Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (434 page)

   
Biochemical testing
: ASM enzyme activity measured in peripheral blood lymphocytes or cultured skin fibroblasts; <10% enzyme activity compared to normal controls diagnoses ASM deficiency. However, it was reported that individuals with the
SMPD1
gene mutation Q292K may have apparently normal enzymatic activity when artificial substrate is used.

   
Bone marrow examination
: Reveals lipid-laden macrophages. However, this procedure is not necessary for diagnosis and should not be performed unless specific clinical indications are present.

   
Molecular testing

   Sequence analysis of
SMPD1
detects mutations in 99% of individuals with enzymatically confirmed ASM deficiency. Over 100 mutations causing ASM deficiency have been published.

   Targeted mutation analysis

   NPD-A mutations are more prevalent in the Ashkenazi Jewish population where the combined carrier frequency for the three common
SMPD1
gene mutations is between 1:80 and 1:100. Three mutations (R496L, L302P, and fsP330) account for approximately 90% of NPD-A disease–causing alleles in individuals of Ashkenazi Jewish background.

   NPD-B mutations are panethnic. Testing for one mutation p.R608del (also known as deltaR608) may account for almost 90% of NPD-B mutant alleles in individuals from North Africa (Tunisia, Algeria, and Morocco), 100% of NPD-B mutant alleles in Gran Canaria Island, and about 20–30% of the NPD type B mutant alleles in persons of North African descent in the United States.

Suggested Readings

Brady RO, Kanfer JN, Mock MB, et al. The metabolism of sphingomyelin. II. Evidence of an enzymatic deficiency in Niemann-Pick disease.
Proc Natl Acad Sci U S A.
1966;55(2): 366–369.

McGovern MM, Schuchman EH. Acid sphingomyelinase deficiency. In: Pagon RA, Bird TC, Dolan CR, et al., eds.
GeneReviews [Internet]
. Seattle, WA: University of Washington, Seattle; 1993–2006 Dec 07 [updated 2009 Jun 25].

NIEMANN-PICK DISEASE, TYPE C (NIEMANN-PICK DISEASE WITH CHOLESTEROL ESTERIFICATION BLOCK)

MIM #257220

   Definition and Classification

Niemann-Pick disease type C (NPD-C) is an autosomal recessive lipid storage disorder caused by mutations in the
NPC1
or
NPC2
genes involved in lipid trafficking, particularly cholesterol, from late endosomes or lysosomes and characterized by progressive neurodegeneration.

   NPD type C1, which is responsible for 95% of cases of NPD-C, is caused by mutations in the
NPC1
gene (18q11.2).

   NPD type C2, which is responsible for 5% of cases of NPD-C, is caused by mutations in the
NPC2
gene (18q11.2).

In addition, the term NPD type D used in a previous edition of this book describes a genetic isolate from Nova Scotia that is biochemically and clinically indistinguishable from NPD-C and that also results from mutation of the
NPC1
gene. Therefore, the previous NPD type D currently is NPD type C1.

   Relevant Tests and Diagnostic Value