Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (431 page)

Wenger DA, Rafi MA, Luzi P, et al. Krabbe disease: genetic aspects and progress toward therapy.
Molec Gen Metab.
2000;
70
:1–9.

Wenger DA, Sattler M, Hiatt W. Globoid cell leukodystrophy: deficiency of lactosyl ceramide betagalactosidase.
Proc Nat Acad Sci U S A.
1974;71:854–857.

MAROTEAUX-LAMY SYNDROME (ARYLSULFATASE B DEFICIENCY; MUCOPOLYSACCHARIDOSIS VI)

MIM #253200

   Definition

Mucopolysaccharidosis type VI is an autosomal recessive lysosomal storage disorder resulting from a deficiency of
N
-acetylgalactosamine-4-sulfatase (arylsulfatase B; ARSB)

   Who Should Be Suspected?

Clinical features and severity are variable but usually include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities, and facial dysmorphism. Intelligence is usually normal.

   Relevant Tests and Diagnostic Value

   Measurement of residual
N
-acetylgalactosamine-4-sulfatase in fibroblasts

   Sequence analysis of the
ARSB
gene (5q14.1)

Suggested Reading

Litjens T, Brooks DA, Peters C, et al. Identification, expression, and biochemical characterization of N-acetylgalactosamine-4-sulfatase mutations and relationship with clinical phenotype in MPS-VI patients.
Am J Hum Genet.
1996;58:1127–1134.

METACHROMATIC LEUKODYSTROPHY (ARYLSULFATASE A DEFICIENCY)

MIM #250100

   Definition

Metachromatic leukodystrophy is a rare autosomal recessive lipidosis caused by a deficiency of arylsulfatase A (ARSA). There are infantile and adult forms caused by the inability to degrade sphingolipid, sulfatide, or galactosylceramide that results in accumulation of sulfatide. The metachromatic leukodystrophies comprise several allelic disorders, including late infantile, juvenile, and adult forms; partial cerebroside sulfate deficiency; and pseudoarylsulfatase A deficiency; and two nonallelic forms: metachromatic leukodystrophy due to saposin B deficiency and multiple sulfatase deficiency or juvenile sulfatidosis, a disorder that combines features of a mucopolysaccharidosis with those of metachromatic leukodystrophy.

   Relevant Tests

Biochemical testing

   
ARSA activity
: Measured in leukocytes or cultured fibroblasts or amniocytes; <10% enzyme activity compared to normal controls is suggestive of metachromatic leukodystrophy. However, this test is not diagnostic due to possible ARSA pseudodeficiency that is 5–20% of normal controls. Pseudodeficiency is difficult to distinguish from true ARSA deficiency by biochemical testing. Therefore, one of the other tests needs to be used for diagnosis confirmation.

   
Urinary excretion of sulfatides
: Measured by thin-layer chromatography, HPLC, and/or mass spectrometric techniques. Amount of sulfatides in metachromatic leukodystrophy is 10- to 100-fold higher than in controls. Urinary sulfatide excretion is referenced on the basis of urinary excretion in 24 hours or to another urinary component such as creatinine (which is a function of muscle mass) or sphingomyelin (newer approach).

   
Metachromatic lipid deposits in a nerve or brain biopsy
: Highly invasive approach used only in exceptional circumstances (such as confirmation of a prenatal diagnosis of
metachromatic leukodystrophy following pregnancy termination)
.

Molecular methods

   
Targeted mutation analysis
: Four most commonly tested mutations in the ARSA gene (22q13.33) are c.459 + 1G>A, c.1204 + 1G>A, Pro426Leu, and Ile179Ser. These four mutations account for 25–50% of the ARSA mutations in European and North American populations. Pseudodeficiency variants (ARSA-PD) are common polymorphisms that result in lower than average but sufficient enzyme activity to avoid sulfatide accumulation and thus do not cause MLD. The two most commonly tested ARSA-PD mutations are missense mutations: c.1049A>G mutation and the polyadenylation-site mutation c.1524 + 96A>G.