Alternative titles; symbolsALPHA-L-FUCOSIDASE DEFICIENCY▼ DescriptionFucosidosis is an autosomal recessive lysosomal storage disease caused by defective alpha-L-...
Alternative titles; symbols
Fucosidosis is an autosomal recessive lysosomal storage disease caused by defective alpha-L-fucosidase with accumulation of fucose in the tissues. Clinical features include angiokeratoma, progressive psychomotor retardation, neurologic signs, coarse facial features, and dysostosis multiplex.
Fucosidosis has been classified into 2 major types. Type 1 is characterized by rapid psychomotor regression and severe neurologic deterioration beginning at about 6 months of age, elevated sweat sodium chloride, and death within the first decade of life. Type 2 is characterized by milder psychomotor retardation and neurologic signs, the development of angiokeratoma corporis diffusum, normal sweat salinity, and longer survival (Kousseff et al., 1976).
▼ Clinical Features
Van Hoof and Hers (1968) found deficiency of alpha-fucosidase activity in the liver of patients with a Hurler-like disorder described by Durand et al. (1967, 1968). Fucose accumulated in all tissues (Durand et al., 1969). Durand et al. (1968) called the condition fucosidosis. The Belgian patient studied by Loeb et al. (1969) was probably related to the 2 Italian patients reported by Durand et al. (1969). Durand et al. (1969) described type 1 fucosidosis and Loeb et al. (1969) described type 2.
Schafer et al. (1971) found deficiency of alpha-L-fucosidase in a 9-year-old child with an unusual spondylometaphyseoepiphyseal dysplasia.
Patel et al. (1972) described a different phenotype resulting from deficiency of alpha-L-fucosidase. The patient, who was not Hurler-like in appearance, showed unusual survival (to at least 20 years) and from age 4 had angiokeratoma of the skin as in Fabry disease (301500). Differing from Fabry disease were severe mental and physical retardation and normal renal function. He also showed anhidrosis and inability to control body temperature. Urinary and leukocyte alpha-L-fucosidase was 10% of normal; obligate heterozygotes had intermediate values. This is, presumably, an example of allelism with production of quite a different clinical picture.
Schoonderwaldt et al. (1980) discussed a possible third type of fucosidosis based on age of onset and length of survival. They described type 3 as a juvenile form of the disease, with less rapid psychomotor and neurologic deterioration than in types 1 and 2, with survival into the twenties in some cases, and in all cases the typical rash of Fabry disease (angiokeratomata). They described 2 Dutch brothers with some characteristics of type 2, but more like type 3 from the point of view of rate of progression and length of survival; however, the brothers did not show angiokeratoma. The skin was distinctively dry and thin, a feature not described in other patients.
Ikeda et al. (1984) studied 3 sisters with the adult form of fucosidosis (type 2 in the classification of Kousseff et al., 1976). They had prominent psychomotor retardation, gargoyle features, and angiokeratoma. Abnormalities were found in macrophages, endothelial cells, fibroblasts, and Schwann cells on rectal biopsy.
Willems et al. (1988) described 2 families, 1 with 3 patients and the other with 2 patients, in each of which both type 1 and type 2 fucosidosis were represented. In 1 family described by Willems et al. (1988), 1 patient survived to almost 20 years of age and showed angiokeratoma, whereas 2 other patients in a cousin sibship died under age 5 years. All 4 parents were traced to common ancestors; thus, the children were presumably homozygous for the same gene defect. In the second family, 1 patient was alive at almost 25 years of age, whereas a sib had died at age 4 years. Both had angiokeratoma. Willems et al. (1988) suggested that environmental factors or 'modifying genes' separate from the fucosidase structural gene may contribute to the phenotype.
Willems et al. (1991) reviewed the literature on 77 patients with fucosidosis. They presented 4 lines of evidence suggesting that the distinction between a severe type 1 form and a less severe type 2 form with survival into adulthood may not reflect true genetic heterogeneity. First, family pedigrees have shown both types within a single family. Second, clinical studies failed to show a clear distinction between types 1 and 2, but rather a seemingly continuous clinical spectrum. Third, no biochemical heterogeneity has been observed. Very low to negligible residual fucosidase enzyme activity has been found in patients of both types. Fourth, the identical DNA mutation has been found in the homozygous state in patients with the rapidly or slowly progressive form of the disease. The authors speculated that types 1 and 2 fucosidosis, rather than representing 2 distinct clinical entities, represent the extremes of a continuous clinical spectrum.
Fleming et al. (1998) described a leu405-to-arg mutation in the FUCA1 gene (612280.0012) in homozygous state in a patient who was 46 years old the time of review in 1997. There was said to be the first report of a patient with fucosidosis living into the fifth decade. The patient had been described by Primrose (1975) at the age of 20 years with progressive physical and mental retardation, short stature, angiokeratoma corporis diffusum, dysostosis multiplex, and generalized muscle wasting. Her parents were consanguineous. By age 46 years she had lost all verbal and most nonverbal communication and was nonambulant and unable to sit unaided. She had suffered continued muscle wasting, several minor long-bone fractures, and 1 chest infection. She had been noted to be unhappy at warm temperatures and had seldom, if ever, been observed to perspire. Her height was 113 cm. Prominent angiokeratomas were present on the thighs, legs, and trunk, and there was a network of fine capillaries on the limbs. There had been little progression of the angiokeratomas from age 20 to 46 years. The authors noted that hypohidrosis and poor temperature regulation is a recognized feature in this disorder.
▼ Biochemical Features
Patients with fucosidosis have difficulty in degrading fucose-containing blood group H and Lewis substances. In 2 affected sibs in a family of Italian extraction, Kousseff et al. (1976) found that Lewis A and B antigens were very high in both red cells and saliva. However, H specificity showed no increase. Because Lewis-specific alpha-fucose is bound to beta-N-acetyl-D-glucosamine by an alpha-1 to -4 linkage, whereas H-specific alpha-fucose is linked to beta-galactose by an alpha-1 to -2 linkage, the fucosidase that is deficient in fucosidosis may be the one for the 1-to-4 linkage, or, alternatively, the mutation may be such that only that specificity is lost. The last possibility is based on the notion that different mutations of the same enzyme molecule are responsible for the 2 types of fucosidosis (and perhaps for the skeletal dysplasia described by Schafer et al., 1971). This idea follows from the one-gene/one-enzyme/many-substrates idea of O'Brien (1975) and the notion that mutation can interfere with one or another but not all substrate specificities.
Gatti et al. (1973) emphasized heterogeneity in fucosidosis. Johnson and Dawson (1985) presented molecular evidence for heterogeneity among patients with fucosidosis. They studied 11 patients with less than 5% of normal alpha-L-fucosidase activity: in 8 patients, fibroblasts synthesized no detectable enzyme protein; in 2, they synthesized normal amounts of the 53,000-Da precursor, but none of the mature 50,000-Da form was detectable; and in 1, they contained small amounts of crossreacting material.
▼ Population Genetics
A majority of earlier-reported cases of fucosidosis were Italian; most of these patients originated from 2 neighboring villages, Grotteria and Mammola, in the southern Italian province of Reggio Calabria (Sangiorgi et al., 1982).
Willems et al. (1999) stated that fewer than 100 patients with fucosidosis had been reported worldwide. The disease occurred at a higher rate in Italy, in the Hispanic-American population of New Mexico and Colorado, and in Cuba.
▼ Molecular Genetics
Darby et al. (1988) found 2 RFLPs in the FUCA gene in Caucasians; the polymorphism information content (PIC) of the combined DNA markers was 0.38. No recombinants were observed between fucosidosis phenotype and these RFLP markers, suggesting that the lesion responsible for fucosidosis is located in the FUCA1 gene.
In the course of Southern blot analysis of the FUCA1 gene in 23 patients with fucosidosis, Willems et al. (1988) found in 5 patients obliteration of an EcoRI restriction site in the open reading frame encoding mature alpha-L-fucosidase. This abnormality was not observed in 80 controls and was thought to be the basic defect responsible for fucosidosis in these patients. Both patients with the severe type 1 form and patients with the less severe type 2 were shown to be homozygous for this presumed mutation. In the remaining 18 patients, no EcoRI site obliteration, major gene deletions, or insertions were detected. The heterogeneity found at the DNA level was not present at the protein level, as all fucosidosis patients investigated had low fucosidase protein (less than 6% of normal) and negligible fucosidase activity in fibroblasts and lymphoblastoid cell lines.
In 6 unrelated Italian patients with fucosidosis, Guazzi et al. (1989) found 3 patterns of mRNA. One patient showed a variant pattern of DNA hybridization with a partial length cDNA; the change represented loss of an EcoRI site. The same patient showed a markedly decreased amount of mRNA on Northern blot hybridization. Two patients apparently lacked mRNA. The other 3 patients showed a transcript similar in size and amount to that observed in controls.
Kretz et al. (1989) demonstrated that the loss of the EcoRI site identified by Willems et al. (1988) and Guazzi et al. (1989) is determined by a C-to-T transition in the FUCA1 gene, which results in the generation of an in-frame TAA stop codon 120-bp upstream of the normal stop codon (612280.0001).
Gordon et al. (1995) described dystonia of lower extremities in an affected 7-year-old boy. There was no alpha-fucosidase activity in his cultured lymphoblasts. He was found to be homozygous for a Q422X mutation, which resulted in loss of an EcoRI restriction site. The authors stated that no previously reported fucosidosis families with this same homozygous mutation showed dystonia.
Cragg et al. (1997) investigated the molecular basis of the deficiency of alpha-L-fucosidase in 8 patients in whom the diagnosis of fucosidosis had been made on clinical and enzymatic grounds. None of the patients had a deletion or gross alteration of the FUCA1 gene. SSCP analysis followed by direct sequencing of amplified exons and flanking regions identified putative disease-causing mutations in 6 of the 8 patients, who had severe forms of the disease and very low residual fucosidase activity and protein. Five of the 6 mutations had not previously been described.
Willems et al. (1999) reviewed the mutational spectrum of fucosidosis. The 22 mutations that had been detected included 4 missense mutations, 17 nonsense mutations, and 1 splice site mutation. All of these mutations led to nearly absent enzymatic activity and severely reduced cross-reacting immunomaterial. Therefore, the observed clinical variability was considered to be due to secondary unknown factors.
▼ Animal Model
In a dog with alpha-L-fucosidase deficiency, Taylor et al. (1986) found that bone marrow transplantation after total lymphoid irradiation raised the level of enzyme activity in both visceral and neural tissues with consequent reduction in the severity of the storage lesions. These results offered hope that early bone marrow transplantation may prevent the development of disease in neurovisceral storage disorders.
Studying the canine model of fucosidosis in a colony of English springer spaniels, Occhiodoro and Anson (1996) determined the nucleotide sequence and predicted amino acid sequence of canine fucosidase, which showed a high level of identity with the human and rat sequences. The study of the gene in the affected animals demonstrated a 14-bp deletion in mRNA. The deletion created a frameshift and introduced a premature translation termination codon at amino acid 152 and was shown to correspond to a deletion of the last 14 bp of exon 1. Rapid PCR-based screening for the mutation was performed on genomic DNA from dogs within the colony, enabling detection of both carrier and homozygous dogs.