Abstract
Niemann–Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder with extensive biological, molecular, and clinical heterogeneity. Recently, numerous studies have tried to shed light on the pathophysiology of the disease, highlighting possible disease pathways common to other neurodegenerative disorders, such as Alzheimer’s disease and frontotemporal dementia, and identifying possible candidate biomarkers for disease staging and response to treatment. Miglustat, which reversibly inhibits glycosphingolipid synthesis, has been licensed in the European Union and elsewhere for the treatment of NPC in both children and adults. A number of ongoing clinical trials might hold promise for the development of new treatments for NPC. The objective of the present work is to review and evaluate recent literature data in order to highlight the latest neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC pathophysiology. Furthermore, ongoing developments in disease-modifying treatments will be briefly discussed.
Highlights
Niemann–Pick disease type C (NPC) (MIM 257220) is an autosomal recessive neurovisceral lysosomal lipid storage disorder due to mutations of either the NPC1 (95% of families)[1] or the NPC2 gene[2]
The exact functions of the NPC1 and NPC2 genes are still to be fully elucidated, mutations in these genes cause a loss of function, resulting in the accumulation of unesterified cholesterol and glycosphingolipids within the late endosome/ lysosome of all cells, leading to downstream effects on cholesterol homeostasis[7,8,9]
NPC represents an autosomal recessive disorder with extensive biochemical, molecular, and clinical variability, which probably results in an underestimation of the burden of NPC cases worldwide
Summary
Niemann–Pick disease type C (NPC) (MIM 257220) is an autosomal recessive neurovisceral lysosomal lipid storage disorder due to mutations of either the NPC1 (95% of families)[1] or the NPC2 gene[2]. The involvement of deep gray nuclei has been confirmed by 123I-FP-CIT (ioflupane I 123 DaTSCAN) single-photon emission computed tomography (SPECT) imaging in a case of NPC, showing a marked, symmetrical loss of dopamine transporter binding, especially in the putamen[57] This pattern has been observed in a heterozygote patient with a “variant phenotype” in filipin staining and with high levels of plasma oxysterols[60]. Global callosal measures correlated significantly with duration of illness and symptom score and at trend level with degree of filipin staining[64] In agreement with these studies, myelin water imaging, a technique that measures the amount of water present within the myelin of white matter tracts[65,35], has shown large reductions of myelin water fraction in large association tracts and the corpus
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