Gabriella Zecchina

Clinical, biochemical and molecular findings in a series of families with hereditary hyperferritinaemia-cataract syndrome.

Hereditary hyperferritinaemia–cataract syndrome (HHCS) is an autosomal dominant disease caused by mutations in the iron responsive element (IRE) of the l‐ferritin gene. Despite the elucidation of the genetic basis, the overall clinical spectrum of HHCS has been less well studied as, to date, only individual case reports have been described. Therefore, we studied a total of 62 patients in 14 unrelated families, with nine different mutations. No relevant symptoms other than visual impairment were found to be associated with the syndrome. A marked phenotypic variability was observed, particularly with regard to ocular involvement (i.e. age range at which cataract was diagnosed in 16 subjects with the C39T: 6–40 years). Similarly, serum ferritin levels varied substantially also within subjects sharing the same mutation (i.e. range for the A40G: 700–2412 µg/l). We followed an HHCS newborn in whom well‐defined lens opacities were not detectable either at birth or at 1 year. The lens ferritin content was analysed in two subjects who underwent cataract surgery at different ages, with different cataract morphology. Values were similar and about 1500‐fold higher than in controls. These observations suggest that: (i) in HHCS the cataract is not necessarily congenital; (ii) in addition to the IRE genotype, other genetic or environmental factors may modulate the phenotype, especially the severity of the cataract.

A new mutation (G51C) in the iron-responsive element (IRE) of L-ferritin associated with hyperferritinaemia-cataract syndrome decreases the binding affinity of the mutated IRE for iron-regulatory proteins

Hereditary hyperferritinaemia–cataract syndrome is an autosomal dominant disorder characterized by a constitutively increased synthesis of l‐ferritin in the absence of iron overload. The disorder is associated with point mutations in the iron‐responsive element (IRE) of l‐ferritin mRNA. We report a new mutation, G51C, identified in two members of a Canadian family, presenting a moderate increase in serum ferritin and a clinically silent bilateral cataract. Gel retardation assays showed that the binding of the mutated IRE to iron‐regulatory proteins (IRPs) was reduced compared with the wild type. Structural modelling predicted that the G51C induces a rearrangement of base pairing at the lateral bulge of the IRE structure which is likely to modify IRE conformation.

New TFR2 mutations in young Italian patients with hemochromatosis

This work describes the identification of two subjects with young-age iron overload carrying new causative mutations in transferrin receptor-2 gene. One was compound heterozygous (Asn411del/Ala444Thr) and the second was homozygous for a mutation affecting RNA splicing (IVS17+5636G>A). Another mutation (His33Asn) and a polymorphism were found in a group of 50 controls.

Two novel mutations in the tmprss6 gene associated with iron‐refractory iron‐deficiency anaemia (irida) and partial expression in the heterozygous form

Arceci, R.J., Sande, J., Lange, B., Shannon, K., Franklin, J., Hutchinson, R., Vik, T.A., Flowers, D., Aplenc, R., Berger, M.S., Sherman, M. L., Smith, F.O., Bernstein, I. & Sievers, E.L. (2005) Safety and efficacy of gemtuzumab ozogamicin in pediatric patients with advanced CD33+ acute myeloid leukemia. Blood, 106, 1183–1188. Bornhauser, M., Illmer, T., Oelschlaegel, U., Schetelig, J., Ordemann, R., Schaich, M., Hanel, M., Schuler, U., Thiede, C., Kiani, A., Platzbecker, U. & Ehninger, G. (2008) Gemtuzumab ozogamicin as part of reducedintensity conditioning for allogeneic hematopoietic cell transplantation in patients with relapsed acute myeloid leukemia. Clinical Cancer Research, 14, 5585–5593. Burnett, A.K., Hills, R.K., Milligan, D., Kjeldsen, L., Kell, J., Russell, N.H., Yin, J.A., Hunter, A., Goldstone, A.H. & Wheatley, K. (2011) Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. Journal of Clinical Oncology, 29, 369–377. Cooper, T.M., Franklin, J., Gerbing, R.B., Alonzo, T.A., Hurwitz, C., Raimondi, S.C., Hirsch, B., Smith, F.O., Mathew, P., Arceci, R.J., Feusner, J., Iannone, R., Lavey, R.S., Meshinchi, S. & Gamis, A. (2012) AAML03P1, a pilot study of the safety of gemtuzumab ozogamicin in combination with chemotherapy for newly diagnosed childhood acute myeloid leukemia: a report from the Children’s Oncology Group. Cancer, 118, 761–769. de Lima, M., Champlin, R.E., Thall, P.F., Wang, X., Martin, T.G., 3rd, Cook, J.D., McCormick, G., Qazilbash, M., Kebriaei, P., Couriel, D., Shpall, E.J., Khouri, I., Anderlini, P., Hosing, C., Chan, K.W., Andersson, B.S., Patah, P.A., Caldera, Z., Jabbour, E. & Giralt, S. (2008) Phase I/ II study of gemtuzumab ozogamicin added to fludarabine, melphalan and allogeneic hematopoietic stem cell transplantation for high-risk CD33 positive myeloid leukemias and myelodysplastic syndrome. Leukemia, 22, 258–264. Petersdorf, S., Kopecky, K., Stuart, R.K., Larson, R. A., Nevill, T.J., Stenke, L., Slovak, M.L., Tallman, M.S., Willman, C.L., Erba, H. & Appelbaum, F.R. (2009) Preliminary Results of Southwest Oncology Group Study S0106: An International Intergroup Phase 3 Randomized Trial Comparing the Addition of Gemtuzumab Ozogamicin to Standard Induction Therapy Versus Standard Induction Therapy Followed by a Second Randomization to Post-Consolidation Gemtuzumab Ozogamicin Versus No Additional Therapy for Previously Untreated Acute Myeloid Leukemia. Blood (ASH Annual Meeting Abstracts), 114, 790. Sakaguchi, H., Watanabe, N., Muramatsu, H., Doisaki, S., Yoshida, N., Matsumoto, K. & Kato, K. (2010) Danaparoid as the prophylaxis for hepatic veno-occlusive disease after allogeneic hematopoietic stem cell transplantation in childhood hematological malignancy. Pediatric Blood & Cancer, 55, 1118–1125. Sibson, K., Steward, C., Moppett, J., Cornish, J. & Goulden, N. (2009) Dismal long-term prognosis for children with refractory acute myeloid leukaemia treated with gemtuzumab ozogamicin and stem cell transplantation: where now? British Journal of Haematology, 146, 342–344. Wadleigh, M., Richardson, P.G., Zahrieh, D., Lee, S.J., Cutler, C., Ho, V., Alyea, E.P., Antin, J.H., Stone, R.M., Soiffer, R.J. & DeAngelo, D.J. (2003) Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood, 102, 1578–1582.