Niemann-Pick disease classification
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Christeen Henen, M.D. [2]
Overview
Classification
Types A and B
Type A Niemann-Pick disease begins during infancy and is characterized by an enlarged liver and spleen (hepatosplenomegaly), failure to thrive, and progressive deterioration of the nervous system. Children affected by this condition generally do not survive past early childhood. Niemann-Pick disease, type A occurs more frequently among individuals of Ashkenazi (eastern and central European) Jewish descent than in the general population. The incidence within the Ashkenazi population is approximately 1 in 40,000 people. The incidence for other populations is unknown.
Type B disease may include signs of hepatosplenomegaly, growth retardation, and problems with lung function including frequent lung infections. Other signs include blood abnormalities such as abnormal cholesterol and lipid levels, and low numbers of (platelets). People affected by this type of Niemann-Pick disease usually survive into adulthood. Niemann-Pick disease, type B occurs in all populations.
Mutations in the SMPD1 gene cause Niemann-Pick disease, types A and B. This gene carries instructions for cells to produce an enzyme called acid sphingomyelinase. This enzyme is found in the lysosomes (compartments that digest and recycle materials in the cell), where it processes lipids such as sphingomyelin. Mutations in this gene lead to a deficiency of acid sphingomyelinase and the accumulation of sphingomyelin, cholesterol, and other kinds of lipids within the cells and tissues of affected individuals.
Type C
Niemann-Pick disease type C (NP-C) is a rare, progressive genetic lysosomal lipid storage disease caused by mutations in the NPC1 or NPC2 gene. It is a highly heterogeneous disease, characterized by visceral, neurological and psychiatric manifestations that can present alone, or in specific or non-specific combinations. Moreover, age at onset and disease course vary greatly from one patient to another, including among siblings. Due to its challenging presentation, especially for non-specialists, the disease often remains undetected for many years, with an average delay in diagnosis of 5–6 years from onset of neurological symptoms. Early diagnosis is essential so that therapy with miglustat, the only available disease-specific therapy approved for NP-C, can be initiated as soon as neurological symptoms appear in order to slow the progression of neurological damage.[1]
Type C is characterized by onset in childhood, although infant and adult onsets are possible. Other signs include severe liver disease, breathing difficulties, developmental delay, seizures, increased muscle tone (dystonia), lack of coordination, problems with feeding, and an inability to move the eyes vertically. People with this disorder can survive into adulthood. The incidence of Niemann-Pick disease, type C is estimated to be 1 in 150,000 people. The disease occurs more frequently in people of French-Acadian descent in Nova Scotia.
Biochemical Transport
The molecular basis for this disease is extremely complex due to the role that endosome formation has on affected patients. Recently, three theories have attempted to explain the buildup of cholesterol in the lysosomes of affected patients of Niemann-Pick Disease Type C due to the malfunction of the protein NPC-1.
- The contention by Neufel et al is that the buildup of mannose 6-phosphate receptors (MPRs) in the late endosome suggests that the retrograde breakdown of cholesterol via the Trans Golgi Network cannot occur.[2]
- Another theory suggests that the blockage of retrograde cholesterol breakdown in the late endosome is due to decreased membrane elasticity and thus the return vesicles of cholesterol to the Trans Golgi Network cannot bud and form.
The support of these theories has considerable evidence using mutant proteins in vitro to determine the buildup of cholesterol in the lysosomes. Researchers have also discovered that the NPC-1 protein may function as a pump of cholesterol.[3]
The overall effect of a malfunction in NPC-1 is that low levels or an absence of the protein lead to the abnormal accumulation of lipids and cholesterol in the cells of people with this condition.
References
- ↑ Mengel, E.; Klünemann, HH.; Lourenço, CM.; Hendriksz, CJ.; Sedel, F.; Walterfang, M.; Kolb, SA. (2013). "Niemann-Pick disease type C symptomatology: an expert-based clinical description". Orphanet J Rare Dis. 8 (1): 166. doi:10.1186/1750-1172-8-166. PMID 24135395. Unknown parameter
|month=ignored (help) - ↑ Neufeld EB, Wastney M, Patel S; et al. (1999). "The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo". J. Biol. Chem. 274 (14): 9627–9635. PMID 10092649.
- ↑ Davies JP, Chen FW, Ioannou YA (2000). "Transmembrane molecular pump activity of Niemann-Pick C1 protein". Science. 290 (5500): 2295–2298. doi:10.1126/science.290.5500.2295. PMID 11125140.