Clinical Information

Lysosomal disorders (LD) are a diverse group of inherited diseases characterized by the intracellular accumulation of macromolecules leading to cell damage and organ dysfunction. Approximately 50 LD have been described with a wide phenotypic spectrum and ranging in severity from neonatal lethal to later onset milder variants.

Although classification is not always straightforward, LD are generally categorized according to the type of storage material that accumulates in the cells and tissues. Major categories include mucopolysaccharidoses, oligosaccharidoses, mucolipidoses, and sphingolipidoses. In many cases, accumulating analytes can be detected in urine. Screening for these disorders typically begins with an analysis to detect disease-specific metabolite patterns or profiles indicative of a LD. The combined analysis of disease-specific markers for LD in multiple tests can allow for the identification of additional disorders that may not be characterized using any of the single tests alone.

Disorders detectable by this approach include the oligosaccharidoses: alpha-mannosidosis, aspartylglucosaminuria, beta-mannosidosis, fucosidosis, Schindler disease, and sialidosis; the sphingolipidoses: GM1 gangliosidosis, Sandhoff disease, galactosialidosis, saposin B deficiency, metachromatic leukodystrophy, multiple sulfatase deficiency, Fabry disease, and Gaucher disease; the mucopolysaccharidoses (MPS) excluding MPS IX (hyaluronidase deficiency); the glycogen storage disorder Pompe disease, free sialic storage disorder, and the mucolipidoses types II and III. Additionally, other disorders such as congenital disorder of glycosylation (CDG) type IIb and deglycosylation disorders such as NGLY1-CDG may also be detected.

The MPS are a subset of lysosomal disorders caused by the deficiency of any one of the enzymes involved in the stepwise degradation of dermatan sulfate, heparan sulfate, keratan sulfate, or chondroitin sulfate (glycosaminoglycans: GAG). Undegraded or partially degraded GAG (also called mucopolysaccharides) are stored in lysosomes and excreted in the urine. Accumulation of GAG in lysosomes interferes with normal functioning of cells, tissues, and organs resulting in the clinical features observed in MPS disorders. There are 11 known enzyme deficiencies that result in MPS. In addition, abnormal GAG storage is observed in multiple sulfatase deficiency and in I-cell disease. Finally, an abnormal excretion of GAG in urine is observed occasionally in other disorders including active bone diseases, connective tissue disease, hypothyroidism, urinary dysfunction, and oligosaccharidoses.

The oligosaccharidoses (glycoproteinoses) are a subset of lysosomal disorders caused by the deficiency of any one of the lysosomal enzymes involved in the degradation of complex oligosaccharide chains. They are characterized by the abnormal accumulation of incompletely degraded oligosaccharides in cells and tissues and the corresponding increase of related free oligosaccharides in the urine. Clinical features can include bone abnormalities, coarse facial features, corneal cloudiness, organomegaly, muscle weakness, hypotonia, developmental delay, and ataxia. Age of onset ranges from early infancy to adult and can even present prenatally.

The sphingolipidoses are a subset of lysosomal disorders caused by a defect in any one of the enzymes that degrade complex ceramide containing lipids. They are characterized by the excessive accumulation of sphingolipids in the tissues, particularly in the central nervous system, resulting in progressive neurodegeneration and developmental regression. In 2 conditions, Fabry disease and Gaucher disease type I, there is only systemic involvement. In many cases, sphingolipidoses can be detected by through oligosaccharide analysis in urine.

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 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 deficiency, sialidosis, and galactosialidosis.

Because of the similarity of features across disorders and their phenotypic variability, clinical diagnosis of LD can be challenging; therefore, the combined analysis of multiple urine screening tests is an important tool for the initial workup of an individual suspected of having a lysosomal disorder. Abnormal results can be followed up with the appropriate enzyme or molecular analysis.