A novel stroke locus identified in a northern Sweden pedigree: linkage to chromosome 9q31-33.

OBJECTIVES: The population of northern Sweden is characterized by reduced genetic diversity and a high incidence of stroke. We sought to reduce genetic variation further, using genealogic analysis in a set of nuclear families affected by stroke, and we subsequently performed a genome-wide scan to identify novel stroke susceptibility loci. METHODS: Through genealogy, 7 nuclear families with a common ancestor, connected over 8 generations, were identified. A genome-wide scan using 449 microsatellite markers was performed with subsequent haplotype analyses. RESULTS: A maximum allele-sharing lod score of 4.81 on chromosome 9q31-q33 was detected. Haplotype analysis identified a common 2.2-megabase interval in the chromosomal region in 4 of the nuclear families, where an overrepresentation of intracerebral hemorrhage was observed. CONCLUSIONS: We have identified a novel susceptibility locus for stroke. Haplotype analysis suggests that a shared genetic factor is of particular importance for intracerebral hemorrhage.

Lack of aggregation of ischemic stroke subtypes within affected sibling pairs.

OBJECTIVE: To establish whether subtypes of ischemic stroke aggregate within ischemic stroke-affected sibling pairs more than expected by chance alone. METHODS: This retrospective family study was based on a pooled analysis of two cohorts of male and female adult sibling pairs with symptomatic ischemic stroke. One hospital-based cohort of 404 individuals (first proband seen August 30, 1999) was recruited from the United States and Canada, and another population-based cohort of 198 individuals (first proband seen April 17, 1997) was recruited from Umeå, Sweden. Subtype diagnoses were based on Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. RESULTS: Agreement for subtype diagnoses within families was poor (mean +/- asymptotic SE kappa = 0.17 +/- 0.04). Occurrence of one ischemic stroke subtype in a proband was not associated with a greater likelihood of that subtype being the qualifying stroke subtype in the sibling. Comparable levels of agreement were seen when restricting the analysis to same-sex sibling pairs (kappa = 0.22 +/- 0.05) to sibling pairs in which the proband's stroke occurred before the age of 65 years (kappa = 0.16 +/- 0.05) or to pairs in which the proband's stroke occurred at or after the age of 65 years (kappa = 0.19 +/- 0.05). CONCLUSIONS: The subtype of ischemic stroke in a proband was a poor determinant of the subtype of ischemic stroke in the respective sibling. This suggests that many genetic risk factors for ischemic stroke may not be specific for one subtype.

Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis.

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disease of early childhood characterized by nonmalignant accumulation and multivisceral infiltration of activated T lymphocytes and histiocytes (macrophages). Cytotoxic T and natural killer (NK) cell activity is markedly reduced or absent in these patients, and mutations in a lytic granule constituent, perforin, were recently identified in a number of FHL individuals. Here, we report a comprehensive survey of 34 additional patients with FHL for mutations in the coding region of the perforin gene and the relative frequency of perforin mutations in FHL. Perforin mutations were identified in 7 of the 34 families investigated. Six children were homozygous for the mutations, and one patient was a compound heterozygote. Four novel mutations were detected: one nonsense, two missense, and one deletion of one amino acid. In four families, a previously reported mutation at codon 374, causing a premature stop codon, was identified, and, therefore, this is the most common perforin mutation identified so far in FHL patients. We found perforin mutations in 20% of all FHL patients investigated (7/34), with a somewhat higher prevalence, approximately 30% (6/20), in children whose parents originated from Turkey. No other correlation between the type of mutation and the phenotype of the patients was evident from the present study. Our combined results from mutational analysis of 34 families and linkage analysis of a subset of consanguineous families indicate that perforin mutations account for 20%-40% of the FHL cases and the FHL 1 locus on chromosome 9 for approximately 10%, whereas the major part of the FHL cases are caused by mutations in not-yet-identified genes.

[Familial hemophagocytic lymphohistiocytosis: diagnosis, treatment and pathophysiological mechanisms]. / Familjär hemofagocyterande lymfohistiocytos. Från dödligt sjuka barn till bot och immunologiskt genombrott.

Familial hemophagocytic lymphohistiocytosis (FHL) is an invariably fatal disease typically seen in infancy and early childhood, with a median survival without therapy of two months. It is characterized by prolonged fever, hepatosplenomegaly, cytopenia, and deficient NK-cell activity and T-cell cytotoxic capacity. Severe neurological symptoms as well as coagulation disorders and abnormalities in liver function and lipid status may also develop. Since the mid 1980's there has been a remarkable increase in our understanding of this disease. In a large-scale international collaborative effort mediated through the Histiocyte Society, diagnostic criteria and an international treatment protocol (HLH-94) based on immunochemotherapy and BMT have been developed. A large proportion of affected children can now be cured and, moreover, successful chemotherapy in utero of FHL has been achieved. It has been shown that the symptoms and signs are mediated through a pronounced hypercytokinemia. Previous suggestions that FHL may be caused by a deficiency in apoptosis were recently confirmed when perforin gene defects were described, which may well explain the disastrous lymphohistiocytic accumulation and subsequent T-cell activation.

Autopsy findings in 27 children with haemophagocytic lymphohistiocytosis.

AIMS: Primary haemophagocytic lymphohistiocytosis (HLH) is a fatal childhood disorder. The diagnosis is difficult to establish, clinically as well as histopathologically, and it is markedly underdiagnosed. Because of these difficulties, we wanted to elucidate the histopathological findings in population-based patient material. METHODS AND RESULTS: The post-mortem findings in 27 children with primary HLH diagnosed in Sweden between 1971 and 1986 was reviewed. Twelve of these patients had an affected sibling and three additional children had parental consanguinity. Some of the children showed generalized disease, whereas in others only one or a few organs were affected. The major histological alteration was an accumulation of primarily lymphocytes, but also of histiocytes, some of which exhibited evidence of haemophagocytosis. The haemophagocytic activity may be difficult to detect if there are pronounced post-mortem changes, particularly in the spleen, and it is therefore preferable to perform the autopsy as soon as possible after death in order to minimize autolysis. Haemophagocytosis was most commonly observed in the spleen (17/24), the lymph nodes (17/23) and the bone marrow (9/23), indicating that a negative bone marrow examination does not rule out this diagnosis. Three additional patients had discrete signs of haemophagocytosis in the bone marrow. In the spleen, the lymph nodes and the bone marrow, lymphocytic depletion, pronounced in some cases, could be observed, even without prior treatment with steroids or cytostatics. In the liver, most of the patients demonstrated an infiltration of lymphocytes into the portal tracts similar to that seen in chronic persistent hepatitis (22/27), a finding which is uncommon in infancy and therefore suggestive of the diagnosis HLH. Other organs involved included the thymus, lungs intestine, pancreas, kidney, heart and striated muscle. CONCLUSIONS: The diagnosis of HLH must be based on clinical, histological and additional laboratory findings. A negative bone marrow examination is common. Previous treatment with steroids and/or cytostatic drugs may attenuate or even eliminate the typical histological findings. Liver findings similar to those in chronic persistent hepatitis are common.