Genetics of Niemann-Pick Disease Clinical Presentation

  • Author: Lynne Ierardi-Curto, MD, PhD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Jan 12, 2010
 

History

  • Niemann-Pick disease (NPD) type A: The clinical presentation and course of type A is relatively uniform and is characterized by normal appearance at birth. The first symptom detected is usually the presence of hepatosplenomegaly at age 3 months. Affected infants exhibit feeding problems, failure to thrive, recurrent infections, and irritability. Few motor milestones are achieved, and the disease course is characterized by psychomotor retardation followed by regression. With advancing age, progressive loss of motor function and deterioration of intellectual capabilities are noted. In the final stages, spasticity and rigidity are evident, and the affected child is completely unable to interact with the environment.
  • Niemann-Pick disease type B
    • The clinical presentation and course in patients with type B disease vary. The condition is diagnosed in most patients in infancy or childhood when enlargement of the liver, spleen, or both is detected during routine physical examination.
    • At diagnosis, patients with Niemann-Pick disease type B also have evidence of mild pulmonary involvement, usually detected as a diffuse reticular or finely nodular infiltration on chest radiograph films.
    • In most patients, hepatosplenomegaly is particularly prominent in childhood; however, with increasing linear growth, the abdominal protuberance decreases and becomes less conspicuous.
    • In mildly affected patients, splenomegaly may not be noted until adulthood, and disease manifestations may be minimal.
    • In most patients with Niemann-Pick disease type B, decreased pulmonary diffusion caused by storage of sphingomyelin in pulmonary macrophages becomes evident in childhood and progresses with age. Severely affected individuals may experience significant pulmonary compromise by age 15-20 years. Such patients have low PO2 values and dyspnea on exertion.
    • Recurrent pneumonia and life-threatening bronchopneumonias may occur, and cor pulmonale has been described. Severely affected patients may also have liver involvement leading to life-threatening cirrhosis, portal hypertension, and ascites.
    • Clinically significant pancytopenia caused by secondary hypersplenism may require partial or complete splenectomy, although removal of the spleen should be avoided because it results in rapid progression of the pulmonary disease.
    • In general, patients with Niemann-Pick disease type B do not have neurologic involvement and are not affected intellectually. However, variant patients with progressive neurologic findings in later childhood have been described.
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Physical

  • Head and neck: Patients with type A disease usually have a cherry-red spot on ophthalmologic examination, resulting from the accumulation of lipid in the retinal ganglion cells. However, a classic cherry-red spot is usually not observed early in the disease. In type B disease, as many as one third of patients also have a cherry-red spot or macular haloes.
  • Abdomen: Hepatosplenomegaly is a common feature. In type A disease, it typically becomes massive. In type B disease, hepatosplenomegaly can widely vary. Some patients with Niemann-Pick disease type B have massive enlargement, whereas others have milder enlargement that may remain unnoticed for years.
  • Neurologic
    • Patients with Niemann-Pick disease type A have progressive neurodegeneration, and attainment of milestones does not progress beyond 10 months in any domain. Motor milestone attainment rarely progresses beyond the ability to sit with assistance. Progression with loss of previously achieved milestones ensues, and patients appear weak and hypotonic. The neurologic degeneration is relentless, leading to a spastic state. Seizures are not common.
    • Most patients with type B disease have normal findings on neurologic examination, although some patients have been described with peripheral neuropathy and learning disabilities. In addition, some patients who have normal early development with loss of language skills and onset of ataxia beginning around the third year of life have been reported.
  • Growth: Patients with moderate-to-severe type B disease typically experience growth retardation in childhood and attain a final adult height that is less than expected based on familial heights.
  • Skin: Examination of the skin in patients with type B disease may reveal extensive bruising. Patients with severe hypersplenism may also have petechiae.
  • Lungs: Findings on auscultation of the lungs are usually normal in the absence of an intercurrent respiratory infection.
  • Cardiac: Cardiac examination findings are usually normal.
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Causes

  • Niemann-Pick disease types A and B result from deficiency of acid sphingomyelinase and lysosomal accumulation of sphingomyelin.
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Contributor Information and Disclosures
Author

Lynne Ierardi-Curto, MD, PhD  Medical Geneticist, Laboratory Corporation of America (LabCorp), Northeast Division, Genetics Services

Disclosure: Nothing to disclose.

Specialty Editor Board

James Bowman, MD  Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago

James Bowman, MD is a member of the following medical societies: Alpha Omega Alpha, American Society for Clinical Pathology, American Society of Human Genetics, Central Society for Clinical Research, and College of American Pathologists

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

David Flannery, MD, FAAP, FACMG  Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia

David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

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  3. Ambrosio C, Serra S, Alexandre M, Malcata A. [Arthralgia, bone pain, positive antinuclear antibodies and thrombocytopenia...diagnosis: Niemann-Pick disease]. Acta Reumatol Port. Jan-Mar 2009;34(1):102-5. [Medline].

  4. Cho YU, Chae JD, Lee WM, et al. [A Case of a Korean Adult Affected by Type B Niemann-Pick Disease: Secondary Sea-blue Histiocytosis and Molecular Characterization.]. Korean J Lab Med. Apr 2009;29(2):97-103. [Medline].

  5. Rodriguez-Pascau L, Gort L, Schuchman EH, Vilageliu L, Grinberg D, Chabas A. Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients. Hum Mutat. Mar 18 2009;[Medline].

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  8. Bayever E, August CS, Kamani N, et al. Allogeneic bone marrow transplantation for Niemann-Pick disease (type IA). Bone Marrow Transplant. 1992;10 Suppl 1:85-6. [Medline].

  9. Fernandez-Burriel M, Pena L, Ramos JC, et al. The R608del mutation in the acid sphingomyelinase gene (SMPD1) is the most prevalent among patients from Gran Canaria Island with Niemann-Pick disease type B. Clin Genet. Mar 2003;63(3):235-6. [Medline].

  10. Hellani A, Schuchman EH, Al-Odaib A, et al. Preimplantation genetic diagnosis for Niemann-Pick disease type B. Prenat Diagn. Dec 15 2004;24(12):943-8. [Medline].

  11. McGovern MM, Aron A, Brodie SE, Desnick RJ, Wasserstein MP. Natural history of type A Niemann-pPck disease; Possible endpoints for therapeutic trials. Neurology. Jan 24/2006;66(2):228-232. [Medline].

  12. McGovern MM, Wasserstein MP, Giugliani R, et al. A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B. Pediatrics. Aug 2008;122(2):e341-9. [Medline].

  13. Mendelson DS, Wasserstein MP, Desnick RJ, Glass R, Simpson W, Skloot G, et al. Type b niemann-pick disease: findings at chest radiography, thin-section CT, and pulmonary function testing. Radiology. Nov 22/2006;238(1):339-345. [Medline].

  14. Schuchman EH. The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. J Inherit Metab Dis. Oct 2007;30(5):654-63. [Medline].

  15. Shah AJ, Kapoor N, Crooks GM, et al. Successful hematopoietic stem cell transplantation for Niemann-Pick disease type B. Pediatrics. Oct 2005;116(4):1022-5. [Medline].

  16. Takahashi T, Suchi M, Desnick RJ, et al. Identification and expression of five mutations in the human acid sphingomyelinase gene causing types A and B Niemann-Pick disease. Molecular evidence for genetic heterogeneity in the neuronopathic and non-neuronopathic forms. J Biol Chem. Jun 25 1992;267(18):12552-8. [Medline].

 
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Autosomal recessive inheritance pattern.
 
 
 
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