Niemann-Pick Disease Physiology - Assignment Example

Niemann-Pick Disease Physiology Niemann-Pick Disease Physiology Niemann-Pick disease (NPD) is a group of rare, severe, inherited autosomal receding metabolic syndromes in which there is a dearth of the enzyme acid sphingomyelinase (ASM). Chromosome groups 11p15.1-p15.4(1) have SMPD1 gene which determine this lysosomal enzyme, whose deficiency leads to accumulation of sphingomyelin, cholesterol and other lipids in the major organs like liver and spleen. Mutation of SMPD1 causes NPD types A and type B (Hamosh & McKusick, 2016). Type C is caused by mutation of NPC gene and is classified as C1 and C (Cvitanović-Šojat et al., 2014). In 1914, Albert Niemann published the original description of NPD. His work was later improved by Ludwig Pick, who described the disease pathology in a sequence of papers in 1930s. Classification of NPD into types A, B and C was introduced in 1961. Type D was also classified but was eliminated after research showed that type D was caused by the same gene as type C1. The prevalence of types A and B has been documented in all races and ethnicities. However, type A is more common among the Jewish population of Ashkenazi with a demographic ratio of 1:40000. Type B records highest patients in Maghreb, Africa and Turkish living in Saudi Arabia. Type A and type B among the rest of the global population is approximated at 1:250000 (Hamosh & McKusick, 2016). Type C is most common among Spanish Puerto Ricans. Variant type C1 has been observed in French Canadian people living in Nova Scotia, Yarmouth County. Estimated global ratio for type C is 1:150000. General prognosis shows that type A patients have a life expectancy period of 18 months, type B have at least 3 years to adulthood while type C is considered least threatening. Signs and symptoms of NPD do not differ much according to the type. Type A is accompanied enlargement of spleen, liver and lymph nodes, which may exist with jaundice, brain damage or hepatomegaly, cherry red spots on retina, feeding difficulties, and progressive loss of early motor skills. Type B is accompanied by hepatosplenomegaly and respiratory hinderances and infections in its later stage. Type C presents itself as cholestatic jaundice or hepatosplenomegaly in the first few months of life, motor skills impairment, enlarged spleen and liver, progressive intellectual retardation, seizures, irregular speech, tremors, and progressive muscle failure, including those of the eyes (Geberhiwot et al., 2018). Associated risk factors with type A is death during infancy, pre-adulthood normal life for types B and C. (Pernick, 2017; Lerardi-Curto, 2018). Pathophysiology NPD researchers consider loss of myelin in the CNS is the main pathogenic factor. Lipids like cholesterol and sphingomyelin exist in cell membranes and are digested by lysosomes. Cholesterol esters are absorbed from the blood stream as LDL through endocytosis to create endosomes in the cells. Enzymes act on endosomes to form lysosomes that can digest fatty acids and cholesterol esters contained in them. An example of such enzymes is ASM which breaks down sphingomyelin and is also found in the lysosomes. The digested molecules could either be digested further or reconstituted into sphingomyelin in Golgi apparatus and the endoplasmic reticulum. Free cholesterol that is released acts as an LDL inhibitor and reduces gradually the amount of cholesterol esters that the cell takes in. Excess cholesterol is stored as a cholesterol ester in this process. NPD patients’ cells cannot do this process (Gavlin & Kligman, n.d.). Type C is caused by an error in the trafficking of cholesterol which leads to accumulation of cholesterol. This is as a result of mutation of genes NPC1 found on chromosome 18 and NPC2 located on chromosome 14, for type C and C1 respectively, that results in cholesterol transport to the brain. The protein product of these genes is responsible for protein transport exogenously both in and out of the lysosome. NPC1 is a transmembrane component and does not exactly act as a catalyst while NCP2 is found within lysosomes and aids in binding cholesterol ester in the conversion. However, after hydrolysis of the esters into free cholesterol, in NPD mutated genes, free cholesterol cannot leave the lysosome to act as an inhibitor to LDL thus lysosomes keep accumulating in the cell and eventually that cell dies. In the brain, the mechanisms inhibiting cholesterol digestion is not very clear but it is known that LDL does not absorb the esters, which are digested endogenously in the brain. Mutation of NPC in this case causes cholesterol to be trapped in organelles that contain glycosphingolipids as the major material (Gavlin & Kligman, n.d.). Type A is caused by three common mutations of SMPD1 gene into 1bpdel fsP330, L302P and R496L, which hinder ASM and are attributed to 90% cases. Type B is also caused by a mutation on chromosome 11 as associated with SMPD1 mutations (Hamosh & McKusick, 2016). Type A is the most severe form with severe levels of ASM. Mutations of SMPD1 are either truncated proteins or missense mutations that impede enzymatic activity of ASM. While ASM hydrolyses sphingomyelin within the lysosomes, its deficiency results in the formation of organelles that accumulate and form the lysosomal inclusion. This phenomenon gives cells the characteristic foamy appearance and eventually kills the cells (Gavlin & Kligman, n.d.). Microscopic description of NPD indicates individual and clusters of foam cells ranging up to 90 microns. These foam cells are also present in Tangier disease and hypercholesteremia. Massive cell destruction also hinders lipid digestion when conditions like sickle cell anemia, thalassemia, chronic renal failure and ITP exist. The cytoplasm has soap bubble-like or mulberry clear vacuoles that vary in size. The nuclei have coarse chromatin and are round and small. During diagnosis, lipid stains indicate a positive stain while negative stains are Periodic Acid-Schiff (PAS) stains. Type C shows macrophages with abnormal cholesterol storage in 60% of the patients and may also have sea blue histiocytes. Tests alternatively done are bone marrow aspiration, liver biopsy, slit-lamp eye exam, and tests to check ASM level. Animal models have been used in research of NPC. Type C affects brain majorly, which accounts for the symptoms like loss of locomotive abilities and intellectual retardation. Type A affects the brain, liver, spleen and kidneys in most cases while type B affects lungs and other major organs, excluding the brain. This is why type B patients do not lose functions associated with brain (Lerardi-Curto, 2018). The organs from healthy animals differ from those of the NPD affected animals greatly. When observed, lungs, livers, brains and spleen sections show a light layer of endothelium in healthy beings and a thick layer of fat, larger than half of the span in the section of an affected organ (Pernick, 2017). Treatment and Research There is no known effective treatment for type A but the symptoms are treated individually (Hamosh & McKusick, 2016). Type B treatments that have been fairly successful are bone marrow transplant or enzyme replacement depending on the stage of illness. Statins may be used to monitor liver function while the cholesterol levels are being kept low. Limited success has been witnessed for organ transplant but prospects for gene therapy and enzyme replacement are promising. Enzyme replacement will ensure that the body has the right mutations to combat ASM hinderance. Gene therapy will rectify the wrongly coded genomes to reduce inhibitors by introducing copies of SMPD1, NPC1 or NPC2 genes to transcribe the normal functioning gene products. The use of neuronal cells is a possibility undergoing research where damaged nerve cells can be replaced (Lerardi-Curto, 2018). Type C patients may use a new drug called miglustat, which Actelion released in January 2009, for their nervous system symptoms (Geberhiwot et al., 2018). Research has been going on in this field. In 2014, EMA allowed experimental use of arimoclomol for treatment of type C. in 2016, the drug received a clinical test window allowance from U.S. Food and Drug Administration where dosing was to be done in placebo-controlled phases. Another experimental drug is 2-hydroxypropyl-β-cyclodextrin (HPbCD) which was done by University of Texas Southwestern Medical Centre by injecting mice with the strain and later the drug. Results after seven days indicated that HPbCD acutely reversed storage defects that were expected in the NPC strain. EMA, NIH and TRND institutions have shown interest in the HPbCD trial phases that FDA is yet to approve. These drugs aim to enhance or correct mutated genes so that inhibition and activation processes can take place correctly (Pernick, 2017; Lerardi-Curto, 2018) Article Critique Case report prepared by He et al. (2016) on “Niemann-Pick disease: report of two cases and review of literature” begins by defining and giving a global prevalence of NPD. This article is based on two studies done in China, where there is a low incidence of NPD and the surgical resection specimens are difficult to obtain. Case one is of a 5-year-old male, whose initial diagnosis was pneumonia but screening shows hepatosplenomegaly. After bone marrow biopsy in Chongqing Children Hospital, NPD was diagnosed. The boy was admitted and put on mild treatment upon which latter tests showed increase in WBC, PLT and ALP in the blood. However, inerocosteal length of liver was down 5cm and 7cm for spleen (He et al., 2016). The patient was operated on, left liver graft with splenectomia and middle hepatic vein. Liver was tough, spleen and diaphragm inflamed, bleeding during separation and also intestinal walls and mesenterium were thick, with minor amounts of ascites. After surgery, liver examination showed swelling at 26*17*6 cm and on the section, it was greasy and necrosis was visible (He et al., 2016). HE staining displayed foam cells in liver and spleen and fused irregular vacuolation in cytoplasm. Necrosis, cirrhosis and pseudo lobule proliferation were also observed. Lymphocyte infiltration was also observed. Histochemical staining gave a negative result with periodic PAS. Foam cells in spleen were positive for CD68, Vimentin and AAT-1 but negative indicators for S-100 and CK. In the second case, subject was a 23-year-old female of NPC type C1 at birth. Recently she had developed jaundice. The liver was indefinable and the spleen inerocosteal length was 7cm (He et al., 2016). there was an increase in WBC and PLT. Similar surgery to case 1 was conducted and beside the hepatosplenomegaly, there was some ascitic fluid. Staining and results were similar to case one. Gaucher disease and NPD showed similar cell sizes though NPD had single nucleus. There were no other similarities seen. The general opinion of a review of this case report requires an excellent in-depth understanding of procedural surgery and physiological understanding of both Gaucher and NPD. It was a positively enlightening treatise. Although He et al. (2016) acknowledge the lack of a conclusive pathogenesis of NPD, their article provides valuable insights into the factors that are involved in the progression of the disease. The use of the cases of the two patients with NPD is an approach to improving the understanding of the disease. The unclear pathogenesis demands further research on the disease to enhance its management. References Cvitanović-Šojat, L., Malenica, M., Kukuruzović, M., Žigman, T., Kužnik, K., & Bielen, A. (2014). Niemann-Pick disease type C: mutations of NPC1 gene and the course of disease. genetic testing, 1, 8. Gavlin A. & Kligman B. (n.d). Niemann-Pick Disease. Retrieved 9 October 2018 from http://education.med.nyu.edu/courses/molecular/conferences/papers/c6b.pdf Geberhiwot, T., Moro, A., Dardis, A., Ramaswami, U., Sirrs, S., Marfa, M. P., ... & Héron, B. (2018). Consensus clinical management guidelines for Niemann-Pick disease type C. Orphanet journal of rare diseases, 13(1), 50. Hamosh A. & McKusick V. A. (2016). Niemann-Pick Disease, Type A: Sphingomyelin Lipidosis Sphingomyelinase Deficiency. Retrieved 9 October 2018 from http://omim.org/entry/257200 He, W., Wang, Z., Zhao, L., Xia, J., & Liu, Q. (2016). Case Report Niemann-Pick disease: report of two cases and review of literature. Int J Clin Exp Pathol, 9(1), 296-301. Lerardi-Curto, L. (2018). Sphingomyelinase Deficiency Treatment and Management. Retrieved 9 October 2018 from https://emedicine.medscape.com/article/951564-overview Pernick, N. (2017). Bone Marrow - Nonneoplastic Systemic Disorders Niemann-Pick Disease. PathologyOutlines.com, Inc. Retrieved 9 October 2018 from http://www.pathologyoutlines.com/topic/bonemarrowniemann.html Read More