Niemann-Pick Diseases
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Introduction to the Niemann-Pick Diseases
The Niemann-Pick (NP) diseases belong to a family of disorders identified as lysosomal storage diseases. There are two distinct sub-families of NP diseases. NP type A (NP-A) and type B (NP-B) diseases are caused by defects in the acid sphingomyelinase gene (ASM). NP type C (NP-C) diseases are caused by defects in a gene involved in LDL-cholesterol homeostasis identified as the NPC1 gene.
Activity of Acid Sphingomyelinase
Niemann-Pick Disease, Types A and B
OMIM Link for Niemann-Pick Types A and B
Both Niemann-Pick disease type A and type B are caused by defects in the lysosomal hydrolase, acid sphingomyelinase (gene symbol ASM). The ASM gene is located on chromosome 11p15.1–p15.4 spanning 5 kb and composed of 6 exons encoding a 629 amino acid glycoprotein. At least 18 mutations have been identified in the ASM gene resulting in types A and B NP disease. There are three disease alleles that represent greater than 90% of the cases of type A NP disease in Ashkenazi Jewish populations. These disease alleles include a single nucleotide deletion resulting in a frame-shift at proline 330 (fsP330) and two different missense mutations, one leading to the substitution of leucine for proline at amino acid 302 (L302P) and the other leading to substitution of arginine for leucine at amino acid 496 (R496L). The carrier allele frequency for these type A mutations is as high as 1 in 80 in Ashkenazi Jewish populations. A single mutation, a 3-base deletion leading to loss of arginine at what would be amino acid position 608 (ΔR608), is commonly associated with type B NP disease. This latter mutation leaves the ASM protein with sufficient residual activity to afford protection from the severe neurological symptoms associated with type A NP disease.
Type A NP disease is associated with a rapidly progressing neurodegeneration leading to death by 2 to 3 years of age. In contrast, type B NP disease has a variable phenotype marked primarily by visceral involvement with little to no neurological detriment. Diagnosis of type B NP disease is usually made in early childhood by the presence of hepatosplenomegaly. The most severely affected type B patients exhibit a progressive pulmonary involvement. Both type A and type B NP disease are characterized by the presence of the "Niemann-Pick" cell. This histologically distinct cell type is of the monocyte-macrophage lineage and is a characteristic lipid-laden foam cell.
The course of type A NP disease is rapid. Infants are born following a typically normal pregnancy and delivery. Within 4–6 months the abdomen protrudes and hepatosplenomegaly will be diagnosed. The early neurological manifestations include hypotonia, muscular weakness and difficulty feeding. As a consequence of the feeding difficulties and the swollen spleen, infants will exhibit a decrease in growth and body weight. By the time afflicted infants reach 6 months of age the signs of psycho-motor deterioration become evident. The infant becomes weaker and progressively hypotonic. Previous developmental milestones such as sitting alone begin to be lost. Ophthalmic examination reveals a cherry-red spot typical of patients with Tay-Sachs disease (another lysosomal storage disease) in about 50% of type A NP disease infants. As the disease progresses spasticity and rigidity increase and infant experience complete loss of contact with their environment. As indicated above, type B NP disease has a much more variable phenotype and most patients do not have neurological involvement and are intellectually normal. There is currently no therapy for either type A or type B NP disease.
Niemann-Pick Disease, Type C
OMIM Link for Niemann-Pick Type C
Niemann-Pick disease type C (NPC) results from an error in the trafficking of exogenous cholesterol, thus it is more commonly referred to as a lipid trafficking disorder even though it belongs to the family of lysosomal storage diseases. The principle biochemical defect in patients with NPC is an accumulation of cholesterol, sphingolipids, and other lipids in the late endosomes/lysosomes (LE/L) of all cells. NPC is a disease characterized by fatal progressive neurodegeneration. The gene, whose mutations lead to NPC is identified as NPC1 and is located on chromosome 18q11–q12 spanning 47 kb and composed of 25 exons. The NPC1 gene encodes a 1278 amino acid protein that contains regions of homology to mediators of cholesterol homeostasis suggesting why LDL-cholesterol accumulates in lysosomes of afflicted individuals. Within the protein are regions of homology to the transmembrane domain of the morphogen receptor patched (of Drosophila melanogaster) and the sterol-sensing domains (SSDs) of SCAP (SREBP cleavage-activating protein; SREBP=sterol regulated element biding protein) and HMG-CoA reductase (HMGR). The NPC1 encoded protein is an integral membrane protein containing 13 putative transmembrane domains. The protein is primarily associated with intralumenal vesicles and multi-vesicular late endosomes. The transmembrane regions of NPC1 are separated by three lumenal loops that contain sites of glycosylation. NPC1 also transiently cyclesthrough the trans-Golgi network. The SSD of NPC1 is composed of 5 of the 13 transmembrane domains. Unlike the SSDs in SCAP and HMGR, the NPC1 SSD does not bind the Insig proteins but does bind cholesterol esters and oxysterols. Mutations in the SSD of NPC1 are commonly found in NPC patients. The major function of NPC1 is to facilitate the movement of cholesterol out of LE/L.
At least 95% of NPC patients contain mutations in the NPC1 locus with the remainder harboring mutations in a second gene identified as NPC2. The NPC2 locus is located on chromosome 14q24.3 spanning 13.5 kb and composed of 5 exons encoding a lysosomal glycoprotein of 151 amino acids. The NPC2 protein was originally identified as epididymal secretory protein (HE1). Like the protein encoded by the NPC1 locus, the NPC2 gene product also binds cholesteryl esters. However, unlike NPC1, NPC2 does not bind oxysterols. The NPC2 protein is a soluble protein found in the lumen of lysosomes. The NPC2 protein is targeted to the lysosomes by binding the mannose-6-phosphate receptor. The NPC2 protein is involved in cholesterol movement out of LE/L in conjunction with NPC1.
One model proposed for the combined actions of NPC1 and NPC2 is that membrane bound NPC1 interacts with the cholesterol that accumulated in intralumenal vesicle membranes and then transfers the cholesterol to soluble NPC2. The action of NPC2 is then to transfer the cholesterol to the limiting membranes of LE/L which allows for cholesterol distribution to other cellular membranes. An alternative model proposes that NPC2 removes cholesterol from intralumenal vesicles of LE/L and then transfers the cholesterol to NPC1 in the limiting membranes of the LE/L.
A genetic isolate of NP disease first identified in patients in Colorado and Nova Scotia, Canada was originally called NP type D (NPD) disease. However, these patients are now known to have harbored specific alleles of the NPC1 locus.
The prevalence of NPC disease is more common than NPA and NPB disease combined, however, as indicated above for NPA, certain ethnic groups have significant disease allele carrier frequency. There can be significant clinical heterogeneity associated with NP-C disease. Most afflicted individuals have progressive neurological disease with early lethality. The characteristic phenotypes associated with "classic" NPC disease are variable hepatosplenomegaly, progressive ataxia, dystonia, dementia and vertical supranuclear gaze palsy (VSGP). These individuals will present in childhood and death will ensue by the second or third decade. Because of the variable clinical phenotypes of NPC disease it has been sub-divided into five presentation classifications: perinatal, early infantile, late infantile, juvenile and adult. VSGP is a characteristic neurological manifestation in NPC disease being found in virtually all juvenile and adult cases of the disease. Like NPA and NPB disease, NPC pathology is characterized by the presence of lipid-laden foam cells in the visceral organs and the nervous system. There is currently no specific treatment for NPC disease.
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Michael W. King, Ph.D / IU School of Medicine / miking at iupui.edu