Assessment of the olfactory function in Italian patients with type 3 von Willebrand disease caused by a homozygous 253 Kb deletion involving VWF and TMEM16B/ANO2.

Type 3 Von Willebrand disease is an autosomal recessive disease caused by the virtual absence of the von Willebrand factor (VWF). A rare 253 kb gene deletion on chromosome 12, identified only in Italian and German families, involves both the VWF gene and the N-terminus of the neighbouring TMEM16B/ANO2 gene, a member of the family named transmembrane 16 (TMEM16) or anoctamin (ANO). TMEM16B is a calcium-activated chloride channel expressed in the olfactory epithelium. As a patient homozygous for the 253 kb deletion has been reported to have an olfactory impairment possibly related to the partial deletion of TMEM16B, we assessed the olfactory function in other patients using the University of Pennsylvania Smell Identification Test (UPSIT). The average UPSIT score of 4 homozygous patients was significantly lower than that of 5 healthy subjects with similar sex, age and education. However, 4 other members of the same family, 3 heterozygous for the deletion and 1 wild type, had a slightly reduced olfactory function indicating that socio-cultural or other factors were likely to be responsible for the observed difference. These results show that the ability to identify odorants of the homozygous patients for the deletion was not significantly different from that of the other members of the family, showing that the 253 kb deletion does not affect the olfactory performance. As other genes may compensate for the lack of TMEM16B, we identified some predicted functional partners from in silico studies of the protein-protein network of TMEM16B. Calculation of diversity for the corresponding genes for individuals of the 1000 Genomes Project showed that TMEM16B has the highest level of diversity among all genes of the network, indicating that TMEM16B may not be under purifying selection and suggesting that other genes in the network could compensate for its function for olfactory ability

Current Management of Patients with Severe von Willebrand Disease Type 3: A 2012 Update

Von Willebrand disease type 3 (VWD3) is the most severe form of this bleeding disorder due to the almost complete deficiency of von Willebrand factor (VWF). VWD3 is inherited as an autosomal recessive trait. While heterozygous carriers exhibit mild or no bleeding symptoms, most patients with VWD3, which is characterized by undetectable levels of VWF antigen (VWF:Ag) and reduced concentrations (<20 IU/dl) of factor VIII (FVIII), show severe bleeding symptoms. Although the incidence of VWD3 is rare, the condition is of considerable interest because of its severe clinical presentation, the need for replacement therapy and the risk of alloantibodies following infusion of plasma-derived VWF concentrates. This review, based on clinical experience, provides an update on the clinical, laboratory and molecular markers of VWD3 that can be useful for determining the optimal therapeutic approach in these patients