Neuraminidase Deficiency with... Health Article

Signs and symptoms

Although the features of galactosialidosis vary greatly, they are very similar to those of neuraminidase deficiency (sialidosis). These progressive symptoms include red spots in the eyes, known as cherry-red macules. Eventually, the corneas may be become cloudy and cataracts and blindness may develop. Hearing loss is also common with galactosialidosis.

Myoclonus are sudden involuntary muscle contractions, which may eventually develop into myoclonic seizures. The myoclonus may become debilitating. Tremors and various other neurological conditions may develop. There may be a progressive loss of muscle coordination, called ataxia, and walking and standing may become increasingly difficult.

Small red skin lesions called angiokeratoma are signs of galactosialidosis. Swollen liver and spleen (hepatosplenomegaly) may develop. Cardiac disease can be one of the major consequences of the disorder.

Symptoms of the more severe forms of galactosialidosis include coarse or malformed facial features and a variety of skeletal malformations (dysostosis multiplex), including short stature. Mental retardation also may be present. Galactosialidosis is one cause of nonimmune hydrops fetalis, the excessive accumulation of fluid in the fetus.

Early-infantile onset

Some findings of the disorder, including facial and skeletal abnormalities, may be apparent at birth. Skeletal x rays may be used to diagnose dysostosis multiplex. Magnetic resonance imaging (MRI) or computer tomography (CT) scans may be used to determine brain atrophy. An electroencephalogram (EEG) may indicate epileptic activity.

Neuraminidase activity

Typically, neuraminidase deficiency is diagnosed by measuring the activity of the enzyme in cultures of fibroblast cells (connective tissue cells) that have been grown from cells obtained by a skin biopsy. Neuraminidase activity usually is measured by testing the ability of fibroblast cell preparations to hydrolyze, or cleave, a synthetic compound such as 4-methylumbelliferyl-D-N-acetylneuraminic acid. Hydrolysis by neuraminidase liberates 4-methylumbelliferone, which is a compound with a fluorescence that can be measured accurately. The normal range of neuraminidase activity in fibroblasts is 95–653 picomoles per min per mg of protein. With galactosialidosis, neuraminidase activity in fibroblasts may be less than 4% of normal.

Beta-galactosidase activity

Beta-galactosidase activity in blood cells is measured in much the same way as neuraminidase activity in fibroblasts. Using the substrate 4-methylumbelliferyl-alpha-D-galactopyranoside, the fluorescence of 4-methylumbelliferone that is liberated through the action of beta-galactosidase is measured.

In severe forms of galactosialidosis, beta-galactosidase activity is less than 15% of normal and neuraminidase activity is less than 1% of normal. The combination of low beta-galactosidase and low neuraminidase in fibroblasts, with normal levels of other lysosomal enzymes, is diagnostic for galactosialidosis.

PPCA activity

The enzymatic activity of PPCA also can be measured in fibroblasts. In the early-infantile form of galactosialidosis, PPCA activity may be completely lacking. A small amount of PPCA activity (2–5% of normal) usually is present in the lysosomes of individuals with other forms of galactosialidosis. The highest levels of PPCA activity are associated with the least severe and later-onset forms of the disorder. Carriers with a single mutated PPGB gene may have only half of the normal level of PPCA activity, although they are without symptoms of the disorder.

Histology

In neuraminidase deficiency with beta-galactosidase deficiency, the lysosomes fill with sialyloligosaccharides and sialylglycopeptides (partially degraded proteins with sialyloligosaccharides still attached). These swollen lysosomes may form inclusion bodies and give cells a vacuolated appearance that is diagnostic of lysosomal storage disease.

Neuraminidase deficiency may be diagnosed by histological, or microscopic, examination of a number of different types of cells that may show this cytosolic vacuolation. These cells include the Kupffer cells of the liver, lymphocytes (white blood cells that produce antibodies), bone marrow cells, epithelial skin cells, fibroblasts, and Schwann cells, which form the myelin sheaths of nerve fibers.

Urine tests

Neuraminidase deficiency may be diagnosed by screening the urine for the presence of sialyloligosaccharides, using chromatography to separate the components of the urine on the basis of size and charge. In unaffected individuals, sialyloligosaccharides are cleaved by neuraminidase and, therefore, are present in the urine in only very low amounts. With neuraminidase deficiency, urine levels of sialyloligosaccharides may be three to five times higher than normal.

Sialylglycopeptides can be detected in the urine under conditions of neuraminidase deficiency. In neuraminidase deficiency with beta-galactosidase deficiency, keratan sulfate, which accumulates because of the low activity of GALNS, also can be identified in the urine.