Overview of Niemann-Pick Disease
Niemann-Pick Disease (NPD) refers to a group of inherited diseases. The three most commonly recognized forms are called Types A, B and C. The name Niemann-Pick derives from two German pediatricians - Albert Niemann, the first doctor to identify the Type A form of the disease in 1914, and Ludwick Pick, who first identified the Type B form of the disease in 1927. Types A and B NPD are both caused by the deficient activity of acid sphingomyelinase (ASM). This enzyme is ordinarily found in special compartments within cells called lysosomes and is required to metabolize a special lipid called sphingomyelin. If ASM is absent or not functioning properly, this lipid cannot be metabolized properly and is accumulated within the cell, eventually causing cell and organ system abnormalities. Although Types A and B NPD are both caused by the same enzyme deficiency and are variants of the same disease, the clinical prognosis for these two groups of patients is very different (see Signs and Symptoms).
Type C NPD, although similar in name, is very different at the biochemical and genetic level. Patients with Type C NPD are not able to metabolize cholesterol properly in lysosomes. Consequently, excessive amounts of cholesterol accumulate within the liver, spleen, and brain. The reason that Type C NPD has the same name as Types A and B NPD is historical in nature. In young children, many of the symptoms of the three NPD types appear similar. In addition, the defect in cholesterol metabolism that occurs in Type C NPD patients sometimes leads to a secondary reduction in ASM activity in cells. Therefore, before the availability of accurate enzyme and gene tests (which first became available in the late 1960s and early 1970s), all three forms of NPD were considered variations of the same disease. There were even descriptions of other disease forms, called Types D, E, and F NPD. We now know that Types A and B NPD are two forms of the same disease caused by abnormalities in the ASM gene, while Types C and D NPD are two forms of a distinct disease caused by abnormalities in a cholesterol-metabolizing gene (NPC1). However, even to this day the diagnosis of Types A and B vs. Type C NPD is occasionally confused, and it is imperative that patients have the diagnosis of NPD performed by individuals experienced in these disorders.
Abnormalities in the ASM Gene that Cause Type A or B NPD
The gene that makes ASM is located on human chromosome 11. Many ASM genes from NPD patients have been studied, and the abnormalities (i.e., mutations) that lead to NPD have been identified. Most patients with Types A and B NPD have unique mutations that occur only in their own family. Knowledge of these mutations helps to confirm the enzymatic diagnosis of NPD and permits accurate carrier detection in other family members. In some ethnic groups, several mutations have been found that occur in more than one family (i.e., "common" mutations). For example, among Ashkenazic Jewish individuals, three mutations called "L302P," "fsP330," and "R496L" account for ~90% of all of the mutations occurring in the ASM genes of Type A NPD patients. Another mutation, called "delta R608," has occurred in several unrelated families with Type B NPD from different ethnic backgrounds. This mutation has never occurred in a family with Type A NPD, and it is a good indicator of Type B NPD.
View a timeline of historical landmarks in Niemann-Pick research.