ABSTRACT
Inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder. Mutations and polymorphisms of the FVII gene were characterized in more than 40 unrelated patients with FVII deficiency. Among the 29 different mutations, the most frequent were Ala294 Val, Ala294Val;404delC, IVS7+7, and Val281 Phe. Four novel mutations (IVS2+1G>C, Arg247 Cys, Glu265 Lys, Asp343 His) were detected. The relationships between genotypes of mutations and polymorphisms of the FVII gene, FVII deficiency, and clinical phenotype were investigated. Homozygosity of the Phe4 Leu, IVS4+1G>A, Cys135 Arg, Ala244 Val, and Ala294 Val;404delC and the double heterozygosity of Tyr68 Cys / IVS3-1G>A, Val252 Met / IVS2+5G>T, Val281 Phe / Cys135 Arg, Ala294 Val / Val281 Phe, Ala294 Val;404delC / Val281Phe, Ala294 Val;404delC / Arg152 stop, Ala294Val;404delC / Gln(-35) stop, Ala294 Val / Val252 Met, Ala294 Val / Gly156 Asp, and Thr359 Met / Asp242 His were related to clinical symptoms. Double heterozygotes for Arg247 Cys / IVS2+1G>C, Ala206 Thr / Pro303 Arg, Leu(-20) Pro / Val252 Met as well as IVS7+7 /Ala294 Val, IVS7+7 /Ala206 Thr, and IVS7+7 / Met298 Ile were asymptomatic. The clinical symptomatology is rather poor in correlation with the FVII activity. Concerning the clinical phanotype, a correlation seems to exist between specific mutations and clinical symptoms.
Subject(s)
Factor VII Deficiency/genetics , Factor VII Deficiency/physiopathology , Factor VII/genetics , Female , Humans , Male , Mutation , Polymorphism, GeneticABSTRACT
Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous neurodegenerative disorder characterised by progressive spasticity of the lower limbs. The SPG4 locus at 2p21-p22 accounts for 40-50% of all AD-HSP families. The SPG4 gene was recently identified. It is ubiquitously expressed in adult and foetal tissues and encodes spastin, an ATPase of the AAA family. We have now identified four novel SPG4 mutations in German AD-HSP families, including one large family for which anticipation had been proposed. Mutations include one frame-shift and one missense mutation, both affecting the Walker motif B. Two further mutations affect two donor splice sites in introns 12 and 16, respectively. RT-PCR analysis of both donor splice site mutations revealed exon skipping and reduced stability of aberrantly spliced SPG4 mRNA. All mutations are predicted to cause loss of functional protein. In conclusion, we confirm in German families that SPG4 mutations cause AD-HSP. Our data suggest that SPG4 mutations exert their dominant effect not by gain of function but by haploinsufficiency. If a threshold level of spastin were critical for axonal preservation, such threshold dosage effects might explain the variable expressivity and incomplete penetrance of SPG4-linked AD-HSP.
Subject(s)
Adenosine Triphosphatases/genetics , Codon, Nonsense/genetics , Exons/genetics , Frameshift Mutation/genetics , Mutation, Missense , Spastic Paraplegia, Hereditary/genetics , Trinucleotide Repeats/genetics , Adenosine Triphosphatases/metabolism , DNA Primers/chemistry , Female , Genes, Dominant , Genotype , Humans , Male , Pedigree , Phenotype , Polymerase Chain Reaction , Polymorphism, Genetic , RNA Splicing/genetics , Restriction Mapping , Sequence Analysis, DNA , SpastinSubject(s)
Acid-Base Equilibrium , Failure to Thrive/physiopathology , Infant, Premature, Diseases/physiopathology , Water-Electrolyte Balance , Acid-Base Equilibrium/drug effects , Acidosis/physiopathology , Bicarbonates/administration & dosage , Humans , Infant, Newborn , Sodium/administration & dosage , Sodium Bicarbonate , Water-Electrolyte Balance/drug effectsABSTRACT
The effect of the obstetrician's choice for delivery route on the early morbidity and mortality of very low birth weight infants in breech presentation (less than or equal to 1500 g) was studied prospectively in 22 children. Criteria of the morbidity were beside antenatal cardiotocogram, the Apgar-score at 1, 5 and 60 min., the cord venous pH-value and the duration of assisted ventilation after immediate delivery. From the first to 28th day of life we continuously analyzed the lowest oxygen pressure, the highest carbon dioxide pressure, therapy with NaHCO3 and the duration of assisted ventilation. But there were no significant differences in morbidity data and mortality between the newborn infants after vaginal and abdominal delivery. However the brief duration of assisted ventilation and brief ventilation time with a FiO2 greater than 0.3, after abdominal delivery were striking despite of a negative starting point of these children. For that reason we are of opinion that a well-timed abdominal delivery of very low birth weight infants in breech presentation shows a favourable influence on the normalization of metabolic and respirations data in the postnatal period and by this on the early morbidity.
