Elio Boeri

Familial nonrandom inactivation linked to the X inactivation centre in heterozygotes manifesting haemophilia A

A basic tenet of the Lyon hypothesis is that X inactivation occurs randomly with respect to parental origin of the X chromosome. Yet, nonrandom patterns of X inactivation are common – often ascertained in women who manifest recessive X-linked disorders despite being heterozygous for the mutation. Usually, the cause of skewing is cell selection disfavouring one of the cell lineages created by random X inactivation. We have identified a three generation kindred, with three females who have haemophilia A because of extreme skewing of X inactivation. Although they have both normal and mutant factor VIII (FVIII) alleles, only the mutant one is transcribed; and, they share an XIST allele that is never transcribed. The skewing in this case seems to result from an abnormality in the initial choice process, which prevents the chromosome bearing the mutant FVIII allele from being an inactive X.

Changes in the quality of life of people with thalassemia major between 2001 and 2009

Background The prolonged survival of patients with thalassemia major as a result of the novel therapeutic strategies introduced in the last decade makes patient quality of life an important issue. This study investigated the changes occurring in overall quality of life in patients with thalassemia in the last decade. Methods This was a population-based cross-sectional survey of quality of life in the entire population with thalassemia major resident in the Liguria region of Italy from 2001 to 2009. The self-administered Short Form-36 (SF-36) questionnaire was used to measure quality of life in patients with thalassemia. Results Forty-nine and 52 eligible patients were assessed in 2001 and 2009, respectively. A total of 43 patients were assessed in both 2001 and 2009. Almost 40% of these 43 patients received deferasirox in 2009, a drug which was not available in 2001. The distribution of ferritin levels was lower in 2009 (median 730) as compared with 2001 (median 1107). Analysis of the raw differences between the two years did not show a significant difference. An improvement was observed in most SF-36 scales in 2009 as compared with 2001, particularly in the Mental Health scale (mean difference in Z score +4.0; 95% confidence interval 0.4–7.5; P = 0.030) and in the Mental Component Summary scale (mean difference in Z score +3.2; 95% confidence interval 0.2–6.2; P = 0.039). Conclusion The challenge associated with new therapies and improvement in mental quality of life dimensions indicates that implementation of effective interventions for screening and evaluation of quality of life is now urgent.

Analysis of 18 novel mutations in the factor VIII gene.

Summary. We describe 18 novel mutations, unreported in the Haemophilia A mutation Databases, that have been identified in a cohort of unrelated, Italian patients affected with haemophilia A (HA). Screening of the factor VIII gene (FVIII) was performed using denaturing high‐performance liquid chromatography (DHPLC) and direct sequencing. Eight mutations were characterized as non‐missense alterations, and the remaining 10 were missense mutations. Heterozygosity for the identified mutations was observed in the female relatives of patients belonging to eight families with sporadic cases. In an attempt to understand better the causative effect of the mutations and the clinical variability of the patients, missense mutation consequences were investigated for: (1) the nature of the new amino acid; (2) the location of the substituted amino acid within crystallographic and theoretical models; and (3) the degree of conservation of the native residue in factor VIII (FVIII) protein and FVIII‐related protein family aligned sequences. These research tools have provided evidence that the mutations we describe involve residues that were conserved, at least in FVIII proteins, in all the species we compared.

Unrelated HSCT in an adolescent affected by congenital erythropoietic porphyria

Abstract: CEP is a rare inborn error of porphyrin–heme synthesis. Clinical manifestations can range from mild to severe and include erythrodontia, reddish‐colored urine, and hemolytic anemia that can be mild or severe and may result in splenomegaly. Completely avoiding exposure to the sun is crucial. Attempts to reduce erythropoiesis and to lower circulating porphyrin levels by means of erythrocyte transfusions have been successful in reducing the expression of the disease. However, the complications of a chronic transfusion regimen are potentially severe. Successful bone marrow transplantation has been reported in CEP. We report a case of successful bone marrow transplantation and prolonged follow‐up in an adolescent CEP patient.

164 PORTAL VEIN THROMBOSIS IN NEWBORN DUE TO PROTEIN C DEFICIENCY

Protein C deficiency is one of the most important cause of thrombosis during early infancy and may have different ways of presentation. We have collected 11 patients, 10 with portal vein thrombosis, 1 with thrombosis of both right and left jugular vein after a Broviac catheter insertion. As far as the time and the trigger event are concerned, we suppose that the thrombosis took place in 9 patients during the neonatal period. Seven out of the nine patients with portal vein thrombosis had umbilical catheterization during neo-natal period (4 due to hyperbilirubinemia and 3 due to prematurity), one patient received surgery in the first day of life because anorectal malformation, whereas we have no information about the last patient. The early symptoms of thrombosis started within the first year of life in 5 patients and within the forth year in 4. In 9 patients the symptoms were, in sequence: splenomegaly, esophageal varices and hypersplenism. The diagnosis of protein c deficiency has been made from 6th month to 14th year after the trigger event. Protein c biological activity values was X = 47% ±9.03 (n.v. 65-128%) and Protein c antigen was X = 51% ±14 (n.v. 68-110%). Antithrombin III (ATIII) was slightly decreased in 7 patients, protein s in 2, factor v below the normal in 3, whereas FII was in the normal range. Four of these patients received Protein c concentrate (Immuno - Vienna), together with heparin treatment during vascular surgery (spleen, renal vein, shunt). In conclusion we can say that all our patients had a more or less marked first type Protein c congenital deficiency. From the pathogenetic point of view we can speculate that the mechanical and chemical action on the vessell wall due to the catheter and the fluid, associated with the prematurity related disorders, can trigger the thrombotic mechanism.