Niemann-Pick Disease

Niemann-Pick disease (NPD) is a rare, inherited, lysosomal storage disorder. The disease is classified on the basis of the genetic mutation. Type A and type B result from mutations in the SMPD-1 gene, resulting in acid sphingomyelinase enzyme deficiency. Type C results from NPC1 or NPC2 gene mutations, which are needed for intracellular transport of lipids. These mutations result in lysosomes that are unable to properly metabolize fat, such as sphingomyelin and cholesterol, resulting in progressive intracellular lipid accumulation and organ damage. Clinical manifestations may include failure to thrive, hepatosplenomegaly, thrombocytopenia, interstitial lung disease, cognitive and motor impairment, and macular cherry-red spots. Progressive neurodegeneration and a short life expectancy are seen in NPD-A, while NPD-B is typically nonneurogenic. Diagnosis of NPD is based on clinical suspicion and can be confirmed by the measurement of sphingomyelinase activity or biomarkers, genetic testing, or biopsy. There is currently no cure for NPD, so management is supportive and focuses on controlling symptoms.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview

Classification and etiology

Niemann-Pick disease (NPD) is an autosomal recessive lysosomal storage disorder that is classified on the basis of the gene mutation and enzyme deficiency:

  • Types A (NPD-A) and B (NPD-B):
    • Sphingomyelin phosphodiesterase 1 (SMPD-1) gene mutation 
    • Results in acid sphingomyelinase (ASM) enzyme deficiency
    • Considered a spectrum of 1 disorder based on enzyme activity:
      • NPD-A: severe, < 5% of enzyme activity
      • NPD-B: 5%–10% of enzyme activity
  • Type C (NPD-C):
    • NPC1 or NPC2 gene mutation 
    • Results in abnormal cholesterol storage

Epidemiology

  • NPD-A and B:
    • Incidence: 1 in 250,000 people
    • More common in those of Ashkenazi Jewish descent
  • NPD-C: 
    • Incidence: 1 in 150,000 people

Pathophysiology

Normal lysosomes:

  • Intracellular digestive units that break down complex structures to be recycled or discarded
  • ASM normally converts sphingomyelin to ceramide and phosphocholine
  • NPD-C1 and C2 proteins are needed for intracellular transport of cholesterol and lipids.

In NPD-A and B:

  • ASM deficiency → accumulation of sphingomyelin in lysosomes
  • Results in cellular damage and tissue deposition → organ damage

In NPD-C:

  • Lack of function in NPD-C1 or C2 → accumulation of cholesterol in lysosomes and mitochondria
  • ↑ Mitochondrial cholesterol → mitochondrial dysfunction →  apoptosis → organ damage
Lysosomal storage pathway

The lysosomal storage pathway:
Niemann-Pick disease (types A and B) results from acid sphingomyelinase deficiency, resulting in a buildup of sphingomyelin.

Image by Lecturio.

Clinical Presentation

The clinical presentation of NPD depends on the type and severity of the disease.

Niemann-Pick disease type A

Disease course:

  • Severe 
  • Presents within the 1st few months of life
  • Rapidly progressive neurodegenerative course
  • Death by 3 years of age

Signs and symptoms:

  • Difficulty feeding
  • Loss of motor skills
  • Hypotonia
  • Absent reflexes
  • Intellectual deterioration
  • Hepatosplenomegaly
  • Recurrent pulmonary infections
  • Respiratory failure
  • Macular cherry-red spot
Cherry-red spot

Fundoscopic image demonstrating a cherry-red spot, which may be seen in Niemann-Pick disease

Image: “Cherry red spot” by Jonathan Trobe, M.D. License: CC BY 3.0

Niemann-Pick disease type B

Disease course:

  • Later onset and less severe than NPD-A
  • Progessive hypersplenism and pulmonary failure
  • Not typically neurodegenerative
  • Life expectancy: early adulthood

Signs and symptoms:

  • Short stature and delayed skeletal maturation
  • Hepatomegaly
  • Liver fibrosis → cirrhosis
  • Hypersplenism → thrombocytopenia 
  • Interstitial lung disease → dyspnea and hypoxia
  • Cognitive impairment and psychiatric disturbance
  • Macular cherry red spot
  • Hyperlipidemia

Niemann-Pick disease type C

Disease course:

  • Onset from prenatal period to adulthood
  • Progressive neurodegenerative disorder
  • Highly variable presentation
  • Life expectancy: early adulthood (most patients)

Signs and symptoms:

  • Ataxia
  • Dystonia
  • Dysarthria
  • Dysphagia
  • Vertical supranuclear gaze palsy (inability to look in a vertical direction)
  • Gelastic cataplexy (loss of muscle tone triggered by laughter)
  • Cognitive impairment
  • Seizures
  • Prolonged neonatal jaundice
  • Hepatosplenomegaly
  • Liver disease → ascites
  • Psychiatric and behavioral disorders
  • Alveolar proteinosis (buildup of lipoproteinaceous material in alveoli)
  • Aspiration pneumonia
  • Respiratory failure

Diagnosis and Management

Diagnosis

Suspicion for NPD is raised on the basis of the clinical features. The diagnosis can be confirmed with the following investigations:

  • NPD-A and B: 
    • Measurement of WBC ASM activity in WBCs
    • Molecular analysis for SMPD-1 mutations
    • Bone marrow biopsy for lipid-laden foam cells (macrophages)
  • NPD-C: 
    • Measurement of plasma oxysterols
    • Molecular analysis for NPC1 and NPC2 mutations 
    • Skin biopsy:
      • Fibroblasts are grown in culture and monitored for their ability to transport and store cholesterol.
      • Largely replaced by the above testing methods
  • Prenatal screening can be done for all types via amniocentesis or chorionic villus sampling.

Management

There is no cure for NPD. Management is supportive and multidisciplinary. 

  • Physical and occupational therapy
  • Nutritional support
  • Antibiotic treatment for recurrent pulmonary infections
  • Investigational therapies:
    • Bone marrow and stem cell transplantation
    • Enzyme replacement
    • Gene therapy

Differential Diagnosis

  • Gaucher disease: most common lysosomal storage disorder. Gaucher disease results from glucocerebrosidase deficiency. There are 3 types of Gaucher disease. The different types have varying presentations and severity, which can include hepatosplenomegaly, thrombocytopenia, easy bruising, bone fractures, and progressive neurologic deterioration. The diagnosis is made with DNA or enzyme analysis. Management depends on the type and includes enzyme replacement, splenectomy, glucosylceramide inhibitors, and bone marrow or stem cell transplantation. 
  • Tay-Sachs disease: lysosomal storage disorder resulting from hexosaminidase A deficiency. There are 3 types of Tay-Sachs disease, and these have variable onsets. Patients may present with macular cherry-red spots, blindness, deafness, cognitive and motor deterioration, dysphagia, dysarthria, spasticity, ataxia, seizures, and psychosis. The diagnosis is made with enzyme activity testing and molecular analysis. Management is supportive. 
  • Pompe disease (glycogen storage disease II): lysosomal and glycogen storage disorder caused by acid alpha glucosidase (GAA) deficiency. There are 3 types of Pompe disease, and these have variable onset and presentations. Clinical manifestations include failure to thrive, feeding difficulty, hypotonia, progressive muscle weakness, hypertrophic cardiomyopathy, and respiratory failure. The diagnosis is made by measuring enzyme activity and molecular gene analysis. Management includes supportive measures and enzyme replacement.
  • Fabry disease: lysosomal storage disorder caused by alpha-galactosidase A (GLA) deficiency. This deficiency results in glycophospholipid deposition in the vascular endothelium and smooth muscle cells. Clinical manifestations include paresthesias involving the hands and feet, purplish skin lesions (angiokeratomas), decreased sweating, cardiovascular complications, and renal disease. The diagnosis is made by measuring GLA enzyme activity. Management includes supportive measures and enzyme replacement.

References

  1. Patterson, M.C. (2020). Overview of Niemann-Pick disease. In Dashe, J.F. (Ed.), UpToDate. Retrieved May 10, 2021, from https://www.uptodate.com/contents/overview-of-niemann-pick-disease
  2. Patel, J.M., Dankhara, N. (2020). Sphingomyelinase deficiency. In Rohena, L.O. (Ed.), Medscape. Retrieved May 10, 2021, from https://emedicine.medscape.com/article/951564-overview
  3. Demczko, M. (2020). Niemann-Pick disease. MSD Manual Professional Version. Retrieved May 10, 2021, from https://www.msdmanuals.com/professional/pediatrics/inherited-disorders-of-metabolism/niemann-pick-disease
  4. Bajwa, H., Azhar, W. (2021). Niemann-Pick disease. StatPearls. Retrieved May 10, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK556129/
  5. Torres, S., et al. (2017). Lysosomal and mitochondrial liaisons in Niemann-Pick disease. Frontiers in Physiology. https://doi.org/10.3389/fphys.2017.00982

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details