Combined deficiency of factor V (612309) and factor VIII (300841) is characterized by bleeding symptoms similar to those in hemophilia (306700) or parahemophilia (227400), caused by single deficiency of FV or FVIII, respectively. The most common symptoms are ... Combined deficiency of factor V (612309) and factor VIII (300841) is characterized by bleeding symptoms similar to those in hemophilia (306700) or parahemophilia (227400), caused by single deficiency of FV or FVIII, respectively. The most common symptoms are epistaxis, menorrhagia, and excessive bleeding during or after trauma. Plasma FV and FVIII antigen and activity levels are in the range of 5 to 30%. Inheritance of F5F8D is autosomal recessive and distinct from the coinheritance of FV deficiency and FVIII deficiency (summary by Zhang and Ginsburg, 2004). - Genetic Heterogeneity of Combined Deficiency of Factor V and Factor VIII Another form of combined deficiency of factor V and factor VII (F5F8D2; 613625) is caused by mutation in the MCFD2 gene (607788) on chromosome 2.
Oeri et al. (1954) presented relatively convincing laboratory data for the existence of a combined deficiency of factors V and VIII. Affected patients demonstrated a moderate bleeding tendency in association with plasma levels of FV and FVIII between ... Oeri et al. (1954) presented relatively convincing laboratory data for the existence of a combined deficiency of factors V and VIII. Affected patients demonstrated a moderate bleeding tendency in association with plasma levels of FV and FVIII between 5% and 30%. Nichols et al. (1997) stated that at least 89 patients with F5F8D belonging to 58 families had been identified.
By reviewing available published data on 46 patients with MCFD2 mutations and 96 patients with LMAN1 mutations, Zhang et al. (2008) found that patients with MCFD2 mutations had lower levels of both FV and FVIII compared to those ... By reviewing available published data on 46 patients with MCFD2 mutations and 96 patients with LMAN1 mutations, Zhang et al. (2008) found that patients with MCFD2 mutations had lower levels of both FV and FVIII compared to those with LMAN1 mutations. Decreased plasma values for both factors were correlated for each patient, suggesting that deficiencies in LMAN1 or MCFD2 exert a similar impact on FV and FVIII. In addition, platelet factor V levels were reduced to the same extent as plasma factor V. Zhang et al. (2008) suggested that MCFD2 plays a primary role in the export of FV and FVIII from the endoplasmic reticulum, whereas LMAN1 plays an indirect role through its interaction with MCFD2.
Nichols et al. (1998) found that the ERGIC53 (LMAN1) gene, encoding a component of the ER-Golgi intermediate compartment, mapped to a YAC and BAC contig containing the critical region for the gene mutant in combined factors V and ... Nichols et al. (1998) found that the ERGIC53 (LMAN1) gene, encoding a component of the ER-Golgi intermediate compartment, mapped to a YAC and BAC contig containing the critical region for the gene mutant in combined factors V and VIII deficiency. A DNA analysis identified 2 different mutations, accounting for all affected individuals in 9 families studied. Previous studies of 9 Sephardic Jewish and Middle Eastern Jewish families identified 2 distinct haplotypes segregating with the disease, suggesting a possibility of 2 independent founder chromosomes. Indeed, the 5 Sephardic Jewish families were found to be carrying a splice donor mutation (601567.0002), whereas 9 affected individuals in the 4 Middle Eastern Jewish families were homozygous for a G insertion (601567.0001). Combined with their previous reports, Zhang et al. (2006) had identified LMAN1 or MCFD2 mutations as the cause of F5F8D in 71 of 76 families. Among the 5 families in which no mutation was identified, 3 were due to misdiagnosis, with the remaining 2 likely carrying LMAN1 or MCFD2 mutations that were missed by direct sequencing. Thus, mutations in one or the other of these genes may account for all cases of F5F8D. Immunoprecipitation and Western blot analysis detected a low level of LMAN1-MCFD2 complex in lymphoblasts derived from patients with missense mutations in LMAN1 or MCFD2, suggesting that complete loss of the complex may not be required for clinically significant reduction in factor V and factor VIII. Zhang et al. (2008) identified 5 different homozygous mutations in the LMAN1 gene (see, e.g., 601567.0003-601567.0005) in individuals from 6 families with combined factor V and VIII deficiency. The families were of Turkish, Iraqi, Iranian, and Italian descent.
Seligsohn et al. (1982) counted 26 separate reported families including those described in their report. Populations from the Mediterranean basin accounted for most cases: Spanish, Italian, Yugoslavian, Greek, Algerian, Oriental Jewish, and Sephardic Jewish. Ashkenazi Jews had not ... Seligsohn et al. (1982) counted 26 separate reported families including those described in their report. Populations from the Mediterranean basin accounted for most cases: Spanish, Italian, Yugoslavian, Greek, Algerian, Oriental Jewish, and Sephardic Jewish. Ashkenazi Jews had not been affected. Seligsohn et al. (1982) related the difference in frequency of the disease in the 2 main branches of Jewry to historical differences in the Diaspora. The highest frequency of F5F8D was found in Jews of Sephardic and Middle Eastern origin living in Israel with an estimated frequency of 1 in 100,000.