Niemann-Pick disease type C

Marie T Vanier MD PhD (Dr. Vanier, Director of Research Emeritus at Institut National de la Santé et de la Recherche Médicale, received honorariums and travel reimbursement from Actelion as a member of an advisory committee and guest speaker, and from Shire for speaking engagements and as a member of a data and safety monitoring board. She received travel expenses from Vtesse as a member of a scientific advisory committee.)
Raphael Schiffmann MD, editor. (Dr. Schiffmann, Director of the Institute of Metabolic Disease at Baylor Research Institute, received research grants from Amicus Therapeutics, Protalix Biotherapeutics, and Shire.)
Originally released November 15, 1997; last updated May 5, 2016; expires May 5, 2019

This article includes discussion of Niemann-Pick disease type C, Niemann-Pick C disease, NPC, neonatal cholestatic rapidly fatal form of Niemann-Pick disease type C, early-infantile neurologic-onset form of Niemann-Pick disease type C, late-infantile neurologic-onset form of Niemann-Pick disease type C, juvenile neurologic-onset form of Niemann-Pick disease type C, and adult neurologic-onset form of Niemann-Pick disease type C. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Niemann-Pick disease type C is an autosomal recessive neurodegenerative lysosomal storage disorder characterized by impaired cellular trafficking of cholesterol and sphingolipids and caused by mutations in either the NPC1 or NPC2 gene. In this article, the author emphasizes the wide spectrum of clinical phenotypes, highlights new developments and difficulties in diagnostic strategies, and discusses the current status in the management and treatment of patients.

Key points

 

• Niemann-Pick disease type C (Niemann-Pick C disease, NPC) has a wide spectrum of clinical phenotypes and is most likely underdiagnosed in adults. A suspicion index tool has been developed.

 

• For laboratory diagnosis, initial orientation tests in plasma measuring particular oxysterols (cholestane-3ß-5α−6ß-triol) or bile acid derivatives, lysosphingomyelin and lyso-SM-509, have been developed; however, these biomarkers are not specific to Niemann-Pick disease type C.

 

• Confirmation of the clinical diagnosis of Niemann-Pick disease type C is based on 2 complementary approaches: molecular study of the NPC1 and NPC2 genes and demonstration of an impaired trafficking of endocytosed cholesterol in living cells (filipin test). The latter test is required whenever 2 pathogenic mutant alleles have not been identified.

 

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

 

• Among experimental therapies, promising results obtained by intrathecal administration of 2-hydroxypropyl-beta-cyclodextrin to mouse and cat models have led to a clinical trial, which is currently entering phase 2b/3.

Historical note and terminology

Historically, the eponym "Niemann-Pick disease" encompassed a heterogeneous group of autosomal recessive lysosomal lipid storage disorders, with common features of hepatosplenomegaly and sphingomyelin storage. In 1958, Crocker and Farber showed a wide variability both in age of onset and clinical expression and in the level of sphingomyelin storage in tissues (Crocker and Farber 1958). This led Crocker to propose a classification of Niemann-Pick disease into 4 subgroups, A to D (Crocker 1961). Type A was characterized by severe, early CNS deterioration and massive visceral and cerebral sphingomyelin storage. Type B showed a chronic course with marked visceral involvement but a sparing of the nervous system. Types C and D were characterized by a subacute nervous system involvement with a moderate and slower course and a milder visceral storage. Type D patients were individualized essentially on their homogenous Nova Scotia Acadian origin.

From 1966 to 1968, Brady and associates demonstrated a severe deficiency in sphingomyelinase activity in tissues from patients with type A and type B, but not in types C and D. From that time, with a turn following seminal observations in a Balb/c murine model of the disorder (Pentchev et al 1984), the concept of Niemann-Pick type C disease evolved from that of a sphingomyelin storage disorder to that of a cholesterol storage disorder (Pentchev et al 1995). This and later work led to the reclassification of the disease as a cellular lipid trafficking disorder.

Today, the denomination "Niemann-Pick C disease" designates disorders characterized by unique abnormalities of intracellular transport of endocytosed cholesterol (Pentchev et al 1985; Pentchev et al 1987; Sokol et al 1988; Liscum et al 1989; Pentchev et al 1995; Patterson et al 2001; Vanier and Millat 2003; Peake and Vance 2010; Vance and Karten 2014; Vanier 2015). Major advances have been the description of 2 genetic complementation groups and the isolation of the underlying genes. NPC1, located at chromosomal segment 18q11, is involved in 95% of the families or more, including those with type D. NPC2, located at chromosomal segment 14q24.3, is involved in rare families (Steinberg et al 1994; Vanier et al 1996; Carstea et al 1997; Greer et al 1998; Naureckiene et al 2000). Although the precise functions of the NPC1 and NPC2 proteins are still elusive, current knowledge supports the idea that these proteins function in a coordinated fashion and that they are involved in the cellular postlysosomal/late endosomal transport of cholesterol and other molecules (Patterson et al 2001; Vanier and Millat 2003; Kwon et al 2009; Peake and Vance 2010; Vanier 2010; Vance and Karten 2014). Stricto sensu, one should, therefore, distinguish between Niemann-Pick disease type C1 (www.ncbi.nlm.nih.gov/omim/257220) and Niemann-Pick disease type C2 (www.ncbi.nlm.nih.gov/omim/607625). Because the clinical manifestations and biochemical abnormalities of types C1 and C2 are similar, the distinction is not always made. The generic terms of "Niemann-Pick disease type C," “Niemann-Pick C disease,” or “NPC” remain widely used in practice and in literature.

On the other hand, it is essential to remember that a diagnosis of "Niemann-Pick disease" without specification of a subgroup is ambiguous and a potential source of error. One should clearly distinguish acid sphingomyelinase deficiencies (due to SMPD1 mutations and including types A, B, and intermediate forms) and Niemann-Pick type C, with alterations in trafficking of endocytosed cholesterol (due to NPC1 or NPC2 mutations). Type D as a distinct entity is no longer justified.

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