Test ID: NPDMS
Niemann-Pick Disease, Types A and B, Full Gene Analysis

Confirmation of a diagnosis of Niemann-Pick disease type A or B 

Carrier screening in cases where there is a family history of Niemann-Pick disease type A or B, but disease-causing mutations have not been identified in an affected individual

Testing includes full gene sequencing of the SMPD1 gene.

• Molecular Genetics-Biochemical Disorders Patient Information Sheet
• Informed Consent for Genetic Testing

Polymerase Chain Reaction (PCR) Followed by DNA Sequence Analysis

(PCR is utilized pursuant to a license agreement with Roche Molecular Systems, Inc.)

Forms:

1. Molecular Genetics-Biochemical Disorders Patient Information Sheet (Supply T527) in Special Instructions

2. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (Supply T576) is available in Special Instructions.

Specimen must arrive within 96 hours of collection.

Submit only 1 of the following specimens:

Preferred

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:        

1. Invert several times to mix blood.

2. Send specimen in original tube.

Specimen Stability Information: Ambient (preferred)/Refrigerated/Frozen

Specimen Type: Cultured fibroblasts

Container/Tube: T-75 or T-25 flask        

Specimen Volume: 1 full T-75 or 2 full T-25 flasks

Specimen Stability Information: Ambient (preferred)/Refrigerated <24 hours

Specimen Type: Skin biopsy

Container/Tube: Sterile container with any standard cell culture media (eg, minimal essential media, RPMI 1640). The solution should be supplemented with 1% penicillin and streptomycin. Tubes can be supplied upon request (Eagle's minimum essential medium with 1% penicillin and streptomycin [Supply T115]).

Specimen Volume: 4-mm punch                                                       

Specimen Stability Information: Refrigerated (preferred)/Ambient

Acceptable:

Specimen Type: Blood spot

Container/Tube: Whatman Protein Saver 903 Paper

Specimen Volume: 5 blood spots

Collection Instructions:

1. Let blood dry on the filter paper at ambient temperature in a horizontal position for 3 hours.

2. Do not expose specimen to heat or direct sunlight.

3. Do not stack wet specimens.

4. Keep specimen dry.

Specimen Stability Information: Ambient (preferred)/Refrigerated

Niemann-Pick disease (types A and B) is an autosomal recessive lysosomal storage disease caused by a deficiency of the enzyme acid sphingomyelinase. The clinical presentation of type A disease is characterized by jaundice, progressive loss of motor skills, feeding difficulties, learning disabilities, and hepatosplenomegaly. Death usually occurs by age 3. Type B disease is generally milder, though variable in its clinical presentation. Most type B patients do not have neurologic involvement and survive to adulthood.

Mutations in the SMPD1 gene are responsible for the clinical manifestations of Niemann-Pick disease types A and B. Although this disease is panethnic, it has a significantly higher frequency in individuals of Ashkenazi Jewish and Northern African descent. The carrier rate for type A in the Ashkenazi Jewish population is 1/90. There are 3 common mutations in the Ashkenazi Jewish population: L302P, R496L, and fsP330, which account for approximately 97% of mutant alleles in this population. The deltaR608 mutation accounts for approximately 90% of the type B mutant alleles in individuals from the Maghreb region of North Africa and 100% of the mutant alleles in Gran Canaria Island.

Targeted mutation analysis (NPD/85322 Niemann-Pick Disease, Types A and B, Mutation Analysis) for these 4 mutations is thought to detect 90% of the mutant alleles leading to acid sphingomyelinase deficiency. Full gene analysis of the SMPD1 gene should be utilized to detect private mutations in individuals with abnormal enzyme activity and 1 or no mutations detected by the panel of common mutations (NPD/85322).

NPD/85322 Niemann-Pick Disease, Types A and B, Mutation Analysis is also the recommended test for carrier screening. For diagnostic testing, SPHT/8481 Sphingomyelinase, Fibroblasts or LDSBS/89406 Lysosomal Disorders Screen, Blood Spot should be performed prior to targeted mutation analysis or full gene analysis.

An interpretive report will be provided.

An interpretive report will be provided.

A small percentage of individuals who are carriers or have a diagnosis of Niemann-Pick disease type A or B may have a mutation that is not identified by this method (eg, large genomic deletions, promoter mutations). The absence of a mutation, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of Niemann-Pick disease type A or B. For carrier testing, it is important to first document the presence of an SMPD1 gene mutation in an affected family member; however, when no mutations are detected by NPD/85322 Niemann-Pick Disease, Types A and B, Mutation Analysis, this test (NPDMS) should be ordered.

In some cases, DNA alterations of undetermined significance may be identified.

Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.

A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

1. Schuchman EH: The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. J Inherit Metab Dis 2007 Oct;30(5):654-663

2. McGovern MM, Schuchman EH: Acid sphingomyelinase deficiency. In GeneReviews (Internet). Edited by RA Pagon, TD Bird, CR Dolan, et al. University of Washington, Seattle. 1993-2006 Dec 07 (updated 2009 June 25)

DNA sequence analysis is utilized to test for the presence of mutations in all 6 coding exons of the SMPD1 gene.(Unpublished Mayo method)

Thursday; 10 am

81479-Unlisted molecular pathology procedure