Niemann-Pick Type C Detection, Fibroblasts
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Niemann-Pick disease type C (NPC)(1) is caused by a defect in cellular cholesterol trafficking that results in the progressive accumulation of unesterified cholesterol in late endosomes/lysosomes. NPC is considered a lipid storage disorder with variable age of onset (range: perinatal period to adulthood), and highly variable clinical presentation. Most individuals are diagnosed during childhood with symptoms that include ataxia, vertical supranuclear gaze palsy, dystonia, progressive speech deterioration, and seizures. Infants may present with or without hepatosplenomegaly and respiratory failure. Those without liver and pulmonary disease may present with hypotonia and developmental delay. Adult-onset NPC is associated with a slower progression and is characterized by psychiatric illness, ataxia, dystonia, and speech difficulties.
The diagnosis of NPC has traditionally relied on the demonstration of impaired cholesterol esterification and positive filipin staining in cultured fibroblasts. Since it has been shown that individuals with NPC also exhibit elevated levels of oxysterol cholestane-3 beta,5 alpha,6 beta-triol (COT), oxysterol testing in plasma (see OXNP / Oxysterols, Plasma) or dried blood spot (see OXYBS / Oxysterols, Blood Spots) is an effective, quick, and less invasive first-tier alternative to cholesterol esterification and filipin staining.
The incidence of NPC is approximately 1 in 120,000 to 150,000 live births. NPC is an autosomal recessive condition and is caused by mutations in either the NPC1 or NPC2 genes. About 95% of individuals with NPC have mutations in the NPC1 gene. Mutations may also be identified in the NPC2 gene; see NPCZ / Niemann-Pick Type C Disease, Full Gene Analysis.
Diagnosis of Niemann-Pick disease type C
Values expected in Niemann-Pick disease type C are below 10% of that found in normal cultured fibroblasts.
Values between 10% and 80% of normal will have to be judged on other diagnostic criteria.
All values will be followed up by filipin staining for cholesterol.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Biochemical testing is unreliable for Niemann-Pick disease type C carrier detection.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
If the results indicate that the patient's cultured fibroblasts esterify cholesterol at a level that is <10% of normal cultured fibroblasts and when filipin staining shows excessive storage of free cholesterol, it will be stated that the patient is positive for Niemann-Pick type C disease. All samples will be stained by filipin to see if a milder biochemical phenotype is the likely cause of the Niemann-Pick disease-like clinical picture.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Niemann-Pick disease, type C1; NPC1. In The Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, McGraw-Hill, 2014. Accessed April 07, 2017. Available at www.omim.org/entry/257220?search=257220&highlight=257220
2. Patterson M: Niemann-Pick Disease type C. Reviewed July 18, 2013. Available at www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=npc;
3. Enns GM, Steiner RD, Cowan TM: Lysosomal Disorders. In Pediatric Endocrinology and Inborn Errors of Metabolism. Edited by K Sarafoglou, GF Hoffmann, KS Roth. New York, McGraw-Hill Medical Division, 2009, pp 740
4. Bauer P, Balding DJ, Klunemann HH, et al: Genetic screening for Niemann-Pick disease type C in adults with neurological and psychiatric symptoms: findings from the ZOOM study. Hum Mol Gen 2013;22(21):4349-4356
5. Patterson MC, Mengel E, Wijburg FA, et al: Disease and patient characteristics in NP-C patients: findings from an international disease registry. Orphanet J Rare Dis 2013;8:12