eMedicine Specialties > Dermatology > Pediatric Diseases

Niemann-Pick Disease

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Santiago A Centurion, MD, Staff Physician, Department of Dermatology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey; Danielle Lann, MD, Staff Physician, Dermatology, UMDNJ-New Jersey Medical School; Naomi Bartnoff, MS, Former Genetics Counselor, Center for Human and Molecular Genetics, University of Medicine and Dentistry of New Jersey, New Jersey Medical School
Contributor Information and Disclosures

Updated: May 29, 2009

Introduction

Background

Niemann-Pick disease (NPD) comprises an autosomal recessively inherited group of congenital lipidoses in which sphingolipids accumulate in cells, especially reticuloendothelial cells, throughout the body.

The following 6 types of Niemann-Pick disease have been described:

  • Type A - Acute neuronopathic form
  • Type B - Visceral form
  • Type C - Chronic neuronopathic form
  • Type D - Nova Scotia variant
  • Type E - Adult form
  • Type F - Sea-blue histiocyte disease

Other variants include an acute form with hydrops; an early form with neonatal hepatitis; and a more slowly evolving, chronic form with progressive neurologic deterioration that extends well into adulthood.

Niemann and Pick, and later Crocker and Farber, defined Niemann-Pick disease on the basis of its clinical and pathologic features in the beginning of the 20th century. The Niemann-Pick group of diseases can be subclassified into 2 categories: (1) those with a primary deficiency in acid sphingomyelinase (ASM) activity (ie, types A and B) and (2) those with defective intracellular processing and transporting of low-density lipoprotein (LDL)–derived cholesterol (ie, type C).

The disease is clinically characterized by progressive degeneration of the central nervous system with visceral accumulation of cholesterol and sphingomyelin. The clinical phenotype is extremely variable, ranging from an acute neonatal form, with mainly liver involvement and rapid neurologic deterioration, to an adult late-onset form, with slowly progressive ataxia and a movement disorder. The late infantile and juvenile forms are considered to be the most common classic presentations, with the insidious onset of ataxia, vertical supranuclear gaze palsy, and cognitive impairment in as many as 80% of patients. Foam-cell infiltration and visceromegaly are common features in all forms, but neurologic involvement occurs only in types A and C and not in type B.

The eMedicine pediatrics article Niemann-Pick Disease may be of interest, as may Lysosomal Storage Disease and Lipid Storage Diseases.

Pathophysiology

The sphingomyelin that accumulates in the lysosomes of Niemann-Pick disease–affected cells is thought to arise from the degradation of the cells and their organelles because it is a major component of all mammalian cell membranes. In Niemann-Pick disease type C, the main lipid that accumulates in patients' cells is not sphingomyelin but cholesterol; however, sphingomyelin metabolism and cholesterol metabolism are closely related.

Sphingomyelinase is an acidic lysosomal hydrolase that catalyses the cleavage of sphingomyelin to phosphoryl choline and ceramide. In patients with Niemann-Pick disease, its activity is deficient in all lysosome-containing tissues. In patients with Niemann-Pick disease type A, the infantile form, sphingomyelinase activity is 0.7% of that of healthy individuals, whereas in patients with adult-onset neuronopathic or nonneuronopathic disease, the activity is 0-19% of that of healthy individuals.

This enzyme defect explains the massive deposition of sphingomyelin in tissues of the reticuloendothelial systems. In patients with the group A variant, sphingomyelin and other lipids are stored in the brain in increased amounts, a finding consistent with the neuronopathic features, whereas in patients with the group B form, the nervous tissue does not appear to store sphingomyelin.

In both healthy individuals and patients with Niemann-Pick disease types A and B, fibroblasts synthesize sphingomyelinase polypeptides with the same molecular mass of 110 kd, in the same amount. During further processing, the 110-kd polypeptide is reduced to a molecular weight of 84 kd. The deficiency of sphingomyelinase is due to intragenic defects.

Findings from experiments conducted so far suggest that the specific defects could be small inframe deletions, inframe additions, or point mutations. The differences in the clinical courses of types A and B suggest that the mutations are different. Sphingomyelinase follows the same intracellular targeting and posttranslational processes as most of the lysosomal hydrolases. However, unlike any other enzyme, the polypeptide exists in 2 forms of different sizes. Each polypeptide is differentially distributed in the tissues. In tissues, such as the brain, the smaller polypeptide (80 kd) is found, whereas the kidneys contain both polypeptides (110 and 80 kd). No precise explanation exists for the occurrence of one form of the polypeptide in some tissues and the presence of both forms in tissues, such as the kidneys.

The discovery of the NPC1 gene by Carstea et al1 in 1997 has stimulated much research in Niemann-Pick disease, the NPC1 gene product, sterol trafficking, and gene therapy in animal models. The NPC1 gene was cloned after it was mapped to the long arm of chromosome 18 by using linkage and positional cloning techniques. The NPC1 complementary DNA (cDNA) sequence suggests a protein of 1,278 amino acids with an estimated molecular mass of 142 kd. Topological analysis of the NPC-1 protein has revealed the existence of 13 transmembrane domains, 7 luminal loops, 6 cytoplasmic loops, and a cytoplasmic tail with a signal sequence for targeting to the endoplasmic reticulum and a dileucine motif that directs the NPC-1 protein to lysosomes.

Of particular importance is the presence of a sterol-sensing region in the NPC1 sequence that has extensive homology to other mediators of cholesterol homeostasis, including 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and sterol regulatory element–binding protein cleavage-activation protein. The region also has homology to the human PATCHED gene, which serves as the transmembrane receptor for sonic hedgehog morphogen. Defective sonic hedgehog morphogen in humans can lead to basal cell nevoid syndrome and holoprosencephaly.

To date, more than 100 NPC1 mutations, mostly missense mutations, have been identified throughout the gene, with no apparent hot spots. Most patients with NPC1 mutations have compound heterozygosity with unique mutations. The 2 known exceptions are a common I1061T mutation that is found in the United Kingdom; in France; and in the upper Rio Grande Valley in the southwestern United States, where it is present in the Hispanic population. The G992W mutation is found in the Acadian population of Nova Scotia.

NPC1 mutations are responsible for the disease in approximately 95% of patients.2 The NPC1 gene was evaluated in 5 Taiwanese/Chinese patients with NPC in the Republic of China. Six novel NPC1 mutations (N968S, G1015V, G1034R, V1212L, S738Stop, and I635fs) were identified, 3 of which were missense mutations located in the cysteine-rich domain.

The function of the NPC-1 protein is of great interest because it could enhance the understanding of the cholesterol exchange among the various subcellular compartments. The accumulation of unesterified cholesterol in NPC-1 lysosomes implies that NPC-1 is involved in the transport of free cholesterol from this organelle.

Three putative functions can be assigned to NPC-1, as outlined below.

  • NPC-1 may function as a cholesterol transporter by directly collecting cholesterol from the membranes of the endosomal-lysosomal system and transporting the lipid to the trans-Golgi network (TGN). Such a function could explain the transient interaction observed between the NPC-1 protein and lysosomes and the TGN. This function could also explain the observation that mutated NPC-1 protein localizes to the membranes of cholesterol-filled organelles but that it is unable to effect cholesterol mobilization.
  • NPC-1 may act as a docking and/or fusion protein that allows cholesterol-filled vesicles to dock and fuse with recycling endosomes for subsequent delivery to the TGN.
  • NPC-1 may act as a pump that drives the movement of cholesterol and possibly other lipids away from the endosome and to the TGN. However, NPC-1 lacks an ATP-binding cassette, which is typical in cellular molecular pumps.

In fibroblasts, the NPC1 gene product is localized to vesicles that test positive for lysosome-associated membrane protein-2 (LAMP2) and negative for the mannose 6-phosphate receptor. These vesicles transiently interact with cholesterol-laden lysosomes to facilitate sterol relocation. The cargo transported by means of this interaction is not limited to sterol but probably also involves glycolipids, which accounts for accumulations of glycolipids, such as GM2-ganglioside, in Niemann-Pick disease type C neurons and fibroblasts.

Sphingomyelin hydrolysis is a key component of a signal transduction pathway involved in cell proliferation, differentiation, and programmed cell death. A number of extracellular agents, including inflammatory cytokines, hormones, growth factors, nitric oxide, and other stressors, trigger the release of ceramide, which acts as an intracellular second messenger to regulate various cellular activities.

To further examine the role of ASM in cell signaling and apoptosis, investigators are using ASM-deficient cells obtained from patients with Niemann-Pick disease type A and cells obtained from ASM-deficient mice. In many instances, fully normal responses were observed, but, in others, the responses differed depending on whether Niemann-Pick disease cells or healthy cells were being tested. Correction of the enzyme deficiency by means of transfection with a plasmid encoding ASM could, in certain circumstances, correct the defect in signaling.

Bone marrow transplantation into newborn ASM knockout mice, performed by using donor cells from healthy animals in the colony, improves survival, delays the onset of ataxia, results in less lipid accumulation, and improves the histologic appearance of the brain and the visceral organs. Naturally occurring murine and feline models of Niemann-Pick disease type C that are clinically, biochemically, and morphologically equivalent to human Niemann-Pick disease type C have been characterized. Studies of apolipoprotein D metabolism in mice with Niemann-Pick disease type C show abnormalities in the apolipoprotein D gene and in protein expression. Plasma levels were increased 6-fold, and higher levels were also found in Niemann-Pick disease type C brain astrocytes and cultured astrocytes.

Because apolipoprotein D is important in cellular cholesterol transport for the synthesis, the assembly, and the maintenance of myelin, its sequestration could reflect the reduced myelin turnover and the deficiency in myelin, which are characteristic of Niemann-Pick disease type C.

One well-known NPC1 gene mutation causes a unique phenotype limited to descendants of a single Acadian ancestor in Nova Scotia, Canada.3

Frequency

United States

Niemann-Pick disease type A occurs most frequently, and it accounts for about 85% of all cases of the disease. Niemann-Pick disease type C affects an estimated 500 children in the United States.

Mortality/Morbidity

  • Patients with Niemann-Pick disease type A die in infancy.
  • Patients with Niemann-Pick disease type B may live a comparatively long time, but many require supplemental oxygen because of lung involvement.
  • The life expectancies of patients with Niemann-Pick disease types C and D are variable. Some patients die in childhood, whereas others who appear to be less drastically affected live into adulthood.

Race

One in 75 Ashkenazi Jews is a carrier.

Sex

Males and females are equally affected.

Age

Niemann-Pick disease affects infants, children, and adults.

  • Niemann-Pick disease type A begins in the individual's first few months of life.
  • Niemann-Pick disease type B has a more variable course, with the first symptoms occurring in early childhood. Many persons with Niemann-Pick disease type B survive into adulthood.
  • Persons with Niemann-Pick disease type C have normal development for their first 2 years or more of life.

Clinical

History

Patients with Niemann-Pick disease (NPD) type A have a progressive neurodegenerative course in infancy, and patients with Niemann-Pick disease type B have nervous system involvement that is linked to the appearance of a cherry-red macula. The amounts and the types of lipid storage in the reticuloendothelial system and the visceral organs in patients with type A and those with type B are also similar.

  • Niemann-Pick disease type A begins in the individual's first few months of life. Symptoms include the following:
    • Feeding difficulties
    • Abdominal enlargement within 3-6 months
    • Progressive loss of early motor skills
    • Rapid decline leading to death by the time the patient is aged 2-3 years
  • Biochemically, Niemann-Pick disease type B is similar to Niemann-Pick disease type A, but the symptoms are more variable.
    • Abdominal enlargement may be detected in early childhood.

      Respiratory infections recur.
    • No neurologic involvement is present.
  • Niemann-Pick disease type C usually affects school-aged children, but the disease may occur at any time from early infancy to adulthood. Symptoms may include the following:
    • Unsteadiness of gait, clumsiness, problems in walking
    • Difficulty in posturing of the limbs
    • Slurred, irregular speech
    • Learning difficulties and progressive intellectual decline
    • Sudden loss of muscle tone, which may lead to falls
    • Seizures
    • Tremors accompanying movement
    • A subclinical course of adult visceral Niemann-Pick disease type C1 appears to be rare.4 Niemann-Pick disease type C may rarely lack neurological symptoms. This adult visceral form of Niemann-Pick disease type C is usually dominated by neurovisceral symptoms, may represent an underdiagnosed disease form, and should be considered in patients with isolated hepatosplenomegaly with foam cells in adulthood.
    • Niemann-Pick disease type C may be first seen with cataplexy, which may lead to its diagnosis.3,5 Cataplexy is rare and evident as a brief episode of bilateral loss of muscle tone with intact consciousness, triggered by a variety of strong emotions and, in particular, with unexpected laughter. The patient may develop "drop attacks" upon laughing. This inherited lipid storage disorder has considerable phenotypic variability.6

Physical

Physical signs include the following:

  • Neurologic features
    • Mental retardation
    • Difficulty with upward and downward eye movements
    • Vertical supranuclear gaze palsy (Vertical supranuclear gaze palsy is highly suggestive of Niemann-Pick disease type C.)
    • Spasticity
    • Seizures
    • Myoclonic jerks
    • Ataxia
  • GI features
    • Hepatosplenomegaly
    • Jaundice
    • Hepatic failure
    • Ascites
  • Growth characteristics - Retarded physical growth
  • Head, ears, eyes, nose, and throat characteristics
    • Cherry-red macular spot
    • Corneal opacification
    • Brown discoloration of the anterior lens capsule
  • Skin characteristics - Nodular xanthoma
  • Blood characteristics
    • Bone marrow foam cells
    • Easy bruisability
    • Anemia
  • Respiratory features - Interstitial pulmonary infiltration
  • Cardiac features - Coronary artery disease

Causes

See Pathophysiology.

An interesting parallel also exists between the up-regulation of apolipoprotein D in mice with Niemann-Pick disease type C and its enhanced expression in oligodendroglia in Alzheimer disease. Neurofibrillary tangles are a common neuropathologic feature of the 2 disorders; this finding suggests a relationship between apolipoprotein D and neurofibrillary tangles. Thus, the expression of apolipoprotein D appears to be coordinately impaired in Niemann-Pick disease type C as part of a generalized defect in cellular cholesterol trafficking.

More on Niemann-Pick Disease

Overview: Niemann-Pick Disease
Differential Diagnoses & Workup: Niemann-Pick Disease
Treatment & Medication: Niemann-Pick Disease
Follow-up: Niemann-Pick Disease
References
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Further Reading

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Keywords

Niemann-Pick disease, NPD, Crocker's syndrome, Crocker syndrome, Crocker-Farber syndrome, Niemann's disease, Niemann disease, Pick's disease, Pick disease, essential lipoid histiocytosis, lipid histiocytosis, phosphatid lipoidosis, phosphatidosis sphingomyelin lipidosis, sphingomyelinosis, sphingomyelin reticuloendotheliosis

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Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Santiago A Centurion, MD, Staff Physician, Department of Dermatology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey
Santiago A Centurion, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, and Sigma Xi
Disclosure: Nothing to disclose.

Danielle Lann, MD, Staff Physician, Dermatology, UMDNJ-New Jersey Medical School
Disclosure: Nothing to disclose.

Naomi Bartnoff, MS, Former Genetics Counselor, Center for Human and Molecular Genetics, University of Medicine and Dentistry of New Jersey, New Jersey Medical School
Disclosure: Nothing to disclose.

Medical Editor

Albert C Yan, MD, Section Chief, Associate Professor, Department of Pediatrics, Section of Dermatology, Children's Hospital of Philadelphia and University of Pennsylvania
Albert C Yan, MD is a member of the following medical societies: American Academy of Dermatology, American Academy of Pediatrics, Society for Investigative Dermatology, and Society for Pediatric Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Van Perry, MD, Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas Health Science Center
Van Perry, MD is a member of the following medical societies: American Academy of Dermatology and American Society for Laser Medicine and Surgery
Disclosure: Nothing to disclose.

CME Editor

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital
Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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