Protein S deficiency: a database of mutations - summary of the first update

Protein S is a vitamin K dependent protein whose inherited deficiency is a well recognized risk factor for venous thrombosis. Its role is to act as activated protein C cofactor in factor Va and VIIIa proteolysis, thus restricting thrombin generation. Its gene lies on chromosome 3, at position 3p11.1-q11.2, and its structural organization has been described. Elucidation of the gene defects responsible for protein S deficiency is proceeding rapidly. A first record of identified mutations was undertaken in 1996 under the auspices of the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee (ISTH SSC) and was published in 1997 (Thromb Haemost 1997; 77: 1201-14). This first database reported mutations identified in 126 protein S-deficient subjects postulated to be detrimental, and 19 mutations that were considered as neutral polymorphisms. The classification proposed by Bertina at the subcommittee meeting in 1991 was used to classify the mutations according to the phenotype observed in deficient subjects, that is type I when both free and total PS antigen levels were decreased, type III when free PS levels were decreased with normal total PS antigen levels, and type II when cofactor activity of PS was decreased while total and free antigen levels were within the normal ranges

Nusinersen Versus Sham Control In Infantile-Onset Spinal Muscular Atrophy

BACKGROUND & para;& para;Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein.& para;& para;METHODS & para;& para;We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included over all survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis.& para;& para;RESULTS & para;& para;In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41 %] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups.& para;& para;CONCLUSIONS & para;& para;Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug.Wo