Fucosidosis

Fucosidosis is a rare autosomal recessive lysosomal storage disorder due to biallelic variants in FUCA1, with deficiency of alpha-L-fucosidase. It causes progressive neurodegeneration, coarse features, dysostosis multiplex and recurrent infection, and varies from a severe infantile form to a milder juvenile form.

Pathophysiology. Alpha-L-fucosidase removes fucose from glycoproteins, glycolipids and oligosaccharides. Deficiency causes storage of fucose rich glycoconjugates in the brain, skin, liver and other tissues.

Type 1 is severe with early regression, and type 2 is milder with angiokeratoma.

The course is not fully predicted by genotype.

• Developmental regression from the second year, spasticity and seizures
• Coarse facial features, and dysostosis multiplex
• Recurrent respiratory infections
• Hepatosplenomegaly and cardiomegaly
• Angiokeratoma corporis diffusum in type 2
• Raised sweat chloride in some, with salt loss
• Short stature, joint stiffness and visual disturbance
• Hearing loss
• Death in childhood in type 1, and survival into adulthood in type 2

• Alpha-L-fucosidase activity in leukocytes, plasma or fibroblasts: markedly reduced.
• FUCA1 sequencing with deletion and duplication analysis.
• Urinary oligosaccharides: fucose rich fragments on analysis.
• Brain MRI: hypomyelination and globus pallidus signal change.
• Radiographs for dysostosis multiplex, and echocardiography.
• Sweat test if cystic fibrosis is suspected clinically.

Differential diagnosis.

• Mucopolysaccharidoses and mucolipidosis
• GM1 gangliosidosis
• Alpha mannosidosis, sialidosis and aspartylglucosaminuria
• Fabry disease (for angiokeratomas)
• Cystic fibrosis (for raised sweat chloride)

• Disease modifying therapy: no enzyme replacement therapy is available. Haematopoietic stem cell transplantation has been reported to slow regression when done early, so discuss with a specialist centre.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, with valproate 10 mg/kg twice daily increasing to 20 mg/kg twice daily or clobazam 0.25 mg/kg daily increasing to 1 mg/kg daily (maximum 40 mg). Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Spasticity: baclofen 0.3 mg/kg daily in divided doses increasing weekly to 2 mg/kg daily (maximum 60 mg), physiotherapy and orthotics.
• Respiratory care: vaccination, chest physiotherapy and prompt antibiotics.
• Feeding and gastrointestinal care: gastrostomy for unsafe swallow, omeprazole 0.7 to 1 mg/kg daily, and macrogol 0.4 to 0.8 g/kg daily.
• Skin care: monitor angiokeratoma, and avoid trauma and heat.
• Cardiac care: treat valve disease and cardiomegaly.
• Hearing and vision: audiology review yearly and hearing aids if needed.
• Palliative care: early involvement in type 1.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis by enzyme assay or variant testing.

Special groups.

• Salt loss in hot climates: encourage fluids and monitor sodium.

Monitoring. Neurological status, seizures and feeding every 3 to 6 months. Echocardiography yearly, and hearing, skeletal and respiratory review yearly.

Referral and escalation. Refer to clinical genetics, metabolic medicine, neurology and palliative care. Emergency for aspiration, status epilepticus or severe respiratory infection.