Neuraminidase Deficiency with... Health Article

Protective protein/cathepsin A

PPCA is required for the transport of neuraminidase to the lysosome. Once inside the lysosome, the enzymatic activity of PPCA may be involved in the activation of neuraminidase. Furthermore, PPCA mediates the association of multiple molecules of neuraminidase and beta-galactosidase, as well as GALNS. In the absence of PPCA, all three enzymes are rapidly degraded in the lysosome. Thus, PPCA protects and stabilizes these enzyme activities. In the absence of PPCA, substrates for these enzymes may accumulate to dangerous levels.

Gangliosides are very complex components of cell membranes. They are made up of a long-chain amino alcohol called sphingosine, a long-chain fatty acid, and a very complex oligosaccharide that contains sialic acid. The lysosomal beta-galactosidase is responsible for hydrolyzing gangliosides.

GALNS catalyzes the first step in the lysosomal breakdown of a special type of sugar called keratan sulfate. Both gangliosides and keratan sulfate may accumulate in galactosialidosis.

In addition to its protective functions, PPCA has at least three enzymatic activities of its own, including the ability to cleave (break apart), or hydrolyze, other proteins. Some of the neurological abnormalities that develop with galactosialidosis may be due to the loss of this activity, particularly PPCAs ability to cleave endothelin-1. This peptide is overabundant and abnormally distributed in the neurons and glial cells of the brain and spinal cord of individuals with galactosialidosis.

Genetic profile

Galactosialidosis is an autosomal recessive disorder that can be caused by any one of a number of different mutations in the gene encoding PPCA. This gene is known as PPGB, for beta-galactosidase protective protein. The disorder is autosomal since the PPGB gene is located on chromosome 20, rather than on the X or Y sex chromosomes. The disorder is recessive because it only develops when both genes encoding PPCA, one inherited from each parent, are abnormal. However, the two defective genes do not need to carry the same mutations. If the two mutations are identical, the individual is a homozygote. If the two mutations are different, the affected individual is called a compound heterozygote.

PPCA mutations

The type of galactosialidosis and the severity of the symptoms depend on the specific mutations that are present. In general, the higher the level of PPCA activity in the lysosomes, the milder the characteristics of galactosialidosis, and the later the onset of disease.

With some mutations of the PPGB gene, very little of the precursor protein to PPCA is produced and there is no mature PPCA in the lysosome. With other mutations, the precursor protein may not be correctly processed into mature protein. Some individuals with severe early-infantile galactosialidosis carry mutations that prevent precursor PPCA from being targeted to the lysosome. The lysosomes of these individuals have no PPCA.

In contrast, individuals with the late-infantile form of galactosialidosis carry at least one mutant PPGB gene whose product can reach the lysosome. However, there may be only a small amount of PPCA in the lysosome; the PPCA may lack enzymatic activity; the PPCA chains may be unable to combine to form the normal twochained form; or the PPCA may be degraded rapidly. Nevertheless, with these mutations, the symptoms of galactosialidosis are mild and progress very slowly with no mental retardation.

Other identified mutations prevent the PPCA molecules from folding properly or shorten the PPCA protein so that it cannot form a complex with the other enzymes.

Compound heterozygotes, with different mutations in their PPGB genes, usually have symptoms that are intermediate in severity between those of homozygotes for each of the two mutations. Occasionally, the symptoms of a compound heterozygote may be more mild than those of either homozygote, because the two mutant PPCA proteins can complement, or compensate, for each other's abnormalities.

Demographics

As an autosomal recessive disorder, neuraminidase deficiency with beta-galactosidase deficiency occurs with equal frequency among males and females. Since it requires two defective copies of the PPGB gene, one inherited from each parent, it is much more common in the offspring of couples who are related to each other (consanguineous marriages), such as first or second cousins.

Galactosialidosis appears to occur with the highest frequency among Japanese. The juvenile/adult form is particularly common among Japanese and specific mutations in the PPGB gene occur with a high frequency in this population.