Genetic Studies on the Pathogenesis of FHL
Magnus Nordenskjöld MD, PhD
Karolinska University Hospital – Stockholm, Sweden
Date of Award
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Familial hemophagocytic lymphohistiocytosis (FHL) is a devastating disease affecting mainly infants and young children. It causes fever, enlarged liver and spleen, as well as depleted blood counts. Without treatment, FHL is invariably fatal, with a median survival after onset of 1-2 months. With the treatment protocol HLH-94, which is based on chemotherapy and immunotherapy followed by bone marrow transplantation, the survival has increased to around 50%.
FHL is considered to be an inherited disease, with an autosomal recessive pattern. This means that each parent to an affected child carries one healthy and one defect gene (i.e. the specific gene causing the disease). The affected child has been unfortunate to inherit the defect gene from both of the parents. The risk for this to happen is 25% for each child (50% risk to inherit the defect gene from the father times 50% from the mother). The disease will not affect an individual with at least one healthy gene.
The symptoms in FHL are caused by an uncontrolled accumulation and activation of immunological cells (white blood cells, mainly T-lymphocytes and macrophages). The underlying reason for this accumulation has until recently been unknown but in early 1999 we published data suggesting that the accumulation of lymphocytes in FHL was due to decreased programmed cell death (cell suicide). This made sense, since if the cells will not enter the path leading to programmed cell death they will instead accumulate, and that is found in these children. We suggested that this might be due to a deficient triggering of this mechanism. Later 1999 a group of researchers (from France, Texas, and our group) were able to confirm this suggestion, when a gene (perforin, chromosome 10) was shown to be deficient in a subset of FHL children. Perforin has its effect by opening (perforating) the cell membrane to allow the influx of toxic substances which initiate the cell death program. Thus, lack of normal perforin will decrease the programmed cell death and cause cell accumulation.
Subsequently it was shown that mutations in the gene Munc 13-4 may also cause FHL and recently our group was involved in identifying a third genetic cause of FHL (the gene syntaxin-11). Nevertheless, our data suggest that for many FHL families the genes casing the disease have not yet been revealed. We have reported that only a minority (20-40%) of the FHL families have perforin defects and in individuals with FHL ethnically originating from Western Europe only 30% have a known genetic defect. Consequently, the major aim with the proposed research project is to find additional genes that may cause FHL. There are a number of substances involved in the regulation of programmed cell death that we intend to study. Moreover, we have DNA from a large number of families without mutations in the genes perforin, Munc 13-4 and syntaxin-11, and we have therefore the potential to make the proposed research project fruitful.
In summary: Our purpose is to find additional gene(s) and mutations that are defect in FHL. This would be of importance for:
1. Diagnosis. The differential diagnosis between FHL (primary HLH) and secondary HLH is at present sometimes very difficult. Since treatment of FHL includes bone marrow transplant, which is not the case in secondary HLH, better diagnostic tools are highly desired, such as a distinct genetic analysis.
2. Genetic counseling: If a child dies of HLH, a distinct information to the family regarding whether the disease is inherited or not is also very valuable.
3. Prenatal diagnosis: Many families who have had a child who suffered from FHL would appreciate the opportunity of early prenatal diagnosis, which could provide them with an option of an early interruption of the pregnancy (at the choice of the family).
4. Therapy: Increased understanding of the cause of the disease might improve treatment further. In addition, with improved genetic diagnosis therapeutic decisions are facilitated and improved, not least the decision on whether to perform a BMT or not in an affected child, and we believe that such knowledge would improve survival further.