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Blood, 1 April 2005, Vol. 105, No. 7, pp. 2658-2663. Prepublished online as a Blood First Edition Paper on December 14, 2004; DOI 10.1182/blood-2004-09-3590. This Article Full Text (PDF) All Versions of this Article: 2004-09-3590v1 105/7/2658    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Feldmann, J. Articles by de Saint Basile, G. Search for Related Content PubMed PubMed Citation Articles by Feldmann, J. Articles by de Saint Basile, G. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 15, 2004 Accepted November 9, 2004 Severe and progressive encephalitis as a presenting manifestation of a novel missense perforin mutation and impaired cytolytic activity Jerome Feldmann, Gael Menasche, Isabelle Callebaut, Veronique Minard-Colin, Brigitte Bader-Meunier, Laurence Le Clainche, Alain Fischer, Francoise Le Deist, Marc Tardieu, and Genevieve de Saint Basile* INSERM U429, Hopital Necker-Enfants Malades, Paris, France LMCP, CNRS UMR7590, Universites Paris 6 & Paris 7, Paris, France Unite d'Immunologie-Hematologie, Hopital Necker-Enfants Malades, Paris, France Departement de Pediatrie, Hopital Bicetre, Le Kremlin-Bicetre, France Service de Pediatrie, Centre Hospitalier Rene Dubos, Cergy Pontoise, France INSERM U429, Hopital Necker-Enfants Malades, Paris, France; Unite d'Immunologie-Hematologie, Hopital Necker-Enfants Malades, Paris, France Service de Neurologie, Hopital Bicetre, Le Kremlin-Bicetre, France * Corresponding author; email: sbasile{at}necker.fr. Mutations in the perforin gene cause familial hemophagocytic lymphohistiocytosis (FHL). The first symptoms of FHL are usually intractable fever, hepatosplenomegaly and pancytopenia. Most FHL patients subsequently develop central nervous system (CNS) manifestations due to infiltration of tissues by activated lymphocytes and macrophages. We report two FHL patients with an atypical phenotype characterized by isolated severe neurological symptoms mimicking chronic encephalitis and leading to an early death. Functional and molecular analyzes revealed the same novel missense mutation in the perforin gene in both patients; this mutation affected the calcium-binding domain of the protein. This missense mutation did not affect perforin maturation or expression in cytotoxic cells but impaired in vitro cytotoxic activity. Diagnosis was delayed in both patients because of the initial neurological expression and the normal expression of perforin in circulating lymphocytes. This emphasizes the importance of early diagnosis of this atypical form of FHL as CNS involvement causes severe, irreversible encephalopathy. This observation also raises the question of the role of some mutations in the neurological expression of FHL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Primary immunodeficiencies: the tip of an iceberg? Claudio Pignata Blood 2005 105: 2626-2627. [Full Text] [PDF] This article has been cited by other articles: R. Urrea Moreno, J. Gil, C. Rodriguez-Sainz, E. Cela, V. LaFay, B. Oloizia, A. B. Herr, J. Sumegi, M. B. Jordan, and K. A. Risma Functional assessment of perforin C2 domain mutations illustrates the critical role for calcium-dependent lipid binding in perforin cytotoxic function Blood, January 8, 2009; 113(2): 338 - 346. [Abstract] [Full Text] [PDF] A. Gurgey, S. Aytac, G. Balta, K. K. Oguz, and F. Gumruk Central Nervous System Involvement in Turkish Children With Primary Hemophagocytic Lymphohistiocytosis J Child Neurol, November 1, 2008; 23(11): 1293 - 1299. [Abstract] [PDF] V. Mateo, M. Menager, G. de Saint-Basile, M.-C. Stolzenberg, B. Roquelaure, N. Andre, B. Florkin, F. le Deist, C. Picard, A. Fischer, et al. Perforin-dependent apoptosis functionally compensates Fas deficiency in activation-induced cell death of human T lymphocytes Blood, December 15, 2007; 110(13): 4285 - 4292. [Abstract] [Full Text] [PDF] L. C. Turtzo, D. D. M. Lin, H. Hartung, P. B. Barker, R. Arceci, and K. Yohay A Neurologic Presentation of Familial Hemophagocytic Lymphohistiocytosis Which Mimicked Septic Emboli to the Brain J Child Neurol, July 1, 2007; 22(7): 863 - 868. [Abstract] [PDF] G. Janka and U. zur Stadt Familial and Acquired Hemophagocytic Lymphohistiocytosis Hematology, January 1, 2005; 2005(1): 82 - 88. [Abstract] [Full Text] [PDF]

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