|Generate QR code
Open Access
Subscription Access
Clinical characteristics and modern approaches to diagnostics and therapy of acid sphingomyelinase deficiency (Niemann–Pick disease type AB)
https://doi.org/10.25557/2073-7998.2025.01.3-12
Abstract
Niemann-Pick disease type A/B is lysosomal storage disease caused by acid sphingomyelinase (ASM) deficiency. The accumulation of sphingomyelin in cells causes damage to various organs, such as the liver and central nervous system. Symptoms of this disease include hepatosplenomegaly, neurological deficiency, and lung disease. There are three main forms of the disease: type A, type B, and intermediate type A/B. Type A is characterized by severe neural degeneration and prominent neurological deficit, while type B is milder with minimal neurological manifestations and signs of lipid accumulation. The intermediate type combines features of both types of Niemann-Pick disease. The diagnosis of Niemann-Pick disease types A/B is made using laboratory tests and results, including ASM activity assessment and genetic mutations in the SMPD1 gene. The gold standard is the enzyme activity assay on dry blood spots. Treatment mainly consists of enzyme replacement therapy (ERT), which improves the condition of the patient, although its effectiveness in neurological symptoms is limited. Alternative methods such as bone marrow transplantation, gene therapy and molecular chaperone therapy are currently being investigated. Despite the advances in the understanding of the pathogenesis and therapy of Niemann-Pick disease types A/B, further investigations are needed to advance early diagnostic methods and develop new therapeutic approaches, especially in the field of gene technology.
Supporting agencies: The study was carried out according to the state assignment of the Ministry of Science and Higher Education of the Russian Federation for the RCMG.
About the Authors
V. V. Shmarin
Research Centre for Medical Genetics; I.M. Sechenov First Moscow State Medical University (Sechenov University)
Russian Federation
Russian Federation
1, Moskvorechie st., Moscow, 115478
8/2, Trubetskaya st., Moscow, 119048
A. A. Vasilenko
Research Centre for Medical Genetics
Russian Federation
Russian Federation
1, Moskvorechie st., Moscow, 115478
V. V. Zarubina
Morozovskaya Children’s City Clinical Hospital
Russian Federation
Russian Federation
1/9, 4th Dobryninsky Lane, Moscow, 119049
T. I. Bocharova
Children’s City Clinical Hospital named after Z.A. Bashlyaeva
Russian Federation
Russian Federation
28, Geroev Panfilovtsev st., Moscow, 125373
E. Yu. Zakharova
Research Centre for Medical Genetics
Russian Federation
Russian Federation
1, Moskvorechie st., Moscow, 115478
References
1. Geberhiwot T., Wasserstein M., Wanninayake S. et al. Consensus clinical management guidelines for acid sphingomyelinase deficiency (Niemann–Pick disease types A, B and A/B). Orphanet J Rare Dis. 2023;18(1):85.
2. Zampieri S., Filocamo M., Pianta A. et al. SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants: HUMAN MUTATION. Human Mutation. 2016;37(2):139–47.
3. Hollak C.E.M., De Sonnaville E.S.V., Cassiman D. et al. Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: Disease spectrum and natural course in attenuated patients. Molecular Genetics and Metabolism. 2012;107(3):526–33.
4. Wasserstein M.P., Desnick R.J., Schuchman E.H. et al. The Natural History of Type B Niemann-Pick Disease: Results From a 10-Year Longitudinal Study. Pediatrics. 2004;114(6):e672–7.
5. McGovern M.M., Aron A., Brodie S.E. et al. Natural history of Type A Niemann-Pick disease: Possible endpoints for therapeutic trials. Neurology. 2006;66(2):228–32.
6. Wasserstein M.P., Aron A., Brodie S.E. et al. Acid sphingomyelinase deficiency: prevalence and characterization of an intermediate phenotype of Niemann-Pick disease. J Pediatr. 2006;149(4):554–9.
7. McGovern M.M., Dionisi-Vici C., Giugliani R. et al. Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency. Genetics in Medicine. 2017;19(9):967–74.
8. Cassiman D., Packman S., Bembi B. et al. Cause of death in patients with chronic visceral and chronic neurovisceral acid sphingomyelinase deficiency (Niemann-Pick disease type B and B variant): Literature review and report of new cases. Mol Genet Metab. 2016;118(3):206–13.
9. Wasserstein M., Godbold J., McGovern M.M. Skeletal manifestations in pediatric and adult patients with Niemann Pick disease type B. J Inherit Metab Dis. 2013;36(1):123–7.
10. McGovern M.M., Wasserstein M.P., Giugliani R. et al. A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B. Pediatrics. 2008;122(2):e341-349.
11. Thurberg B.L., Wasserstein M.P., Schiano T. et al. Liver and skin histopathology in adults with acid sphingomyelinase deficiency (Niemann-Pick disease type B). Am J Surg Pathol. 2012;36(8):1234–46.
12. Mendelson D.S., Wasserstein M.P., Desnick R.J. et al. Type B Niemann-Pick disease: findings at chest radiography, thin-section CT, and pulmonary function testing. Radiology. 2006;238(1):339–45.
13. Pavlů‐Pereira H., Asfaw B., Poupčtova H. et al. Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty‐five Czech and Slovak patients. A multi‐approach study. J of Inher Metab Disea. 2005;28(2):203–27.
14. Quinn P.J. Sphingolipid symmetry governs membrane lipid raft structure. Biochimica et Biophysica Acta (BBA) – Biomembranes. 2014;1838(7):1922–30.
15. Podbielska M., Ariga T., Pokryszko-Dragan A. Sphingolipid Players in Multiple Sclerosis: Their Influence on the Initiation and Course of the Disease. IJMS. 2022;23(10):5330.
16. Kirkegaard T., Roth A.G., Petersen N.H.T. et al. Hsp70 stabilizes lysosomes and reverts Niemann–Pick disease-associated lysosomal pathology. Nature. 2010;463(7280):549–53.
17. Schuchman E.H., Desnick R.J. Types A and B Niemann-Pick disease. Molecular Genetics and Metabolism. 2017;120(1–2):27–33.
18. Buccinna B., Piccinini M., Prinetti A. et al. Alterations of myelinspecific proteins and sphingolipids characterize the brains of acid sphingomyelinase‐deficient mice, an animal model of Niemann–Pick disease type A. Journal of Neurochemistry. 2009;109(1):105–15.
19. Kinnunen P. Sphingomyelinase Activity of LDL A Link between Atherosclerosis, Ceramide, and Apoptosis? Trends in Cardiovascular Medicine. 2002;12(1):37–42.
20. Charruyer A., Grazide S., Bezombes C. et al. UV-C Light Induces Raft-associated Acid Sphingomyelinase and JNK Activation and Translocation Independently on a Nuclear Signal. Journal of Biological Chemistry. 2005;280(19):19196–204.
21. Kornhuber J., Muller C.P., Becker K.A. et al. The ceramide system as a novel antidepressant target. Trends in Pharmacological Sciences. 2014;35(6):293–304.
22. Da Veiga Pereira L., Desnick R.J., Adler D.A. et al.Regional assignment of the human acid sphingomyelinase gene (SMPD1) by PCR analysis of somatic cell hybrids and in situ hybridization to 11p15.1→p15.4. Genomics. 1991;9(2):229–34.
23. Mihaylova V., Hantke J., Sinigerska I. et al. Highly variable neural involvement in sphingomyelinase-deficient Niemann-Pick disease caused by an ancestral Gypsy mutation. Brain. 2006;130(4):1050–61.
24. Simonaro C.M., Desnick R.J., McGovern M.M. et al. The Demographics and Distribution of Type B Niemann-Pick Disease: Novel Mutations Lead to New Genotype/Phenotype Correlations. The American Journal of Human Genetics. 2002;71(6):1413–9.
25. Ferlinz K., Hurwitz R., Vielhaber G. et al. Occurrence of two molecular forms of human acid sphingomyelinase. Biochemical Journal. 1994;301(3):855–62.
26. McGovern M.M., Pohl-Worgall T., Deckelbaum R.J. et al. Lipid abnormalities in children with types A and B Niemann Pick disease. J Pediatr. 2004;145(1):77–81.
27. Wang R., Qin Z., Huang L. et al. SMPD1 expression profile and mutation landscape help decipher genotype–phenotype association and precision diagnosis for acid sphingomyelinase deficiency. Hereditas. 2023;160(1):11.
28. Dardis A., Zampieri S., Filocamo M. et al. Functionalin vitro characterization of 14SMPD1 mutations identified in Italian patients affected by Niemann Pick Type B disease. Hum Mutat. 2005;26(2):164–164.
29. Pittis M.G., Ricci V., Guerci V.I. et al. Acid sphingomyelinase: Identification of nine novel mutations among Italian Niemann Pick type B patients and characterization of in vivo functional in-frame start codon: MUTATIONS IN BRIEF. Hum Mutat. 2004;24(2):186–7.
30. Jones I., He X., Katouzian F., Darroch P.I., Schuchman E.H. Characterization of common SMPD1 mutations causing types A and B Niemann-Pick disease and generation of mutation-specific mouse models. Mol Genet Metab. 2008;95(3):152–62.
31. Simonaro C.M., Park J.H., Eliyahu E. et al. Imprinting at the SMPD1 Locus: Implications for Acid Sphingomyelinase–Deficient Niemann-Pick Disease. The American Journal of Human Genetics. 2006;78(5):865–70.
32. Oliva P., Schwarz M., Mechtler T.P. et al. Importance to include differential diagnostics for acid sphingomyelinase deficiency (ASMD) in patients suspected to have to Gaucher disease. Molecular Genetics and Metabolism. 2023;139(1):107563.
33. Piraud M., Pettazzoni M., Lavoie P. et al. Contribution of tandem mass spectrometry to the diagnosis of lysosomal storage disorders. J of Inher Metab Disea. 2018;41(3):457–77.
34. Kuchar L., Sikora J., Gulinello M.E. et al. Quantitation of plasmatic lysosphingomyelin and lysosphingomyelin-509 for differential screening of Niemann-Pick A/B and C diseases. Anal Biochem. 2017; 525: 73-77.
35. Voorink-Moret M., Goorden S.M.I., Van Kuilenburg A.B.P. et al. Rapid screening for lipid storage disorders using biochemical markers. Expert center data and review of the literature. Molecular Genetics and Metabolism. 2018;123(2):76–84.
36. Breilyn M.S., Zhang W., Yu C., Wasserstein M.P. Plasma lyso-sphingomyelin levels are positively associated with clinical severity in acid sphingomyelinase deficiency. Mol Genet Metab Rep. 2021;28:100780.
37. Diaz G.A., Jones S.A., Scarpa M. et al. One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency. Genet Med. 2021;23(8):1543–50.
38. Wasserstein M., Lachmann R., Hollak C. et al. A randomized, placebo-controlled clinical trial evaluating olipudase alfa enzyme replacement therapy for chronic acid sphingomyelinase deficiency (ASMD) in adults: One-year results. Genetics in Medicine. 2022;24(7):1425–36.
39. Hollak C.E., van Weely S., van Oers M.H., Aerts J.M. Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest. 1994;93(3):1288–92.
40. Boot R.G., Renkema G.H., Verhoek M. et al. The human chitotriosidase gene. Nature of inherited enzyme deficiency. J Biol Chem. 1998;273(40):25680–5.
41. Porter F.D., Scherrer D.E., Lanier M.H. et al. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Sci Transl Med. 2010;2(56):56ra81.
42. Romanello M., Zampieri S., Bortolotti N. et al. Comprehensive Evaluation of Plasma 7-Ketocholesterol and Cholestan-3β,5α,6β-Triol in an Italian Cohort of Patients Affected by Niemann-Pick Disease due to NPC1 and SMPD1 Mutations. Clin Chim Acta. 2016;455:39–45.
43. Di Rocco M., Vici C.D., Burlina A. et al. Screening for lysosomal diseases in a selected pediatric population: the case of Gaucher disease and acid sphingomyelinase deficiency. Orphanet J Rare Dis. 2023;18(1):197.
44. Hickey R.E, Baker J. Newborn screening for acid sphingomyelinase deficiency in Illinois: A single center’s experience. J of Inher Metab Disea. J Inherit Metab Dis. 2024;47(6):1363-1370.
45. McGovern M.M., Wasserstein M.P., Kirmse B. et al. Novel first-dose adverse drug reactions during a phase I trial of olipudase alfa (recombinant human acid sphingomyelinase) in adults with Niemann–Pick disease type B (acid sphingomyelinase deficiency). Genetics in Medicine. 2016;18(1):34–40.
46. Wasserstein M.P., Jones S.A., Soran H. et al. Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency. Mol Genet Metab. 2015;116(1–2):88–97.
47. Cassiman D., Packman S., Bembi B. et al. Cause of death in patients with chronic visceral and chronic neurovisceral acid sphingomyelinase deficiency (Niemann-Pick disease type B and B variant): Literature review and report of new cases. Mol Genet Metab. 2016;118(3):206–13.
48. O’Neill R.S., Belousova N., Malouf M.A.. Pulmonary Type B Niemann-Pick Disease Successfully Treated with Lung Transplantation. Case Reports in Transplantation. 2019;2019:1–5.
49. Mannem H., Kilbourne S., Weder M. Lung transplantation in a patient with Niemann–Pick disease. The Journal of Heart and Lung Transplantation. 2019;38(1):100–1.
50. Uyan Z.S., Karadağ B., Ersu R. et al. Early pulmonary involvement in Niemann‐Pick type B disease: Lung lavage is not useful. Pediatric Pulmonology. 2005;40(2):169–72.
51. Nicholson A.G., Wells A.U., Hooper J. et al. Successful Treatment of Endogenous Lipoid Pneumonia due to Niemann–Pick Type B Disease with Whole-Lung Lavage. Am J Respir Crit Care Med. 2002;165(1):128–31.
52. Jin H.K., Carter J.E., Huntley G.W., Schuchman E.H. Intracerebral transplantation of mesenchymal stem cells into acid sphingomyelinase-deficient mice delays the onset of neurological abnormalities and extends their life span. J Clin Invest. 2002;109(9):1183–91.
53. Barbon C.M., Ziegler R.J., Li C. et al. AAV8-mediated hepatic expression of acid sphingomyelinase corrects the metabolic defect in the visceral organs of a mouse model of Niemann-Pick disease. Mol Ther. 2005;12(3):431–40.
54. Miranda S.R., Erlich S., Friedrich V.L. et al.. Hematopoietic stem cell gene therapy leads to marked visceral organ improvements and a delayed onset of neurological abnormalities in the acid sphingomyelinase deficient mouse model of Niemann-Pick disease. Gene Ther. 2000;7(20):1768–76.
55. Samaranch L., Perez-Canamas A., Soto-Huelin B. et al. Adeno-associated viral vector serotype 9–based gene therapy for Niemann-Pick disease type A. Sci Transl Med. 2019;11(506):eaat3738.
56. Beretta G., Shala A.L. Impact of Heat Shock Proteins in Neurodegeneration: Possible Therapeutical Targets. Annals of Neurosciences. 2022;29(1):71–82.
Review
For citations:
Shmarin V.V., Vasilenko A.A., Zarubina V.V., Bocharova T.I., Zakharova E.Yu. Clinical characteristics and modern approaches to diagnostics and therapy of acid sphingomyelinase deficiency (Niemann–Pick disease type AB). Medical Genetics. 2025;24(1):3-12. (In Russ.) https://doi.org/10.25557/2073-7998.2025.01.3-12
Views:
233
Email this article 