Niemann Pick Disease

Niemann Pick Disease

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Niemann Pick Disease is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • lipid histiocytosis
  • lipidosis, sphingomyelin
  • NPD
  • sphingomyelinase deficiency
  • juvenile dystonic lipidosis
  • DAF syndrome

Disorder Subdivisions

  • Nieman Pick disease Type A (acute neuronopathic form)
  • Nieman Pick disease Type B
  • Nieman Pick disease Type C (chronic neuronopathic form)
  • Nieman Pick disease Type D (Nova Scotia variant)
  • Nieman Pick disease Type E
  • Nieman Pick disease Type F (sea-blue histiocyte disease)

General Discussion

Niemann-Pick disease (NPD) is a group of rare inherited disorders of fat metabolism. At least five types of Niemann-Pick disease have been identified (NPD types A, B, C, D, and E). Symptoms of types A and B occur as a result of a deficiency of the enzyme acid sphingomyelinase (ASM), which is needed to break down sphingomyelin, a fatty substance found mostly in the brain and nervous system. This deficiency results in abnormal accumulation of excessive amounts of sphingomyelin in many organs of the body such as the liver, spleen, and brain. Symptoms of type C occur because of impaired trafficking of large molecules within cells, which results in the accumulation of excessive amounts of cholesterol and other lipids (glycosphingolipids) tissues throughout the body. The metabolic defect in type C can lead to a secondary reduction in ASM activity in some cells.



The division of Niemann Pick disease into groups A, B, C and D was proposed by Allan Crocker in 1961 after he and Sidney Farber had expanded the category of Niemann-Pick disease by applying the diagnosis to all patients with "foam cells" and lipid storage in the tissues. This had led to the inclusion of older and less severely affected people than those originally described by Niemann and Pick.



Symptoms common to all types of Niemann-Pick disease include yellow discoloration of the skin, eyes, and/or mucous membranes (jaundice), progressive loss of motor skills, feeding difficulties, learning disabilities, and an abnormally enlarged liver and/or spleen (hepatosplenomegaly). The different types of Niemann-Pick disease are inherited as autosomal recessive traits.

Symptoms

Certain characteristics are common to all types of Niemann-Pick disease. Symptoms may include poor feeding habits, failure to grow and gain weight at the expected rate (failure to thrive), physical and mental impairment, swelling (distention) of the abdomen, and/or vomiting. Abnormal enlargement of the liver and spleen (hepatosplenomegaly) occurs in all types of this disorder, but the severity of the symptoms varies greatly. In some cases, swelling of the lymph nodes may also occur (lymphadenopathy). Some children with Niemann-Pick disease have yellow discoloration of the skin, eyes, and/or mucous membranes (jaundice). Abnormal amounts of sphingomyelin, cholesterol, glycosphingolipids, and bis (monoacylglycero)-phosphate accumulate in the organs of the chest and abdomen. In some cases, affected individuals may experience neurological impairment including loss of speech, impairment of voluntary muscle movements (myoclonus), convulsions, and/or dementia.



Niemann-Pick disease type A is the most common form of the disease. Activity of the acid sphingomyelinase (ASM) enzyme ranges from none to 1% of normal. The abnormal accumulation of fats in various parts of the body occurs in the developing fetus. Between the ages of six months to 12 months, low levels of the enzyme sphingomyelinase results in the abnormal enlargement of the liver and spleen (hepatosplenomegaly) and abnormalities of the nervous system. Affected infants may experience poor feeding habits and failure to thrive, which may become apparent during the first few weeks of life.



Additional symptoms may include abdominal swelling (distention), vomiting, diarrhea, fever (pyrexia), bright red spots in the eyes (macula), and/or a brownish-yellow skin discoloration. Abnormal enlargement of the liver occurs more often than enlargement of the spleen. A gradual decline of motor and intellectual function resulting in a degenerative muscle weakness and floppiness may also occur. An affected infant may lose the ability (regression) to hold his or her head up, sit up, or manipulate objects. In some cases, seizures and uncontrolled involuntary muscle movements (spasticity) may also occur. The severity of the symptoms increases rapidly and life-threatening complications usually occur early during childhood.



Individuals with Niemann Pick disease Type B have ASM enzyme activity that is approximately 10% of normal. Symptoms of Niemann-Pick disease type B begin during infancy or early childhood and typically include an abnormally enlarged liver and spleen (hepatosplenomegaly). Bright red spots in the eyes may be present in some affected individuals. The symptoms of this type of Niemann-Pick disease progress more slowly than other types. Nervous system impairment in type B is minimal in comparison to other types. Affected children have an abnormally slow growth rate and may have an increased susceptibility to repeated lung (respiratory) infections. The severity of Niemann-Pick disease type B varies greatly from case to case.



The onset of Niemann-Pick disease Type C (NPC) usually occurs in children between the ages of three and 10. However, NPC can present at any time from fetal life to late adulthood. Life threatening complications may occur at any time. The liver and spleen are often enlarged (hepatosplenomegaly) in infants and children, but many affected individuals do not have enlarged organs, particularly those who present later in life. Other symptoms include a yellowish discoloration of the skin, eyes, and/or mucous membranes (jaundice), progressive impairment of voluntary movements (because of ataxia, dystonia or ataxia), seizures, and/or tremors. Additional symptoms include an inability to form words and speak clearly (dysarthria); difficulty swallowing (dysphagia), and sudden loss of muscle tone, manifest as head drops or falls, brought on by emotional excitement, particularly laughter (gelastic cataplexy).



A characteristic symptom associated with Niemann-Pick disease type C is difficulty or loss of rapid up and down eye movements (vertical supranuclear gaze palsy). Over time, horizontal rapid eye movements are also impaired, and are eventually lost.



Individuals with Niemann-Pick disease type C are unable to transport lipids efficiently within cells. As a result, excessive amounts of cholesterol and glycosphingolipids accumulate in the liver, spleen, and brain. The slow progression of symptoms generally leads to the loss of mental and motor function in early adulthood. Death usually occurs in the late second or third decade from aspiration pneumonia, but patients have survived into their seventh decade.



Niemann-Pick disease type D (Nova Scotia variant) is biochemically and clinically inseparable from type C, and results from mutations in NPC1 gene. The group was created to define patients who shared a common ancestor from Nova Scotia.



Niemann-Pick disease type E is a variant of Type C but typically does not begin until adulthood. Symptoms may include a moderately enlarged liver and spleen. In most cases, no neurological impairment is present. In rare cases, neurological symptoms may include the impaired ability to coordinate movement (ataxia), progressive dementia, and impaired eye movements (ophthalmoplegia).



Another possible form of the disease, which affects people of Spanish descent, has been named Niemann-Pick disease type F or sea-blue histiocyte disease. The disorder is characterized by abnormal (sea blue) cells in the blood and/or bone marrow. Symptoms may include an abnormally enlarged liver or spleen, scarring of the liver (cirrhosis), and bright red spots in the eyes (macula). Impairment of the neurological system is minimal. It is not clear if this is a mild form of Niemann-Pick disease type B, a separate form of Niemann-Pick disease, or a completely different disorder altogether.

Causes

Niemann Pick disease is a group of rare disorders that are inherited as autosomal recessive genetic traits.



Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.



Type A and B

Niemann Pick disease types A and B are caused by an abnormality in the gene for acid sphingomyelinase (ASM) that leads to a deficiency of this enzyme.



Symptoms of Niemann-Pick disease types A and B develop due to a deficiency of ASM. This results in the abnormal accumulation of a fatty substance (i.e., sphingomyelin) in various organs of the body including the brain, liver, and/or spleen. In Niemann-Pick disease type B, sphingomyelin rarely accumulates in the brain, which is why Niemann-Pick disease type B is rarely associated with neurological abnormalities.



The defective gene responsible for Niemann Pick disease types A and B has been mapped to the short arm (p) of chromosome 11 (11p15.4-p15.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22, and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 11p15.4-p15.1" refers to band 15.4-15.1 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.



Type C and D

Niemann Pick disease types C and D are caused by an abnormality in one of two specific genes for cholesterol metabolism (NPC1 and NPC2) that leads to a reduction in cholesterol metabolism. The majority of affected individuals have a mutation in the NPC1 gene. Fewer than 15 patients have been identified with mutations in the NPC2 gene.



The symptoms of Niemann-Pick disease type C develop as a consequence of impaired trafficking of cholesterol and other lipids within cells. Free cholesterol accumulates in peripheral tissues (liver, spleen and bone marrow), whereas complex fats (glycosphingolipids) are the predominant stored compounds in the brain. Cholesterol accumulation often leads to a secondary deficiency of acid sphingomyelinase.



The defective genes responsible for Niemann-Pick disease type C, termed NPC1 and NPC2, have been mapped to the long arm (q) of chromosome 18 (18q11-q12) and the long arm (q) of chromosome 14 (14q24.3), respectively. More than 150 different gene mutations have been identified in NPC1. The most frequent mutation, occurring in 15% of cases in Western Europe, is I1061T. Another mutation (G992W) has been found almost uniformly in persons with the Nova Scotia variant (Niemann-Pick disease D). Two affected persons have been identified with gene mutations in the NPC2 gene.

Affected Populations

Niemann-Pick disease affects males and females in equal numbers. These diseases have been identified in people of all races.



The number of individuals affected by Niemann-Pick disease type A appears to be higher in families of Ashkenazi Jewish ancestry with one in 80 potentially being carriers for the disease. Type B is also more common in Tunisia, Morocco, and Algeria. According to one estimate, Niemann-Pick disease type B affects approximately 1,000 individuals worldwide.



The prevalence of Niemann-Pick disease type C in Western Europe has been estimated to be 1 in 150,000. More than 300 individuals are affected by Niemann-Pick disease type C in the United States. Type C occurs more frequently in the Spanish-American population of southern New Mexico and Colorado. The term Niemann-Pick disease type D is used to describe a specific population of Acadians from Nova Scotia, Canada, and their descendants.

Standard Therapies

Diagnosis

The diagnosis of Niemann-Pick disease is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests.



The diagnosis of Niemann-Pick disease types A or B is confirmed by a blood test that reveals low levels of the acid sphingomyelinase (ASM) enzyme in white blood cells. DNA testing can be used to identify ASM gene mutations. Carrier testing and prenatal diagnosis are available if a specific ASM gene mutation is identified in an affected family member.



The diagnosis of Niemann-Pick disease type C is made by testing a sample of cells obtained by skin biopsy for their ability to transport cholesterol and other lipids. Transport of cholesterol is determined by measuring the conversion of one form of cholesterol (free cholesterol) to another (cholesterol ester). The process is known as esterification. Storage of cholesterol is demonstrated by staining the cells with a compound that glows under ultraviolet light (filipin). DNA testing can be used to identify over 90% of individuals with a NPC1 gene mutation. DNA testing for NPC2 gene mutations is available on a research basis only. Carrier testing and prenatal diagnosis are available if a NPC1 mutation has been identified in an affected family member.



Treatment

Treatment for individuals with Niemann-Pick disease is symptomatic and supportive. No specific treatment is available for any type of this disease. Supportive care from these specialists may be helpful: pulmonologist for respiratory problems; cardiologist for heart problems; liver and spleen specialist; nutritionist; physical therapist; gastroenterologist and learning specialist.



Individuals with types C and D are often placed on low cholesterol diets. However, such diets and drugs that lower cholesterol levels in the body have not been effective in halting the progress of the disease.



Genetic counseling will be of benefit for affected individuals and their families.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.



For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



Paul Orchard, MD, is the principal investigator for a study being carried out at the University of Minnesota Medical Center of treatment of several inborn errors of metabolism, including Niemann-Pick disease, by bone marrow transplantation. For information, visit the ClinicalTrials.gov web site or contact Dr. Orchard at: (612) 626-2961 or orcha001@umn.edu.



Actelion Ltd., a Swiss biopharmaceutical company, is studying the drug miglustat (Zavesca) as a possible treatment for people with Niemann Pick type C. Initial research demonstrated that miglustat is crossing the blood-brain barrier and suggests that the drug may be restoring function of brain cells (neurons) affected by the disease process. The study includes both adult and juvenile patients. Further study is necessary to determine the long-term safety and effectiveness of this potential treatment for individuals with Niemann Pick type C. The research is being carried out at Columbia University in the United States and The Royal Manchester Children's Hospital in the United Kingdom. For information, visit the company's web site (www.actelion.com) or contact the company at:



Gewerbestrasse 16

4123 Allschwil

Switzerland



Bone marrow transplantation is being tested as a possible treatment for Niemann-Pick disease (NPD) types A and B. Bone marrow transplantation is not recommended for individuals who have severe neurological symptoms. More research is needed to determine the long-term safety and effectiveness of this procedure as a treatment for Niemann-Pick disease types A and B. For more information about bone marrow transplantation, contact:



Dr. Edward Schuchman

Phone: 212-659-6711

Fax: 212-849-2447

e-mail: edward.schuchman@mssm.edu



The Genzyme Corporation and Mount Sinai Medical Center have completed a clinical trial of enzyme replacement therapy. For more information about this trial, contact:



Dr. Robert Desnick

Phone: (212) 659-6700

Email: rjdesnick@mssm.edu



Genzyme manufactures acid sphingomyelinase, which was granted FDA orphan drug status in 2000 for the treatment of Niemann- Pick disease type B.



Both Dr. Schuchman and Dr. Desnick are members of the staff of the International Center for Types A and B Niemann-Pick Disease, a newly formed organization that provides information and support for patients with Niemann-Pick disease types A and B, as well as support to scientists and physicians. Contact information is as follows:



Charlene Pearlman

Department of Human Genetics

Box 1498

Mount Sinai School of Medicine

1425 Madison Ave.

New York, NY 10029

Tollfree: (800) 673-4685

Phone: (212) 659-6779



Dr. Carole Oddoux is in the process of setting up a genetic test for Niemann-Pick disease type A. Blood samples are needed from individuals who are known to be carriers of NPD for use as controls in the validation of the test. Please contact Dr. Oddoux if you would be willing to donate such specimens.



Carole Oddoux, Ph.D.

NYU Medical Centre

Human Genetics Prog, MSB 136

550 First Avenue

New York, NY 10016

Phone: 212-263-7621

Fax: 212-562-2642; 212-263-7590

Email: oddouc01@med.nyu.edu



In 2003, the Second International Conference on NPD Type C was held in Tucson, Arizona. Several possible future therapeutic strategies were outlined and, in addition, there is a report on possible gene replacement or repair and other work, including information on continuing research by Dr. Peter Lobel. Dr. Lobel is credited with discovering the NPC2 C gene. This report can be accessed by contacting the National Niemann-Pick Disease Foundation. (See the Resources section of this report for contact information). This foundation's Web site provides other information on recent and current research.



Dr. Marc Patterson, the lead investigator for current research underway at Columbia University on Niemann-Pick disease type C, is available for inquiries from patients and their families. His information is as follows:



Marc C. Patterson, MD

Head, Division of Pediatric Neurology

Columbia University Medical Center

Harkness Pavilion, HP5-542

180 Fort Washington Avenue

New York NY 10032-3791

Phone: 212-305-6038

Fax: 212-305-1253

Email: mcp73@columbia.edu.

References

TEXTBOOKS

Patterson MC. Niemann-Pick Disease, type C. In: NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:485.



Menkes JH., au., Pine JW, et al., eds. Textbook of Child Neurology, 5th ed. Baltimore, MD: Williams & Wilkins; 1995:101-4.



Buyse ML., ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:1252-3.



Fauci AS, et al., eds. Harrison's Principles of Internal Medicine, 14th Ed. New York, NY: McGraw-Hill, Inc; 1998:2175.



Lyon G, et al., eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. New York, NY: McGraw-Hill Companies; 1996:55-57, 238-40.



Pentchev PG, Vanier MT, Suzuki K, Patterson MC. Type C Niemann-Pick disease: a cellular cholesterol lipidosis. In: Scriver CR, et al., eds. The Metabolic and Molecular Basis of Inherited Disease, 7th Ed. New York, NY; McGraw-Hill Companies, Inc.;1995.



Patterson MC, Vanier MT, Suzuki K, et al. Niemann-Pick disease type C: a lipid trafficking disorder. In: Scriver, et al., eds. The Metabolic and Molecular basis of Inherited Disease, 8th Ed. New York, NY; McGraw-Hill Co., Inc.;2000.



Bennett JC, Plum F., eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:



Behrman RE., ed. Nelson Textbook of Pediatrics, 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:



Adams, RD, et al., eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill, Companies; 1997:



JOURNAL ARTICLES

Lachmann RH, te Vruchte D, Lloyd-Evans E, et al., Treatment with miglustat reverses the lipid-trafficking defect in Niemann-Pick disease type C. Neurobiol Dis. 2004;654-8.



Naureckiene S, Sleat DE, Lackland H, et al. Identification of HE1 as the second gene of Niemann-Pick C disease. Science. 2000;290:2298-301.



Kolodny EH, Niemann-Pick disease. Curr Opin Hematol. 2000;7:48-52.



Hsu YS, et al., Niemann-Pick disease type C (a cellular cholesterol lipidosis) treated by bone marrow transplantation. Bone Marrow Transplant. 1999;24:103-7.



Jan MM, et al., Nova Scotia Niemann-Pick disease (type D): clinical study of 20 cases. J Child Neurol. 1998;13:75-8.



Liscum L, et al., Niemann-Pick disease type C. Curr Opin Lipidol. 1998;9:131-5.



Carstea ED, et al., Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science. 1997;277:228-31.



Loftus SK, et al., Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. Science. 1997;277:232-5.



Pennisi E, Newfound gene holds key to cell's cholesterol traffic. Science. 1997;277:180-1.



Carstea ED, Polymeropoulos MH, Parker CC, et al. Linkage of Niemann-Pick disease type C to human chromosome 18. Proc Natl Acad Sci USA. 1993;90:2002-4.



Paterson CC, The effect of cholesterol-lowering agents on hepatic and plasma cholesterol in Niemann-Pick disease type C. Neurology. 1993;43:61-4.



Peyrat MF, et al., Prenatal diagnosis of Niemann-Pick type C disease: current strategy from an experience of 37 pregnancies at risk. Am J Hum Genet. 1992;51:111-22.



Levran O, et al., Identification and expression of a common missense mutation (l302p) in the acid sphingomyelinase gene of Ashkenazi Jewish type A Niemann-Pick disease patients. Blood. 1992;80:2081- 7.



Hulette CM, et al., Adult onset Niemann-Pick disease type C presenting with dementia and absent organomegaly. Clin Neuropathol. 1992;11:293-7.



Bayever E, et al., Bone marrow transplantation for Niemann-Pick type 1A disease. J Inherit Metab Dis. 1992;15:919-28.



Filling-Katz MR, et al., Ophthalmologic manifestations of type b Niemann-Pick diseases. Metab Pediatr Syst Opthalmologic. 1992;15:16-20.



Winsor EJ, et al., Genetic and demographic aspects of Nova Scotia Niemann-Pick disease (type D). Am J Human Genet. 1978;30:530-8.



FROM THE INTERNET

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The johns Hopkins University: Entry No. 257220 Last Update: 10/7/03, Entry No. 607616 Last update 3/13/03, Entry No. 257200 Last Update 3/13/03.



Patterson MC. (Updated 9/10/01). Niemann-Pick Disease, Type C. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://genetests.org (accessed 10/03).



McGovern M. Niemann-Pick Disease. eMedicine.com, topic 2889, last Update 6/6/02.

Resources

CLIMB (Children Living with Inherited Metabolic Diseases)

Climb Building

176 Nantwich Road

Crewe, CW2 6BG

United Kingdom

Tel: 4408452412173

Fax: 4408452412174

Email: enquiries@climb.org.uk

Internet: http://www.CLIMB.org.uk



National Tay-Sachs and Allied Diseases Association, Inc.

2001 Beacon Street

204

Brookline, MA 02146-4227

USA

Tel: (617)277-4463

Fax: (617)277-0134

Tel: (800)906-8723

Email: info@ntsad.org

Internet: http://www.NTSAD.org



National Niemann-Pick Disease Foundation, Inc.

401 Madison Avenue

Suite B

PO Box 49

Fort Atkinson, WI 53538-0049

Tel: (920)563-0930

Fax: (920)563-0931

Tel: (877)287-3672

Email: nnpdf@nnpdf.com

Internet: http://www.nnpdf.org



NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801

Bethesda, MD 20824

Tel: (301)496-5751

Fax: (301)402-2186

Tel: (800)352-9424

TDD: (301)468-5981

Internet: http://www.ninds.nih.gov/



Ara Parseghian Medical Research Foundation

3530 E. Campo Abierto

Suite 105

Tucson, AZ 85718-3327

USA

Tel: (520)577-5106

Fax: (520)577-5212

Email: victory@parseghian.org

Internet: http://www.parseghian.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Instituto de Errores Innatos del Metabolismo

Carrera 7 No 40 - 62

Bogota,

Colombia

Tel: 5713208320

Email: abarrera@javeriana.edu.co

Internet: http://www.javeriana.edu.co/ieim/programas_ieim.htm



Hide & Seek Foundation for Lysosomal Disease Research

6475 East Pacific Coast Highway Suite 466

Long Beach, CA 90803

Tel: (877)621-1122

Fax: (866)215-8850

Email: info@hideandseek.org

Internet: http://www.hideandseek.org



For a Complete Report

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