What is Niemann-Pick Disease?

Niemann-Pick disease is an inherited genetic disorder characterized by abnormal lipid metabolism, resulting in the accumulation of fats in various organs, particularly the liver, spleen, brain and bone marrow. The signs and symptoms vary in severity depending on the genetic mutation and type of disease. There are four main types of Niemann-Pick disease: Type A, Type B, Type C1 and Type C2. Type A and Type B are more prevalent in people of Ashkenazi Jewish descent. 1. Niemann-Pick Type A The age of onset is 3 months, and affected individuals usually do not survive past childhood. Typical symptoms are hepatosplenomegaly (enlarged liver and spleen), delayed growth rate, and progressive loss of mental and motor ability after age 1. Some may also develop eye abnormalities or interstitial lung disease that can lead to respiratory failure. 2. Niemann-Pick Type B The age of onset is in mid-childhood, and people with this type can survive into adulthood. Common symptoms are similar to Type A, but less severe, and involves hepatosplenomegaly, recurrent lung infections, short stature and thrombocytopenia (low platelets count). Some may have eye abnormalities or mental retardation. 3. Niemann-Pick Type C1 The signs and symptoms generally appear in childhood, and affected individuals may survive into adulthood. Common symptoms observed include ataxia (trouble in motor coordination), vertical supranuclear gaze palsy (cannot move eyes vertically), dystonia, speech problems and progressive intellectual disability. 4. Niemann-Pick Type C2 Clinical symptoms for Type C2 are similar to that of Type C1, but they differ in the genetic cause. Niemann-Pick disease types A and B are caused by mutations in the SMPD1 gene, which encodes the acid sphingomyelinase enzyme. This enzyme helps to break down and recycle lipids in the lysosomes. It is responsible for converting sphingomyeline to ceramide, binding to cholesterol and forming other lipids for normal structure and functioning. Mutations in the SMPD1 gene can eliminate or reduce the enzyme activity of acid sphingomyelinase. This results in the inefficient breakdown and accumulation of lipids. Excessive accumulation of fats can cause toxicity in cells, leading to malfunctioning of tissues and organs. Four specific mutations in the SMPD1 gene, R496L, L302P, fsp330 and delta608, are more commonly found in people of Ashkenazi Jewish descent. Mutations that cause type A (R496L, L302P, fsp330) result in the complete loss of acid sphingomyelinase activity, whereas the mutation that cause type B (delta608) results in partial enzyme activity. Niemann-Pick Types C1 and C2 are caused by mutations in the NPC1 and NPC2 genes, respectively. Both of these genes also encode proteins that are needed for the movement of cholesterol and lipids within cells. Defective NPC1 and NPC2 genes result in the toxic accumulation of lipids and cholesterol within cells and damage to tissues and organs. References: Ishii H, Takahashi T, Toyono M, Tamura M, Harada K, Yoshida M, Nishikawa Y, Enomoto K, Takada G (2006). Acid sphingomyelinase deficiency: Cardiac dysfunction and characteristic findings of the coronary arteries . Journal of Inherited Metabolic Disease. 29(1): 232-234. Jones I, He X, Katouzian F, Darroch PI, Schuchman EH (2008). Characterization of Common SMPD1 Mutations Causing Types A & B Niemann-Pick Disease and Generation of Mutation-Specific Mouse Models. Molecular genetics and metabolism. 95(3): 152-162. Jose CP, Ferreira MD, Schreiber-Agus N, Carter SM, Klugman S, MDa, Gregg AR, Gross SJ (2014). Carrier testing for Ashkenazi Jewish disorders in the prenatal setting: navigating the genetic maze. American Journal of Obstetrics and Gynecology. 211(3): 197-204. Wasserstein MP, Schuchman EH (2006)