Niemann-Pick Disease

Niemann-Pick disease (NPD), also known as sphingomyelinase deficiency, is a rare, inherited, lysosomal storage disorder. The disease is classified on the basis of the genetic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations. 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 Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and 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 Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive, hepatosplenomegaly, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. 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.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Classification and etiology

Niemann-Pick disease (NPD) is an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancelysosomal storage disorder that is classified on the basis of the gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations and enzyme deficiency:

  • Types A (NPD-A) and B (NPD-B):
    • Sphingomyelin phosphodiesterase 1 (SMPD-1) gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations 
    • 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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations 
    • 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 Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids 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 Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. 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 Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver fibrosis → cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
  • Hypersplenism → thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia 
  • Interstitial lung disease → dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). 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 Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables presentation
  • Life expectancy: early adulthood (most patients)

Signs and symptoms:

  • Ataxia
  • Dystonia Dystonia Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia
  • Dysarthria
  • Dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia
  • Vertical supranuclear gaze palsy (inability to look in a vertical direction)
  • Gelastic cataplexy (loss of muscle tone Muscle tone The state of activity or tension of a muscle beyond that related to its physical properties, that is, its active resistance to stretch. In skeletal muscle, tonus is dependent upon efferent innervation. Skeletal Muscle Contraction triggered by laughter)
  • Cognitive impairment
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Prolonged neonatal jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
  • Hepatosplenomegaly
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease → ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
  • Psychiatric and behavioral disorders
  • Alveolar proteinosis (buildup of lipoproteinaceous material in alveoli)
  • Aspiration pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
  • Respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. 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 Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of 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.
Visceral symptoms as a key diagnostic sign for the early infantile form of niemann-pick disease

Histopathological liver biopsy showing swollen Kupffer cells with a foamy cytoplasm, typical for NPD-C

Image: “Histopathological liver biopsy findings” by Federal State Budget Institution, Research Center for Obstetrics, Gynecology and Perinatology, Federal State Budget Institution, 117997 Oparina str. 4, Moscow, Russia. License: CC BY 4.0

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 Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow and stem cell transplantation
    • Enzyme replacement
    • Gene therapy

Differential Diagnosis

  • Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease: most common lysosomal storage disorder. Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease results from glucocerebrosidase deficiency. There are 3 types of Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease. The different types have varying presentations and severity, which can include hepatosplenomegaly, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, easy bruising, bone fractures, and progressive neurologic deterioration. The diagnosis is made with DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure 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 Tay-Sachs disease Tay-Sachs disease is an autosomal recessive lysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot on physical examination. Tay-Sachs Disease: lysosomal storage disorder resulting from hexosaminidase A deficiency. There are 3 types of Tay-Sachs disease Tay-Sachs disease Tay-Sachs disease is an autosomal recessive lysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot on physical examination. Tay-Sachs Disease, and these have variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables 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 Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables onset and presentations. Clinical manifestations include failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive, feeding difficulty, hypotonia, progressive muscle weakness, hypertrophic cardiomyopathy Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiomyopathy, which is characterized by an asymmetric increase in thickness (hypertrophy) of the left ventricular wall, diastolic dysfunction, and often left ventricular outflow tract obstruction. 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 Fabry disease Fabry disease (FD), also known as Anderson-Fabry disease, is an X-linked recessive lysosomal storage disorder and the 2nd most common of the lysosomal storage disorders. Fabry disease is caused by a deficiency in the alpha-galactosidase enzyme (alpha-Gal A), resulting in the accumulation of the glycosphingolipid globotriaosylceramide (Gb3) in lysosomes. 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 Paresthesias Subjective cutaneous sensations (e.g., cold, warmth, tingling, pressure, etc.) that are experienced spontaneously in the absence of stimulation. Respiratory Alkalosis involving the hands and feet, purplish skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the 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

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