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The Genetics of Fucosidosis

Øivind Nilssen, Senior Scientist
Department of Medical Genetics
University Hospital of Tromsø, Norway                       

Fucosidosis belongs to the lysosomal storage disorders (LSDs). This group of disorders was first recognized in 1963, by L. Hers who reported storage of non-degraded material in the lysosomes of patients with Pompe’s disease. Lysosomal storage disorders are caused by lysosomal dysfunction usually as a consequence of deficiency of a single enzyme required for the metabolism of lipids, glycoproteins (sugar containing proteins) or so-called mucopolysaccharides. Lysosomal storage disorders are rare disorders. Individually, they occur with incidences of less than 1:100.000, however, as a group the incidence is about 1:5000 - 1:10.000.

Since the disorders usually are caused by deficiency of single enzymes they are regarded as monogenic which means that the diseases are caused by mutations in single genes.
Like our chromosomes our genes come in pairs, according to the laws of Mendel. With two exceptions, Hunters syndrome and Fabrys disease, all Lysosomal storage disorders are inherited in an autosomal recessive fashion. Autosomal means that the defective gene may be located on any chromosome other than the sex chromosomes, X and Y. Recessive means that carrier parents are clinically normal and that disease is only expressed in children who receive two disease genes of a pair, one from each parent.

Carrier parents are said to be heterozygous, carrying one normal and one mutant gene; whereas affected children are said to be homozygous, carrying two mutant genes. The children’s risk of receiving one disease gene from each carrier parent is one in four. The proband may be the only affected family member, but if any others are affected, they are almost invariably in the same sib-ship, not elsewhere in the kindred. These are the observations and laws of autosomal recessive inheritance that also applies to fucosidosis.

Fucosidosis:

Fucosidosis was first described in 1966, in 2 Italian sibs with progressive mental retardation and neurologic deterioration, by Durand and co-workers,. Later, Loeb and co-workers (1969) showed these patients to lack the activity of lysosomal alpha-L-fucosidase.

During the normal turnover of sugar-containing proteins and lipids alpha-fucosidase works in concert with other lysosomal enzymes in the degradation of large branched sugar molecules. In this process alpha-fucosidase is involved in the cleavage of fucose from these large chains of sugars. Consequently, lack of alpha-fucosidase activity results in the intracellular accumulation of specific sugars containing fucose moieties. These sugars may exist as free oligosaccharides or they may be linked to the amino acid asparagine or to lipids.

Initially, at least two clinical subtypes were described for fucosidosis. One severe form, type I, and one milder form, type II. However, recent data suggest that types I and II represent two extremes of a continuum within a wide spectrum of severity.

So far, less than 100 patients have been reported in the literature. However, a large international survey by Willems and co-workers show that the ethnic origin of fucosidosis has a worldwide distribution and that patients have been identified in more than 20 different countries from Europe, North and South-America, Asia and Africa. The majority of reported patients are from Italy and from the southwestern part of U.S.A. Consanguinity was reported in 40 percent of the 45 families identified.  In Italy, many of the patients are concentrated in the Reggio Calabria area. In the U.S.A the majority of the patients are descendants of early Spanish settlers in New Mexico and Colorado. Why is there relatively high disease prevalence in these populations? One possibility is the so-called founder effect. Founder effect means that a high frequency of a mutant gene may occur in a population founded by a small ancestral group if one or more of the founders were carriers of the mutant gene.

However, founder effect cannot be the only explanation for the relatively high incidence in Italy since several different disease-causing mutations have been identified in Italian patients. Hence, a simple explanation would be that there is a generally high frequency of fucosidase mutations in these populations. Another possibility is that intensive screening for fucosidosis by the research groups of P. Durand in Italy and D. Wenger and S. Goodman in Colorado might have lead to very effective case detection. Thus, the high prevalence in Italy and Colorado may result from bias of ascertainment. If this is the case one should expect fucosidosis to be under diagnosed in other populations.

The gene and the mutations.

The gene encoding the alpha-fucosidase, FUCA 1, was found to be located to the short arm of chromosome 1, by Carrit and co-workers, in 1982. The determination of the complete gene sequence was based on the works of Fukushima (1985), Occhiodoro (1989 and Kretz (1992).

The FUCA 1 gene spans 23.000 base pairs. One base is equivalent to one of the four “letters” A, C, T or G, making up the genetic code. The gene contains 8 regions that are functionally important since they have coding function. These are called exons whereas all intervening DNA is called introns. The coding region of the FUCA 1 gene contains 1383 base pairs with the capacity to encode a protein of 461 amino acids, the alpha- fucosidase enzyme.

Willems and co-workers (1999) recently published a spectrum of disease-causing mutations. This spectrum was based on the study of 40 patients. Twenty-two mutations were identified. Most mutations were private as they rarely occurred in more than one family. However, one particular mutation, named Q281X, stands out with a high frequency since it was detected in families from Italy, France, Canada and Cuba. Most mutations were predicted to directly inactivate the production of alpha-fucosidase. They are so called nonsense, or frame-shifting mutations. Only three of the mutations are of the missense type as they result in the replacement of one amino acid with another. All mutations, including the missense mutations, result in nearly absent alpha-fucosidase activity.

Is there a relationship between type of mutation and clinical severity?

It has been suggested that the clinical variability is genetically determined by different mutations in the FUCA 1 gene. Several lines of evidence controvert this hypothesis. 1) Family pedigree studies show clinical variability within the same family. 2) No heterogeneity at the biochemical level has been observed. In a survey of 77 patients all had negligible levels of residual alpha-fucosidase activity. 3) Identical mutations have been found in homozygous states both in patients with rapidly progressing and slowly progressing fucosidosis.

Clinical variability between patients with identical genotypes (mutations) is not unusual for lysosomal storage disorders. It has been observed for alpha-mannosidosis, Krabbe disease, Sanfilippo disease type B, Tay-Sachs disease, Gaucher disease, among others. For many of the lysosomal storage disorders, the observed clinical variability is not due to the nature of the mutation, but rather to secondary unknown genetic and probably also environmental factors. Thus, for fucosidosis, as for many other lysosomal storage disorders, there will always be a problem predicting the clinical outcome of a patient from the genotype of one single gene.  The identification contributing genetic and environmental factors will be the challenge of the future.

Fucosidosis: Main Page | Overview | Fact Sheet |

Updated: July 4, 2006