title: Severe and progressive encephalitis as a presenting manifestation of a novel missense perforin mutation and impaired cytolytic activity.
abstract: 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 2 FHL patients with an atypical phenotype characterized by isolated severe neurologic symptoms mimicking chronic encephalitis and leading to an early death. Functional and molecular analyses 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 neurologic 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 neurologic expression of FHL.
authors.affiliation: Inistitut National de la Santé et de la Recherche Médicale (INSERM) U429, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris, Cedex 15, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Feldmann
authors.forename: Gaël
authors.initials: G
authors.lastname: Ménasché
authors.forename: Isabelle
authors.initials: I
authors.lastname: Callebaut
authors.forename: Véronique
authors.initials: V
authors.lastname: Minard-Colin
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bader-Meunier
authors.forename: Laurence
authors.initials: L
authors.lastname: Le Clainche
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Françoise
authors.initials: F
authors.lastname: Le Deist
authors.forename: Marc
authors.initials: M
authors.lastname: Tardieu
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint Basile
mesh_terms: D000595:Amino Acid Sequence; D002675:Child, Preschool; D003594:Cytoplasmic Granules / Q000276:immunology; D004660:Encephalitis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D005260:Female; D015616:Histiocytosis, Non-Langerhans-Cell / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007223:Infant; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008279:Magnetic Resonance Imaging; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D054353:Perforin; D010641:Phenotype; D052899:Pore Forming Cytotoxic Proteins; D017434:Protein Structure, Tertiary; D012720:Severity of Illness Index
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin