Niemann -Pick Disease

1. PHM142 Fall 2013 Instructor: Dr. Jeffrey Henderson Niemann-Pick Disease Wednesday, December 4th, 2013 Erin Bezzina Alexandra Farrell Leigha Laporte Alex Raptis

2. What is Niemann-Pick Disease? • Lysosomal storage disease affecting metabolism • Caused by deficiency of either acid sphingomyelinase or • Niemann-Pick C proteins • Rare, progressive, eventually fatal • Autosomal recessive inheritance • 3 main types: A, B, and C Incidence • Type A and B: 1 in 250, 000 • Type C: 1 in 120, 000 • Higher incidence in certain populations

3. Under normal conditions… SMase = acid sphingomyelinase

4. Under normal conditions… Niemann-Pick C1 Niemann-Pick C2 Both proteins are involved in cholesterol and lipid transport and storage to various cellular organelles

5. Type A and B Type C Mutation in Niemann-Pick C1 (NPC1 – on chromosome 18) or C2 (NPC2 – on chromosome 14) genes Mutation in sphingomyelinphosphodiesterase 1 (SMPD1) gene (Chromosome 11) Dysfunction in acid sphingomyelinase protein Dysfunction in NPC1 or NPC2 proteins Accumulation of sphingomyelins Decrease in ceramides Abnormal storage of lipids and cholesterol

6. Symptoms • Type A • -Hepatosplenomegaly • -Cherry-red macula on retina • -Lung disease + respiratory infections • -Neurologic and psychomotor deterioration • -Developmental delay Type C -Hepatosplenomegaly -Fetal ascites/ liver disease -Hypotonia -Vertical supranuclear gaze palsy -Cataplexy -Epilepsy • Type B • -Hepatosplenomegaly • -Liver + lung dysfunction • -Atherogenic lipid profile • -Thrombocytopenia • -Neurological symptoms do not normally occur, but intermediate forms between Type A and B exist

7. Diagnosis Type A and B Acid sphingomyelinase deficiency • Examine ASM activity in peripheral blood lymphocytes or cultured fibroblasts • Most patients have < 10% residual enzyme activity compared to normal • Genetic Testing - analysis of SMPD1 gene • Type A- Arg498Leu, Leu304Pro, Phe333Serfs*52 • Type B- Arg610del

8. Diagnosis Type C Filipin staining • In cultured fibroblasts, examine ability of cell to transport cholesterol after loading with LDL • Stain with filipin and use fluorescence to examine presence of unesterified cholesterol in a punctuate pattern around the nucleus Genetic testing • Sequence the entire NPC1 and NCP2 genes and look for sequence variants and deletions

9. Filipin Stain

10. Treatment • No cure • Healthy, low-cholesterol diet • Treatment of symptoms • Examples: • Hypotonia/tremor: anticholinergic agents • Cataplexy: clomipramine, protriptyline, modafinil • High cholesterol levels: statins • Physiotherapy for management of ataxia

11. Type A Treatment No effective treatment Type B Treatment • Bone marrow transplantation • Encouraging results • Enzyme replacement and gene therapy • Phase 1b trial

12. Type C Treatment • Miglustat (Zavesca) • Approved on March 23, 2010 in Canada • Competitive inhibitor of glucosylceramide synthase • Slows progression of neurological manifestations in humans

13. References - Acetlion Pharmaceuticals Ltd. (2010, March 23). Zavesca (miglustat) first treatment available in Canada for rare progressive Niemann-Pick type C disease.Retrieved November 30, 2013, from http://www.marketwired.com/press-release/Zavesca-Miglustat-First-Treatment-Available-Canada-Rare-Progressive-Niemann-Pick-Type-SIX-ATLN-1136457.htm -Canadian Pharmacists Association. (2013). Compendium of Pharmaceuticals and Specialties, online version (e-CPS). Retrieved November 30, 2013 from http://www.e-therapeutics.ca.myaccess.library.utoronto.ca/cps.showMonograph.action. -Karten, B., Peake, K. B., & Vance, J. E. (2009). Mechanisms and consequences of impaired lipid trafficking in Niemann–Pick type C1-deficient mammalian cells. Biochimica et BiophysicaActa (BBA)-Molecular and Cell Biology of Lipids, 1791(7), 659-670. -Niemann-Pick Disease Foundation (2013, June 28).Niemann-Pick Disease Overview. Retrieved November 30, 2013, from http://www.nnpdf.com/npdisease_01.html -Niemann-Pick Disease Foundation. (2013, October 25). Enzyme Replacement Therapy – Type B. Retrieved November 30, 2013, from http://www.nnpdf.ca/npresearch_11.html. -Pagon, R. A., Bird, T. D., Dolan, C. R., Stephens, K., Adam, M. P., McGovern, M. M., & Schuchman, E. H. (2006). Acid Sphingomyelinase Deficiency. -Patterson, M., & Vanier, M. T. (2004). Niemann-Pick disease type C.Glycolipid storage disorders. Adis Communications, Abingdon, 79-89 -Patterson, M. C., Hendriksz, C. J., Walterfang, M., Sedel, F., Vanier, M. T., & Wijburg, F. (2012). Recommendations for the diagnosis and management of Niemann–Pick disease type C: An update. Molecular genetics and metabolism, 106(3), 330-344.. -Schuchman, E. H. (2007). The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann–Pick disease. Journal of inherited metabolic disease, 30(5), 654-663. -Schuchman, E. H. (2010). Acid sphingomyelinase, cell membranes and human disease: Lessons from Niemann–Pick disease. FEBS letters, 584(9), 1895-1900. -Shah, A.J., Kapoor, N., Crooks, G.M., Parkman, R., Weinberg, K.I., Wilson, K., & Kohn, D.B. (2005). Successful hematopoietic stem cell transplantation for Niemann-Pick disease type B. Pediatrics, 116(4):1022-1025. doi: 10.1542/peds.2005-0867. -Tängemo, C., Weber, D., Theiss, S., Mengel, E., & Runz, H. (2011). Niemann-Pick Type C disease: characterizing lipid levels in patients with variant lysosomal cholesterol storage. Journal of lipid research, 52(4), 813-825. -Vanier, M.T. (2010). Niemann-Pick disease type C. Orphanet Journal of Rare Diseases, 5(16). doi: 10.1186/1750-5-16.

14. Summary • Lysosomal storage disease affecting metabolism • Caused by an autosomal recessive mutation deficiency of either acid sphingomyelinase(SMase)or Niemann-Pick C proteins (NPC). • 3 Main Types: • Type A & B: Deficiency in SMase Accumulation of sphingomyelins and a reduction in ceramides • Symptoms: Hepatosplenomegaly, neurodegeneration (Type A only) • Diagnosis: Based on SMase activity • Treatment: Based on symptoms • Type C: Deficiency in NPC1 & NPC2  Abnormal storage of lipids and cholesterol • Symptoms: Hepatosplenomegaly, epilepsy, fetal ascites, hypotoxia • Diagnosis: Based on filipin stain of fibroblasts for cholesterol content • Treatment: Miglustat (slows progression of neurological symptoms)