Laboratory Studies
Niemann-Pick disease (NPD) types A and B are diagnosed by measuring the ASM activity in white blood cells. This test can be performed after a small blood sample is obtained from individuals who are suspected of having the disease. Although this test can be used to identify persons with Niemann-Pick disease type A or B, it is not reliable in identifying carriers.
Carriers of Niemann-Pick disease type A or B can be identified by means of DNA testing because the SMPD1 gene, which codes for ASM, has been mapped to band 11p15, and many of its mutations have been identified. This test is particularly useful in the Ashkenazi Jewish community in which known mutations account for more than 92% of the mutations surveyed and in the Maghreb Northern African population in which a single mutation accounts for virtually all cases. In other populations, the mutations must first be identified in each family before DNA testing can be performed.
Prenatal diagnosis of Niemann-Pick disease is possible with chorionic villi sampling or amniocentesis, which are performed early in the pregnancy. [13, 14, 15]
Niemann-Pick disease type C was initially diagnosed by obtaining a skin biopsy sample, growing the fibroblasts in the laboratory, and then studying their ability to transport and store cholesterol. Until recently, this approach was the criterion standard for diagnosis, [16] now superseded by several sensitive and specific blood biomarkers. However, the skin biopsy approach for diagnosis may still remain useful. The transport of cholesterol in the cells is studied by measuring the esterification or conversion of the cholesterol from one form to another. The storage of cholesterol is assessed by staining the cells with filipin, a compound that glows under ultraviolet light. Both of the transport and storage tests mentioned should be performed because relying on one or the other can cause the diagnosis to be missed. Platt et al reported on a possible biological marker in blood for Niemann-Pick disease type C. [17]
In type B patients, the amount of sphingomyelin staining in skin was much lower than that in the liver, with detection facilitated by the lysenin affinity–staining method, the red Chromagen giving contrast against the blue counterstain. [18]
Imaging Studies
Cross-sectional imaging is well suited for detecting this multisystem disease and assessing the various manifestations; findings can be highly suggestive of the diagnosis when seen in combination. [19]
Serial 2-deoxy-2[(18)F]fluoro-D-glucose positron emission tomography in patients with Niemann-Pick disease type C may show a characteristic, unique pattern of brain metabolic abnormality, postulated as a "biomarker" to assess neurologic progression and possible treatment responses. [20] More experience with this concept is needed.
Other Tests
See Patient Education.
Next-generation sequencing panels for diagnosis has advantages and limitations. [21]
A Niemann-Pick disease type C gene variation database has been created (Niemann-Pick Disease Type C Gene Variation Database). [22] This database aims to provide a comprehensive overview, including information on the functional consequences and associated haplotypes for professionals and nonprofessionals dealing with Niemann-Pick disease type C on a clinical, diagnostic, research, or personal basis.
The diagnosis of Niemann-Pick disease type C can be challenging, necessitating biochemical diagnosis by cholesterol staining with cultured skin fibroblasts and confirmed by the analysis of genetic mutations of the NPC1 or NPC2 gene. However, a simpler biochemical approach has been described using a blood smear with filipin staining. [23] A rapid method has been devised to quantitate novel bile acids in biological fluids to facilitate early diagnosis of Niemann-Pick type C disease. [24]
Histologic Findings
Electron microscopy of skin and liver biopsy specimens may suggest the diagnosis of type C Niemann-Pick disease if vacuolation or hepatocytes containing myelin figures are evident, reflecting accumulated lipids. [25]
-
Autosomal recessive inheritance pattern.
