title: Congenital deficiency of vitamin K dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex.
abstract: Hereditary combined deficiency of the vitamin K dependent coagulation factors is a rare bleeding disorder. To date, only eleven families have been reported in the literature. The phenotype varies considerably with respect to bleeding tendency, response to vitamin K substitution and the presence of skeletal abnormalities, suggesting genetic heterogeneity. In only two of the reported families the cause of the disease has been elucidated as either a defect in the gamma-carboxylase enzyme (1) or in a protein of the vitamin K 2,3-epoxide reductase (VKOR) complex (2). Here we present a detailed phenotypic description of two new families with an autosomal recessive deficiency of all vitamin K dependent coagulation factors. In both families offspring had experienced severe or even fatal perinatal intracerebral haemorrhage. The affected children exhibit a mild deficiency of the vitamin K dependent coagulation factors that could be completely corrected by oral substitution of vitamin K. Sequencing and haplotype analysis excluded a defect within the gamma-carboxylase gene. The finding of highly increased amounts of vitamin K epoxide in all affected members of both families indicated a defect in a protein of the VKOR-multienzyme-complex. Further genetic analysis of such families will provide the basis for a more detailed understanding of the structure-function relation of the enzymes involved in vitamin K metabolism.
authors.affiliation: Institute of Human Genetics, University of Würzburg, Biozentrum, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Oldenburg
authors.forename: B
authors.initials: B
authors.lastname: von Brederlow
authors.forename: A
authors.initials: A
authors.lastname: Fregin
authors.forename: S
authors.initials: S
authors.lastname: Rost
authors.forename: W
authors.initials: W
authors.lastname: Wolz
authors.forename: W
authors.initials: W
authors.lastname: Eberl
authors.forename: S
authors.initials: S
authors.lastname: Eber
authors.forename: E
authors.initials: E
authors.lastname: Lenz
authors.forename: R
authors.initials: R
authors.lastname: Schwaab
authors.forename: H H
authors.initials: HH
authors.lastname: Brackmann
authors.forename: W
authors.initials: W
authors.lastname: Effenberger
authors.forename: U
authors.initials: U
authors.lastname: Harbrecht
authors.forename: L J
authors.initials: LJ
authors.lastname: Schurgers
authors.forename: C
authors.initials: C
authors.lastname: Vermeer
authors.forename: C R
authors.initials: CR
authors.lastname: Müller
mesh_terms: D001779:Blood Coagulation Factors / Q000378:metabolism; D019735:Carbon-Carbon Ligases / Q000235:genetics; D005192:Family Health; D005260:Female; D005808:Genes, Recessive; D006470:Hemorrhage / Q000209:etiology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D006899:Mixed Function Oxygenases / Q000009:adverse effects / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017421:Sequence Analysis; D014812:Vitamin K / Q000493:pharmacokinetics; D014813:Vitamin K Deficiency / Q000151:congenital / Q000209:etiology* / Q000235:genetics; D064417:Vitamin K Epoxide Reductases
chemical_list: D001779:Blood Coagulation Factors; D014812:Vitamin K; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase