Introduction

Fucosidosis is a rare lysosomal storage disease characterised by a severe lack of alpha-fucosidase enzyme activity, causing a buildup of certain sugars(fucose-containing glycolipids and fucose-containing glycoproteins) in the body. The severity and symptoms of fucosidosis vary and can affect multiple areas of the body, especially the brain. It may result in progressive neurological deterioration, growth retardation, skin changes, skeletal disorders, and coarse facial features.¹ Fucosidosis has a frequency lower than 1 in 200,000 live births, and the life expectancy depends on the type and severity of fucosidosis.² Approximately 43% of patients pass away within the first decade of life, and 41% pass away after age 20.³ The most likely causes of death due to fucosidosis before the age of 10 are respiratory and neurological symptoms.²

This article focuses on the neurological symptoms and brain involvement of fucosidosis. The inexorable and sometimes rapid neurological deterioration caused by fucosidosis often significantly affects the patient’s quality of life.³ Understanding the neurological manifestations can help us recognise signs of fucosidosis early on, get an early diagnosis, and allow healthcare providers to deliver tailored management plans.²

Pathophysiology of fucosidosis

Genetic basis and enzyme deficiency

A mutation in the FUCA1 gene causes fucosidosis. The FUCA1 gene encodes for the enzyme alpha-L-fucosidase, and mutations in this gene are linked to a severely reduced production of alpha-fucosidase.² Alpha-L-fucosidase is important for the breakdown of sugar molecules attached to certain fats and proteins, including fucose-containing glycolipids and fucose-containing glycoproteins.¹ When these sugar molecules are not broken down by the body at a rate proportional to their production, they can accumulate in human cells and cause cells to malfunction or die.²

Fucosidosis is an autosomal recessive genetic disorder, indicating that each sibling of a patient with the same biological parents has a 25% chance of also having the condition, a 50% chance of being healthy but carrying the gene, and a 25% chance of being healthy without carrying the gene.³

Mechanism of neurological involvement

Neurones are known to be particularly sensitive to damage caused by lysosomal dysfunction, partially because of their inability to proliferate.⁴ Processes include, but are not limited to:

• damage directly caused by substrate accumulation⁵
• inflammatory responses⁵
• impaired intracellular transport⁵
• autophagy disturbances⁵

These can all contribute to the dysfunction of neurones. 

Type I and II fucosidosis

There are two main types of fucosidosis:

• Type I: characterised by rapidly progressive neurologic deterioration, causing severe brain dysfunction and death usually within the first decade of life³
• Type II: has a less severe disease course and slower progression of neurological symptoms. Patients typically survive into adulthood³

Neurological symptoms in fucosidosis

The clinical presentations of fucosidosis can be varied. Neurological symptoms in fucosidosis may include:

• Intellectual disability
• Progressive mental health deterioration
• Seizures
• Loss of ability to sit, stand, walk alone and speak
• Decline in psychomotor abilities
• Loss of joint motion in arms and legs
• Spastic quadriparesis
• Hyperreflexia

In rare cases, symptoms may also include focal dystonia, impaired hearing and Eustachian tube dysfunction.³

Other non-neurological symptoms include:

• Growth retardation¹
• Skin changes¹
• Skeletal disorders¹
• Coarse facial features¹
• Visceromegaly²

Brain involvement in fucosidosis

Imaging findings

Among magnetic resonance imaging (MRI) findings, abnormalities in white and grey matter are observed in individuals with fucosidosis. For the white matter, hypomyelination with widespread, confluent, progressive and symmetrical signal abnormalities in the periventricular and subcortical areas is observed.³ In the grey matter, diffuse hypomyelination with signal alteration in the globus pallidus is often observed in individuals with fucosidosis.³

In CT scans, generalised cerebral and cerebellar atrophy are typically found in patients with type II fucosidosis.³ Other findings may include ventricular dilatation and focal areas of hypodensity, and increased cerebellar volume.³ At early stages of fucosidosis, there may also be an increased cerebellar volume.³ In patients who survive beyond 30 years of age, loss of brain volume is seen in areas both above and below the tentorium, especially in the frontal lobes.³

Histopathological changes

One of the most significant histopathological changes is neuronal loss in grey matter structures.⁶ Cellular abnormalities are also observed in nerve cell bodies, including cell bodies that are enlarged and appear empty, or bodies that are filled with slightly basophilic material.⁶ The accumulation of glycolipids may also contribute to the formation of intracellular inclusion bodies with parallel or concentric lamellae.⁶,⁷

Sometimes, nerve fibers lose a significant amount of their myelin sheath, and the white matter becomes gliotic.⁷ There may also be a lack of Purkinje cells, which are essential for regulating movement or posture, and other functions, including cognition and emotion.⁷

Diagnosis of fucosidosis

Diagnosis is made based on clinical symptoms or signs, and biochemical tests to measure levels of fucosylated oligosaccharides and glycoproteins.⁸ Genetic testing is usually required to further confirm the diagnosis.⁸

Differential diagnosis

Multiple conditions, including type 1 to 7 mucopolysaccharidoses, Gaucher’s disease, Fabry’s disease and juvenile idiopathic arthritis, also share similar symptoms with fucosidosis.⁸ Through careful diagnostic evaluation with biochemical and genetic testing, similar conditions can be excluded.⁸

Management and treatment strategies

Management of fucosidosis is based on the symptoms of individual patients, since a particular treatment method may not be suitable for all cases.² Treatment methods may include bone marrow transplant(BMT), hematopoietic stem cell transplantation (HSCT), and umbilical cord blood transplantation (UCBT).²

At advanced stages of fucosidosis, some patients may choose to undertake symptomatic treatment instead of trying to reverse the disease burden through transplantations.² Since respiratory and neurological symptoms are the most common causes of death within the first decade of life, it is important to address these symptoms early on.²

Treatment methods to alleviate respiratory symptoms include the use of airway clearance systems, albuterol, nasal polyp removal bimonthly nasal endoscopy.² To manage neurological symptoms, anti-epileptic therapy(levetiracetam) or botulinum toxin injections to control seizures, baclofen to treat dystonia, and physical or occupational therapy may be recommended.²

FAQs

When do symptoms of fucosidosis appear?

Symptoms of fucosidosis may develop from 1 to 23 months in an infant or from 2 to 11 years of age as a child.⁸

Can fucosidosis be passed from parents to their children?

Yes. Fucosidosis is an inherited, autosomal recessive disorder. If both parents are carriers of the defective gene, there is a 25% chance that their children will develop fucosidosis.

Summary

With a frequency lower than 1 in 200,000, fucosidosis is an autosomal recessive genetic disorder that causes a buildup of certain sugars in the body. The condition is caused by a mutation in the gene that encodes for the enzyme alpha-fucosidase, which is responsible for breaking down fucose-containing glycolipids and fucose-containing glycoproteins. This mutation, in turn, causes a lack of activity and the enzyme, leading to the buildup of these sugars. The buildup of these sugars can have widespread effects on our body, especially our brain. 

Life expectancy of individuals with fucosidosis varies based on the type and severity of fucosidosis, where some live up to 10 years of age, and others survive into adulthood. Among people who pass away due to the condition within the first decade of life, respiratory and neurological symptoms are the most likely cause of death. When substances build up in neurones, a complex series of pathological processes leads to significant neuronal loss, cellular abnormalities and demyelination. Signs of brain involvement in fucosidosis can be observed in magnetic resonance imaging(MRI) findings, CT scan findings, and under the microscope. For MRI, abnormalities in white and grey matter are observed. For CT scans, generalised cerebral and cerebellar atrophy are one of the major findings. Under the microscope, many histopathological changes can be found, such as enlarged cell bodies, formation of abnormal lamellar intracellular inclusion bodies, prominent demyelination, lack of Purkinje cells, and gliosis

Neurological symptoms of fucosidosis may include intellectual disability, motor deterioration, seizures, impaired psychomotor abilities, loss of join motion in arms and legs, spastic quadriparesis and hyperreflexia. Diagnosis is made based on clinical signs or symptoms, biochemical tests and genetic tests. Using the results of biochemical and genetic tests, a tailored management plan is made for individual patients. Treatment methods include blood marrow transplant (BMT), hemopoietic stem cell transplantation (HSTC), and umbilical cord blood transplantation (UCBT). Supportive treatment is also offered to help manage symptoms, especially at advanced stages of fucosidosis. To manage seizures, anti-epileptic therapy (levetiracetam) or botulinum toxin injections may be recommended. Baclofen is used to treat dystonia. To help with the neurological deterioration that often significantly affects the day-to-day life of patients, physical and occupational therapy are also commonly recommended.