About Gaucher Disease and Acid Sphingomyelinase Deficiency (ASMD or Niemann-Pick A/B)

Gaucher disease and acid sphingomyelinase deficiency (ASMD, Niemann-Pick A and B) are rare autosomal recessive lysosomal enzyme deficiency disorders with phenotypic overlap. Both diseases are due to genetic mutations that result in enzyme deficiency and a subsequent accumulation of lysosomal material in the cells of the macrophage/monocyte lineage.1-3

 

Gaucher disease is caused by a deficiency in glucocerebrosidase (GBA) enzyme activity, encoded by the GBA gene.1  Deficiency or absence of this enzyme leads to a build-up of glycosylceramide (Gl1) and glucosylsphingosine (LysoGl1, LysoGb1) in macrophage lysosomes (Gaucher cells), giving them a crinkled tissue paper appearance.

 

ASMD is caused by mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene that results in deficiency of the enzyme acid sphingomyelinase (ASM) and a subsequent accumulation of sphingomyelin and other lipids in cells, giving them a characteristic foamy appearance (Niemann-Pick cells).1, 3-5

 

Cellular substrate accumulation eventually leads to tissue and organ damage and both diseases present with similar symptoms: anemia, thrombocytopenia, splenomegaly, and bone involvement such as bone pain, osteopenia, osteonecrosis, and fractures.1 Both diseases have a wide phenotypic spectrum with severe neuronopathic forms and chronic visceral forms. ASMD also has an intermediate chronic neurovisceral form. Some symptoms differ between diseases: skin manifestations, an atherogenic dyslipidemia, and pulmonary involvement is more commonly associated with ASMD, whereas musculoskeletal involvement is specific to Gaucher disease.2, 5, 6

 

Incidence

Prevalence of Gaucher disease Type 1 (non-neuronopathic): 1 in 50,000-100,000 in the general population, worldwide;7 and approximately 1 in 350-450 people of Ashkenazi Jewish heritage8. The incidence of ASMD is estimated at 0.5 per 100,000 births.2

Program Eligibility

The Lantern Project* offers both enzyme assays with reflex to DNA sequencing for Gaucher disease and ASMD for individual patients with:

  1. Symptoms suggestive of Gaucher disease or ASMD
  2. Presumptive positive newborn screens for either disorder

*This testing program is not appropriate for carrier testing as enzyme assay will not reliably detect carriers

About the Test

Testing algorithm:

  • Gaucher disease:
    • β-glucosidase enzyme activity, if deficient, will reflex to GBA sequencing and LysoGl1 (LysoGb1)
    • β-glucosidase enzyme activity, if normal, will reflex to acid sphingomyelinase enzyme assay and if deficient, will reflex to SMPD1 sequencing
  • ASMD:
    • Acid sphingomyelinase enzyme activity, if deficient, will reflex to SMPD1 sequencing
  • If either enzymes or sequencing have already been performed, these tests can be ordered individually
Specimen Requirements

β-glucosidase and Acid Sphingomyelinase Enzyme Assays

  • Dried blood spots are preferred, but whole blood is also acceptable.

SMPD1 and GBA Gene Sequencing

  • Dried blood spots (DBS) are preferred, but whole blood is also acceptable. A saliva sample can be used if only gene sequencing is being ordered.

Bundled Testing (Enzyme assay with reflex to sequencing and biomarker testing)

  • Dried blood spots (DBS) are preferred, but whole blood is also acceptable. A saliva sample cannot be used for enzyme assay.

 

Click Here for detailed sample instructions and required quantities.

Methodology

Enzyme Assays

  • β-glucosidase and Acid Sphingomyelinase activity is measured on dried blood spots (DBS) via Flow Injection Tandem Mass Spectrometry (FIA/MS/MS).

Biomarker Assay 

  • Glucosylsphingosine (LysoGb1) is measured on dried blood spots via Liquid Chromatography Tandem Mass Spectrometry (LC/MS/MS).

Gene Sequencing Assays

  • SMPD1 sequencing is performed utilizing long range PCR followed by NGS and analysis of all coding exons and 10bp of flanking intronic regions. This assay cannot detect variants in regions of the exome that are not covered, such as deep intronic, promoter, and enhancer regions, areas containing large numbers of tandem repeats. Copy number variation (CNV) of three exons or more is reported. Single exon CNVs can also be predicted, but reported after follow-up confirmation is performed.
  • GBA sequencing is performed using NGS and analysis of all coding exons and 10bp of flanking intronic regions. This assay cannot detect variants in regions of the exome that are not covered, such as deep intronic, promoter, and enhancer regions, areas containing large numbers of tandem repeats. Copy number variation (CNV) is assessed by MLPA.
Turn-Around-Times (TATs)

β-glucosidase and Acid Sphingomyelinase Enzyme Assays: 3 days

SMPD1 and GBA Gene Sequencing: 3 Weeks

Ordering Instructions

Other Conditions in the Lantern Project

  • To learn more about The Lantern Project, Click Here
  • To learn more about Fabry disease, Click Here
  • To learn more about Pompe disease, Click Here
  • To learn more about Mucopolysaccharidosis I (MPS I) and Other MPS Disorders, Click Here
  • To learn more about Limb-Girdle Muscular Dystrophy (LGMD) and Other Proximal Muscle Weakness, Click Here

References

  1. Baris HN, Cohen IJ, Mistry PK. Gaucher disease: the metabolic defect, pathophysiology, phenotypes and natural history. Pediatr Endocrinol Rev. 2014;12:72-81.
  2. McGovern MM, Avetisyan R, Sanson BJ, Lidove O. Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD). Orphanet J Rare Dis. 2017;12(1):41.
  3. Wasserstein MP, Schuchman EH. Acid sphingomyelinase deficiency. NCBI GeneReviews (2015). Available at: https://www.ncbi.nlm.nih.gov/books/NBK1370/. Accessed July 19, 2018.
  4. Kaplan P, Andersson HC, Kacena KA, et al. The clinical and demographic characteristics of nonneuronopathic Gaucher disease in 887 children at diagnosis. Arch Pediatr Adolesc Med. 2006;160:603-608.
  5. McGovern MM, Dionisi-vici C, Giugliani R, et al. Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency. Genet Med. 2017;19(9):967-974.
  6. Simpson WL, Hermann G, Balwani M. Imaging of Gaucher disease. World J Radiol. 2014;6:657-668.
  7. Mistry PK, Cappellini MD, Lukina E, et al. Consensus conference: a reappraisal of Gaucher disease – diagnosis and disease management algorithms. Am J Hematol. 2011;86(1):110-5.
  8. Bronstein S, Karpati M, Peleg L. An update of Gaucher mutations distribution in the Ashkenazi Jewish population: prevalence and country of origin of the mutation R496H. Isr Med Assoc J. 2014;16:683-685.

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