Diagnostic workup and management of patients with suspected Niemann-Pick type C disease

Abstract

Niemann-Pick type C (NP-C) disease is a neurovisceral disorder caused by mutations in the NPC1 and NPC2 genes. It is characterized by lysosomal storage of a broad range of lipids as a result of abnormal intracellular lipid trafficking. Typically patients develop neurodegeneration; however, the speed of disease progression is variable. The exact functions of NPC1 and NPC2 proteins have not been determined and therefore the molecular pathophysiology of NP-C is still not clearly understood. Due to the disease's rarity and clinical heterogeneity, delays from symptom onset to diagnosis and treatment initiation are common. Current therapeutic approaches focus on multidisciplinary symptom control and deceleration (rather than reversal) of disease progression. Thus identification of cases at early stages of disease is particularly important. Recent advances in genetic and biochemical testing have resulted in the generation of relatively non-invasive, quick and cost-effective laboratory assays that are highly sensitive and specific and have the capacity to enhance the clinicians' ability to reach a diagnosis earlier. Miglustat is a compound recently licensed in many countries for the treatment of NP-C that has been shown to decelerate neurological regression, whereas many other promising drugs are currently being trialled in preclinical models or human studies. This review summarizes key clinical, genetic and biochemical features of NP-C, suggests a simple diagnostic investigation strategy and gives an overview of available therapeutic options as well as potential novel treatments currently under development.

Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer

“…Overexpression of FXR1, a member of the Fragile X-related family of RNA-binding proteins, has been associated with suppression of cellular senescence and cancer 74 . NPC2 regulates the transport of cholesterol through the late endosomal/lysosomal system and mutations in this gene have been associated with Niemann-Pick disease type C2, a disease with a broad range of visceral, neurological and psychiatric clinical presentations 75 .…”

2-Hydroxypropyl-β-cyclodextrins and the Blood-Brain Barrier: Considerations for Niemann-Pick Disease Type C1

“…There are no approved pharmacologic drugs for the treatment of NPC1 in the United States [ 3 ]. Miglustat, a partial inhibitor of the synthesis of some glycosphingolipids, has been approved for NPC1 in several countries outside the United States and is used off-label in the United States [ 4 ]. Miglustat reduces the substrates that eventually lead to endosomal accumulation but has no effect on the cholesterol deposits, and has limited efficacy in slowing the worsening of neurological manifestations [ 3 ].…”

The expanding spectrum of movement disorders in genetic epilepsies

“…Furthermore, it is increasingly recognized that non-epileptic, atypical movements manifest in several genetic and neurometabolic syndromes which also feature epilepsy. [5][6][7][8][9][10][11][12] The increasing availability of video-electroencephalogram (EEG) has facilitated differentiation of paroxysmal movements from epileptic seizures, thereby increasing clinical awareness of such epilepsy-dyskinesia phenotypes (Videos S1-S5, online supporting information).…”