History and Overview

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

More than twenty years ago Lowden and O'Brien suggested that patients suffering from isolated sialidase (nauraminidase) deficiency could be divided into at least two groups, type I and type II, according to onset and severity of symptoms. Type I sialidosis, which is also referred to as the cherry-red spot (in the maculae of the eye)/myoclonus (twitching or clonic spasm) syndrome, is a relatively mild disease that occurs in the second decade of life. Typical symptoms are progressive loss of vision associated with nystagmus (involuntary, cyclical movement of the eyeball), ataxia (defective muscle coordination) and grand mal-seizures. The visual handicap is often associated with impaired color vision and/or night blindness. In type I sialidosis, somatic and bony abnormalities are absent and intelligence is normal. Sialidosis type II is distinguished from the milder form of the disorder by much earlier onset of the symptoms. These symptoms may include abnormal somatic features such as coarse facies, dysostosis multiplex (incomplete ossification), enlarged liver and spleen, developmental delay and mental retardation. Type II disease has been divided further into congenital and infantile forms according to age of disease onset.

The enzyme:

There are at least three human neuraminidase, or sialidase, enzymes. They can be distinguished by their cellular location, by substrate specificity and by pH optima. It is the lysosomal neuraminidase (N-acetyl-a-neuraminidase) that is lacking in sialidosis patients.

During normal turnover of sugar containing proteins lysosomal neuraminidase is involved in the stepwise degradation of large, branched sugar chains. Neuraminidase is required in the first step in an ordered degradation process and, consequently, lack of neuraminidase activity results in accumulation of rather large sugar chains of six to ten residues. These, sugar compounds accumulate in lysosomes and result in vacuolated lymphocytes and bone marrow cells, clearly visible in the type II form but absent in the type I form of the disorder. Vacuolization is also observed in other cell types such as skin fibroblasts and nerve cells.

The lysosomal neuraminidase displays very complex interactions with other important enzymes. This has complicated the genetic and biochemical analyses as well as the clinical diagnosis. Lysosomal neuraminidase is only active when bound to another enzyme called cathepsin (PPCA). Furthermore, two other enzymes, b-galactosidase and a sulfatase, add to this complex. This is called a multi-enzyme complex. A primary defect in cathepsin (PPCA) causes the lysosomal disorder Galactosialidosis, which results from a “disturbance” in the assembly of the multi-enzyme complex. The disease presents with clinical signs strikingly similar to those of sialidosis. However, sialidosis patients and individuals with combined deficiencies of neuraminidase and b-galactosidase suffer from two distinct and separate genetic disorders.

Sialidosis is also genetically separate and should not be confused with the free sialic acid-storage diseases such as Salla Disease (SD) and Infantile Sialic Acid-Storage Disease (ISSD). SD and ISSD result from a deficient lysosomal mebrane protein, sialin. Sialic acid storage disorders can be divided into those in which free sialic acid is stored and those in which bound sialic acid accumulates. Sialidosis belongs to the latter group.

The gene and the mutations:

Like most lysosomal storage disorders sialidosis shows autosomal recessive inheritance. The gene encoding lysosomal neuraminidase, neu-1, was independently identified and characterized by Bonten et al (1996) and Pshezhetsky et al (1997). The gene was localized to the short arm of chromosome 6 (6p21). Later, Milner et al (1997) showed that the gene spanned 3.500 base pairs. One base pair is equivalent to one of the four “letters” A, C, T, and G, making up the genetic code. The gene is composed of 6 regions that have coding function. They are called exons. Together, the exons encode a continuous array of 415 amino acids which folds into a three-dimensional protein structure, the lysosomal neuraminidase.

About 25 mutations have been identified in the neuraminidase gene of unrelated patients with sialidosis. The mutations analyzed to date are scattered all over the gene. They include point mutations that result in subtle alterations in amino acid composition of the protein as well as small deletions or insertions in the DNA that result in truncated enzymes. The patients studied come from multiple origins reflecting a wide geographic distribution of the disease. Mutations have been identified in patients from Japan, Africa (African American), Mexico, Italy, Greece, Germany, Holland, China, Spain, Turkey and Poland. The majority of type I patients have been Italian. However, little information exists with regard to prevalence, population genetics and demographic aspects of sialidosis.

Genotype/phenotype correlation:

Bonten et al (2000) and Lukong et al (2000) have studied the effect of specific mutations on the predicted structure and stability of the neuraminidase, its residual enzyme activity and its ability to enter the lysosomes. Based on their findings, Bonten et al (2000) classified the mutant neuraminidases in three distinct groups: 1) catalytically inactive and not lysosomal; 2) catalytically inactive, but localized in lysosome; 3) catalytically active and lysosomal.

There was a close correlation between the subcellular distribution, residual activity and the clinical severity of the disease. Patients with the severe type II disease had mutations from the first group, whereas patients with a mild form of type I disease had at least 1 mutation from the third group. Mutations from the second group were mainly found in juvenile type II patients with intermediate clinical severity. Thus, in contrast to what is seen in other lysosomal storage disorders such as fucosidosis, a-mannosidosis, Krabbe disease and Gaucher disease, there appear to be a direct relationship between the specific mutation and the clinical severity in sialidosis patients. Bonten et al (2000) give a reasonable explanation for this phenomenon. However, prediction of the clinical outcome of a patient based on the genotype alone should be carried out with caution. At the level of the individual patient, other genes, in combination with environmental factors may play a role.

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