Introduction

Fucosidosis is a rare genetic disease that affects the body’s ability to break down a type of sugar known as fucose, which is found attached to some fats and proteins. It affects people assigned female at birth (AFAB) and people assigned male at birth (AMAB) equally and is very rare, with an incidence of less than 1 in 200,000. Fucosidosis is a lysosomal storage disorder caused by a genetic mutation of the FUCA1 gene. This mutation causes a lack of the enzyme alpha-L-fucosidase, which is produced by lysosomes in the cells to break down fucose. Consequently, fucose-containing compounds accumulate throughout the body, mainly in the brain and central nervous system (CNS).^1,2

People with fucosidosis present with symptoms of developmental delay, both intellectually and physically. Additionally, people may develop some skeletal deformities and might experience seizures and muscle stiffness. Furthermore, some may experience deterioration of motor skills and would need to learn them again. Their facial appearance will be affected by the presence of thick skin, a prominent forehead, and less defined facial features, like eyes and mouth. Their body skin might become thicker, and some red spots called angiokeratomas can develop, which result from the widening and breaking of blood vessels near the skin.^1,2

Some internal organs, such as the liver, spleen and heart, may be affected and become enlarged (known as hepatomegaly, splenomegaly and cardiomegaly, respectively). The person’s immune system might also suffer from this condition, leaving them more vulnerable to infections.^1,2

Fucosidosis usually appears in the early years of life; however, it can also arise in adolescence.³ It can progress rapidly or slowly depending on each case, and may lead to severe complications and eventually fatality.^4,5 Currently, there is no cure available for fucosidosis, and the treatment aims to manage the symptoms to, ultimately, improve the person’s quality of life. 

Diagnostic methods

Since fucosidosis is a very rare disease, obtaining a correct diagnosis might be a lengthy and complicated process. Diagnosis involves the intervention of a multidisciplinary healthcare team specialising in different body systems like cardiologists, neurologists, medical geneticists, and orthopaedic specialists. Furthermore, diagnosis will require the use of different laboratory tests and imaging techniques.

Clinical evaluation

A thorough physical examination must be conducted if a diagnosis of fucosidosis is suspected; this is completed for infants or adolescents presenting with skeletal and facial deformities, accompanied by deteriorating mental or motor functions. Additionally, losing the ability to carry out certain activities, such as walking or talking, is commonly seen in fucosidosis. The presence of seizures and frequent muscle stiffness may point the diagnosis towards fucosidosis.²

Furthermore, the physician will palpate (examine by touch) the abdomen to look for any enlargement of organs, including the liver or spleen. Similarly, an X-ray might be requested to check for any increase in the size of the heart.² 

Family history

Fucosidosis is a genetic disorder passed down in an autosomal recessive pattern – both parents will carry (they are called ‘carriers’) the mutated FUCA1 gene, even if they show no symptoms and do not have the condition. If a child receives a mutated copy of the gene from both parents, they may develop fucosidosis.²

As such, inquiring about the family’s medical history and whether any family members have similar symptoms or an established diagnosis of fucosidosis is helpful to determine whether the person has fucosidosis.^1,2

Laboratory tests

As mentioned, the internal organs can be affected in fucosidosis through the accumulation of fucose-containing compounds. Carrying out baseline tests to estimate hepatic (liver) function and hepatic enzyme levels could help determine the extent of damage in the liver. Furthermore, kidney function might be tested by measuring the levels of urea, creatinine, and different electrolytes.^1,2,3

Electron microscopy might be employed to observe biopsy samples from different organs, like the liver or skin, to check for the presence of abnormal vesicles inside the cells.²

Genetic testing

Genetic testing is very important in obtaining an accurate diagnosis; this involves collecting samples and observing a specific sequence of the DNA that codes for the enzyme alpha-L-fucosidase.^1,2

The test will look for the presence of any mutation on the FUCA1 gene. Since the person inherits a copy of the gene from each parent, they may have copies with the same mutation or different mutations of the FUCA1 gene.^1,2

Prenatal diagnosis

Fucosidosis can be detected before birth through the use of advanced tests, such as amniocentesis or chorionic villus sampling (CVS). Amniocentesis involves collecting a sample from the amniotic fluid that surrounds the foetus in the womb. CVS is done by collecting cells from the placenta by inserting a needle through the belly or a small tube through the cervix.^1,2

These tests are offered to pregnant women who carry the mutated FUCA1 gene or have a family history of the disease to check whether fucosidosis has been passed to the foetus.^1,2

Specific tests used in fucosidosis diagnosis

Enzyme activity assays

Enzyme activity assays are tests used to confirm a diagnosis of fucosidosis.² The levels of alpha-L-fucosidase are measured in the person’s plasma and other cell samples. The cells mainly tested are a type of white blood cell called leukocytes. A positive diagnosis is offered when the test results reveal low levels of the alpha-L-fucosidase enzyme.^1,2

Urinary oligosaccharide analysis

An important procedure that can aid in confirming a diagnosis involves collecting urine samples and testing for the presence of oligosaccharides and glycolipids/glycoproteins, which contain fucose. If these compounds are detected in the sample, a diagnosis of fucosidosis is more likely.¹ 

Molecular genetic testing

Molecular genetic testing is used when the presence of fucosidosis is suspected and enables the clinician to detect whether there are any mutations this can be done either by looking at the FUCA1 gene if fucosidosis is deemed the most probable diagnosis, or at the whole exome (the parts of genomes that code for proteins and enzymes) if the diagnosis is unclear and other conditions are suspected.^2,5,6

Neuroimaging

Neuroimaging is carried out using imaging techniques, like magnetic resonance imaging (MRI scan) or computed tomography (CT scan). An MRI scan will show the accumulation of fucose-containing molecules in the white and grey matter of the brain.⁴

A CT scan may show a decrease in the size of the cerebrum or cerebellum; this may be the cause for the deterioration in mental health and motor skills, such as standing and speaking.²  

Challenges in diagnosis

Fucosidosis is classed as a lysosomal storage disorder (LSD), which encompasses disorders resulting from the lack of certain enzymes and the accumulation of the compounds they normally break down. Many conditions exist under this category and are similar in their symptoms, which renders diagnosis tricky and difficult, especially since fucosidosis is a very rare condition; for example, alpha-mannosidosis and aspartylglucosaminuria develop at a very young age and affect the central nervous system, amongst other body systems. The persons affected by these conditions could show skeletal deformities and intellectual disability.^1,4 

Summary

Fucosidosis is a rare genetic disease classified among lysosomal storage disorders. It is characterised by a decrease in the production of the alpha-L-fucosidase, which breaks down a type of sugar called fucose. Eventually, compounds that contain fucose start to accumulate throughout the body and affect its normal function. The person’s brain and central nervous system are primarily impacted, and this manifests through intellectual and progressive physical disability. Different internal organs could become enlarged and less efficient.

Due to its rarity and similarity to other disorders in presentation, making an accurate diagnosis is tricky and requires different procedures and testing. A physical examination is not sufficient on its own to determine whether the person has this condition; however, it forms a good starting point when combined with a detailed family history and baseline laboratory tests.

Neuroimaging techniques, such as MRI and CT, allow clinicians to look for any changes in the brain tissue. These will show signs of oligosaccharide deposits and possible shrinking of the brain tissue. Furthermore, oligosaccharides might be detected in the urine samples of those who have fucosidosis.

A diagnosis is confirmed primarily through enzyme activity assays that assess the levels of alpha-L-fucosidase in plasma and leukocytes, which will be absent or very low. Additionally, genetic testing can be utilised to identify any changes in the FUCA1 gene that codes for the alpha-L-fucosidase enzyme and further reinforce the diagnosis.