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Identifying patients with Fabry disease
Identifying patients with metachromatic leukodystrophy
Identifying patients with saposin B deficiency
Identifying patients with multiple sulfatase deficiency
Identifying patients with mucolipidosis II (I-cell disease)
See Fabry Disease Testing Algorithm in Special Instructions.
Urinary excretion of ceramide trihexosides can be suggestive of Fabry disease, while excretion of sulfatide with or without ceramide trihexosides 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). 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. Symptoms may include acroparesthesias (pain crises), multiple angiokeratomas, reduced or absent sweating, corneal opacity, renal insufficiency leading to end-stage renal disease, and cardiac and cerebrovascular disease. There are renal and cardiac variant forms of Fabry disease that may be underdiagnosed. Females 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. 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. Symptoms may include hypotonia, clumsiness, diminished reflexes, slurred speech, behavioral problems, and personality changes. Individuals with MLD typically show an increased excretion of sulfatides in urine.
Low arylsulfatase A activity has 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 sulfatides 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).
Saposin B deficiency is a rare autosomal recessive disorder with symptoms that mimic MLD. Age of onset dictates the clinical subtypes of saposin B deficiency. Individuals with saposin B deficiency have normal arylsulfatase A activity. In urine, individuals with saposin B deficiency have an increased excretion of sulfatides and may also show increased excretion of ceramide trihexosides.
Multiple sulfatase deficiency (MSD) is another rare autosomal recessive disorder that mimics the symptoms of MLD. In addition, individuals with MSD also may have clinical manifestations that resemble mucopolysaccharidoses. MSD results in deficiencies in all sulfatases including arylsulfatase A and B. Individuals with MSD have an increased excretion of sulfatides in their urine.
Mucolipidosis II, also known as I-cell disease, is a rare autosomal recessive disorder with features of both mucopolysaccharidoses and sphingolipidoses. It is characterized by congenital or early infantile manifestations including coarse facial features, short stature, skeletal anomalies, cardio- and hepatomegaly, and developmental delays. This is a progressive disorder and death typically occurs in the first decade of life. Individuals with I-cell disease typically show an increased excretion of ceramide trihexosides and sulfatides in urine.
An interpretive report will be provided.
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
-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
-ARSU / Arylsulfatase A, 24 Hour, Urine
To exclude multiple sulfatase deficiency (MSD), simultaneous determination of ARSB / Arylsulfatase B, Fibroblasts and I2SW / Iduronate-2-sulfatase, Whole Blood (or I2SBS / Iduronate-2-sulfatase, Blood Spot) is recommended.
Evidence of both ceramide trihexoside and sulfatide accumulation suggests diagnosis of mucolipidosis II (I-cell disease) or saposin B deficiency. Follow-up testing to rule-out I-cell disease may include:
-NAGS / Hexosaminidase A and Total Hexosaminidase, Serum
-AGAS / Alpha-Galactosidase, Serum, or ANAS / Alpha-N-Acetylglucosaminidase, Serum.
Molecular genetic testing is required to confirm saposin B deficiency.
See Fabry Disease Testing Algorithm in Special Instructions.
Specific enzymatic assays should be used to confirm positive results.
In rare instances a normal excretion of ceramide trihexosides may be seen in individuals who are carriers of or affected with Fabry disease. If Fabry disease is clinically suspected, see Fabry Disease Testing Algorithm in Special Instructions for additional testing recommendations.
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2. Kuchar L, Ledvinova J, Hrebicek M, et al: Prosaposin deficiency and saposin B deficiency (activator-deficient metachromatic leukodystrophy): report on two patients detected by analysis of urinary sphingolipids and carrying novel PSAP gene mutations. Am J Med Genet A 2009 Feb 15;149A(4):613-621
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