eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Niemann-Pick Disease

Author: Margaret M McGovern, MD, PhD, Professor and Chair of Pediatrics, Stony Brook University, New York
Contributor Information and Disclosures

Updated: May 27, 2009

Introduction

Background

Niemann-Pick disease (NPD) is a lipid storage disorder that results from the deficiency of a lysosomal enzyme, acid sphingomyelinase. The original description of Niemann-Pick disease referred to what is currently termed Niemann-Pick disease type A, which is a fatal disorder of infancy characterized by failure to thrive, hepatosplenomegaly, and a rapidly progressive neurodegenerative course that leads to death by age 2-3 years. Since this original description, 6 subtypes of Niemann-Pick disease have been described, including type B (which is a nonneuronopathic form observed in adults) and other rarer forms that result from defects in cholesterol metabolism. All 6 subtypes are inherited as autosomal recessive traits and display variable clinical features.

Pathophysiology

Niemann-Pick disease types A and B result from the deficient activity of sphingomyelinase, a lysosomal enzyme encoded by a gene located on chromosome bands 11p15.1-p15.4.^1,2 The enzymatic defect results in pathologic accumulation of sphingomyelin (which is a ceramide phospholipid) and other lipids in the monocyte-macrophage system, the primary site of pathology in patients with Niemann-Pick disease. Additional progressive deposition of sphingomyelin in the central nervous system results in the neurodegenerative course observed in type A, which shares systemic disease manifestations with type B. Severity of systemic involvement varies in affected individuals. Systemic involvement includes progressive lung disease, hepatosplenomegaly, short stature, and pancytopenia.³

The complete sphingomyelinase genomic region has been isolated and sequenced. A total of 12 mutations that cause Niemann-Pick disease types A and B have been identified, namely, 9 single-base substitutions and 3 small deletions.

Frequency

International

Niemann-Pick disease is a rare disorder that occurs in all races,^4,5 although Niemann-Pick disease type A is more common in persons of Ashkenazi Jewish descent.

Race

Niemann-Pick disease types A and B occur in all races, although type A disease occurs more frequently in individuals of Ashkenazi Jewish descent, in whom the carrier frequency is approximately 1 in 80. Guidelines for carrier screening in individuals of Ashkenazi Jewish descent have been established.⁶

Sex

Niemann-Pick disease types A and B are autosomal recessive disorders, equally affecting males and females.

Age

Type A disease is fatal in early childhood. In contrast, patients with type B disease survive to adulthood, although most present in childhood with hepatosplenomegaly.

Clinical

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. Few motor milestones are achieved, and the disease course is characterized by psychomotor retardation followed by regression. With advancing age, the loss of motor function and deterioration of intellectual capabilities are progressively debilitating, and in later stages, spasticity and rigidity are evident, and affected infants are completely unable to interact with their 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 alveolar infiltration 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.
  • 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.

Physical

• Head and neck: Patients with type A disease usually have a cherry-red spot on ophthalmologic examination. In type B disease, up to half 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.

Causes

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

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