title: Misdiagnosis of Niemann-Pick disease type C as Gaucher disease.
abstract: Niemann-Pick disease type C (NPC) is a model for inborn errors of metabolism whose gene product mediates molecular trafficking rather than catabolizing macromolecules, as in classic lipidoses. We report the case of an infant who presented with hepatosplenomegaly without neurological abnormalities. Decreased activity of acid β-glucosidase and elevated serum chitotriosidase and tartrate-resistant acid phosphatase on repeated measurements led to initial diagnosis of Gaucher disease (GD). Failure to respond to enzyme replacement therapy after one year, however, put the diagnosis in question. Cholesterol esterification assays in cultured skin fibroblasts and NPC gene analysis led to the correct diagnosis of NPC. The patient had markedly reduced cholesterol esterification and was a compound heterozygote for a known and a novel mutation in the NPC gene (395delC and 2068insTCCC), which are both predicted to lead to protein truncation. Although the full phenotype of NPC involves hepatosplenomegaly and neurodegenerative disease, the initial presentation in a pediatric patient may be restricted to visceral disease. Of interest, this patient had decreased activity of leukocyte acid β-glucosidase activity and elevated serum chitotriosidase to levels often seen in GD. Although acid β-glucosidase activity in leukocytes was low, it was in the normal range in skin fibroblasts. Therefore, diagnostic delay may occur in NPC due to false positive testing for GD. Diagnosis of NPC requires a high index of suspicion and should be considered in a patient with hepatosplenomegaly even in the absence of neurodevelopmental signs. Prompt diagnosis will become increasingly important as effective therapies are developed for NPC.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520-8064, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Lo
authors.forename: Joseph
authors.initials: J
authors.lastname: McNamara
authors.forename: Margherita R
authors.initials: MR
authors.lastname: Seashore
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Mistry
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000627:therapeutic use; D000135:Acid Phosphatase / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism; D004252:DNA Mutational Analysis; D003951:Diagnostic Errors; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D056947:Enzyme Replacement Therapy; D004951:Esterification; D005260:Female; D005776:Gaucher Disease / Q000097:blood / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005962:Glucosylceramidase / Q000097:blood; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006529:Hepatomegaly / Q000209:etiology; D006579:Heterozygote; D006596:Hexosaminidases / Q000097:blood; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000097:blood; D008562:Membrane Glycoproteins / Q000235:genetics; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000097:blood / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D010641:Phenotype; D011237:Predictive Value of Tests; D013163:Splenomegaly / Q000209:etiology; D000071681:Tartrate-Resistant Acid Phosphatase; D019564:Unnecessary Procedures
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; D002788:Cholesterol Esters; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D017485:1-Deoxynojirimycin; C059896:miglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D006596:Hexosaminidases; C086400:chitotriosidase; D005962:Glucosylceramidase