Clinical Information

Sialic acid (SA), or N-acetyl-neuraminic acid, is a component of carbohydrates, glycoproteins, and gangliosides which are important for the human nervous system. SA can be measured in urine as free sialic acid or in a conjugated form, bound to oligosaccharides. Sialic acid disorders are a subset of lysosomal storage disorders caused by defective protein transport or enzyme deficiency that result in multisystem organ disease. Analysis of free and total sialic acid and their ratio in urine can detect the following conditions: free sialic acid storage disorder, sialuria, N-acetylneuraminate pyruvate lyase (NPL) deficiency, sialidosis, and galactosialidosis.

Free sialic acid storage disorder (FSASD) is a rare lysosomal storage disorder that is caused by a defect in sialin, a sialic acid membrane exporter also known as SLC17A5. This defect results in increased stored free sialic acid in the lysosomes. Individuals with FSASD demonstrate the hallmark feature of progressive neurologic issues such as hypotonia, cerebellar ataxia, short stature, and cognitive impairment. Brain imaging may show central hypomyelination, cerebellar atrophy, and thinning of the corpus callosum. Infants and children with more severe disease may also have coarse facial features and organomegaly, such as enlarged liver and heart. A congenital form of the disease has been reported in which patients present with nonimmune hydrops fetalis. Historically, FSASD was divided into several conditions based on early to later age at disease presentation and severity: infantile free sialic acid storage disease, intermediate severe Salla disease, and Salla disease. These conditions are now considered to represent the spectrum of FSASD. There are no approved therapies for FSASD at present. Urine sialic acid analysis will show elevated free sialic acid and a high ratio of free to total sialic acid in individuals with FSASD. FSASD is an autosomal recessive condition caused by biallelic pathogenic variants in the SLC17A5 gene.

There are two additional rare disorders that show elevated free sialic acid: sialuria and N-acetylneuraminate pyruvate lyase (NPL) deficiency. Sialuria is an autosomal recessive disorder caused by pathogenic variants in the GNE gene that results in onset of symptoms such as organomegaly and developmental delay in infancy. NPL deficiency is also inherited in an autosomal recessive manner due to pathogenic variants in the NPL gene. Individuals with NPL deficiency develop progressive cardiomyopathy and mild skeletal myopathy in childhood. There are no approved therapies for these conditions, and so treatment is supportive.

Sialidosis is caused by a deficiency of the enzyme neuraminidase which results in accumulation of sialyloligosaccharides in lysosomes. Individuals with sialidosis can present with a continuum of clinical features ranging from severe disease (type II) to a milder and more slowly progressive course (type I). These clinical features range from early developmental delay, coarse facial features, short stature, dysostosis multiplex, and hepatosplenomegaly to late onset cherry-red spot myoclonus syndrome. Seizures, hyperreflexia, and ataxia have been reported in more than 50% of later onset patients. A congenital form of the disease has been reported in which patients present with fetal hydrops or neonatal ascites. Urine sialic acid analysis will show a low ratio of free to total sialic acid in individuals with sialidosis, as they have increased excretion of conjugated SA. Analysis of urine oligosaccharides (OLIGU / Oligosaccharide Screen, Random, Urine) is also recommended for patients with a suspected diagnosis of sialidosis. Sialidosis an autosomal recessive condition caused by biallelic pathogenic variants in the NEU1 gene.

Galactosialidosis also presents with a continuum of clinical features ranging from severe and rapidly progressive disease to a milder and more slowly progressive course; clinical features of the early infantile type include fetal hydrops, edema, ascites, visceromegaly, dysostosis multiplex, coarse facies, and cherry red spot(s) in the retina. The majority of patients have milder presentations, which include ataxia, myoclonus, angiokeratoma, cognitive and neurologic decline. Urine sialic acid will show a low ratio of free to total sialic acid in individuals with galactosialidosis, as they have increased excretion of conjugated SA. Analysis of urine oligosaccharides is also recommended for patients with a suspected diagnosis of galactosialidosis. Galactosialidosis is an autosomal recessive condition caused by biallelic pathogenic variants in the CTSA gene.

Patients with an abnormal urine sialic acid result suggestive of any of the sialic acid disorders should have follow up confirmatory testing with the appropriate enzyme or molecular test.