Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (435 page)

Biochemical testing

   The diagnosis of NPD-C can be confirmed by demonstrating impaired exogenously supplied cholesterol esterification in cultured fibroblasts or by cytologic technique—filipin staining—to demonstrate the intracellular accumulation of cholesterol in cultured fibroblasts.

   Note: These methods are unreliable for carrier testing due to significant overlap of results between patients and controls.

Histology:
Tissue biopsies and tissue lipid analysis are now rarely needed. These tests include examination of the bone marrow, spleen, and liver, which contain foamy cells (lipid-laden macrophages); sea-blue histiocytes may be seen in the marrow in advanced cases.

Electron microscopy:
The skin, rectal neurons, liver, or brain may show polymorphous cytoplasmic bodies.

Imaging:
MRI of the brain is usually normal until the late stages of the illness. At that time, marked atrophy of the superior/anterior cerebellar vermis, thinning of the corpus callosum, and mild cerebral atrophy may be seen. Increased signal in the periatrial white matter, reflecting secondary demyelination, may also occur. Magnetic resonance spectroscopy may be more sensitive in NPD-C than standard MRI.
Molecular methods:

   Sequence analysis: Detects 80–90% of mutations in
NPC1
gene and close to all mutations in
NPC2
gene. Approximately 200 mutations have been described in NPD-C1. Most affected individuals with NPD-C1 have mutations unique to their family.

   Deletion/duplication analysis: Few partial and whole gene deletions have been reported for NPD-C1. No large insertions or deletions have been reported in NPD-C2.

   Other Considerations

Cholestatic jaundice occurs in some patients. Foamy Niemann-Pick cells and “seablue” histiocytes with distinctive histochemical and ultrastructural appearances are found in the bone marrow. In the childhood-onset form, death usually occurs at age 5–15. Adult-onset forms, with insidious onset and slower progression, have also been reported (NPD-E and -F).

Suggested Readings

Argoff CE, Kaneski CR, Blanchette-Mackie EJ, et al. Type C Niemann-Pick disease: documentation of abnormal LDL processing in lymphocytes.
Biochem Biophys Res Commun.
1990;171:38–45.

Patterson M. Niemann-Pick disease type C. In: Pagon RA, Bird TC, Dolan CR, et al., eds.
GeneReviews [Internet]
. Seattle, WA: University of Washington, Seattle; 1993–2000 Jan 26 [updated 2008 Jul 22].

SANFILIPPO TYPE A SYNDROME (HEPARAN SULFATASE DEFICIENCY; MUCOPOLYSACCHARIDOSIS IIIA)

MIM #252900

   Definition

The Sanfilippo syndrome is an autosomal recessive lysosomal storage disease due to impaired degradation of heparin sulfate caused by mutations in the gene encoding
N
-sulfoglucosamine sulfohydrolase (SGSH; 17q25,3).

   Who Should Be Suspected?

The clinical features are severe mental defect with relatively mild somatic features (moderately severe claw hand and visceromegaly, little or no corneal clouding or skeletal [e.g., vertebral] change). The presenting problem may be marked overactivity, destructive tendencies, and other behavioral aberrations in a child of 4–6 years of age. Onset of clinical features usually occurs between 2 and 6 years; severe neurologic degeneration occurs in most patients between 6 and 10 years of age, and death occurs typically during the second or third decade of life. Type A usually presents as the most severe, with earlier onset and rapid progression of symptoms and shorter survival.

   Relevant Tests and Diagnostic Value

Measurement of heparin sulfate in the urine is diagnostic.

   Other Considerations

   Mucopolysaccharidosis III includes four types, each due to the deficiency of a different enzyme: heparan
N
-sulfatase (type A); alpha-
N
-acetylglucosaminidase (type B); acetyl CoA:alpha-glucosaminide acetyltransferase (type C); and
N
-acetylglucosamine-6-sulfatase (type D).