As a result, these compounds collect in body tissues and cells, causing them to become dysfunctional or die. 

Lysosomal storage diseases are a group of around 50 to 70 diseases that are characterised by dysfunctional lysosomes (or lysosomal enzymes).² They are inherited metabolic diseases that can affect different parts of the body like the brain, skin, heart and nervous system, and are estimated to affect about one in every 5,000 live births. Research into cures for these diseases is ongoing, however there is not yet an approved treatment for many lysosomal storage diseases.

Genetics of fucosidosis 

Fucosidosis is inherited in an autosomal recessive pattern.¹ In our cells, we have two copies of each gene, one inherited from each parent. You will only develop fucosidosis if both copies of your FUCA1 gene are mutated (i.e., you have inherited a mutated copy of FUCA1 from both of your parents). Parents of an individual with an autosomal recessive condition usually carry just one copy of the mutated gene and, therefore, don’t show symptoms of the condition. When both parents carry a mutated copy of the FUCA1 gene, there is a 25% chance they will have a child that develops fucosidosis, a 50% chance that their child will be a carrier of the mutated gene (meaning they will have one copy of the mutated gene and are unlikely to show symptoms or become ill), and a 25% chance that their child will not inherit a copy of the mutated gene. 

Fucosidosis affects those assigned to males equally at birth and those assigned to females equally. It is estimated that incidence is less than 1 in 200,000 live births.¹ Though it is rare, fucosidosis has been identified in more than 20 countries, and its incidence rate may be higher in some regions of Southern Italy, Cuba, Tunisia and some populations of the USA.

Diagnosis

A diagnosis of fucosidosis may be confirmed through a variety of specialised tests:^1,3,4

• Electron microscopic examination: when examined under an electron microscope, abnormalities may be seen in cells within tissue samples taken from the skin, liver, spleen, kidney, or heart. 
• Imaging test: magnetic resonance imaging (MRI) and computer-assisted tomography (CT scan) of the brain may be used to confirm degeneration of the white matter in the brain. 
• Enzyme assays: enzyme tests may be used to confirm that alpha-L-fucosidase activity is reduced in certain cell types, such as leukocytes (white blood cells) and fibroblasts (a cell that helps the formation of connective tissue). 
• Urine analysis: a urine test may be used to check for increased levels of some fucose-containing compounds in the urine. 
• Genetic testing: tests to check for two copies of the mutated FUCA1 gene may also be used to confirm a diagnosis.
• Chorionic villus sampling (CVS): fucosidosis can be diagnosed prenatally through CVS. Foetal tissue samples are taken for enzyme assay testing. 
• Amniocentesis: This is also used to diagnose fucosidosis prenatally. In this test, a sample of the fluid that surrounds the baby is taken and studied. 

Treatment and clinical trials 

Currently, there is no way to reverse or cure fucosidosis. Instead, treatment of fucosidosis focuses on alleviating the symptoms experienced by each individual. Antibiotic therapy may be used for those experiencing recurrent respiratory infections.⁴ Fluid replacement may be suggested to individuals with excessive sweating to help counter the effects of dehydration. Genetic counselling is recommended for impacted individuals and their families. 

Some research has been done into bone marrow transplantation as a potential treatment.⁵ In young children with fucosidosis, bone marrow transplants from an unrelated donor showed an improvement in symptoms. Performing transplants earlier, before all the symptoms manifest, may be more effective than transplanting later. However, further research is needed to determine the long-term effectiveness and safety of the treatment. 

Outlook 

In more severe cases, fucosidosis can lead to death early in life, usually between the ages of 5 and 10. With milder forms, the disease progresses more slowly, and many patients reach adulthood. Researchers don’t yet know why symptoms can be more severe in some than others.

Diseases with similar symptoms 

Some disorders have symptoms similar to those present in fucosidosis. Comparing these diseases can be used for a differential diagnosis. 

Fabry disease

Fabry disease is a rare genetic disease that is caused by a deficiency in the alpha-galactosidase A enzyme.⁶ Low levels or inactivity of the alpha-galactosidase A enzyme result in a buildup of fatty materials in the body, particularly in the eyes, kidneys and cardiovascular system. While fucosidosis affects males and females in equal numbers, Fabry disease primarily affects males, but a milder form of the disease is more common in females. Like fucosidosis, Fabry disease can cause clusters of small, dark red spots of the skin (angiokeratomas) and hearing loss. Other symptoms of Fabry disease include cloudiness in the front part of the eye, burning sensations in the hands and feet, and decreased sweating. 

Alpha-mannosidosis 

Alpha-mannosidosis is another rare genetic disease. The deficient enzyme in alpha-mannosidosis is the alpha-D-mannosidase.⁷ This deficiency causes a build-up of complex sugars in body cells, like in fucosidosis. It’s inherited as an autosomal recessive trait. Some children inherit a severe, rapidly progressive form of the illness, whereas others experience milder symptoms. Like fucosidosis, alpha-mannosidosis can cause hearing loss, skeletal abnormalities, and a delay in motor skill development. Other symptoms of alpha-mannosidosis are immune deficiency, an enlarged tongue and muscle weakness. 

Summary

Fucosidosis is a rare genetic condition that can have a debilitating impact on individuals and their families. It is caused by mutations in the FUCA1 gene, which directs the production of the alpha-L-fucosidase enzyme. A deficiency in this enzyme causes a buildup of complex sugars in cells, causing them to die. Symptoms of fucosidosis include intellectual disability, coarse facial features, hearing impairments, and developmental delays. In severe cases, patients develop symptoms during infancy and do not survive childhood. In milder cases, symptoms show up later, and affected people can live into mid-adulthood. Research for treatment therapies is ongoing, but treatment currently focuses on managing symptoms.