Following on from past installments of “A rare disease a day” Hunter syndrome, Gaucher disease, Tay-Sachs, Morquio syndrome, Fabry disease and Sanfilippo syndrome, Krabbe Disease it is now the turn of Niemann-Pick Disease.
In Niemann–Pick (NP) disease sphingomyelin accumulates in lysosomes. Mutations in the SMPD1 gene cause Niemann–Pick types A and B preventing the body from making acid sphingomyelinase. Mutations in NPC1 or NPC2 cause Niemann–Pick disease, type C. The incidence varies from 1 in 40,000 (In Ashkenazi Jews) for type A to 1 in 250,000 in other populations, while type C is 1 in 150,000. NPA is usually fatal by 18 months whereas NPB and NPC patients may live into their teens or adulthood.
NP results in enlargement of the liver and spleen, these inturn may cause reduced appetite, abdominal distension, pain, and thrombocytopenia. In addition the disease results in unsteady gait, slurred speech and difficulty swallowing. There are many other symptoms of the disease such as abnormal posturing of the limbs, trunk, and face, impaired voluntary rapid eye movements, gradual loss of intellectual abilities, dementia, seizures, enlarged bone marrow cavities, thinned cortical bone, distortion of the hip bone and sleep disorders.
As for treatments for the disease, Miglustat is approved in the EU for treatment of progressive neurological manifestations in adult and pediatric patients with NPC. It is not approved in the US. 2-hydroxypropyl-β-cyclodextrin delays onset of clinical symptoms and reduces accumulation of cholesterol and gangliosides within neuronal cells. A clinical trial is planned with the NIH TRND program.
Chaperone research for NPC includes oxysterol derived chaperones of Niemann-Pick type C1. In addition, fibroblasts carrying NPC1 missense mutations were treated with the proteasome inhibitor MG132 or glycerol 10%, (a chemical chaperone)which resulted in a significant increase of NPC1 protein levels. Recent work has shown treatment with the RyR antagonist DHBP (1,1′-diheptyl-4,4′-bipyridium) as a potent inducer of NPC1 protein, increasing its steady-state level in a dose-dependent manner. In addition the calcium channel blockers diltiazem or verapamil, resulted in a dose-dependent increase in the steady-state level of NPC1 protein in fibroblasts homozygous for the NPC1 I1061T allele.
Significant research has focused on cholesterol absorption inhibitors superior to ezetimibe, while gene therapy has reached the non-human primate stage using adeno-associated virus serotype 2 (AAV2) to deliver human acid sphingomyelinase (hASM). High throughput screens using RNAi have also been used to identify modulators of cholesterol accumulation in NPC.
Foundations representing the patients with the disease and raising funds for research are the Ara Parseghian Medical Research Foundation and the National Niemann-Pick Disease foundation, Inc. Research on Niemann-Pick still appears relatively early stage, especially for A and B.
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