Clinical Information

Urinary excretion of ceramide trihexosides (CT) can be suggestive of Fabry disease, while excretion of sulfatide with or without CT can be suggestive of metachromatic leukodystrophy, multiple sulfatase deficiency, mucolipidosis II (I-cell disease), or saposin B deficiency.

Fabry disease is an X-linked recessive lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A (alpha-Gal A). Affected individuals accumulate glycosphingolipids in the lysosomes throughout the body, particularly in the kidney, heart, and brain. Severity and onset of symptoms are dependent on the amount of residual enzyme activity. Symptoms may include acroparesthesias (pain crises), multiple angiokeratomas, reduced or absent sweating, corneal opacity, renal insufficiency leading to kidney failure, and cardiac and cerebrovascular disease. There are renal and cardiac variant forms of Fabry disease that may be underdiagnosed. Female patients who are carriers of Fabry disease can have clinical presentations ranging from asymptomatic to severely affected, and they may have alpha-Gal A activity in the normal range. Regardless of the severity of symptoms, individuals with Fabry disease may show an increased excretion of CT in urine.

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder most frequently caused by a deficiency of the arylsulfatase A enzyme. Various sulfatides accumulate in the brain, nervous system, and visceral organs, including the kidney and gallbladder and are excreted in the urine. Based on age of onset, the 3 clinical forms of MLD are late-infantile, juvenile, and adult, with late-infantile being the most common. All result in progressive neurologic changes and leukodystrophy demonstrated on magnetic resonance imaging. Symptoms may include hypotonia, clumsiness, diminished reflexes, slurred speech, behavioral problems, and personality changes. Individuals with MLD show an increased urinary excretion of sulfatides without CT.

Saposin B deficiency is a rare condition with clinical features that mimic MLD; however, individuals with saposin B deficiency have normal arylsulfatase A activity. Individuals with saposin B deficiency typically have an increased urinary excretion of both sulfatides and CT.

Low arylsulfatase A activity has been found in some clinically normal parents and other relatives of MLD patients. Individuals with this "pseudodeficiency" have been recognized with increasing frequency among patients with other apparently unrelated neurologic conditions as well as among the general population. This has been associated with a fairly common alteration in the arylsulfatase A gene (ARSA), which leads to low expression of the enzyme (5%-20% of normal). These individuals do not have metachromatic deposits in peripheral nerve tissues, and their urine sulfatides content is normal.

Multiple sulfatase deficiency (MSD) is a rare autosomal recessive disorder caused by a defect in SUMF1, which is required for post-translational activation of the family of 17 sulfatase enzymes, including arylsulfatase A and B. The clinical features of MSD include those of late-infantile MLD, dysmorphic features similar to the mucopolysaccharidoses, and ichthyosis as seen in steroid sulfatase deficiency. Individuals with MSD typically have an increased urinary excretion of sulfatides as well as increased urinary glycosaminoglycans (MPSQU / Mucopolysaccharides Quantitative, Random, Urine).

Mucolipidosis II, also known as I-cell disease, is a rare autosomal recessive disorder with features of both mucopolysaccharidoses and sphingolipidoses. I-cell disease is a progressive disorder characterized by congenital or early infantile manifestations including coarse facial features, short stature, skeletal anomalies, cardio- and hepatomegaly, and developmental delays. Individuals with I-cell disease have abnormal oligosaccharide profiles (OLIGU / Oligosaccharide Screen, Random, Urine) and may show an increased urinary excretion of both CT and sulfatides.