Fucosidosis (ORPHA:349)
A rare lysosomal storage disease characterized by widespread tissue buildup of glycolipids and oligosaccharides rich in fucose. Patients present with broad clinical characteristics such as intellectual disability, developmental delay associated with psychomotor regression and bone abnormalities, visceromegaly, hyperhidrosis, and dermatological abnormalities.
Epidemiology
To date, less than 200 cases have been reported in the literature. The estimated incidence is less than 1/200,000 births, but is higher in some regions of Southern Italy, Cuba, Tunisia, and some populations in the USA.
Clinical description
The disease manifests in a spectrum ranging from a rapidly progressing severe form which starts approximately at 6 months of age (type I) to a moderate form with slower evolution (type II). Clinical symptoms and signs primarily include neurological damage leading to intellectual deficiency, psychomotor regression, speech difficulties, posture and walking difficulties, seizures and spasticity. They are often accompanied by coarse facial features, small stature, and dermatological abnormalities such as angiokeratomas. Other symptoms include cardiomyopathy, hepatosplenomegaly, dysostosis multiplex, joint contractures, recurrent lung infections and eye problems.
Etiology
The disease results from mutations in the FUCA1 gene (1p36-p34) which encodes the lysosomal α-L-fucosidase enzyme that catalyzes the hydrolysis of α-L-fucose residues in glycoproteins and oligosaccharides. Loss of function mutations in FUCA1 lead to a defect in synthesis or to the production of a non-functional enzyme and results in intralysosomal accumulation of fucosylated oligosaccharides and glycoproteins. To date, 60 pathogenic and likely pathogenic variants have been reported in the literature or genetic databases.
Diagnostic methods
Diagnosis is based primarily on clinical symptoms and signs as well as biochemical tests measuring fucosylated oligosaccharides and glycoprotein overload. An increase in fucosylated oligosaccharides in urine, accompanied by a reduction of α-L-fucosidase protein activity in the blood, is a strong indication of fucosidosis. The diagnosis may be further confirmed by genetic testing.
Differential diagnosis
Lysosomal storage diseases of the mucopolysaccharidosis type (MPS type 1 to 7), sphingolipidoses (Gaucher's and Fabry's disease), oligosaccharidoses (mannosidosis and Shindler's disease), and juvenile idiopathic arthritis all share some clinical features with fucosidosis. Careful clinical examination, biochemical analysis, and molecular genetic testing allow the exclusion of these diseases.
Antenatal diagnosis
Antenatal screening may be performed by amniocentesis or chorionic villus sampling for families with a pathogenic variant.
Genetic counseling
Inheritance is autosomal recessive. Genetic counseling is recommended to at-risk couples to inform them that there is a 25% chance of having an affected child at each pregnancy.
Management and treatment
Early diagnosis with a multi-systemic supportive care approach, and a multidisciplinary follow-up, can improve the quality of life and the longevity of these patients. Treatment consists of symptom-specific supportive care, such as antibiotic therapy for chronic respiratory infections, and fluid replacement for hyperhidrosis. Hematopoietic stem cell transplantation from bone marrow performed before the onset of severe symptoms may be effective but long-term results have yet to be determined.
Prognosis
In fucosidosis type I, severe neurologic deterioration happens rapidly and death from cachexia usually occurs between 5 and 10 years of age. In fucosidosis type II, neurological deterioration has a slower progression and most patients reach adulthood. There is no known correlation between location of the pathogenic variant in the FUCA1 gene and severity of clinical symptoms.

                            Last update: 
                            July 2023


                            - Expert reviewer(s): 
                            Dr Elzbieta CIARA  - Pr Aleksandra JEZELA-STANEK  - Dr Karolina STEPIEN