Niemann-Pick Disease, Type A: Clinical Case of 5 Months Old Patient

Background. Niemann-Pick disease, type A is a rare hereditary disease from the group of lysosomal storage diseases, it is characterized by early onset and progressive course. Description of this disease’s clinical cases is crucial for early diagnosis and adequate management due to its rarity, rapid progression, and the development of new pathogenetic therapy methods.

Clinical case description. The disease manifested on the second month of the patient’s life with poor weight gain, frequent pneumonia, hepatosplenomegaly, diffuse muscular hypotonia, delayed motor development, and progressive neurological symptoms. Laboratory testing has revealed significant decrease in sphingomyelinase activity in blood. The heterozygous deletion c.996del in exon 2 of the SMPD1 gene has been revealed via direct automatic sequencing; it leads to frameshifting p.F333Sfs*52 (inherited from mother). Moreover, the previously described pathogenic nucleotide variant c.1252C>T (heterozygous) has been revealed in exon 3 of the SMPD1 gene; it leads to translation arrest p.Arg418* (inherited from father). Cherry-red spots were diagnosed at fundospcopy. The diagnosis of Niemann-Pick disease, type А was established according to clinical signs and molecular genetic testing results.

Conclusion. The detection of physical and motor development delay, diffuse muscular hypotonia, hepatosplenomegaly, cherry-red spots at ophthalmological examination, lung involvement, recurrent pneumonia, and progressive neurological symptoms in a child during the first months of life indicates that this patient has Niemann-Pick disease, type А. Early molecular genetic testing is crucial for timely choosing the management approach and further genetic counselling of the family.

1. Niemann A. Ein unbekanntes Krankheitsbild. Jahrb Kinderheillkd. 1914;9:1.

2. Pick L. Über die lipoidzellige splenohepatomegalie typus Niemann-Pick als stoffwechselerkrankung. Med Klin (Munich). 1927;23:1483–1486.

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

4. Pfrieger FW. The Niemann-Pick type diseases — A synopsis of inborn errors in sphingolipid and cholesterol metabolism. Prog Lipid Res. 2023;90:101225. https://doi.org/10.1016/j.plipres.2023.101225

5. Niemann-Pick disease. In: Genes and Disease [Internet]. National Center for Biotechnology Information (US). Bethesda (MD): National Center for Biotechnology Information (US); 1998. Available online: https://www.ncbi.nlm.nih.gov/books/NBK22176. Accessed on December 20, 2023.

6. Vashakmadze ND, Zhurkova NV. NiemannPick Disease: Seven Questions about it. Voprosy sovremennoi pediatrii — Current Pediatrics. 2023;22(6):572–576. (In Russ). https://doi.org/10.15690/vsp.v22i6.2702

7. Cerón-Rodríguez M, Vázquez-Martínez ER, García-Delgado C, et al. Niemann-Pick disease A or B in four pediatric patients and SMPD1 mutation carrier frequency in the Mexican population. Ann Hepatol. 2019;18(4):613–619. https://doi.org/10.1016/j.aohep.2018.12.004

8. 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. https://doi.org/10.1186/s41065-023-00272-1

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

10. Kingma SD, Bodamer OA, Wijburg FA. Epidemiology and diagnosis of lysosomal storage disorders; challenges of screening. Best Pract Res Clin Endocrinol Metab. 2015;29(2):145–157. https://doi.org/10.1016/j.beem.2014.08.004

11. Prevalence of rare diseases: Bibliographic data. Orphanet Report Series, Rare Diseases collection. 2023 Number 1: Diseases in alphabetical order. Available online: http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf. Accessed on December 10, 2023.

12. Jones SA, McGovern M, Lidove O, et al. Clinical relevance of endpoints in clinical trials for acid sphingomyelinase deficiency enzyme replacement therapy. Mol Genet Metab. 2020;131(1-2): 116–123. https://doi.org/10.1016/j.ymgme.2020.06.008

13. Nicholson AG, Florio R, Hansell DM, et al. Pulmonary involvement by Niemann-Pick disease. A report of six cases. Histopathology. 2006;48(5):596–603. https://doi.org/10.1111/j.1365-2559.2006.02355.x

14. Freitas HMP, Mançano AD, Rodrigues RS, et al. Niemann-Pick disease type B: HRCT assessment of pulmonary involvement. J Bras Pneumol. 2017;43(6):451–455. https://doi.org/10.1590/S1806-37562017000000062

15. Levran O, Desnick RJ, Schuchman EH. Type A Niemann-Pick disease: a frameshift mutation in the acid sphingomyelinase gene (fsP330) occurs in Ashkenazi Jewish patients. Hum Mutat. 1993;2(4):317–319. https://doi.org/10.1002/humu.1380020414

16. Ricci V, Stroppiano M, Corsolini F, et al. Screening of 25 Italian patients with Niemann-Pick A reveals fourteen new mutations, one common and thirteen private, in SMPD1. Hum Mutat. 2004;24(1):105. https://doi.org/10.1002/humu.9258

17. Qureshi K, Abdulmajeed ZG, Saleem S, et al. Niemann-Pick Disease Type A: A Rare Disease With a Fatal Outcome. Cureus. 2022;14(2):21955. https://doi.org/10.7759/cureus.21955

18. Ngoenmak T, Somran J, Foonoi M, et al. Case report of a novel variant in SMPD1 of Niemann-Pick disease type A with a liver histology from Thailand. Glob Pediat. 2024;7:100096. https://doi.org/10.1016/j.gpeds.2023.100096

19. Semyachkina AN, Bukina TM, Kurbatov MB, et al. Niemann–Pick A disease in children. Rossiyskiy Vestnik Perinatologii i Pediatrii = Russian Bulletin of Perinatology and Pediatrics. 2008;(4):52–57. (In Russ).

20. Hartnett ME, Kavalaraki M, Bhagat N, Zhao CS. Cherry-Red Spot. In: American Academy of Ophthalmology: Official website. January 12, 2024. Available online: https://eyewiki.aao.org/Cherryred_spot. Accessed on June 05, 2024.

21. Sen Sarma M, Tripathi PR. Natural history and management of liver dysfunction in lysosomal storage disorders. World J Hepatol. 2022;14(10):1844–1861. https://doi.org/10.4254/wjh.v14.i10.1844

22. Imrie J, Mengel KE, Cassiman D, et al. Cause of death in patients with attenuated acid sphingomyelinase deficiency: Comprehensive literature review and report of new cases. Mol Genet Metab. 2016;117:S60. https://doi.org/10.1016/j.ymgme.2015.12.298

23. 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. https://doi.org/10.3390/biom14020211

24. Pan YW, Tsai MC, Yang CY, et al. Enzyme replacement therapy for children with acid sphingomyelinase deficiency in the real world: A single center experience in Taiwan. Mol Genet Metab Rep. 2023;34:100957. https://doi.org/10.1016/j.ymgmr.2023.100957ё