Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (430 page)

   Sequence analysis of the IDUA gene.

Suggested Reading

Hall CW, Liebaers I, Di Natale P, et al. Enzymic diagnosis of the genetic mucopolysaccharide storage disorders.
Methods Enzymol.
1978;50:439–456.

I-CELL DISEASE (MUCOLIPIDOSIS II)

MIM #252500

   Definition

I-cell disease is an autosomal recessive disorder resulting from mutations in GNPTAB gene (12q23.2) causing deficient activity of
N
-acetylglucosamine1-phosphotransferase. This results in abnormal lysosomal enzyme localization and phosphorylation and buildup of lysosomal substrates.

   Who Should Be Suspected?

Clinical features resemble Hurler syndrome, but without corneal changes or increased mucopolysaccharides in urine. Congenital dislocation of the hip, thoracic deformities, hernia, and hyperplastic gums are evident soon after birth.

   Relevant Test and Diagnostic Value

Sequence analysis of the
N
-acetylglucosamine-1-phosphotransferase gene.

Suggested Readings

Canfield WM, Bao M, Pan J, et al. Mucolipidosis II and mucolipidosis IIIA are caused by mutations in the GlcNAc-phosphotransferase alpha/beta gene on chromosome 12p. (Abstract.)
Am J Hum Genet.
1998;63:A15.

Tiede S, Storch S, Lubke T, et al. Mucolipidosis II is caused by mutations in GNPTA encoding the alpha/beta GlcNAc-1-phosphotransferase.
Nature Med.
2005;11:1109–1112.

KRABBE DISEASE (GLOBOID CELL LEUKODYSTROPHY; GALACTOCEREBROSIDASE DEFICIENCY)

MIM #234200

   Definition

Krabbe disease is an autosomal recessive disorder caused by mutations in the galactosylceramidase (
GALC
) gene (14q31) with pathology involving the white matter of the CNS as well as abnormalities of the peripheral nervous system. Although most patients present within the first 6 months of life (“infantile” or “classic” disease); others present later in life, including in adulthood.

   Relevant Tests and Diagnostic Value

Biochemical testing—enzyme assay
: GALC activity is deficient (0–5% of normal) in leukocytes isolated from whole heparinized blood or in cultured skin fibroblasts. However, measuring GALC enzyme activity for carrier testing is unreliable because of the wide range of enzymatic activities observed in carriers and noncarriers.

Molecular testing

   Targeted mutation analysis: The 809G>A mutation is often found in individuals with the late-onset form of Krabbe disease.

   Sequence analysis of the entire coding region, intron–exon boundaries, and 5′-untranslated region: Detects 100% of the disease-causing mutations and polymorphisms.

   Deletion/duplication analysis: Deletions involving single exons and multiple exons have been detected. A 30-kb deletion accounts for approximately 45% of the mutant alleles in individuals of European ancestry and 35% of the mutant alleles in individuals of Mexican heritage with infantile Krabbe disease.

   Other Considerations

Conjunctival biopsy shows characteristic ballooned Schwann cells. Brain biopsy (massive infiltration of unique multinucleated inclusion-containing globoid cells in white matter due to accumulation of galactosylceramide; also diffuse loss of myelin, severe astrocytic gliosis).

CSF protein electrophoresis shows increased albumin and α-globulin and decreased β- and γ-globulin (same as in metachromatic leukodystrophy).

Suggested Readings

Svennerholm L, Vanier, MT, Hakansson G, et al. Use of leukocytes in diagnosis of Krabbe disease and detection of carriers.
Clin Chim Acta.
1981;112:333–342.