Ceramide Trihexoside/Sulfatide Accumulation in Urine Sediment, Urine
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Fabry disease is an X-linked recessive lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A (alpha-Gal A). Reduced enzyme activity results in accumulation of glycosphingolipids in the lysosomes throughout the body, in particular, the kidney, heart, and brain. Severity and onset of symptoms are dependent on the residual enzyme activity. Males with <1% activity have the classic form of Fabry disease. Symptoms can appear in childhood or adolescence and usually include acroparesthesias (pain crises), multiple angiokeratomas, reduced or absent sweating, and corneal opacity. Renal insufficiency, leading to end-stage renal disease and cardiac and cerebrovascular disease, generally occur in middle age. Males with >1% activity may present with either of 2 variant forms of Fabry disease (renal or cardiac) with onset of symptoms later in life. Individuals with the renal variant typically present in the third decade of life with the development of renal insufficiency and, ultimately, end-stage renal disease. Individuals with the renal variant may or may not share other symptoms with the classic form of Fabry disease. Individuals with the cardiac variant are often asymptomatic until they present with cardiac findings such as cardiomyopathy, mitral insufficiency, or conduction abnormalities in the fourth decade. The cardiac variant is not associated with renal failure. Variant forms of Fabry disease may be underdiagnosed. Females who are carriers of Fabry disease can have clinical presentations ranging from asymptomatic to severely affected, and may have alpha-Gal A activity in the normal range.
Individuals with Fabry disease, regardless of the severity of symptoms, may show an increased excretion of ceramide trihexoside in urine.
Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of the arylsulfatase A enzyme, which leads to the accumulation of various sulfatides in the brain, nervous system, and visceral organs, including the kidney and gallbladder. The 3 clinical forms of MLD are late-infantile, juvenile, and adult, depending on age of onset. All result in progressive neurologic changes and leukodystrophy demonstrated on magnetic resonance imaging. Late-infantile MLD is the most common (50%-60% of cases) and typically presents between 1 and 2 years of age with hypotonia, clumsiness, diminished reflexes, and slurred speech. Progressive neurodegeneration occurs with a typical disease course of 3 to 10 years. Juvenile MLD (20%-30% of cases) is characterized by onset between 4 and 14 years. Typical presenting features are behavior problems, declining school performance, clumsiness, and slurred speech. Neurodegeneration occurs at a somewhat slower and more variable rate than the late-infantile form. Adult MLD (15%-20% of cases) has an onset after puberty and can be as late as the fourth or fifth decade. Presenting features are often behavior and personality changes, including psychiatric symptoms; clumsiness, neurologic symptoms, and seizures are also common. The disease course has variable progression and may occur over 2 to 3 decades.
Individuals with MLD typically show an increased excretion of sulfatides in urine.
Extremely low arylsulfatase A levels have been found in some clinically normal parents and other relatives of MLD patients. These individuals do not have metachromatic deposits in peripheral nerve tissues, and their urine content of sulfatide is normal. 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 polymorphism in the arylsulfatase A gene, which leads to low expression of the enzyme (5%-20% of normal). These patients can be difficult to differentiate from actual MLD patients.
As an aid in identifying patients with Fabry disease
As an aid in identifying patients with metachromatic leukodystrophy
No evidence of ceramide trihexosides or sulfatide accumulation suggests normal enzyme activities.
Evidence of ceramide trihexoside accumulation suggests decreased or deficient alpha-galactosidase activity. Follow-up testing with the specific enzyme assay is recommended: AGA / Alpha-Galactosidase, Leukocytes; AGABS / Alpha-Galactosidase, Blood Spot; and AGAS / Alpha-Galactosidase, Serum.
Evidence of sulfatide accumulation suggests decreased or deficient arylsulfatase A activity. Follow-up with the specific enzyme assay is recommended: ARSAW / Arylsulfatase A, Leukocytes, ARST / Arylsulfatase A, Fibroblasts; and ARSU / Arylsulfatase A, Urine.
See Fabry Disease Testing Algorithm in Special Instructions.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Specific enzymatic assays should be used to confirm positive results.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
No evidence of ceramide trihexoside/sulfatide accumulation
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Eng CM, Ioannou YA, Desnick RJ: Chapter 150: Alpha-galactosidase A deficiency: Fabry disease. In Scriver's The Online Metabolic and Molecular Basis of Inherited Disease (OMMBID). Edited by D Valle, AL Beaudet, B Vogelstein, et al. McGraw-Hill Companies, Inc.
2. Enns GM, Steiner RD, Cowan TM: Metachromatic leukodystrophy. In Pediatric Endocrinology and Inborn Errors of Metabolism. Edited by K Sarafoflou, GF Hoffmann, KS Roth, et al. McGraw-Hill Companies, 2009, pp 742-743
3. De Schoenmakere G, Poppe B, Wuyts B, et al: Two-tier approach for the detection of alpha-galactosidase A deficiency in kidney transplant recipients. Nephrol Dial Transplant 2008;23:4044-4048
4. Mehta A, Hughes DA: Fabry Disease. GeneReviews. Edited by RA Pagon, TD Bird, CR Dolan, et al. University of Washington, Seattle. Last updated March 2011
5. Spada M, Pagliardini S, Yasuda M, et al: High incidence of later-onset Fabry disease revealed by newborn screening. Am J Hum Genet 2006;79:31-40
6. von Figura K, Gieselmann V, Jaeken J: Chapter 148: Metachromatic Leukodystrophy. In Scriver's The Online Metabolic and Molecular Basis of Inherited Disease (OMMBID). Edited by D Valle, AL Beaudet, B Vogelstein, et al. McGraw-Hill Companies, Inc.