This article includes discussion of Niemann-Pick disease type C, Niemann-Pick C disease, NPC, NP-C, 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, adult neurologic-onset form of Niemann-Pick disease type C, NP-C1, and NP-C2. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
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.
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• Niemann-Pick disease type C (Niemann-Pick C disease, NPC) has a very broad spectrum of clinical phenotypes and is most likely underdiagnosed in adults.
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• For laboratory diagnosis, initial orientation tests in plasma measuring particular oxysterols (cholestane-3ß-5α−6ß-triol) or bile acid derivatives, lyso-SM-509 (now PPCS) and lyso-sphingomyelin, have been developed. These biomarkers are sensitive but not specific to Niemann-Pick disease type C.
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• Confirmation of the clinical diagnosis of Niemann-Pick disease type C is primarily based on molecular study of the NPC1 and NPC2 genes. Whenever 2 pathogenic mutant alleles have not been identified, demonstration of an impaired trafficking of endocytosed cholesterol in living cells (filipin test) is very useful to confirm the diagnosis.
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• 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.
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• Among experimental therapies, 2 compounds are under clinical trials: intrathecal administration of 2-hydroxypropyl-beta-cyclodextrin (HPBCD) (currently in extension of phase 2b/3), oral administration of arimoclomol (in extension of phase 2/3), and intravenous administration of HPBCD (phase 1/2).
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 (20). This led Crocker to propose a classification of Niemann-Pick disease into 4 subgroups, A to D (19). 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. Patients with a retrospective diagnosis of Niemann-Pick C disease were published in the 1960s and 1970s under numerous 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 (107; 100). Type D was later shown to belong to the same disease entity as type C.
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 (104), the concept of Niemann-Pick type C disease evolved from that of a sphingomyelin storage disorder to that of a cholesterol storage disorder (107). 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 (105; 106; 138; 70; 107; 100; 157; 103; 150; 151). 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 (142; 154; 12; 36; 91). 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 (100; 157; 63; 103; 153; 150; 148; 109). 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 rarely 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) from 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.