Search

Juvenile hemochromatosis is an early-onset autosomal recessive disorder of iron overload resulting in cardiomyopathy, diabetes and hypogonadism that presents in the teens and early 20s (refs. 1,2). Juvenile hemochromatosis has previously been linked to the centromeric region of chromosome 1q (refs. 3 6), a region that is incomplete in the human genome assembly. Here we report the positional cloning of the locus associated with juvenile hemochromatosis and the identification of a new gene crucial to iron metabolism. We finely mapped the recombinant interval in families of Greek descent and identified multiple deleterious mutations in a transcription unit of previously unknown function (LOC148738), now called HFE2, whose protein product we call hemojuvelin. Analysis of Greek, Canadian and French families indicated that one mutation, the amino acid substitution G320V, was observed in all three populations and accounted for two-thirds of the mutations found. HFE2 transcript expression was restricted to liver, heart and skeletal muscle, similar to that of hepcidin, a key protein implicated in iron metabolism(7-9). Urinary hepcidin levels were depressed in individuals with juvenile hemochromatosis, suggesting that hemojuvelin is probably not the hepcidin receptor. Rather, HFE2 seems to modulate hepcidin expression.

Animal models indicate that the antimicrobial peptide hepcidin (HAMP; OMIM 606464) is probably a key regulator of iron absorption in mammals. Here we report the identification of two mutations (93delG and 166C–>T) in HAMP on 19q13 in two families with a new type of juvenile hemochromatosis.

Waldenstrom’s macroglobulinernia is a low-grade lymphoplasmacytoid lymphoma characterized by CD20 expression on malignant cells. Several studies have indicated that the anti-CD20 monoclonal antibody rituximab has activity against this disease. Thus, we performed a prospective study in which 17 previously untreated patients with symptomatic macroglobulinernia were treated with rituximab 375 mg/m(2) intravenously for 4 weeks. Three months after completion of rituximab, patients without evidence of progressive disease received repeat 4-week courses of this agent. Six patients (35%) achieved a partial response after extended treatment with rituximab. Median time to response was 3 months. The median time to progression (TTP) for all patients was 13 months. One of 6 responding patients has progressed at 10 months, while the other 5 patients remain progression free with a follow-up range of > 22-40 months. Eight patients (47%) were rated as stable disease, and their median TTP was 9 months. Treatment with rituximab was well tolerated and was not associated with myelosuppression; one third of the patients experienced infusion-related toxicity, usually fever and chills of mild degree. Our prospective trial of extended rituximab therapy for previously untreated patients with Waldenstrom’s macroglobulinernia indicates that this agent is active, well tolerated, and might be associated with a long period without the need for further treatment. Studies that will combine rituximab with chemotherapy or with other monoclonal antibodies might be of interest.

Purpose : Waldenstrom’s macroglobulinemia (WM) is a low-grade lymphoplasmacytic lymphoma in which CD20 is usually expressed on tumor cells. There is evidence that patients with WM may benefit from treatment with the anti-CD20 monoclonal antibody rituximab. We performed a prospective phase 11 study to clearly define the activity of rituximab in patients with this disease. Patients and Methods: Twenty-seven patients with WM were treated with rituximab 375 mg/m(2) intravenously (IV) for 4 weeks. Three months after completion of rituximab, patients without evidence of progressive disease received repeat 4-week courses of this agent. All patients were symptomatic, their median age was 72 years, and 15 patients were previously untreated. Results: Twelve patients (44%; 95% confidence interval, 25.5% to 64.7%) achieved a partial response after treatment with rituximab. Median time to response was 3.3 months (range, 2.2 to 7.1 months). Responses occurred in six (40%) of 15 previously untreated patients and in six (50%) of 12 pretreated patients. Patients with a serum immunoglobulin M less than 40 g/L had a significantly higher response rate. The median time to progression for all patients was 16 months, and with a median follow-up of 15.7 months, nine of 12 responding patients remain free of progression. Treatment with rituximob was well tolerated, with approximately one fourth of patients experiencing some mild form of infusion-related toxicity, usually fever and chills. Conclusion: Our prospective data indicate that rituximab is well tolerated and active in patients with WM. Previously untreated and pretreated patients seem to benefit equally. Repeat 4-week courses of rituximab may prolong the duration of response of the disease, but this observation requires confirmation in prospective, randomized trials. Furthermore, studies that will combine rituximab with chemotherapy may be relevant. (C) 2002 by American Society of Clinical Oncology.

Study of the Hpa I polymorphism 3’ to the beta-globin gene in the Greek population revealed absence of the site in 238 beta-S chromosomes, in contrast to a much larger sample of chromosomes carrying the beta-A gene, where this site was consistently positive. Subsequent haplotype analysis of the beta-globin gene cluster in 82 beta-S chromosomes demonstrated that 79 (96%) belonged to haplotype #19, while the three exceptions (all Hpa I negative) could be explained by a delta-beta recombination event. Haplotype #19 was never encountered in a parallel study of the 83 beta-A chromosomes. Comparison of the above results with similar surveys in other parts of the world and consideration of various historical events suggest that the beta-S mutation was introduced into Greece over the last few centuries by the Saracen raids and/or by settlements of North African slaves brought in by the Arabs, Franks, Venetians, or Ottoman Turks, who have occupied the country over the last millennium.

Haematological and clinical characteristics have been examined in 30 patients with homozygous sickle cell (SS) disease, 28 with sickle cell-beta-degrees thalassaemia, and 21 with sickle cell-beta+ thalassaemia. The latter could be divided into three groups on their molecular basis and HbA levels, four subjects with an IVS-2 nt 745 mutation having 3-6% HbA (designated Sbeta+ thalassaemia type I), 14 subjects with an IVS-1 nt 110 mutation having 8-15% HbA (designated Sbeta+ thalassaemia type II), and three subjects with an IVS-1 nt 6 mutation having 20-25% HbA (designated Sbeta+ thalassaemia type III). Comparisons were conducted between SS disease, Sbeta-degrees thalassaemia, and Sbeta+ thalassaemia type II. Compared to SS disease, both thalassaemia syndromes had higher HbA2 levels and red cell counts and lower mean cell haemoglobin content (MCHC), mean cell volume (MCV) and MCH, and Sbeta-degrees thalassaemia had higher HbF and reticulocyte counts. Compared to Sbeta-degrees thalassaemia, Sbeta+ thalassaemia had a higher haemoglobin and MCHC. Clinically, persistence of splenomegaly was more common in Sbeta-degrees and Sbeta+ thalassaemia type II compared to SS disease. Few significant differences occurred between SS disease, Sbeta-degrees and Sbeta+ thalassaemia type II in Northern Greece suggesting that the 8-15% HbA in the latter condition was insufficient to modify the clinical course.

Animal models indicate that the antimicrobial peptide hepcidin (HAMP; OMIM 606464) is probably a key regulator of iron absorption in mammals. Here we report the identification of two mutations (93delG and 166C--T) in HAMP on 19q13 in two families with a new type of juvenile hemochromatosis.