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.

Objectives:

• 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.

Introduction

Lysosomal storage diseases are characterized by inherited deficiencies of 1 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 to ceramide and phosphocholine. As a result, sphingomyelin 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 4 subtypes: type A, B, C, and E. Type A is known as the infantile neurovisceral form with very low acid sphingomyelinase (ASM) activity and is usually fatal before the age of 3. 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. NPD 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 with 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]

Etiology

NPD is inherited in an autosomal recessive pattern, meaning both copies of the gene must have mutations for the disease to manifest. 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 the NPC1 (located on chromosome 18) and NPC2 (located on chromosome 14) genes. Mutations in these genes cause abnormal or defective protein formation, impairing the movement of lipids out of cells and leading to their accumulation within cells.[3] 

Epidemiology

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 among French Acadians in Nova Scotia.[4]

Pathophysiology

NPD types A and B are caused by mutations in the SMPD1 gene, leading to a marked decrease in ASM activity. The enzyme ASM is mainly present in lysosomes and converts sphingomyelin to ceramide and phosphocholine. In ASMD, sphingomyelin and its precursors accumulate in lysosomes, leading to cellular damage. There are over 180 mutations of the SMPD1 gene, some with residual ASM activity up to 30%. Due to a dramatic reduction in protein half-life, the condition may phenotypically be type A. Allelic heterogeneity accounts for most of the variability in severity between types A and B. The mutations can be missense, frameshift, nonsense, or frame deletions. The predominant mutation varies by region. 

NPC is further classified into types C1 and C2 based on pathogenic mutations in the NPC1 or NPC2 genes, respectively. NPC1 is the predominant subtype, affecting about 95% of patients, with over 30 distinct sequence alterations identified. 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, leading to an excessive buildup of cholesterol within lysosomes. Consequently, toxic cholesterol accumulation results in cellular and organ damage.[5][6]

Histopathology

Due to the ineffective transport system, the affected cells become enlarged, sometimes reaching 90 micrometers in diameter, as sphingomyelin and cholesterol accumulate. 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

NPD type A presents in the first few months of life, usually before 3 months of age, as hepatosplenomegaly and growth retardation. By the age of 1 year, neurological symptoms appear as psychomotor retardation and regression of developmental milestones. All patients with NPD type A have a classical eye finding called the 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, 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, dysphonia, dysphagia, and severe liver and lung disease.

The following findings are expected during examination of the body systems.

Gastrointestinal

• Hepatomegaly
• Splenomegaly

Pulmonary

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

Integumentary

• Jaundice

Cardiovascular

• Thrombocytopenia
• Hypercholesterolemia

Rheumatologic

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

Ocular

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

Neurologic

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

Evaluation

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 the special stain 'filipin' to measure enzyme activity. DNA testing can be used to identify genes that cause type C disease.[9] Once the diagnosis is confirmed, special attention should be paid to the spread and manifestations of the disease 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 is done for interstitial lung disease. 
• 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 sphingomyelin and its derivatives, macrophage markers, and oxysterols.[10][11]

Treatment / Management

For type A and B NPD, there is no cure. Supportive care is the mainstay of treatment. Physicians aim to keep low blood lipid levels with statins, and liver function is 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 NPD and Gaucher disease by decreasing glucocerebroside production. It is approved in Europe, Canada, and Japan, but not yet in the United States.[13] 

Differential Diagnosis

Other lysosomal storage diseases should be included in the differential diagnosis, 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, leading to the accumulation of glucocerebroside within cells rather than sphingomyelin, as seen in Niemann-Pick disease. Tay-Sachs disease, although it does not present with hepatosplenomegaly, neurodegeneration, developmental delay, and cherry-red spot on the macula, is a prominent feature. 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 considered based on the initial presentation.

Prognosis

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 quality of life is not so good.

Type C

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

Complications

NPD 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 NPD is fatal and often untreatable, the sooner it is recognized, the better the chance to slow down its progression and limit the complications. NPD is an autosomal recessive disease, which means both parents must be affected or carriers of the disease gene for it to be passed on to their children. Carriers of an autosomal recessive disease do not show signs and symptoms of the disease, but they can pass the defective gene to the next generation. So if both 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

NPDhas 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, an endocrinologist, a neurologist, and a genetic counselor. Also, family care, nursing support, and social support are integral to 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 and restrictions on issuing marriage licenses to 2 people with the same disease. The screening of children and pregnant women who visit clinicians is an effective strategy to limit the disease, but it 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, in theory, can cure the disease. Active collaboration and discussion between interprofessional team members lead to a better understanding of the progression and control of the disease.

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Disclosure: Hamza Bajwa declares no relevant financial relationships with ineligible companies.

Disclosure: Waqas Azhar declares no relevant financial relationships with ineligible companies.