The hematological status of 81 infants with Down syndrome was reviewed retrospectively. Twenty babies had no hematological evaluation, 33 had a normal hematological status, and 28 had at least one abnormality, either of hematocrit, white cell count, or platelet count. Among these were 18 babies with increased hematocrit, one with decreased hematocrit, four with decreased platelet count, one with increased white cell count, three with increased hematocrit and decreased platelet count, and one with increased platelet count and increased white cell count. Some of these babies were evaluated for neoplasia or sepsis; however, in all the abnormal blood findings disappeared by 3 weeks without evidence of malignancy or infection. We conclude that hematological abnormalities with a benign natural history are common in Down syndrome infants.
RFLP analysis in Duchenne/Becker muscular dystrophy (D/BMD) has been limited by the lack of informative marker loci at the 3' end of the dystrophin gene. Recently a CACA repeat polymorphism was described in the 3' untranslated end of the dystrophin gene which we have found helpful in genotype assignments of D/BMD families when an RFLP approach is required. The CACA repeat marker has 2 common alleles (1 and 2) that are easily visualized by a nonradioactive PCR method followed by polyacrylamide gel electrophoresis. We present 2 families which demonstrate the use of this polymorphism. Since 35-50% of females are heterozygous, this locus is a useful marker in RFLP analysis of D/BMD families.
The Z (Glu342Lys) variant of a 1 -antitrypsin is common in populations of North European descent. The mutation causes individual a 1 -antitrypsin molecules to assemble into polymer chains in the endoplasmic reticulum of hepatocytes. Z homozygotes (PiZZ) have circulating levels of a 1 -antitrypsin w15% of normal and are predisposed to hepatic cirrhosis and severe, early-onset emphysema. The risk of clinically significant disease associated with the heterozygote PiMZ state is minimal. We describe a case phenotyped as PiZZ during family screening, but with surprisingly preserved circulating a 1 -antitrypsin levels. Genotyping revealed compound heterozygosity for the Z mutation and a novel, "pseudo-Z" mutation. Biochemical and ion-mobility mass spectrometry characterisation of pseudo-Z a 1 -antitrypsin showed that it readily populated a polymerogenic intermediate state under physiological conditions.Cell biological studies of a series of a 1 -antitrypsin variants indicated these effects involved disruption of a hydrogen bond stabilising the F-helix-linker region of the protein structure. These data strongly support the hypothesis that stability of this region co-regulates formation of the polymerogenic intermediate. Whilst the intermediate form of pseudo-Z a 1 -antitrypsin is more stable than that of the true Z variant, the resultant polymers all share a characteristic neoepitope. Pseudo-Z a 1 -antitrypsin is thus a useful model for in vitro screening of potential lead compounds to bind the polymerogenic intermediate state, improving the ability to develop novel therapies to treat a 1 -antitrypsin deficiency. Our data predict that the likelihood of severe disease in the PiZ/Pseudo-Z compound heterozygote state will be increased relative to the PiMZ state, but far lower than for PiZZ individuals. Polymerisation causes circulating deficiency of a 1 -antitrypsin while predisposing to hepatic cirrhosis and severe, early-onset emphysema. Targeting the conformational transitions underlying polymerisation via ligand binding and stabilisation of the physiological native state is therefore a goal of drug design in a 1 -antitrypsin deficiency. To complement previous structure-led approaches we have developed NMR spectroscopy and nanospray mass spectrometry as mediumthroughput screening tools for such ligands. The coupling of these techniques combines highly sensitive detection of ligand binding with assessment of binding sites, stoichiometry, cooperativity and binding constants. We have used the TTAI peptide, developed within an existing programme of drug design, as a test case. The data demonstrate highly co-operative, slow, tight binding of two copies of the peptide in adjacent parts of the a 1 -antitrypsin molecule. TTAI peptide binding is shown to induce widespread conformational change all over the molecule with the exception of b-sheet C. These data prove the utility of NMR spectroscopy and nanospray mass spectrometry in characterising ligand binding whilst providing a highly detailed template for use in specific screen...
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