Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597 [ClinicalTrials.gov].).

Severe type I plasminogen (PLG) deficiency has been causally linked to a rare chronic inflammatory disease of the mucous membranes that may be life threatening. Here we report clinical manifestations, PLG plasma levels, and molecular genetic status of the PLG gene of 50 patients. The most common clinical manifestations among these patients were ligneous conjunctivitis (80%) and ligneous gingivitis (34%), followed by less common manifestations such as ligneous vaginitis (8%), and involvement of the respiratory tract (16%), the ears (14%), or the gastrointestinal tract (2%). Four patients showed congenital occlusive hydrocephalus, 2 with Dandy-Walker malformation of cerebellum. Venous thrombosis was not observed. In all patients, plasma PLG levels were markedly reduced. In 38 patients, distinct mutations in the PLG gene were identified. The most common genetic alteration was a K19E mutation found in 34% of patients. Transient in vitro expression of PLG mutants R134K, delK212, R216H, P285T, P285A, T319_N320insN, and R776H in transfected COS-7 cells revealed significantly impaired secretion and increased degradation of PLG. These results demonstrate impaired secretion of mutant PLG proteins as a common molecular pathomechanism in type I PLG deficiency. IntroductionPlasminogen (PLG) plays an important role in intra-and extravascular fibrinolysis, wound healing, cell migration, angiogenesis, and embryogenesis. 1 Plg is primarily synthesized by liver tissue. 2 However, other minor sources identified in mice include adrenal gland, kidney, brain, testis, heart, lung, uterus, spleen, thymus, and gut tissue. 3 In humans, the cornea has been described as an extrahepatic site of PLG synthesis. 4 Inherited PLG deficiency in humans can be divided into 2 types: true PLG deficiency (type I, or hypoplasminogenemia) and dysplasminogenemia (type II). In the former, both immunoreactive PLG level and functional activity are reduced, while the latter shows a normal or slightly reduced level of immunoreactive PLG while functional activity is significantly decreased. It has been shown by several authors since 1995 that homozygous or compound-heterozygous type I PLG deficiency is a major cause of a rare inflammatory disease affecting mainly mucous membranes in different body sites. 5,6 The most common clinical manifestation is ligneous conjunctivitis, characterized by development of fibrin-rich, woodlike ("ligneous") pseudomembranous lesions. Involvement of the cornea may result in blindness. Other, less common manifestations are ligneous gingivitis, otitis media, ligneous bronchitis and pneumonia, involvement of the gastrointestinal or female genital tract, juvenile colloid milium of the skin, and congenital occlusive hydrocephalus. 6 In severely affected patients, prognosis is poor and treatment options are few. Worldwide, more than 150 patients with this disease have been reported since 1847, the date of first description. 6,7 From the Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany; For personal use o...

The Joint Outcome Study Investigators 7Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.

Summary.  Factor X is a vitamin K‐dependent, liver‐produced serine protease that serves a pivotal role in coagulation as the first enzyme in the common pathway to fibrin formation. Inherited factor X deficiency is a rare autosomal recessive bleeding disorder that is estimated to occur in 1:1 000 000 individuals up to 1:500 carriers. Several international registries of FX‐deficient patients have greatly expanded the knowledge of clinical phenotype. A proposed classification of severity is based on FX:C activity measurements: an FX:C measurement <1% is severe, an FX:C measurement of 1–5% is moderate and an FX:C measurement of 6–10% is mild. Levels above 20% are infrequently associated with bleeding and heterozygotes are usually asymptomatic. Among patients with FX:C levels <10%, unlike moderate or severe haemophilia A and B, mucocutaneous bleeding symptoms such as epistaxis and menorrhagia occur in the majority. In addition, patients with moderate–severe deficiency may have symptoms similar to that of haemophilia A and B, including haemarthrosis, intracranial haemorrhage, and gastrointestinal bleeding. Genotype characterization may offer important clues about clinical prognosis. More than 80 mutations of the F10 gene have been identified, most of which are missense mutations. There is no specific FX replacement product yet readily available, but fresh frozen plasma and prothrombin complex concentrates can be used for treatment of bleeding symptoms and preparation for surgery.

Objective: Although studies have documented higher prevalence of abuse in children with ADHD, no studies have investigated childhood reports of abuse in individuals identified with ADHD in adulthood. Method: Forty ADHD women, 17 ADHD males, 17 female controls, and 40 male controls complete the Childhood Trauma Questionnaire and other measures of psychosocial functioning. Results: Emotional abuse and neglect are more common among men and women with ADHD as compared to controls. Sexual abuse and physical neglect are more commonly reported by females with ADHD. Although childhood abuse is significantly correlated with depression and anxiety in adulthood, having ADHD is a better predictor of poorer psychosocial functioning in adulthood. Conclusion: Clinicians are alerted that patients with ADHD symptoms have a high probability of childhood abuse.