Severe and progressive encephalitis as a presenting manifestation of a novel missense perforin mutation and impaired cytolytic activity.
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.
Feldmann
Jérôme
J
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.
Ménasché
Gaël
G
Callebaut
Isabelle
I
Minard-Colin
Véronique
V
Bader-Meunier
Brigitte
B
Le Clainche
Laurence
L
Fischer
Alain
A
Le Deist
Françoise
F
Tardieu
Marc
M
de Saint Basile
Geneviève
G
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
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin