Respiratory disease in Niemann-Pick type C2 is caused by pulmonary alveolar proteinosis

Griese M, Brasch F, Aldana VR, Cabrera MM, Goelnitz U, Ikonen E, Karam BJ, Liebisch G, Linder MD, Lohse P, Meyer W, Schmitz G, Pamir A, Ripper J, Rolfs A, Schams A, Lezana FJ. Respiratory disease in Niemann‐Pick type C2 is caused by pulmonary alveolar proteinosis. Niemann‐Pick diseases are hereditar...

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Published in:	Clinical genetics Vol. 77; no. 2; pp. 119 - 130
Main Authors:	Griese, M, Brasch, F, Aldana, VR, Cabrera, MM, Goelnitz, U, Ikonen, E, Karam, BJ, Liebisch, G, Linder, MD, Lohse, P, Meyer, W, Schmitz, G, Pamir, A, Ripper, J, Rolfs, A, Schams, A, Lezana, FJ
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-02-2010 Wiley-Blackwell
Subjects:	Alveoli Amino Acid Sequence Animal models Animals Base Sequence Biological and medical sciences Carrier Proteins - blood Carrier Proteins - chemistry Carrier Proteins - genetics Cholesterol Data processing Errors of metabolism Exons Female Frameshift Mutation Fundamental and applied biological sciences. Psychology General aspects. Genetic counseling Genetics Genetics of eukaryotes. Biological and molecular evolution Glycoproteins - blood Glycoproteins - chemistry Glycoproteins - genetics Humans Infant Infants Lipids Lipids (lysosomal enzyme disorders, storage diseases) Liver Lung Lung diseases Macrophages Medical genetics Medical sciences Metabolic diseases Mice Molecular and cellular biology Molecular Sequence Data Mutation Niemann-Pick disease Niemann-Pick Disease, Type C - complications Niemann-Pick Disease, Type C - diagnostic imaging Niemann-Pick Disease, Type C - pathology Niemann-Pick type C2 Proteins pulmonary alveolar proteinosis Pulmonary Alveolar Proteinosis - complications Pulmonary Alveolar Proteinosis - diagnostic imaging Pulmonary Alveolar Proteinosis - pathology Radiography Respiratory diseases Respiratory Tract Diseases - complications Respiratory Tract Diseases - diagnostic imaging Respiratory Tract Diseases - etiology Respiratory Tract Diseases - pathology Spleen Surfactants tachypnea therapeutic lung lavage Human Niemann-Pick disease Lung disease Nervous system diseases Respiratory disease Lung Metabolic diseases Lipids Infant Concentration Enzymopathy Genetic disease Cerebral disorder therapeutic lung lavage Treatment tachypnea Pulmonary alveolar proteinosis Central nervous system disease Niemann-Pick type C2 Genetics Lipoidosis
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Summary:	Griese M, Brasch F, Aldana VR, Cabrera MM, Goelnitz U, Ikonen E, Karam BJ, Liebisch G, Linder MD, Lohse P, Meyer W, Schmitz G, Pamir A, Ripper J, Rolfs A, Schams A, Lezana FJ. Respiratory disease in Niemann‐Pick type C2 is caused by pulmonary alveolar proteinosis. Niemann‐Pick diseases are hereditary neurovisceral lysosomal lipid storage disorders, of which the rare type C2 almost uniformly presents with respiratory distress in early infancy. In the patient presented here, the NPC2 exon 4 frameshift mutation c.408_409delAA caused reduced NPC2 protein levels in serum and lung lavage fluid and the synthesis of an aberrant, larger sized protein of around 28 kDa. Protein expression was strongly reduced also in alveolar macrophages. The infant developed failure to thrive and tachypnea. Lung lavage, computer tomography, and histology showed typical signs of pulmonary alveolar proteinosis with an abnormal intraalveolar accumulation of surfactant as well as macrophages. An NPC2‐hypomorph animal model also showed pulmonary alveolar proteinosis and accumulation of macrophages in the lung, liver, and spleen long before the mice died. Due to the elevation of cholesterol, the surfactant had an abnormal composition and function. Despite the removal of large amounts of surfactant from the lungs by therapeutic lung lavages, this treatment was only temporarily successful and the infant died of respiratory failure. Our data indicate that respiratory distress in NPC2 disease is associated with a loss of normal NPC2 protein expression in alveolar macrophages and the accumulation of functionally inactive surfactant rich in cholesterol.
Bibliography:	ArticleID:CGE1325 istex:C9336B2C9A4783A80BDC43C8AF3980904C616ABA ark:/67375/WNG-P7GW8LLZ-F ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0009-9163 1399-0004
DOI:	10.1111/j.1399-0004.2009.01325.x