Clinical, Immunological and Genetic Analyses of ALPS

National Institute Of Allergy And Infectious Diseases

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Abstract

Research accomplishments of this project include: 1) Further clarified the diagnosis and classification designation of subtypes of ALPS, following a NIH sponsored International ALPS workshop in September 2009 leading to a consensus among all clinical and basic science researchers studying ALPS and related conditions. This was accomplished by identifying a new genetic cause of ALPS like disorder by identification of mutations affecting RAS pathway in 6 patients. 2) Provided below is the current classification scheme that we have devised for ALPS patients based on the particular molecular defect present: ALPS-FAS : mutations in the TNFRSF6 (tumor necrosis factor receptor superfamily 6) gene, encodes the protein CD95 (Fas). ALPS-sFas: somatic mutant: TNFRSF6 gene defect in the double negative T (DNT) cell population. ALPS-FASLG: mutations in TNFSF6 gene, encodes the protein CD95 ligand (Fas ligand). ALPS-CASP10: mutations in CASP10 gene, encodes caspase-10. ALPS-U: associated mutation unidentified to date. During the last year we clarified that the cause of disordered FAS protein function leading to ALPS is based on haploinsuffiiciency caused by mutations affecting the extracellular portion of the protein in some patients. This is a newly emerging unique mechanism of genetic dysfunction. With support from NCBI we have implemented a web based publication of the existing databases of pathogenic FAS mutations, by far the commonest cause of ALPS, which is publicly available and can be used for diagnostic help by referring to NCBI NIH ALPS website <http://www.ncbi.nlm.nih.gov/lovd/home.php?select_db=FAS>. 3) Interplay between and Fas pathway, IL15 and Eomesodermin leading to immune dysregulation was identified using murine model of ALPS studied in conjunction with patients. 4) Characterized and separated related disorders of apoptosis with variant clinical phenotypes into ALPS Related Disorders as defined during the 2009 NIH ALPS workshop. CEDS:Caspase Eight Deficiency State due to mutations in the CASP8 gene, encodes caspase 8. RALD: RAS associated autoimmune leukoproliferative disorder due to mutations in NRAS, KRAS and related genes. KRAS gene association with this disorder was discovered during this year by us as well as investigators from Japan working independently. This is further corroboration of somatic genetic defects affecting RAS pathway genes in a immunodysregulatory disorder like RALPS. Until recently RAS gene defects were thought only to cause cancer. 5) RALD: Patients with this ALPS like syndrome caused by somatic mutations in NRAS and KRAS are currently classified separately as ALPS related apoptosis disorders. These patients with somatic NRAS and KRAS mutations present with autoimmune phenomena, massive splenomegaly, modest lymphadenopathy and normal or only marginally elevated TCR alpha/beta+ DNT cells. Their lymph node histopathology is also not typical of ALPS-FAS. Additionally, these patients show abnormalities of the myeloid compartment, with chronic persistent monocytosis, mimicking juvenile myelomonocytic leukemia (JMML) in otherwise asymptomatic younger patients. 6) Further characterized the pathophysiology and clinical phenotype of the second largest subgroup of ALPS patients in our cohort with somatic mutations in the FAS gene mostly limited to their ALPS signature cells, also known as double negative T lymphocytes. 7) Extended the use of PET scans as an imaging modality in patients with ALPS associated lymphadenopathy as a tool to monitor patients with suspected ALPS associated cancer of the lymphoid system (lymphoma). We have identified lymphomas associated with ALPS-FAS in approximately 10% of our patients. Ongoing critical surveillance for lymphoma and its early diagnosis and treatment has been pursued over the last 15 years of longitudinal follow up of these patients. 8) Continued enrolling patients in a clinical protocol to study the safety and efficacy of valproic acid in ALPS associated lymphoproliferation and hypersplenism.