Intrafamilial Polymorphism of Clinical Symptoms in Patients with Niemann-Pick Disease Type A

Introduction. Niemann-Pick disease type A (NPD type A) is the most severe form of acid sphingomyelinase deficiency, a rare inherited disorder of the lysosomal storage disorders with autosomal recessive inheritance caused by biallelic pathogenic variants in the SMPD1 gene. Since 2023, enzyme replacement therapy with olipudase alfa has been used to treat patients with NPD in Russia. This therapy does not alter the prognosis for neurological forms of the disease, as it does not penetrate the blood-brain barrier. Therefore, the only effective treatment, along with symptomatic therapy, for the systemic manifestations of NPD type A is hematopoietic stem cell transplantation, which does not prevent central nervous system damage. Early laboratory diagnostics using biochemical and molecular genetic diagnostic methods are crucial for timely diagnosis and treatment of patients with this form of the disease.

Aim: to describe intrafamilial polymorphism of clinical symptoms of NPD, type A using the example of two siblings from the same family.

Materials and methods. Clinical observation and diagnostics were conducted at the National Medical Research Center for Children’s Health of the Russian Ministry of Health from 2012 to 2026 in a single family in which the first proband with clinical symptoms characteristic of NBP type A was identified in 2012. Acid sphingomyelinase activity was measured in dried blood spots using tandem mass spectrometry, and nucleotide variants in the SMPD1 gene were identified using Sanger sequencing. Familial segregation analysis was performed for the proband and eight family members.

Results. Diagnosis of the first proband revealed a significant decrease in acid sphingomyelinase activity in the patient’s spinal cord. Sequencing revealed the presence of two pathogenic heterozygous variants in the SMPD1 gene: c.996del (p.Phe333Serfs52) and c.1252C>T (p.Arg418). Carriage of the pathogenic causative variants in the SMPD1 gene was confirmed in the parents. The second proband was diagnosed on the second day of life. As a result of the timely diagnosis, immunotherapy (bone marrow transplant) was prescribed, which determined the child’s prognosis.

Conclusion. Using two siblings from the same family as an example, polymorphism in the clinical symptoms of NPD type A was demonstrated. Early diagnosis of this form of the disease significantly improves the prognosis and enables timely initiation of therapy.

1. Schuchman EH, Wasserstein MP. Types A and B Niemann-Pick disease. Best Pract Res Clin Endocrinol Metab. 2015;29(2):237–247. doi: 10.1016/j.beem.2014.10.002

2. McGovern MM, Dionisi-Vici C, Giugliani R, et al. Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency. Gen Med. 2017;19(9):967–974. doi: 10.1038/gim.2017.7

3. Brady RO, Kanfer JN, Mock MB, Fredrickson DS. The metabolism of sphingomyelin. II. Evidence of an enzymatic deficiency in Niemann-Pick diseae. Proc Nat Acad Sci. 1966;55(2):366–369. doi: 10.1073/pnas.55.2.366

4. Wasserstein MP, Desnick RJ, Schuchman EH, et al. The natural history of type B Niemann-Pick disease: results from a 10-year longitudinal study. Pediatrics. 2004;114(6):e672–e677. doi: 10.1542/peds.2004-0887

5. Quintern LE, Weitz G, Nehrkorn H, et al. Acid sphingomyelinase from human urine: purification and characterization. Biochim Biophys Acta. 1987;922(3):323–336. doi: 10.1016/0005-2760(87)90055-5

6. Breiden B, Sandhoff K. Mechanism of secondary ganglioside and lipid accumulation in lysosomal disease. Int J Mol Sci. 2020;21(7):2566. doi: 10.3390/ijms21072566

7. Qureshi K, Abdulmajeed ZG, Saleem S, et al. Niemann-Pick disease type A: a rare disease with a fatal outcome. Cureus. 2022;14(2):e21955. doi: 10.7759/cureus.21955

8. Sako S, Oishi K, Ida H, Imagawa E. Allele frequency of pathogenic variants causing acid sphingomyelinase deficiency and Gaucher disease in the general Japanese population. Hum Genome Var. 2024;11(1):24. doi: 10.1038/s41439-024-00282-z

9. 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. doi: 10.1186/s41065-023-00272-1

10. Tirelli C, Rondinone O, Italia M, et al. The genetic basis, lung involvement, and therapeutic options in Niemann-Pick disease: a comprehensive review. Biomolecules. 2024;14(2):211. doi: 10.3390/biom14020211

11. Baranov AA, Namazova-Baranova LS, Gundobina OS, et al. Managing children with gaucher disease: modern clinical recommendations. Pediatric Pharmacology. 2016;13(3):244–250. EDN: WIOAVT

12. Zhurkova NV, Vashakmadze NV, Surkov AN, et al. Niemann-Pick disease, type A: clinical case of 5 months old patient. Current Pediatrics. 2024;23(3):188–196. doi: 10.15690/vsp.v23i3.2762 EDN: WMFXIF

13. Rusakova AA, Mazanova NN, Movsisyan GB, et al. Clinical, biochemical and molecular-genetic features of selective screening of Russian patients with Niemann-Pick disease types A, B and A/B. Results of the selective screening program. Medical genetics. 2025;24(8):14–28. doi: 10.25557/2073-7998.2025.08.14-28 EDN: MIFPDE

14. Zampieri S, Filocamo M, Pianta A, et al. SMPD1 mutation update: database and comprehensive analysis of published and novel variants. Hum Mutat. 2016;37(2):139–147. doi: 10.1002/humu.22923

15. Schuchman EH, Desnick RJ. Types A and B Niemann-Pick disease. Mol Genet Metab. 2017;120(1-2):27–33. doi: 10.1016/j.ymgme.2016.12.008