Neuraminidase Deficiency with... Health Article

Definition

Neuraminidase deficiency with beta-galactosidase deficiency, commonly-known as galactosialidosis, is a rare inherited metabolic disorder with multiple symptoms that can include skeletal abnormalities, mental retardation, and progressive neurological degeneration.

Description

Neuraminidase deficiency with beta-galactosidase deficiency, or galactosialidosis, is a very rare genetic disorder with progressive signs and symptoms that are almost identical to those of neuraminidase deficiency alone, a disorder that is often called sialidosis. These symptoms can include skeletal and facial abnormalities, seizures, vision and hearing loss, cardiac and kidney problems, and mental retardation. However, as with sialidosis, the severity of the symptoms of galactosialidosis vary greatly.

Galactosialidosis is also known as Goldberg syndrome, after M. F. Goldberg and colleagues who first described the disorder in 1971. The disorder is also sometimes called protective protein/cathepsin A (or PPCA) deficiency, deficiency of lysosomal protective protein, or deficiency of cathepsin A.

Galactosialidosis is caused by a mutation, or change, in the gene encoding an enzyme called protective protein/cathepsin A (PPCA). PPCA forms a very large multi-enzyme complex with three other enzymes: beta-galactosidase, N-acetylgalactosamine-6-sulfate sulfatase (GALNS), and alpha-N-acetylneuraminidase. The latter enzyme is commonly referred to as neuraminidase or sialidase. Whereas sialidosis is caused by a mutation in the gene encoding neuraminidase, a mutation in the gene encoding PPCA can affect the activities of all of the enzymes in the complex. However neuraminidase is the enzyme that is most dependent on PPCA. Without functional PPCA, there is little or no neuraminidase activity. Although beta-galactosidase activity is reduced, a significant amount of active enzyme remains. Therefore, the symptoms of neuraminidase deficiency with beta-galactosidase deficiency are more similar to those of sialidosis than to those of beta-galactosidase deficiency. Mutations in the gene encoding beta-galactosidase can result in the disorders known as GM1-gangliosidosis (beta-galactosidosis) or Morquio B disease.

Galactosialidosis is subdivided into three types, depending on the age of onset: severe, neonatal or early-infantile; milder, late-infantile; and juvenile/adult. The juvenile/adult form is the most common. There also is an atypical form of galactosialidosis. The type and severity of the disorder depends on the specific mutation(s) present in the genes encoding PPCA.

Lysosomal storage diseases

Neuraminidase, beta-galactosidase, PPCA, and GALNS are all enzymes that function inside lysosomes. Lysosomes are membrane-bound spherical compartments or vesicles within the cytosol (fluid part) of cells. Lysosomes contain more than 50 different enzymes that are responsible for digesting, or hydrolyzing, large molecules and cellular components. These include proteins, polysaccharides (long, linear or branched chains of sugars), and lipids, which are large, insoluble biomolecules that are usually built from fatty acids. The smaller breakdown products from the lysosome are recycled back to the cytosol.

Galactosialidosis is one of at least 41 genetically distinct lysosomal storage diseases. In these disorders, some of the macromolecules in the lysosome cannot be degraded. Instead, these large molecules, or their partial-breakdown products, accumulate, and the lysosomes swell to the point that cellular function is disrupted.

Neuraminidase deficiency

Neuraminidase removes sialic acid from the ends of oligosaccharides, which are relatively short chains of sugars. Sialic acid, also known as N-acetylneuraminic acid, is a type of sugar molecule that often is at an end of an oligosaccharide. These oligosaccharides with terminal sialic acid residues may be attached to proteins, called glycoproteins.

Neuraminidase deficiency prevents the breakdown of oligosaccharides and glycoproteins that contain sialic acid and leads to the accumulation and excretion of these substances. It also can lead to the production of abnormal proteins. Following protein synthesis, some lysosomal enzymes reach the lysosome in an inactive form and require further processing for activation. One such processing step is the neuraminidase-catalyzed removal of sialic acid residues from oligosaccharides on enzymes. Thus, under conditions of neuraminidase deficiency, other lysosomal enzymes may not behave properly.