Niemann-Pick Type C Disease—Pathophysiology and Future Perspectives for Treatment
Niemann-Pick Type C Disease—Pathophysiology and Future Perspectives for Treatment
US Neurology, 2010;6(1):88–94
Abstract
Niemann-Pick type C (NPC) disease is a rare and fatal inherited metabolic disorder that results in intracellular accumulation of cholesterol and glycolipids within the endosomal/lysosomal system. Central nervous system (CNS) involvement is especially prominent as evidenced by ataxia and progressive decline of motor skills and intellectual function. Defects in either the NPC1 or NPC2 protein, both of which are thought to be involved in the egress of cholesterol and other lipids out of the endosomal/lysosomal system, leads to NPC disease. The pathogenic cascade is not well understood, and currently there is no corrective therapy for NPC patients. However, some compounds tested in animal models of NPC disease have shown promise in slowing disease onset and progression, and administration of these drugs in combination has provided evidence of synergy and enhanced clinical benefit. This favorable outcome indicates that combinatorial therapies using small molecules likely represent the best therapeutic option available to NPC patients at this time.
Keywords
Cholesterol, glycosphingolipids, combination therapy, cyclodextrin, miglustat, lysosomal disease
Disclosure: Cristin D Davison has no conflicts of interest to declare. Steven U Walkley, DVM, PhD, is an author on a patent for the use of miglustat in the treatment of Niemann- Pick type C.
Acknowledgments: The authors would like to thank the National Institutes of Health (NIH NS053677), Dana’s Angels Research Trust (DART), and the Ara Parseghian Medical Research Foundation for support and gratefully acknowledge collaborative interactions with Dr D Ory, Dr Y Ioannou, and Dr F Platt.
Received: May 9, 2010 Accepted: June 28, 2010 Citation: US Neurology, 2010;6(1):88–94
Correspondence: Steven U Walkley, DVM, PhD, Department of Neuroscience, Pathology, and Neurology, Albert Einstein College of Medicine, 1410 Pelham Parkway, Kennedy 618, Bronx, NY 10461. E: steve.walkley@einstein.yu.edu
Lysosomal diseases are rare metabolic disorders that result from inherited defects in the endosomal/lysosomal system and often lead to severe clinical disease and premature death. The endosomal/ lysosomal system is a vital recycling center that plays a critical role in intracellular signaling and homeostatic events, including a primary role in the breakdown and salvage of most cellular components. Endosomal/lysosomal dysfunction leads to a complex disease cascade, with the most recognizable feature being the intracellular accumulation of unmetabolized products. Since the precise role of the lysosomal system is not the same in cells with different metabolic signatures, the overall pathologic features typically vary by both disease and cell type. In approximately two-thirds of lysosomal diseases there is significant central nervous system (CNS) involvement. Niemann-Pick Type C (NPC) disease is one such lysosomal disorder and is characterized by prominent intracellular accumulation of unesterified cholesterol and several glycosphingolipids (GSLs).1,2 While many cell types are affected in NPC disease, the storage of unmetabolized products is especially severe in cells of the CNS and leads to a variety of pathologic changes and to neuronal dysfunction. Intraneuronal storage is accompanied by many other well-known pathologic changes, including the formation of meganeurites, the growth of ectopic dendrites, and the widespread occurrence of neuroaxonal dystrophy.3 Patients with NPC disease typically present with vertical supranuclear gaze palsy (VSGP) and learning difficulties, followed by ataxia, seizures, dystonia, respiratory dysfunction, and progressive mental decline.1,4–6 Most patients succumb to NPC disease in adolescence, although disease onset is variable and adult-onset cases of NPC disease have been reported.7
Niemann-Pick Type C Disease—A Brief History
The discovery of Niemann-Pick disease is attributed to Albert Niemann, a German pediatrician, and Ludwig Pick, a German pathologist. In 1914, Niemann provided a report of a child with CNS impairment and enlarged liver and spleen (hepatosplenomegaly).8 Several years later in the 1920s, Pick analyzed tissues from children with these clinical signs and established this as a new, distinct disease. Niemann-Pick disease was subsequently separated into four different types (A, B, C, and D) by Crocker in the late 1950s based on varying clinical and biochemical data.9
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Cholesterol, glycosphingolipids, combination therapy, cyclodextrin, miglustat, lysosomal disease
