bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychological and social impact of carrier screening for cystic fibrosis among pregnant women — a pilot study
Authors: Clausen Hans , Brandt Niels Jacob , Schwartz Marianne , Skovby Flemming
Published: July 2010

The aim of the current study was to assess the psychological and social impact of ΔF508 carrier screening for cystic fibrosis among pregnant women. The impact of carrier screening was assessed in terms of anxiety, perception of health, reproductive decisions, retention of results, and sharing of information with relatives by two self‐administered questionnaires sent to 160 women with a positive and 200 women with a negative test result. While no attempt was made to make women accept or decline testing, 22–28% of those tested found it difficult to reject the test when offered. Women with a positive test result became more anxious than did women with a negative result. However, their perception of future health did not change. Most carriers shared the information about their result with relatives and friends. Carriers had the best retention of pretest information and test result, although a third of the carriers believed that they could not have a child with cystic fibrosis when the partner's test for ΔF508 and five other mutations were negative. Most women with a negative test result did not remember their result correctly a year after testing. Few women with a positive result changed their reproductive plans because of the result of the test.
Biliary malformation with renal tubular insufficiency in two male infants: third family report
Authors: Papadia F. , Pollice L. , Natale B. , Bellantuono R. , Conti P. , Carnevale F.
Published: July 2010

We report two male sibs, born to non‐consanguineous healthy parents, who showed arthrogryposis, cholestatic jaundice and tubular renal insufficiency. The liver biopsy of the first case showed scanty hypoplastic biliary ducts. This association, first reported by Lutz and Richner in 1973, is a distinct syndrome, characterized by intra‐extrahepatic biliary hypoplasia, and described in McKusick's catalogue under the number 210550. All reported cases were males and consanguinity was found in two families. For these reasons, the possibility of an autosomal recessive or of an X‐linked transmission should be considered. A similar association, in reports by Nezelof, Di Rocco, and Saraiva, without intra‐extrahepatic atresia but with a cholestatic pigmentary liver disease was considered as another condition (no. 301820) by McKusick in 1992.
Ehlers‐Danlos syndrome type IV caused by Gly400Glu, Gly595Cys and Glyl003Asp substitutions in collagen III: clinical features, biochemical screening, and molecular confirmation
Authors: Mackay Katrina , Raghunath Michael , Superti‐Furga Andrea , Steinmann Beat , Dalgleish Raymond
Published: July 2010

Three patients with Ehlers‐Danlos syndrome type IV (EDS IV) and biochemical evidence of structural defects in collagen III were investigated for mutations within the collagen III gene (COL3A1). Single strand conformation polymorphism analysis of α1(III) cDNA indicated the presence of different heterozygous sequence changes in each of the patients. Nucleotide sequencing revealed mutations leading to the substitution of glycine 400 with glutamic acid, glycine 595 with cysteine, and glycine 1003 with aspartic acid. EDS IV is a life‐threatening disorder which, as the clinical histories of our patients and their families show, still often escapes diagnosis. Biochemical and molecular studies can clarify the diagnosis and help provide appropriate management and counselling.
Partial trisomy 6p due to maternal t(1;6) translocation
Authors: Song Minghao , Li Luyun
Published: July 2010

Partial trisomy 6p with duplications ranging from 6p21 to 6p25 is emerging as an established syndrome. A case of duplication of segment p22‐p25 of the short arm of chromosome 6 as the result of a maternal t (1;6)(q44;p22.2) translocation in a mentally retarded girl with congenital anomalies is reported here. The associated phenotypic anomalies are compared with other reported cases of duplication 6p involving adjacent regions.
Homozygous deletion of exon 18 leads to degradation of the lysosomal α‐glucosidase precursor and to the infantile form of glycogen storage disease type II
Authors: Ausems Margreet G. E. M. , Kroos Marian A. , Van der Kraan Magna , Smeitink Jan A. M. , Kleijer Wim J. , van Amstel Hans Kristian Ploos , Reuser Arnold J. J.
Published: July 2010

We describe two unrelated Dutch patients with typical symptoms of infantile glycogen storage disease type II (GSD II) and virtual absence of acid α‐glucosidase activity in leukocytes and cultured skin fibroblasts. The patients were identified as homozygotes for a deletion of exon 18 of the acid α‐glucosidase gene (GAA). The in‐frame deletion manifests at the protein level in a characteristic way: the enzyme precursor is smaller than normal and degraded in the endoplasmic reticulum or Golgi complex. These cases present an evident example of a genotype‐phenotype correlation in glycogen storage disease type II.
Down syndrome with partial duplication and del (21) syndrome: study protocol and call for collaboration. Study I: clinical assessment
Authors: Barnicoat A. J. , Bonneau J. L. , Boyd E. , Docherty Z. , Fennell S.J. , Huret J. L. , King M. , Maltby E. L. , McManus S. , Pilz D. T. , Shafei‐Benaissa E. , Super M. , Tolmie J.
Published: July 2010

We report on the clinical and cytogenetic assessment of five cases of Down syndrome phenotype with either a partial duplication of chromosome 21 or a normal karyotype, and we quote a case of del (21q) syndrome. Down syndromes with a partial duplication of chromosome 21 (as well as cases of del (21q), which are partly the phenotypic countertype of trisomy 21) are of paramount importance in the understanding of genes involved in the phenotype of Down syndrome. The goal is to find the relevant genes implicated in the main traits of Down syndrome (i.e. mental retardation, Alzheimer disease, and serious visceral malformations). Such a goal, in our opinion, cannot be reached just by publishing the genotype and the phenotype of a small cohort of patients: 1. a sufficient number of accurate cases is needed, and 2. data have to be computerized for definite conclusions to be reached. The main aims of this report are to present our study protocol and to invite colleagues to participate in a collaborative study in order to collect a maximum of these (rare) cases.
An improved method for the detection of Down's syndrome aneuploidy in uncultured amniocytes
Authors: Pierluigi M. , Perfumo C. , Cavani S. , Lehrach H. , Nizetic D. , Bricarelli F. Dagna
Published: July 2010

We report a modified method for the rapid detection of aneuploidies directly on human uncultured amniocytes that simplifies and shortens the entire experimental procedure, yielding signals which allow correct diagnosis of trisomy 21 in 97% of cases. The improvement is based on two points: 1) use of cosmid pockets specific for the Down's syndrome minimal region as FISH probes, and 2) a modified protocol for the fixation and preparation of amniocytes.
The phenotype of a 45, X male with a Y/18 translocation
Authors: Gimelli Giorgio , Cinti Roberta , Varone Paolo , Naselli Arturo , Battista Eliana Di , Pezzolo Annalisa
Published: July 2010

In this report, we describe a male infant with a 45, X karyotype; the entire short arm and the centromere of the Y chromosome were translocated onto the short arm of chromosome 18, resulting in an unbalanced dicentric chromosome. Breakpoints were identified by in situ fluorescence hybridization (FISH) on the proximal Yq11 and 18p11.2. Both Y and 18 centromeric alphoid sequences were identified on the derived 18 chromosome. Clinical features were compatible with 18p‐ syndrome and no Turner stigmata were present in our propositus. Short stature was likely to be related to the deletion of 18p and/or Yq, where a gene involved in stature determination has been located proximal to a gene involved in spermatogenesis (AZF).
Two supernumerary marker chromosomes, derived from chromosome 6 and 9, in a boy with mild developmental delay
Authors: Aalfs Cora M. , Jacobs Marja E. , Nieste‐Otter Marlëlle A. , Hennekam Raoul C. M. , Hoovers Jan M. N.
Published: July 2010

We report on a boy with two supernumerary marker chromosomes which were identified by fluorescence in situ hybridization and derived from chromosome 6 and 9. In lymphocytes, a mosaic karyotype was found: 46,XY (17%)/47,XY,r(6) (24%)/47,XY,r(9) (20%)/48,XY,r(6),r(9) (39%). Only minor dysmorphic features and mild developmental delay were present. Despite extensive fluorescence in situ hybridization studies using a large panel of probes, we were unable to characterize the marker chromosomes in more detail, mainly because no probes for the chromosome regions involved were available to us. In order to reach a better understanding of the clinical relevance of small supernumerary marker chromosomes, it will be necessary to create a widely available set of probes, covering all chromosome regions.
Preimplantation genetic testing for Huntington disease and certain other dominantly inherited disorders
Authors: Schulman Joseph D. , Black Susan H. , Handyside Alan , Nance Walter E.
Published: July 2010

Preimplantation genetic testing (PGT) on embryos from couples at risk for Huntington disease can achieve disease prevention in offspring without disclosure of parental genotype. This strategy may also be applicable to other extremely deleterious dominant traits.
Neurofibromatosis/Noonan phenotype: a variable feature of type 1 neurofibromatosis
Authors: Colley A. , Donnai D. , Evans D. G. R.
Published: July 2010

Since January 1989 we have ascertained patients with neurofibromatosis type 1 (NFl) as part of our genetic register in the North West of England. This register has now identified 453 affected cases from 235 families. The first 94 individuals were specifically examined for features of the Noonan phenotype. This was present in 12/94 sequentially identified individuals with NFl, including six individuals from three families. However, three cases occurred in a further family, where Noonan syndrome appeared to segregate separately from NFl. We have provided evidence for the chance association of Noonan syndrome and NFl and that the Noonan phenotype occurs as a feature in some NFl families. However, there is now little evidence of a separate NFl/Noonan syndrome entity or of NFl features occurring in classical Noonan syndrome.
Phocomelia, ectrodactyly, skull defect and urinary system anomaly: Schinzel‐phocomelia syndrome?
Authors: Evliyaoglu N. , Temoçin A. K. , Altmtas D. U. , Duman N. , Satar N. , Siileymanova D.
Published: July 2010

This report describes a girl with phocomelia of the right upper limb, ectrodactyly, sacral hypoplasia and a large skull defect, but with normal growth and mental development. Ultrasonography and intravenous pyelography showed bilateral hydronephrosis and dilated ureters. We conclude that this patient may represent Schinzel‐phocomelia syndrome with additional urinary tract anomalies.
Association analyses of NsiI RFLP of human insulin receptor gene in hypertensives
Authors: Schrader Andrew P. , Zee Robert Y. L. , Morris Brian J.
Published: July 2010

Plasma angiotensinogen is elevated in essential hypertensives and shows a strong correlation with blood pressure. Patients with hypertension often display insulin resistance and we have found previously an association of a Rsal RFLP in intron 9 of the insulin receptor gene (INSR) with hypertension. Since insulin resistance is accompanied by hyperinsulinaemia and insulin can stimulate angiotensinogen production, we hypothesized that hypertension‐associated genotypes of INSR may be associated with elevation in plasma angiotensinogen. We used PCR to detect a Nsil RFLP in exon 8 of INSR and examined its relationship with plasma angiotensinogen, as well as hypertension, in 134 Caucasian hypertensives with two hypertensive parents and in 126 normotensives. Plasma angiotensinogen tracked weakly with the major allele of the Nsil RFLP in hypertensives (p=0.08). Moreover, the frequency of this allele was higher in lean hypertensives than in lean normotensives (p<0.05) and in normolipidaemic hypertensives than normolipidaemic normotensives (p<0.02). The present study thus suggests that there could be a relationship of plasma angiotensinogen with INSR genotype, and of each with hypertension.
Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension
Authors: Wang William Y. S. , Zee Robert L , Morris Brian J.
Published: July 2010

The renin‐angiotensin system is involved in control of blood pressure and salt and fluid homeostasis. Genes for components of this system have been of major focus in research on the causation of the common, complex, polygenic trait, essential hypertension (HT). Association of an A→C variant at nucleotide 1166 of the angiotensin II type 1 receptor (AT1R) gene with HT, but an absence of linkage of this locus with this disease, has been reported recently. Since confirmation in a different setting is imperative, we performed a cross‐sectional case‐control study of the A1166C variant in a well‐characterized group of 108 Caucasian HT subjects with a strong family history (two affected parents) and early onset disease. Genotyping was by mismatch polymerase chain reaction/BfrI restriction fragment length polymorphism analysis. Frequency of the C1166allele was 0.40 in HTs and 0.29 in normotensives. The difference in genotype (χ2= 13, P = 0.0015) and allele (χ2= 5.3, P = 0.02) frequencies between the two groups was significant (odds ratio for CC vs AA+AC= 7.3 [95% CI, 1.9–31.9). The present results implicate the AT1R gene, or a locus in linkage disequilibrium with the variant tested, in the causation of essential HT.
Interstitial deletion of long arm of chromosome no. 5 with growth hormone deficiency‐an emerging syndrome?
Authors: Krishna Jyoti , Myers Terry L , Bourgeois Michael J. , Tonk Vijay
Published: July 2010

5p‐is a well‐defined syndrome, but phenotypic correlations of 5q are poorly described in the literature. We present a case of a female child with interstitial deletion in the 5q13.1q15 region. Comparison of the clinical features of this patient with others reported in the literature suggests an emerging clinical syndrome defined by short stature, failure to thrive, mental retardation, slanting palpebral fissures, malformed ears, short neck and depressed nasal bridge. Based on our endocrine testing, we hypothesize that the short stature could be, in part, due to growth hormone deficiency. The recent assignment of growth hormone receptor gene to the short arm of chromosome 5 and the presence of several genes for growth factors and growth factor receptors on 5q raise interesting possibilities for the explanation of short stature in such cases.
A Cys634Gly substitution of the RET proto‐oncogene in a family with recurrence of multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis
Authors: Seri Marco , Celli Iacopo , Betsos Nicola , Claudiani Franco , Camera Gianni , Romeo Giovanni
Published: July 2010

Germ‐line mutations of the RET proto‐oncogene, involving five cysteine residues at codons 609, 611, 618, 620 and 634, are associated with two variants of the inherited cancer syndrome multiple endocrine neoplasia type 2: type 2A and familial medullary thyroid carcinoma. The association of multiple endocrine neoplasia type 2A with the dermatological disorder cutaneous lichen amyloidosis has already been reported, and mutations in the Cys634 have been identified in different families. We describe here an additional pedigree in which multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis cosegregate. A Cys634Gly was identified by direct sequencing of the RET proto‐oncogene exon 11 in the affected individuals. The mutation creates a new HaeIII site, and restriction analysis performed on all family members rules out the presence of the altered allele in two children and consequently the risk of developing thyroid tumors. These results emphasize the role of molecular analysis of the RET proto‐oncogene in diagnosing presymptomatically those individuals at risk of inheriting the disease allele.
Genetic epidemiology of Duchenne and Becker muscular dystrophy in Slovenia
Authors: Peterlin B. , Zidar J. , Meznarič‐Petruša M. , Zupančič N.
Published: July 2010

Most population studies on Duchenne (DMD) and Becker (BMD) muscular dystrophies predated the discovery of the gene and its product dystrophin. The diagnosis of these conditions and consequent epidemiological estimates were therefore limited to clinical criteria. In our study of the Slovene population the prevalence and cumulative incidence of DMD and BMD were calculated by including additional diagnostic tests: deletion screening in the dystrophin gene as well as dystrophin immunocytochemistry. The minimal prevalence rates, 2.9/100000 for DMD, 1.2/100000 for BMD, and the minimal cumulative DMD incidence rate of 13.8/100000 are in the range of lower estimates compared to studies world‐wide. However, we found a high BMD cumulative incidence rate of 5.7/100000 and a high proportion of BMD versus DMD cumulative incidence rate (41.3%). Our results imply that the epidemiological figures for BMD might have been underestimated in the past.
Delineation of a ring chromosome 16 by the FISH‐technique: a case report with review
Authors: Conte Robert A. , Kleyman Svetlana M. , Kharode Chaula , Verma Ram S.
Published: July 2010

We report on a new case with ring chromosome 16. Initially, the cytogenetic findings with GTG‐banding revealed a 46, XY, r(16)(::p13.3 → q24::)/46, XY karyotype. This is the first case of r(16) co‐existing with a normal cell line with minimal clinical consequences. The ring appeared to be monocentric and stable. A ring chromosome can result in a loss of varied segments of one or both chromosome arms or may involve telomere‐telomere fusion without loss of genetic material. Thus it was imperative to use the latest molecular cytogenetic techniques for evaluation of this ring chromosome. It is believed that the ring chromosome retained specific telomeric sequences unique to 16q and that there was no loss of genetic material during the ring formation. Apparently, either a 16p telomere‐16q telomere fusion or a fusion between the 16q telomere and a distal segment of the 16p13 band may explain the mechanism of ring formation. In either case, loss of genetic material is assumed to be negligible. A more descriptive karyotype of the proband was determined to be: 46, XY, r(16)(::pter or ::p13.3 → qter::)/46, XY. The fluorescent in‐situ hybridization technique using various DNA probes provided this finer characterization.
Analysis of the (CAG)n repeat causing Huntington's disease in a Mexican population
Authors: Alonso Ma Elisa , Yescas Petra , Cisneros Bulmaro , Martínez Claudia , Silva Guadalupe , Ochoa Adriana , Montañez Cecilia
Published: July 2010

We investigated the allele distribution of the polymorphic (CAG)n repeat in the IT15 gene in 96 normal subjects from the Mexican population and 83 unrelated patients with Huntington's disease. Our results show that the size distributions of normal and affected alleles do not overlap. Normal alleles range from 13 to 32 triplets, with 18 being the most frequent allele, while HD alleles contain 37 to 76 repeats with 42 being the most frequent. One allele in the range of intermediate alleles was found (32 repeats) in a normal subject. The juvenile onset cases in this study are associated with an expansion greater than 49 repeats. In the available parent‐offspring pairs, paternal alleles show instability with an expansion of 28 repeats in one case.
The cholesteryl ester transfer protein (CETP) locus as a candidate gene in abdominal aortic aneurysm
Authors: Ramsbottom Dorothy , O'Neill Anne , Sexton Donna M. , Gafoor Rafael A. , Bouchier‐Hayes David , Croke David T.
Published: July 2010

Abdominal aortic aneurysm (AAA) is a relatively common disease of the elderly presenting as progressive dilatation of the abdominal aorta. The condition shows a pronounced tendency to cluster in families, indicating a genetic component in the disease aetiology. We have screened the cholesteryl ester transfer protein (CETP) gene, which has been proposed as a candidate gene in AAA, by means of SSCP, DNA sequencing and restriction analysis in a cohort of patients with AAA and a matching control group drawn from the Irish population. The analysis has demonstrated sequence variation at four sites in the CETP gene: an A‐T transversion in exon 9 (producing a Lys309‐Stop codon substitution), a G‐A transition in exon 14 (producing a conservative Va1421‐Ile substitution), a C‐T transition in intron 12 and a G‐A transition in intron 15. None of the last three sites corresponded with sites of functional significance in the protein, suggesting that this reflects neutral polymorphism at the CETP locus. Furthermore, the frequencies of these four polymorphisms in the AAA patient and control groups were not significantly different. These data therefore suggest that CETP may be excluded as a candidate gene in abdominal aortic aneurysm.
Analysis of 65 Turkish patients with congenital aplastic anemia (Fanconi anemia and non‐Fanconi anemia): Hacettepe experience
Authors: Altay Çiǧjdem , Alikaşifoǧlu Mehmet , Kara Abdurrahman , Tunçbilek Ergül , Özbek Namik , Schroeder‐Kurth Trautte M.
Published: July 2010

During the last 14 years, 65 unrelated patients were diagnosed as having constitutional aplastic anemia (CAA). In 52 of 65 patients the diepoxybutane (DEB) test was positive. Comparison of several hematological and clinical parameters in Fanconi anemia (FA) (DEB+) and non‐Fanconi anemia (non‐FA) (DEB‐) patients disclosed no statistically significant differences. The study indicated that in Turkey there were no peculiarities in associated congenital abnormalities in FA and non‐FA. The rate of consanguinity was 78% in FA and 46% in non‐FA, suggesting that also among the non‐FA group recessively inherited disorders are hidden. The mean age at diagnosis in FA was 7.7 ± 4.4 (1.8–12) and in non‐FA 7.8 ± 3.8 (2–15) years. Nine out of 52 FA and five out of 13 non‐FA patients died during the follow‐up period. Five of the 52 FA patients developed malignancies, three of them had acute myeloblasts leukemia (AML), one a squamous cell carcinoma of the gingiva, and another a hepatocellular carcinoma. Peliosis hepatica occurred in three of the FA and one of the non‐FA patients. A total of seven patients stayed in remission without any medication. The remaining 58 patients were given 2–5 mg/kg of oxymetholone and 5 mg prednisolone treatment. Because of sustained remission, oxymetholone therapy was terminated in four of the 45 FA and two of the 13 non‐FA patients. Detailed examination of the pedigrees of all of patients indicated the presence of multiple congenital anomalies. In seven of 52 FA and one of 13 non‐FA patients there was increased risk for AML and/or other cancers among family members.
Pearson marrow pancreas syndrome: a molecular study and clinical management
Authors: Seneca Sara , Meirleir Linda De , Scbepper Jean De , Balduck Nadine , Jochmans Kristin , Liebaers Inge , Lissens Willy
Published: July 2010

Human mitochondrial DNA (mt DNA) lesions can cause a heterogeneous group of mitochondrial degenerative disorders. We report on a 5‐year‐old patient suffering from the full‐blown picture of Pearson syndrome. His symptoms started in the first year of life with failure to thrive, followed by chronic diarrhoea and lactic acidosis at 18 months of age. Analysis of mitochondrial DNA revealed large amounts of mt DNA molecules with a 2.7 kb deletion in all tissues examined. The diagnosis of Pearson syndrome was made initially in the absence of haematological disturbances. In the following months neutropenia, sideroblastic anaemia and hypoparathyroidism developed. Daily administration of dichloroacetate (DCA) and bicarbonate controls the lactic acidosis, while episodic treatments with filgastrim (Neupogen®) reverse episodes of severe neutropenia. Calcium and vitamin D supplementation compensate for the hypoparathyroidism. Chronic administration of DCA and supportive treatment for a long period help to stabilize patients with multiorgan dysfunction.
APO E Polymorphism in Spanish and Moroccan populations
Authors: Valveny N. , Esteban E. , Kandil M. , Moral P.
Published: July 2010

Apolipoprotein E (apoE) gene polymorphism was analyzed by polymerase chain reaction in one Moroccan and six Spanish populations, a total of 660 individuals. No significant differences were observed between samples, and the mean relative frequencies (with 95% confidence intervals) found were 0.104 (0.069–0.139) for the e4 allele, 0.855 (0.813–0.897) for e3 and 0.041 (0.015–0.067) for e2. Frequencies of the e4 allele were low in comparison to Northern European populations, but similar to those reported for other South‐European populations. The presence of a rare mutation, E2 Christchurch, in one Basque individual was confirmed by sequence analysis.
Brachydactyly in a child with duplication‐deficiency subsequent to t(15;20)(q25.2;p12.2)mat. Candidate regions on one or both chromosomes?
Authors: Pfeiffer R. A. , Kändler Chr. , Sieber E. , Rauch A. , Trautmann U.
Published: July 2010

We report a child with a duplication‐deficiency subsequent to t(15;20)(q25.2;p12.2), transmitted in at least 5 generations, who showed features of 15q—syndrome. We speculate that brachydactyly‐most likely because of brachymesophalangism‐is a feature of the phenotype of this chromosomal aberration and points to candidate gene(s) in this region. A similar brachydactyly was, however, reported with dup(20pl‐pter).
Malignant hyperthermia susceptibility, an autosomal dominant disorder?
Authors: Fagerlund T. H. , Islander G. , Twetman E. Ranklev , Berg K.
Published: July 2010

A large series of Swedish nuclear families, in which malignant hyperthermia (MH) reactions had occurred during anaesthesia, have been examined with respect to malignant hyperthermia susceptibility. In vitro contracture tests (IVCT) of muscle strips were conducted to diagnose MH status. Included in this series were some families where only one of the parents was tested by IVCT, while in 79 of the families both parents were tested by IVCT. Six known mutations in the gene encoding the calcium release channel of sarcoplasmic reticulum in skeletal muscle (the RYR1 gene), believed to cause MHS in man, were searched for in 41 nuclear families. The present paper focuses on findings in eight families, where both parents were malignant hyperthemia negative (MHN), while at least one child was either malignant hyperthermia susceptible (MHS) or malignant hyperthermia equivocal (MHE). There was no suggestion of non‐paternity. The RYR1 mutations investigated were Arg163Cys, Gly341Arg, Ile403Met, Arg614Cys, Gly2433Arg and Arg2434His. No family had any of the six RYR1 mutations searched for.
Association of the renin gene polymorphism with essential hypertension in a Chinese population
Authors: Chiang Fu‐Tien , Hsu Kwan‐Lih , Tseng Chuen‐Den , Lo Huey‐Ming , Chern Tser‐Hau , Tseng Yung‐Zu
Published: July 2010

To study the association of renin gene polymorphism with essential hypertension in the Chinese population, 86 hypertensive and 107 normotensive subjects were enrolled from an epidemiologic survey. Leukocyte DNA was extracted and digested with Hind HI and Bgl I restriction enzymes. Southern hybridization was done with digoxigenin‐incorporated renin gene probes generated by polymerase chain reaction. The restriction fragments were detected by anti‐digoxigenin antibody and enzyme methods. Two Hind III polymorphysms of the renin gene (8.7kb and 6.2kb) were identified. The allele frequences were 129(75%) and 43(25%), respectively, in hypertensives; they were 139(65%) and 75(35%), respectively, in normotensives (χ2= 4.074, p = 0.044). The genotypes of 8.7/8.7,8.7/6.2 and 6.2/6.2 were significantly different between hypertensives and normotensives, being 45(52%), 39(45%), 2(3%) and 48(45%), 43(40%), and 16(15%), respectively (χ2= 9.002, p = 0.011). The Bgl I polymorphism did not show a difference between hypertensives and normotensives. Thus, we conclude that the renin gene Hind III polymorphysm is associated with hypertension in this Chinese population.
Recurrent brachial plexus neuropathy in a family with subtle dysmorphic features‐a case of hereditary neuralgic amyotrophy
Authors: Ørstavik Kristin , Ro Hans , Ørstavik Karen Helene
Published: July 2010

Brachial plexus neuropathy is a disorder which usually occurs sporadically, and is characterized by pain and varying degrees of weakness in one or both upper limbs. Some patients experience recurrent episodes. The hereditary form is usually associated with dysmorphic features. We describe a mother and son with recurrent episodes. Despite very slight dysmorphic features, we believe this is a case of the inherited form.
Moving towards a syndrome: a review of 20 cases and a new case of non‐mosaic tetrasomy 9p with long‐term survival
Authors: Tonk Vijay S.
Published: July 2010

Tetrasomy 9p is a rare syndrome that has now been described in nearly a score of cases. We present a new case of i(9p) that presented to us early in infancy with significant dysmorphological features, including growth retardation, psycho‐motor delay, hemifacial microsomia, auditory canal atresia, high‐arched palate, bulbous nose, strabismus, epicanthic folds, congenital heart disease, dislocated hips, hypoplastic external genitalia, simian palmar creases, dysplastic nails and small digits. Chromosomal analysis revealed a 47,XX,idic(9)(q12) karyotype on GTG‐ and C‐banding studies on peripheral blood lymphocytes. Fluorescent in situ hybridization (FISH) studies confirmed the origin of the extra chromosome. A review of the literature and a comparative analysis of the several well‐documented cases of i(9p) revealed a pattern of recurring features, including ear malformations, skeletal and joint problems (especially dislocations), hypoplasia of nails and digits, palatal abnormalities, hypertelorism, urogenital anomalies and developmental retardation. In the light of this analysis, we feel that tetrasomy 9p will soon be considered a clinically recognizable syndrome.
Cardio‐facio‐cutaneous (CFC) syndrome — a distinct entity? Report of three patients demonstrating the diagnostic difficulties in delineation of CFC syndrome
Authors: Wieczorek Dagmar , Majewski Frank , Giliessen‐Kaesbach Gabriele
Published: July 2010

We report on three patients with probable cardio‐facio‐cutaneous (CFC) syndrome. They present clinical findings of this condition such as: growth failure, heart defects, typical craniofacial appearance, ectodennal abnormalities, and developmental delay. We also give a detailed review of the previously published articles on CFC syndrome and discuss the differences between CFC, Noonan, and Costello syndromes. Other differential diagnoses are considered.
Interstitial deletion 2(p11.2p13): a rare chromosomal abnormality
Authors: Wenger Sharon L , McPherson Elizabeth W.
Published: July 2010

We report on an infant with a karyotype of 46,XY,del(2) (p11.2p13), the fourth reported case in the literature. At birth, the child had eventration of the diaphragm. His phenotype was suggestive of a connective tissue disorder with scoliosis, pectus carinatum, long slender fingers, camptodactyly, cryptorchidism, hypertonia and myopia. His facial appearance was mildly dysmorphic and strongly resembled a previously reported patient with the same deletion. The child expired at 2 months of age. Some generalizations can be made about the phenotype for del(2)(p11.2p13), despite reporting of cases at different ages.
A T > C transition causing a Leu > Pro substitution in a conserved region of the arylsulfatase A gene in a late infantile metachromatic leukodystrophy patient
Authors: Regis Stefano , Filocamo Mirella , Stroppiano Marina , Corsolini Fabio , Gatti Rosanna
Published: July 2010

A T >C transition (L428P) was detected in the arylsulfatase A alleles of a late infantile metachromatic leukodystrophy patient. The mutation causes a Leu > Pro substitution in exon 8. It lies in a region conserved among arylsulfatases. The mutation was not detected in 37 other patients and in 57 normal controls.
A DNA polymorphism at the angiotensin II type 1 receptor (AT1R) locus and myocardial infarction
Authors: Berge K. E. , Bakken A. , Bøhn M. , Erikssen J. , Berg K.
Published: July 2010

Two hundred and thirty‐five survivors of myocardial infarction (MI) were compared to 384 controls with respect to distribution of genotypes and gene frequencies in the A1166C polymorphism at the angiotensin II type 1 receptor (AT1R) locus. No differences in allele frequencies or genotype distribution were observed when all patients were compared with all controls. When comparing CC homozygotes with the combined group of CA heterozygotes and AA homozygotes (CA/AA), a difference in borderline significance between the MI group and controls was observed (p = 0.05). In males alone, this difference was much more pronounced because of the larger proportion of males with the CC genotype in MI cases than in male controls (p = 0.01). No significant differences were observed between female cases and controls. No interaction between the insertion/deletion (I/D) polymorphism at the angiotensin I‐converting enzyme (ACE) locus and the polymorphism at the AT1R locus was detected. When subdividing the subjects into a “low‐risk” and a “high‐risk” group, based on levels of apolipoprotein B (apoB) and body mass index (BMI), and whether or not the person used lipid‐lowering drugs, the frequency of CC homozygotes in male cases of the “low‐risk” group differed significantly compared to the frequency in male controls of the “low‐risk” group (p < 0.001). No differences were observed in females, but the number of “low‐risk” group female cases was low (n = 3). Thus, CC homozygosity appears to be associated with MI in Norwegian males, especially among those with a “low‐risk” phenotype.
Apolipoprotein E polymorphism in the Greek population
Authors: Sklavounou Ekaterini , Economou‐Petersen Effrosini , Karadima Georgia , Panas Marios , Avramopoulos Dimitris , Varsou Angeliki , Vassilopoulos Dimitris , Petersen Michael B.
Published: July 2010

The APOE gene is located on chromosome 19, and the three common alleles are designated ε2, ε3, and ε4. The ε4 allele is associated with increased plasma cholesterol, atherosclerosis and cardiovascular disease, Alzheimer's disease, and decreased longevity. The objective of the present study was to estimate the distribution of APOE alleles in the Greek population by DNA analysis. The material consisted of 216 voluntary, healthy Greek blood donors (146 males/70 females). The APOE allele frequencies were ε2: 5.3%, ε3: 88.2%, ε4: 6.5%. The ε4 allele frequency of 6.5% in the Greek population is, together with the frequency in the Chinese population, among the lowest in the world.
Lipoprotein(a) in plasma, arterial wall, and thrombus from patients with aortic aneurysm
Authors: Papagrigorakis Emmanouel , Iliopoulos Dimitrios , Asimacopoulos P. J. , Safi Hazim J. , Weilbaecher Donald J. , Ghazzaly Karima G. , Nava Mauro L. , Gaubatz John W. , Morrisett Joel D.
Published: July 2010

The plasma concentration of lipoprotein(a) [Lp(a)] is highly correlated with the incidence of cardiovascular and peripheral vascular disease. A positive physiological role for Lp(a) has not yet been clearly identified, although elevated plasma levels in pregnant women, long‐distance runners, subjects given growth hormone, patients after cardiovascular surgery, and patients with cancer, diabetes, or renal disease suggest its involvement in tissue synthesis and repair. The hypothesis that Lp(a) is involved in repair/reinforcement of the aorta was tested in 38 patients undergoing surgery for aortic aneurysm. In 29 patients 1 day before surgery, the mean plasma Lp(a) protein level was 10.7 mg/dl. At about 1, 2, and 8 weeks after surgery, the level was 14.1, 15.1, and 15.2 mg/dl, respectively. These levels are significantly higher than those of a comparable group of normal subjects (6.4 mg/dl; n = 274). Specimens of resected aortic aneurysm showed extensive medial degeneration, discontinuous elastic fibers, and deposition of mucopolysaccharides; these specimens were treated with a detergent‐containing buffer to extract entrapped lipoproteins. The mean Lp(a) protein level in aortic wall extracts was 14.6 ng/mg tissue; these individual values were significantly associated with plasma Lp(a) levels before surgery (r2= 0.31, p = 0.0003). The mean Lp(a) protein level in aortic thrombus extracts was substantially higher at 69.6 ng/mg tissue; these individual levels also were significantly associated with plasma Lp(a) concentrations before surgery (r2= 0.68, p < 0.0001). The observations that: (i) plasma Lp(a) protein is about 1.7‐fold higher in patients with aortic aneurysms than in normal subjects; and (ii) that Lp(a) protein in the aneurysmic thrombus is about 4.8‐fold higher than in the aortic wall suggest that this lipoprotein plays a significant and direct role in thrombus formation and in reinforcement of the aneurysmic aortic wall.
Studies on effects of Lp(a) lipoprotein on gene expression in endothelial cells in vitro
Authors: Berge K. E. , Djurovic S. , Muller H. J. , Alestrøm P. , Berg K.
Published: July 2010

The reason(s) for the atherogenic properties of Lp(a) lipoprotein is still unclear, and several mechanisms have been studied. Alterations in gene expression in endothelial cells (ECs) could be important with respect to risk for coronary heart disease (CHD). We have tested the effects of Lp(a) lipoprotein or the apolipoprotein of Lp(a) lipoprotein (apo(a)) on cultured human umbilical vein endothelial cells (HUVECs) with respect to: (1) the level of endothelin‐1 (ET‐1) mRNA; (2) release of ET‐1 into the culture medium; (3) plasminogen activator inhibitor‐1 (PAI‐1) secretion into the culture medium and; (4) total gene expression in HUVECs, examined by a polymerase chain reaction (PCR)‐based technique, differential display‐reverse transcription‐PCR (DD‐RT‐PCR). Lp(a) lipoprotein reduced the level of ET‐1 mRNA as well as the release of ET‐1. The reduction of ET‐1 in the medium was even more pronounced when HUVECs were incubated with apo(a), but we found no effect of apo(a) on ET‐1 mRNA level. Neither Lp(a) lipoprotein nor apo(a) had a significant influence on PAI‐1 secretion. DD‐RT‐PCR revealed 11 fragments that could represent differences between cells exposed or not exposed to Lp(a) lipoprotein. Following subcloning and sequencing, 18 sequences that differed between exposed and unexposed cultures were obtained. Four of the subcloned fragments have up to now been used as a probe for northern blot analyses, and one fragment was confirmed to be regulated by Lp(a) lipoprotein. In conclusion, Lp(a) lipoprotein is shown to control ET‐1 mRNA levels and the function of at least one more gene, the nature of which is unknown.
Analysis of the mechanism of lipoprotein(a) assembly
Authors: Koschinsky Marlys L. , Marcovina Santica M. , May Lorraine F. , Gabel Brent R.
Published: July 2010

We have assessed the ability of a battery of purified recombinant apolipoprotein(a) (r‐apo(a)) derivatives to bind to immobilized low‐density lipoprotein (LDL) by ELISA. Removal of the apo(a) kringle IV type 8 and type 9 sequences dramatically reduced apo(a) binding to LDL. The binding of apo(a) to LDL was effectively inhibited by arginine, lysine, the lysine analogue ε‐aminocaproic acid and proline; comparable inhibition was observed using the 17K and KIV5–8 r‐apo(a) derivatives, suggesting a direct role for sequences contained in the latter species in mediating the initial non‐covalent interactions which precede specific disulfide bond formation. We also determined that r‐apo(a) binds directly to a synthetic apoB peptide spanning amino acid residues 3732–3745; this interaction appeared to be mediated by sequences present in apo(a) kringle IV types 8 and 9, and could be inhibited by arginine, lysine and proline. The results of this study indicate that the efficiency of Lp(a) assembly is a direct function of the initial non‐covalent interactions between apo(a) and LDL; in addition, these studies suggest that Cys3734 in apoB mediates covalent linkage with apo(a) by virtue of the ability of the apoB sequences surrounding this residue to directly interact with apo(a) KIV type 9.
The lysine‐binding function of Lp(a)
Authors: Boonmark Nataya W. , Lawn Richard M.
Published: July 2010

The atherogenicity of Lp(a) is attributable to the binding of its apolipoprotein(a) component to fibrin and other plasminogen substrates. It can attenuate the activation of plasminogen, diminishing plasmin‐dependent fibrinolysis and transforming growth factor‐β activation. Apolipoprotein(a) contains a major lysine‐binding site in one of its kringle domains. Destroying this site by site‐directed mutagenesis greatly reduces the binding of apolipoprotein(a) to lysine and fibrin. Transgenic mice expressing wild‐type apolipoprotein(a) have a 5‐fold increase in the development of lipid lesions, as well as a large increase in the focal deposition of apolipoprotein(a) in the aorta, compared to the lysine‐binding site mutant strain and to non‐transgenic litter mates. Although the adaptive function of apolipoprotein(a) remains obscure, a gene with similar structure has evolved by independent remodeling of the plasminogen twice during the course of mammalian evolution.
LDL‐unbound apolipoprotein(a) and carotid atherosclerosis in hemodialysis patients
Authors: Kronenberg Florian , Trenkwalder Evi , Sturm Wolfgang , Kathrein Hermann , König Paul , Neyer Ulrich , Gröchenig Ernst , Utermann Gerd , Dieplinger Hans
Published: July 2010

High lipoprotein{a) [Lp(a)] plasma concentrations, which are genetically determined by apo(a) size polymorphism, are directly associated with an increased risk for atherosclerosis. Patients with end‐stage renal disease (ESRD), who show an enormous prevalence of cardiovascular disease, have elevated plasma concentrations of Lp(a). In recent studies we were able to show that apo(a) size polymorphism is a better predictor for carotid atherosclerosis and coronary artery disease in hemodialysis patients than concentrations of Lp(a) and other lipoproteins. Less than 5% of apo(a) in plasma exists in a low‐density lipoprotein (LDL)‐unbound form. This “free” apo(a) consists mainly of disintegrated apo(a) molecules of different molecular weight, ranging from about 125 to 360 kDa. LDL‐unbound apo(a) molecules are elevated in patients with ESRD. The aim of this study was therefore to investigate whether the LDL‐unbound form of apo(a) contributes to the prediction of carotid atherosclerosis in a group of 153 hemodialysis patients. The absolute amount of LDL‐unbound apo(a) showed a trend to increasing values with the degree of carotid atherosclerosis, but the correlation of Lp(a) plasma concentrations with atherosclerosis was more pronounced. In multivariate analysis the two variables were related to neither the presence nor the degree of atherosclerosis. Instead, the apo(a) phenotype took the place of Lp(a) and LDL‐unbound apo(a). After adjustment for other variables, the odds ratio for carotid atherosclerosis in patients with a low molecular weight apo(a) phenotype was about 5 (p < 0.01). This indicates a strong association between the apo(a) phenotype and the prevalence of carotid atherosclerosis. Finally, multivariate regression analysis revealed age, angina pectoris and the apo(a) phenotype as the only significant predictors of the degree of atherosclerosis in these patients. In summary, it seems that LDL‐unbound apo(a) levels do not contribute to the prediction of carotid atherosclerosis in hemodialysis patients. However, this does not mean that “free”, mainly disintegrated, apo(a) has no atherogenic potential.
Schizophrenia genetics at the millennium: cautious optimism
Authors: Gottesman Irving I. , Moldin Steven O.
Published: July 2010

The views expressed here are the personal opinions of the authors and should not be taken to imply agreement or endorsement by the National Institutes of Health or the Federal Government.

As the new millennium approaches, research into the genetic aspects of schizophrenia has already made an impressive start toward an integrated model which is discovering roles for genetic agents, environmental agents and experiences, and chance factors. The best model follows that proposed for understanding such complex diseases as coronary artery disease and diabetes. Genetic information has come from both genetic epidemiology and molecular genetics. Evidence for gene regions on 6p and 8p gives the strongest support for harboring schizophrenia susceptibility genes, based on international collaborative studies that “generally” replicate one another; evidence for regions on 3p, 5q, 9p, 20p, and 22q, while less compelling, will encourage focused work. Determining the steps between the regions and the phenotype will challenge the next generation of scientists.
Frequency analysis of autosomal dominant cerebellar ataxias in Japanese patients and clinical characterization of spinocerebellar ataxia type 6
Authors: Watanabe Hidetaka , Tanaka Fumiaki , Matsumoto Michiyo , Doyu Manabu , Ando Tetsuo , Mitsuma Terunori , Sobue Gen
Published: July 2010

Using a molecular diagnostic approach, we investigated 101 kindreds with autosomal dominant cerebellar ataxias (ADCAs) from the central Honshu island of Japan, including spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2), Machado‐Joseph disease (MJD), dentatorubral and pallidoluysian atrophy (DRPLA) and spinocerebellar ataxia type 6 (SCA6). In our unselected series, MJD was the most common type of ADCA, accounting for 33.7% followed by DRPLA (19.8%), SCA2 (5.9%) and SCA6 (5.9%). No SCA1 mutations were identified. We analysed the clinical features of six molecular confirmed SCA6 kindreds: in each family, there was an expanded allele in the αdA‐voltage dependent calcium channel comprising between 23 and 25 CAG repeats. The mean age at onset of symptoms was 43 ± 13 years. The clinical features consisted predominantly of cerebellar ataxia, dysarthria and horizontal nystagmus, which was generally consistent with ADCA type 3. However several new clinical features were found in some patients: dramatic anticipation, rapid disease progression, severe ataxia associated with action tremor or action myoclonus, and very early onset, which are not described as the classical features of ADCA type 3.
ACTH receptor mutation in a girl with familial glucocorticoid deficiency
Authors: Slavotinek Anne M. , Hurst Jane A. , Dunger David , Wilkie Andrew ONI
Published: July 2010

Familial glucocorticoid deficiency (FGD) has long been recognised as a clinical entity, but molecular studies have so far been performed in only a few individuals. We describe a girl born to consanguineous Pakistani parents with clinical and biochemical features of FGD who is homozygous for the R146H mutation of the adrenocorticotropic hormone (ACTH) receptor gene. This mutation creates a new restriction enzyme site in the ACTH receptor gene, allowing accurate characterisation of the mutation without DNA sequencing. Our patient is the third child reported to be homozygous for the R146H mutation. Interestingly, she has a tall stature, a clinical finding reported in several children who have ACTH insufficiency and mutations of the ACTH receptor gene. We suggest that mutation analysis of the ACTH receptor gene be considered in children with clinical features of FGD and tall stature.
The 4q‐syndrome: delineation of the minimal critical region to within band 4q31
Authors: Robertson Stephen P. , O'Day Kelly , Bankier Agnes
Published: July 2010

A consistent phenotype has been associated with deletion of the distal long arm of chromosome 4. An invariant requirement for the phenotype in cases described so far has been the deletion of material from within band 4q31 but few other cases have been described that further aid the delineation of the minimum critical region sufficient for the expression of the phenotype. We report a child with a small interstitial deletion within band 4q31 who exhibits most of the features of the established 4q‐phenotype.