AUTHOR INFORMATION

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Authored by Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine

Margaret McGovern, MD, PhD, is a member of the following medical societies: American Academy of Pediatrics, and American Society of Human Genetics

Edited by James Bowman, MD, Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Margaret McGovern, MD, PhD
Editor's Email:	James Bowman, MD

eMedicine Journal, June 22 2006, VOLUME 7, Number 6

INTRODUCTION

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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 NPD referred to what is currently termed NPD 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 NPD 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: NPD 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. 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 NPD. 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.

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

Frequency:

• Internationally: NPD is a rare disorder that occurs in all races, although NPD type A is more common in persons of Ashkenazi Jewish descent.

Race: NPD 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.

Sex: NPD types A and B are autosomal recessive disorders, affecting males and females equally.

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

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History:

• 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.



• NPD type B:


• • The clinical presentation and course in patients with type B disease are variable. 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 NPD 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 NPD 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 NPD 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 be quite variable. Some patients with NPD type B have massive enlargement, while others have milder enlargement that may remain unnoticed for years.



• Neurologic


• • Patients with NPD 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: NPD types A and B result from deficiency of acid sphingomyelinase and lysosomal accumulation of sphingomyelin.

DIFFERENTIALS

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GM1 Gangliosidosis
Gaucher Disease

WORKUP

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Lab Studies:

• Acid sphingomyelinase activity: The diagnosis is confirmed with measurement of the enzyme in peripheral blood white cells or in cultured fibroblasts.



• Complete blood count: Pancytopenia may be present secondary to the enlarged spleen.



• Cholesterol: Total cholesterol levels are elevated with a reduced high-density lipoprotein (HDL) fraction.



• Serum chemistry: Transaminase levels may be elevated.

Imaging Studies:

• Chest radiography reveals a typical reticulonodular pattern of infiltration, even in patients with no overt pulmonary symptoms.



• Bone age in patients with NPD type B can lag up to 2 years behind the chronologic age.

Other Tests:

• Acid sphingomyelinase mutation analysis: Sequencing of the gene is available in research laboratories and permits identification of precise gene mutations. This information is useful for genotype-phenotype correlation. Three common type A mutations (L302P, R496L, fsP330) predict the severe infantile form of the disease in homozygotes or compound heterozygotes for these 3 mutations. One common type B allele (deltaR608) is associated with milder disease. In addition, genotype information allows identification of carriers among at-risk family members and allows prenatal diagnosis using fetal DNA analysis.



• Pulmonary function test: Testing typically reveals decreased oxygen diffusion.

TREATMENT

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Medical Care: At present, no specific treatment is available for patients with any NPD subtypes, and treatment is symptomatic.

• Orthotopic liver transplantation in an infant with type A disease and amniotic cell transplantation in several patients with type B disease have been attempted with little or no success.



• Bone marrow transplantation in a patient with NPD type B was successful in reducing spleen and liver volumes, the sphingomyelin content of the liver, the number of Niemann-Pick cells in the marrow, and infiltration of the lungs detected radiologically. However, no long-term information is available because the patient died 3 months after transplantation.



• To date, lung transplantation has not been performed in any patient with type B disease who was severely compromised.



• Future prospects for treatment of patients with NPD type B include enzyme replacement and gene therapies.



• No specific treatment exists for patients with type A disease. Some patients have undergone stem cell transplantation, but reports of the outcomes have not yet occurred.

Surgical Care: Although patients may have massive splenomegaly, splenectomy should be avoided whenever possible because removal of the spleen is accompanied by deterioration of pulmonary status, which is caused by increased storage of sphingomyelin in the lung parenchyma.

Consultations:

• Geneticist: Evaluation and ongoing care by a trained metabolic geneticist should occur.



• Pulmonologist: Patients with NPD type B should undergo annual pulmonary function testing and evaluation.

Diet:

• Pediatric patients with NPD type B require frequent meals to promote growth. Many patients have early satiety because of organomegaly. For some patients, supplements with high levels of kilojoules are useful.



• In patients with NPD type A, feeding becomes a major difficulty as the disease progresses. Discussion with the family to determine a strategy for providing calories should occur.

Activity: Patients with type B disease should avoid contact sports because of the risk of splenic rupture.

MEDICATION

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Therapy using medications currently is not a component of the standard of care in patients with NPD.

FOLLOW-UP

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Further Inpatient Care:

• Pulmonary infections occur frequently in patients with NPD types A and B. Patients with type A disease may require inpatient care during severe episodes.

Complications:

• Splenic rupture: Patients with NPD type B are at risk for splenic rupture and should avoid contact sports.



• Liver failure: A small number of patients with NPD type B develop liver failure and may be candidates for liver transplantation.



• Pulmonary disease: Pulmonary disease is progressive in patients with type B disease and may result in oxygen dependance.

Prognosis:

• Type A disease is fatal in early childhood.



• Prognosis in patients with type B disease varies widely and presumably is related to the underlying mutations in the gene coding for sphingomyelinase.

Patient Education:

• Counsel families regarding genetic risk and the availability of prenatal testing.



• For excellent patient education resources, visit eMedicine’s Cholesterol Center and Statins Center. Also, see eMedicine’s patient education articles High Cholesterol, Cholesterol FAQs, and Atorvastatin (Lipitor).

MISCELLANEOUS

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Medical/Legal Pitfalls:

• The availability of prenatal diagnosis must be discussed with at-risk families.

TEST QUESTIONS

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CME Question 1: A 2-month-old infant is noted to have splenomegaly during a health maintenance visit. Which of the following inborn errors of metabolism is most likely to present in this manner?

A: Niemann-Pick disease
B: Phenylketonuria
C: Maple syrup urine disease
D: Tay-Sachs disease
E: Galactosemia

The correct answer is A: The presence of organomegaly should prompt a workup for a storage disorder. Of the choices listed, Niemann-Pick disease is a lysosomal storage disease that can manifest as splenomegaly in infants. Although Tay-Sachs disease is also a lysosomal storage disorder, it is not associated with organomegaly. If patients with phenylketonuria remain untreated, they present with developmental delay and pigmentary changes. Patients with maple syrup urine disease present with acidosis and overwhelming illness. Galactosemia is characterized by hypoglycemia.

CME Question 2: A 12-year-old boy who has essentially been healthy is noted to have hepatosplenomegaly on routine physical examination. Review of the records reveals that hepatosplenomegaly was palpable during the previous routine examination. CBC, sedimentation rate, viral and catscratch disease titers, and monospot test results are negative. Which of the following procedures is the most appropriate next step in evaluating the cause?

A: Obtain a bone marrow aspiration.
B: Refer the patient to a gastroenterologist for liver biopsy.
C: Schedule a repeat examination in 6 months.
D: Perform a bone scan.
E: Refer the patient for lysosomal enzyme testing.

The correct answer is E: In a patient with organomegaly, lysosomal storage diseases should be included among the differential diagnoses. Evaluation and diagnosis in such a patient can be obtained by measuring lysosomal enzyme levels in peripheral blood. Invasive procedures, such as liver biopsy and bone marrow aspiration, may provide evidence of storage disease but are not necessary to establish a diagnosis.

Pearl Question 1 (T/F): Niemann-Pick disease (NPD) type A is most common in persons of Ashkenazi Jewish descent.

The correct answer is True: NPD type A is one of several diseases occurring more commonly in the Ashkenazi Jewish population. Others include Tay-Sachs disease, Canavan disease, Gaucher disease, Fanconi anemia, and familial dysautonomia.

Pearl Question 2 (T/F): Cherry-red spots are pathognomonic for Niemann-Pick disease.

The correct answer is False: Cherry-red spots occur in a number of disorders, including Tay-Sachs disease and Niemann-Pick disease.

Pearl Question 3 (T/F): Patients with Niemann-Pick disease (NPD) and splenomegaly should undergo splenectomy.

The correct answer is False: Splenectomy in patients with NPD type B leads to exacerbation of the pulmonary complications of the disorder and should be recommended only for uncontrollable bleeding.

Pearl Question 4 (T/F): A couple with a child with Niemann-Pick disease type A has a 25% risk of having a similarly affected child in the next pregnancy.

The correct answer is True: Niemann-Pick disease is inherited as an autosomal recessive trait; therefore, a couple with an affected child has a 25% risk of having another child with the disorder in each pregnancy.

BIBLIOGRAPHY

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• 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].
• Schuchman EH, Desnick RJ: Niemann-Pick disease types A and B: acid sphingomyelinase deficiency. In: Metabolic and Molecular Bases of Inherited Disease. 7th ed. McGraw-Hill; 1997.
• 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 1992 Jun 25; 267(18): 12552-8[Medline].

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