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  • Updated 02.17.2024
  • Released 11.15.1997
  • Expires For CME 02.17.2027

Niemann-Pick disease type C



Niemann-Pick disease type C is an autosomal recessive neurodegenerative lysosomal storage disorder caused by mutations in either the NPC1 or NPC2 gene. It is characterized by impaired cellular trafficking of cholesterol, which leads to cholesterol and sphingolipid storage in various tissues, and a complex pathogenic cascade. In this article, the author discusses the wide spectrum of clinical phenotypes, ranging from systemic neonatal to neurologic adult-onset forms, the change of paradigm regarding diagnostic strategies, with a combination of plasma biomarkers and genetic testing, and the current status in the management and treatment of patients. Knowledge regarding the role of NPC1 and NPC2 proteins in cellular cholesterol trafficking is also updated.

Key points

• Niemann-Pick disease type C has a very broad spectrum of clinical phenotypes and is most likely underdiagnosed in adults.

• For laboratory diagnosis, initial orientation tests in plasma measuring particular oxysterols (cholestane-3ß-5α−6ß-triol)(C-triol) or bile acid derivatives and PPCS (formerly lysoSM509), if possible, associated with lyso-sphingomyelin, now constitute the first-line testing for Niemann-Pick disease type C in most cases. These biomarkers are sensitive but not specific to Niemann-Pick disease type C.

• Confirmation of the clinical diagnosis of Niemann-Pick disease type C is primarily based on molecular study of the NPC1 and NPC2 genes. Whenever two pathogenic variant alleles cannot be identified, demonstration of impaired trafficking of endocytosed cholesterol in living cells (filipin test) may still be needed as the most specific functional test.

• Miglustat is the first disease-modifying pharmacological agent aiming to stabilize or slow the progression of neurologic manifestations in NPC. It is currently approved for this indication in 42 countries, but it is not approved for Niemann-Pick disease type C by the Food and Drug Administration in the United States.

• Among experimental therapies, four compounds have been or are currently under study in clinical trials: oral administration of arimoclomol, intrathecal or intravenous administration of 2-hydroxypropyl-beta-cyclodextrin, oral administration of N-acetyl-L-leucine, and oral administration of AZ-3102.

Historical note and terminology

Historically, the eponym "Niemann-Pick disease" encompassed autosomal recessive lysosomal lipid storage disorders with common features of hepatosplenomegaly and sphingomyelin storage. In 1958, Crocker and Farber showed in 18 patients a wide variability in age of onset, clinical expression, and level of sphingomyelin storage (23). This led Crocker to propose a classification of Niemann-Pick disease into three main groups, A, B and C (22). Type C was characterized by a subacute nervous system involvement with a moderate and slower course than type A, and a milder visceral sphingomyelin storage than types A and B. Patients that were similar but all of Nova Scotia Acadian origin were individualized as type D (later shown to belong to type C). From 1966 to 1968, Brady and associates demonstrated a severe deficiency in acid sphingomyelinase activity in tissues from patients with type A (corresponding to the original cases of A. Niemann and L. Pick) and with type B, but not in those from patients with types C and D.

The defect underlying types C and D remained an enigma, but patients with a retrospective diagnosis of Niemann-Pick disease type C were published in the 1960s and 1970s under various names: juvenile Niemann-Pick disease, juvenile dystonic lipidosis, atypical cerebral lipidosis, neurovisceral storage disease with vertical supranuclear ophthalmoplegia, maladie de Neville, DAF syndrome, adult dystonic lipidosis, adult neurovisceral lipidosis, giant cell hepatitis, and lactosyl ceramidosis (112). In 1982, a consensus was reached in a meeting in Prague (31) that Niemann-Pick disease type C was a distinct and specific entity. Soon after, following seminal observations by Peter Pentchev and collaborators, the concept of Niemann-Pick disease type C evolved to that of a cholesterol--rather than sphingomyelin--storage disorder (113; 114; 115; 144; 77; 163; 112). Today, “Niemann-Pick disease type C " designates disorders characterized by unique abnormalities of intracellular transport of endocytosed cholesterol and ancillary sphingolipid storage (158).

Major later advances have been the description of two genetic complementation groups and the isolation of the underlying genes. NPC1, located at chromosomal segment 18q11, is involved in 95% or more of the families (including those with type D). NPC2, located at chromosomal segment 14q24.3, is involved in rare families (150; 159; 18; 44; 101). Although the global functions of the NPC1 and NPC2 proteins are not fully understood, their sequential role in egress of endocytosed cholesterol from the cellular late endosomal/lysosomal compartment is now well established (71; 117; 127).

In the strict sense, one should distinguish between Niemann-Pick disease type C1 ( and Niemann-Pick disease type C2 ( The distinction is made from the genotype, but because the clinical manifestations and biochemical abnormalities of types C1 and C2 are similar, the generic terms of "Niemann-Pick disease type C," “Niemann-Pick C disease,” or “NPC” remain widely used in practice and in literature.

Finally, it is essential to remember that any mention of a diagnosis as "Niemann-Pick disease" without specification of a subgroup--either acid sphingomyelinase deficiency (SMPD1 mutations), or Niemann-Pick C (NPC1 or NPC2 mutations)--is ambiguous and a potential source of error in genetic counseling or even management of patients.

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