Congenital deficiency of vitamin K dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex.
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.
Oldenburg
J
J
Institute of Human Genetics, University of Würzburg, Biozentrum, Germany.
von Brederlow
B
B
Fregin
A
A
Rost
S
S
Wolz
W
W
Eberl
W
W
Eber
S
S
Lenz
E
E
Schwaab
R
R
Brackmann
H H
HH
Effenberger
W
W
Harbrecht
U
U
Schurgers
L J
LJ
Vermeer
C
C
Müller
C R
CR
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
D001779:Blood Coagulation Factors; D014812:Vitamin K; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase