Niemann-Pick Disease

Continuing Education Activity

The management of Niemann-Pick disease and new approaches have been recently introduced. To achieve optimal outcomes, the basic and clinical aspects of Niemann-Pick disease must be clearly defined. This activity reviews the etiology, epidemiology, and pathophysiology of Niemann-Pick disease and focuses on the evaluation, management, and complications of the disease, and highlights the interprofessional team's role in fostering the best possible outcomes to patients with Niemann-Pick disease.


  • Identify the risk of getting Niemann-Pick disease in children of carrier parents.
  • Describe the investigations used in diagnosing Niemann-Pick disease.
  • Review the current treatment options available for the management of patients diagnosed with Niemann-Pick disease.
  • Explain the interprofessional team's role in planning care and highlight the importance of coordinated communication with other professionals in improving clinical outcomes and lowering complications.


Lysosomal storage diseases are characterized by inherited deficiencies of one or more lysosomal enzymes involved in the degradation of lipids and their products. Niemann-Pick disease (NPD) is a lysosomal storage disease caused by acid sphingomyelinase deficiency (ASMD), which catalyzes the hydrolysis of sphingomyelin (SM) to ceramide and phosphocholine. As a result, SM and its precursor lipids begin to accumulate in lysosomes, mainly in macrophages. These lipid-laden macrophages deposit in the liver, spleen, lungs, and brain causing hepatosplenomegaly, cytopenias, lung disease, and neurologic symptoms.[1]

Traditionally, NPD is classified into four subtypes: type A, B, C, and E. Type A is known as infantile neurovisceral form with very low acid sphingomyelinase (ASM) activity and is usually fatal before the age of three. It affects younger children and results in neurological deficits and impaired growth. Type B is less severe and is characterized by variable visceral symptoms and minimal neurological involvement. The most common visceral symptoms in these phenotypes include hepatosplenomegaly, thrombocytopenia, and interstitial lung disease. Niemann-Pick disease type C (NPC) has a heterogeneous clinical presentation and includes systemic, neurologic, and psychiatric involvement. It usually affects adults but can occur during any phase of life. Early-onset NPC manifests as infantile jaundice, hepatosplenomegaly, or isolated splenomegaly, and usually, these symptoms precede neurological involvement. In about 50% of adult patients, NPC can manifest without or minimal hepatosplenomegaly, so the presence of isolated splenomegaly in patients with neurological or psychiatric illnesses favors NPC. Type E is a less common variant of NPD that develops in adulthood. The most common neurologic manifestations of NPD include cognitive or motor developmental delay in childhood-onset cases, vertical supranuclear gaze palsy, ataxia, dysarthria, dysphagia, and dystonia.[2]


Niemann-Pick disease (NPD) is inherited in an autosomal recessive pattern, which means both copies of the gene must have mutations for the manifestation of the disease. NPD types A and B are caused by missense mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. Over 180 mutations in SMPD1 have been identified. NPD type C is caused by mutations in NPC1 (located on chromosome 18) and NPC2 (located on chromosome 14) genes. The mutations in these genes lead to abnormal or defective formation of proteins, which impair the movement of lipids out of the cells, leading to their accumulation within the cells.[3] 


Niemann-Pick disease (NPD) types A and B affect 1 in 250,000 individuals. The prevalence is high in Ashkenazi Jewish descent, where it affects 1 in 40,000 individuals. NPD type C affects 1 in 150,000 persons. Type C is more prevalent in French-Acadian descent in Nova Scotia.[4]


Niemann-Pick disease types A and B are caused by mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene, leading to a strongly decreased activity of acid sphingomyelinase (ASM). The enzyme ASM is mainly present in lysosomes and converts sphingomyelin (SM) to ceramide and phosphocholine. In ASMD, SM and its precursor lipids accumulate in lysosomes and cause cellular damage.

Niemann-Pick disease type C (NPC) is further classified as type C1 or type C2 based on the pathogenic mutations in the NPC1 or NPC2 genes, respectively. NPC1 is the predominant subtype affecting about 95% of the patient population. NPC1 and NPC2 proteins are present in late endosomes and lysosomes and are involved in the transport and intracellular mobilization of cholesterol and sterols. The loss of function of NPC1 and/or NPC2 proteins blocks cholesterol egress from lysosomes, resulting in an excessive build-up of cholesterol in lysosomes. Consequently, toxic cholesterol accumulation results in cellular and organ damage.[5][6]


Due to the ineffective transport system, the affected cells become enlarged, sometimes as big as 90 micrometers in diameter, due to the accumulation of sphingomyelin and cholesterol. Histology shows lipid-laden macrophages in the marrow, also called foam-cells. Numerous small vacuoles of relatively uniform size are created, which give the cytoplasm a foamy appearance. Electron microscopy shows electron-opaque, concentrically laminated inclusions within the macrophage cytoplasm.

History and Physical

Nieman-Pick disease (NPD) type A presents in the first few months of life, usually before three months of age, as hepatosplenomegaly and growth retardation. By the age of one year, neurological symptoms appear as psychomotor retardation and regression of developmental milestones. All patients with NPD type A have a classical eye finding called cherry-red spot. These children usually do not survive past early childhood. NPD type B presents in mid-childhood and is not as severe as type A. These patients have hepatosplenomegaly, interstitial lung disease (ILD), causing recurrent lung infections, thrombocytopenia, and slowed bone growth. About one-third of patients with type B NPD have the cherry-red spot and neurological symptoms. NPD type C can present at any age but usually affects children. Affected individuals can have ataxia, dystonia, supranuclear gaze palsy (SNGP), dysphonia, dysphagia, and severe liver and lung disease.

The following findings can be expected while examining the body systems.


  • Hepatomegaly
  • Splenomegaly


  • Interstitial lung disease
  • Decreased diffusion capacity
  • Recurrent lung infections


  • Jaundice


  • Thrombocytopenia
  • Hypercholesterolemia


  • Impaired growth of long bones
  • Slowed mineralization of bones
  • Coxa vara


  • Bright cherry-red fovea centralis surrounded by a white or pale macula
  • Corneal opacification
  • Brown discoloration of the anterior lens capsule


  • Ataxia
  • Dystonia
  • Dysphagia
  • Dysphonia
  • Developmental delay and/or regression
  • Mental retardation
  • Peripheral neuropathy
  • Gelastic catatonia
  • SNGP
  • Tremors[1][7][8]


For suspected NPD type A pr B, a blood sample is drawn, and the activity of ASM is measured in leukocytes. In the case of low enzyme activity, additional gene testing can further evaluate the disease. 

For NPD type C, a skin biopsy is taken and stained with a special stain, 'filipin,' to measure the enzyme activity. DNA testing can be done to look for genes that cause type C disease.[9]

Once the diagnosis is confirmed, special attention should be paid to look for disease spread and manifestations in the following systems.

  • Liver
    • Liver enzymes should be measured periodically. Liver elastography or liver biopsy should be done in case of severe liver disease.
  • Pulmonary
    • Spirometry should be done periodically. High-resolution computed tomography (HRCT) is done for interstitial lung disease (ILD). 
  • Hematologic
    • Measure platelet counts and spleen volume.
  • Cardiovascular
    • Measure HDL-cholesterol and LDL-cholesterol.
  • Neurological
    • A complete neurological exam should be performed at every visit. 
  • Eye
    • Fundoscopy to look for the cherry-red spot on the macula. 
  • Exercise Intolerance
    • Spirometry and exercise intolerance test.
  • Pain and Fatigue
    • A questionnaire should be used for grading.
  • Severity of Disease
    • Measure the quantity of SM and its derivatives, macrophage markers, and oxysterols.[10][11]

Treatment / Management

For type A and B Niemann-Pick disease (NPD), there is no cure. Supportive care is the mainstay of treatment. Physicians try to keep low blood lipids levels with statins, and liver functions are monitored. If thrombocytopenia leads to bleeding episodes, transfusion of blood products may be required. For patients with ILD, oxygen is provided. Organ transplant has also been tried but with limited success. Enzyme replacement therapies and gene therapies are undergoing trials and may become the mainstay of treatment in the future.[12]

For type C disease, supportive care is also the mainstay of treatment. Physical therapy is provided for neurological symptoms. Pain is managed with analgesics. Miglustat is a glucosylceramide synthase inhibitor and helps in Niemann-Pick disease and Gaucher disease by decreasing glucocerebroside production. It is approved in Europe, Canada, and Japan but is not yet approved in the United States.[13] 

Differential Diagnosis

Other lysosomal storage diseases should be kept in the differentials, especially Gaucher disease, Tay-Sachs disease, and Metachromatic leukodystrophy. Gaucher disease also presents with hepatosplenomegaly and cytopenias, but bone pain and lesions are more prominent. The deficient enzyme in Gaucher disease is glucocerebrosidase, which leads to the accumulation of glucocerebroside inside cells instead of sphingomyelin, which is found in Niemann-Pick disease. Tay-Sachs disease, although it does not present with hepatosplenomegaly, neurodegeneration, developmental delay, and cherry-red spot on the macula, are prominent features. The deficient enzyme here is hexosaminidase A which causes a buildup of GM2 gangliosides. Metachromatic leukodystrophy causes central and peripheral demyelination and can manifest as ataxia or other neurological symptoms.[14] 

Apart from these, other diseases affecting the liver and brain should be kept in mind based on the initial presentation.


Type A

It is almost always fatal, and affected children are unlikely to live beyond 4 years of age.

Type B

These children have a slightly better prognosis than type A and may live till late childhood or early adulthood. But they develop many complications from the disease, so the life quality is not so good.

Type C

The prognosis depends on the time of the initial presentation. If it affects in infancy, the chances are very poor for survival beyond 5 years of age. If it affects after 5 years, then patients may live to the age of 20 years. But each patient has a slightly different outlook depending on the severity and presentation of the disease.[15]


Niemann-Pick disease is a progressive disease, and quite often, complications develop with time. 

  • The initial involvement of the liver can transform into fulminant hepatic failure.
  • Deterioration of the lungs can result in respiratory insufficiency.
  • Progressive neurodegeneration can cause dementia, seizures, and schizophrenia-like psychosis.
  • Severe thrombocytopenia can result in internal or external bleeding.
  • Coronary artery and valvular heart disease
  • Bones become deformed, causing enlarged bone marrow cavities, thinned cortical bone, or coxa vara.[16]

Deterrence and Patient Education

Although Niemann-Pick disease is fatal and often untreatable, the sooner it is recognized, the better is the chance to slow down its progression and limit the complications. Niemann-Pick disease is an autosomal recessive (AR) disease, which means both the parents must be affected or carriers of the genes for the disease to pass on to their children. Carrier persons of an AR disease do not show signs and symptoms of the disease, but they can pass the defective gene to the next generation. So if both the parents are carriers, each pregnancy has a 25% chance of producing a child with the disease. Parental counseling should be done, and genetic testing should be offered to families who may be carriers of the disease.

Enhancing Healthcare Team Outcomes

Niemann-Pick disease has negative repercussions for many organs, and with or without treatment, it has high morbidity and mortality. The condition is best managed by an interprofessional team that includes a hepatologist or gastroenterologist, endocrinologist, neurologist, and genetic counselor. Also, family care, nursing support, and social support are an integral part of the management. A lead consultant should be in charge of patient care, and a nurse specialist, along with other specialists in the respective fields, should be involved to cover all the aspects of the disease. Patient education is crucial, and social worker involvement, including a geneticist, is essential. In some parts of the world, preventive strategies include prenatal screening, restrictions on issuing marriage licenses to two people with the same disease. The screening of children and pregnant women who visit clinicians is an effective strategy to limit the disease but is not cost-effective yet. The social worker should ensure that the caregivers and patients have adequate support and financial resources to continue with treatment. Nurses should educate patients on the importance of treatment compliance to avoid or halt serious complications and monitor treatment progress. Pharmacists may soon play a greater role as new drug products assist in gene therapy or enzyme replacement therapy that can theoretically cure the disease.

Active collaboration and discussion between interprofessional team members will lead to a better understanding of the progression and control of the disease. [Level 5]

Article Details

Article Author

Hamza Bajwa

Article Editor:

Waqas Azhar


2/16/2021 8:32:45 PM

PubMed Link:

Niemann-Pick Disease



Thurm A,Chlebowski C,Joseph L,Farmer C,Adedipe D,Weiss M,Wiggs E,Farhat N,Bianconi S,Berry-Kravis E,Porter FD, Neurodevelopmental Characterization of Young Children Diagnosed with Niemann-Pick Disease, Type C1. Journal of developmental and behavioral pediatrics : JDBP. 2020 Feb 17;     [PubMed PMID: 32073546]


Eskes ECB,Sjouke B,Vaz FM,Goorden SMI,van Kuilenburg ABP,Aerts JMFG,Hollak CEM, Biochemical and imaging parameters in acid sphingomyelinase deficiency: Potential utility as biomarkers. Molecular genetics and metabolism. 2020 Feb 12;     [PubMed PMID: 32088119]


Xu Y,Zhang Q,Tan L,Xie X,Zhao Y, The characteristics and biological significance of NPC2: Mutation and disease. Mutation research. 2019 Oct - Dec;     [PubMed PMID: 31843136]


Bianconi SE,Hammond DI,Farhat NY,Dang Do A,Jenkins K,Cougnoux A,Martin K,Porter FD, Evaluation of age of death in Niemann-Pick disease, type C: Utility of disease support group websites to understand natural history. Molecular genetics and metabolism. 2019 Apr;     [PubMed PMID: 30850267]


Pará C,Bose P,Pshezhetsky AV, Neuropathophysiology of Lysosomal Storage Diseases: Synaptic Dysfunction as a Starting Point for Disease Progression. Journal of clinical medicine. 2020 Feb 25;     [PubMed PMID: 32106459]


Cawley NX,Sojka C,Cougnoux A,Lyons AT,Nicoli ER,Wassif CA,Porter FD, Abnormal LAMP1 glycosylation may play a role in Niemann-Pick disease, type C pathology. PloS one. 2020;     [PubMed PMID: 31999726]


Kresojević N,Mandić-Stojmenović G,Dobričić V,Petrović I,Brajković L,Stefanova E,Svetel M,Kostić V, Very Late-Onset Niemann Pick Type C Disease: Example of Progressive Supranuclear Palsy Look-Alike Disorder. Movement disorders clinical practice. 2020 Feb;     [PubMed PMID: 32071943]


Patterson M, Niemann-Pick Disease Type C 1993;     [PubMed PMID: 20301473]


Warren M,Shimura M,Wartchow EP,Yano S, Use of electron microscopy when screening liver biopsies from neonates and infants: experience from a single tertiary children's hospital (1991-2017). Ultrastructural pathology. 2020 Jan 3;     [PubMed PMID: 31900039]


Chugani HT, Positron Emission Tomography in Pediatric Neurodegenerative Disorders. Pediatric neurology. 2019 Nov;     [PubMed PMID: 31416725]


Hammond N,Munkacsi AB,Sturley SL, The complexity of a monogenic neurodegenerative disease: More than two decades of therapeutic driven research into Niemann-Pick type C disease. Biochimica et biophysica acta. Molecular and cell biology of lipids. 2019 Aug;     [PubMed PMID: 31002946]


Aldosari MH,de Vries RP,Rodriguez LR,Hesen NA,Beztsinna N,van Kuilenburg ABP,Hollak CEM,Schellekens H,Mastrobattista E, Liposome-targeted recombinant human acid sphingomyelinase: Production, formulation, and in vitro evaluation. European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V. 2019 Apr;     [PubMed PMID: 30818011]


Pineda M,Walterfang M,Patterson MC, Miglustat in Niemann-Pick disease type C patients: a review. Orphanet journal of rare diseases. 2018 Aug 15;     [PubMed PMID: 30111334]


Breiden B,Sandhoff K, Lysosomal Glycosphingolipid Storage Diseases. Annual review of biochemistry. 2019 Jun 20;     [PubMed PMID: 31220974]


Chen KJ,Jin RM,Shi CC,Ge RL,Hu L,Zou QF,Cai QY,Jin GZ,Wang K, The prognostic value of Niemann-Pick C1-like protein 1 and Niemann-Pick disease type C2 in hepatocellular carcinoma. Journal of Cancer. 2018;     [PubMed PMID: 29483961]


Jezela-Stanek A,Chorostowska-Wynimko J,Tylki-Szymańska A, Pulmonary involvement in selected lysosomal storage diseases and the impact of enzyme replacement therapy: A state-of-the art review. The clinical respiratory journal. 2020 Jan 8;     [PubMed PMID: 31912638]