bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute myelogenous leukemia with the t(3;12)(q26;p13) translocation: Case report and review of the literature
Authors: Voutsadakis Ioannis A. , Maillard Natacha
Published: January 2003

Translocations involving the EVI1/MDS1 gene at 3q26 and the TEL gene at 12p13 are comparatively common in acute leukemia, but a translocation between the two genes has been reported only in a handful of cases. We report an additional case of acute myelogenous leukemia (AML) preceded by a myelodysplastic syndrome (MDS) with the translocation t(3;12)(q26;p13) in a 36‐year‐old woman. The translocation was present early in the disease and long before the MDS progressed to AML 3 years after diagnosis. At the time of progression to AML, an additional chromosomal abnormality, a monosomy 22, was discovered. The patient was treated with the protocol MAQ, which comprised mitoxantrone, aracytine, and quinine, as her blasts expressed the p‐glycoprotein, but she failed to obtain remission. A second treatment with the same protocol resulted in only minimal response. The patient was treated again with high‐dose Ara‐C and idarubicine in an attempt to achieve a response before allogeneic unrelated transplantation, but she did not respond to the treatment and died shortly thereafter. A review of the literature revealed 12 other cases of the t(3;12)(q26;p13) translocation. Characteristics of those cases are reviewed in this article. Am. J. Hematol. 72:135–137, 2003. © 2003 Wiley‐Liss, Inc.
Long term follow‐up after splenectomy performed for immune thrombocytopenic purpura (ITP)
Authors: Schwartz Joseph , Leber Melissa D. , Gillis Shmuel , Giunta Austin , Eldor Amiram , Bussel James B.
Published: January 2003

Splenectomy is the only treatment of ITP known to have “curative” effects in a substantial fraction of patients. However, the true long‐term outcome is uncertain and controversial because published series have not adjusted for the duration of follow‐up. This IRB‐approved retrospective study included all patients with ITP who underwent splenectomy between 1988‐1993 at three major medical centers and required a minimum postoperative 5‐year follow‐up. Complete response (CR) was defined as all postsplenectomy platelet counts >150 × 109/L without treatment; partial response (PR) as platelet counts ≥50 × 109/L without treatment; and failure as platelet counts <50 × 109/L or receiving therapy after splenectomy. Seventy‐five patients identified with ITP underwent splenectomy from 1988 to 1993. Three patients died prior to 5‐year follow‐up, and 56 of the 72 patients (78%) were evaluable with follow‐up for five years or longer, median 7.5 years. The immediate postoperative complete remission rate was 77%; 57% of patients have remained in prolonged CR. Thirty‐seven patients (66%) have not required any therapy after splenectomy. Eight patients had platelet counts >150 × 109/L for 4–8.5 years before relapsing; no clear plateau was attained in the remission curve. There was no operative mortality. Ten patients (18%) reported minor postoperative bleeding episodes. No life‐threatening infections, significant heart disease, or pulmonary hypertension developed after splenectomy in the 434 patient‐years of follow‐up. This study helps to define the long‐term results of splenectomy for ITP. Am. J. Hematol. 72:94–98, 2003. © 2003 Wiley‐Liss, Inc.
Thrombophilic genotypes, natural anticoagulants, and plasma homocysteine in myeloproliferative disorders: Relationship with splanchnic vein thrombosis and arterial disease
Authors: Amitrano L. , Guardascione M.A. , Ames P.R.J. , Margaglione M. , Antinolfi I. , Iannaccone L. , Annunziata M. , Ferrara F. , Brancaccio V. , Balzano A.
Published: January 2003

The contribution of pro‐thrombotic factors towards the development of arterial disease (AD) and splanchnic vein thrombosis (SVT) was retrospectively evaluated in 79 patients (39M, 40F, mean age 55 ± 16 years) with myeloproliferative disorders (MPD) (essential thrombocythemia [n = 26], primary proliferative polycythemia [n = 27], and idiopathic myelofibrosis [n = 26]). Of these, 18 had AD and 17 SVT, the remaining 44 were non‐thrombotic (NT). Plasma concentrations of natural anticoagulants, plasma homocysteine (HC), IgG anticardiolipin antibodies (aCL), and thrombophilic genotypes (methylenetetrahydrofolate reductase C677T, factor V Leiden, prothrombin G20210→A) were determined. Isolated protein C deficiency was found in 23% of patients from the SVT group, in 5% from the AD group, in 6.8% from the NT group, and in 1% of historical controls (P = 0.0001). The prevalence of thrombophilic genotypes and that of the other natural anticoagulants did not differ across the groups. The proportion of patients with elevated plasma HC was 66% in the AD group, 27% in the non‐thrombotic group, 12% in the SVT group and 4.5% in the control group (P < 0.0001). Patients with AD had higher plasma HC (24.4 ± 23 μmol/L) than NT patients (12.3 ± 7.7 μmol/L), SVT patients (9 ± 4.9 μmol/L), and healthy controls (7.9 ± 3 μmol/L) (P < 0.0001). In a logistic regression model lower protein C was independently associated with SVT, whereas elevated plasma HC was independently associated with AD. Measurement of plasma HC and protein C in MPD may identify patients more likely to suffer arterial disease and splanchnic vein thrombosis and who may require plasma HC lowering in the former case. Am. J. Hematol. 72:75–81, 2003. © 2003 Wiley‐Liss, Inc.
Severe chronic neutropenia: Treatment and follow‐up of patients in the Severe Chronic Neutropenia International Registry
Authors: Dale David C. , Cottle Tammy E. , Fier Carol J. , Bolyard Audrey Anna , Bonilla Mary Ann , Boxer Laurence A. , Cham Bonnie , Freedman Melvin H. , Kannourakis George , Kinsey Sally E. , Davis Robert , Scarlata Debra , Schwinzer Beate , Zeidler Cornelia , Welte Karl
Published: January 2003

Severe chronic neutropenia (SCN) is defined as an absolute neutrophil (ANC) of less than 0.5 × 109/L, lasting for months or years. Congenital, cyclic, and idiopathic neutropenia are principal categories of SCN. Since 1994, the Severe Chronic Neutropenia International Registry (SCNIR) has collected data to monitor the clinical course, treatments, and disease outcomes for SCN patients. This report summarizes data for 853 patients, almost all treated with daily or alternate‐day recombinant human granulocyte colony‐stimulating factor (G‐CSF or Filgrastim). G‐CSF treatment increased the ANC overall from 0.34 × 109/L ± 0.018 pre‐treatment to 3.70 × 109/L ± 0.18 during the first year of treatment. For most patients, the responses were durable with patients remaining on the same dose of G‐CSF for many years. Long‐term hematological observations showed stable mean leukocyte and neutrophil counts and gradually increasing hemoglobin levels. Thrombocytopenia developed in 4% of patients. As of January 1, 2000, myelodysplasia (MDS) or acute myelogenous leukemia (AML) has occurred in 35 of 387 patients with congenital neutropenia with a cumulative risk of 13% after 8 years of G‐CSF treatment. This event occurred without a predictable relationship to the duration or dose of G‐CSF treatment. No patients with cyclic or idiopathic neutropenia developed MDS or AML. Other important adverse events included hepatomegaly, osteoporosis, vasculitis, glomerulonephritis, and deaths in 4 of 14 cases requiring splenectomy. Growth and development and the outcome of pregnancy appeared to be unaffected by G‐CSF treatment. These data indicate that congenital, cyclic, and idiopathic neutropenia can be effectively treated with long‐term G‐CSF. The risk of leukemia, osteoporosis, other potentially adverse events, and pregnancy outcome need to be further evaluated with continuing long‐term observations. Am. J. Hematol. 72:82–93, 2003. © 2003 Wiley‐Liss, Inc.
Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease
Authors: Steinberg Martin H. , Voskaridou Ersi , Kutlar Abdullah , Loukopoulos Dimitris , Koshy Mabel , Ballas Samir K. , Castro Oswaldo , Barton Franca
Published: January 2003

Fetal hemoglobin (HbF) level and the HbF responses to hydroxyurea (HU) vary among patients with sickle cell disease and are, at least in part, genetically regulated. We hypothesized that siblings with sickle cell disease are likely to share the same parental β‐like globin gene clusters with their cis‐acting regulatory sequences and therefore, if regulation of this response is linked to the β‐globin gene cluster, might have concordant HbF responses to HU. Accordingly, we studied 26 families (30 sib pairings), 20 with sickle cell anemia (three families had three siblings) and 6 families with HbS‐β‐thalassemia (one family had three siblings, and one family consisted of monozygotic twins), to see if siblings with sickle cell disease had discordant or concordant changes in HbF during HU treatment. Intraclass correlation coefficients (r) showed a high, positive correlation between sibs for HbF levels before and during HU treatment and a concordant change in HbF response from baseline to treatment‐associated levels. Changes in mean corpuscular volume (MCV) paralleled HbF levels, while the expected correlations between treatment‐associated fall in leukocyte count and increase in MCV were also present. Our results provide additional evidence that some elements that regulate HbF expression are linked to the β‐globin gene cluster. Am. J. Hematol. 72:121–126, 2003. © 2003 Wiley‐Liss, Inc.
Monocytic leukemia with CALM/AF10 rearrangement showing mediastinal emphysema
Authors: Nakamura Fumihiko , Maki Kazuhiro , Arai Yukihiro , Nakamura Yuichi , Mitani Kinuko
Published: January 2003

The t(10;11)(p12‐14;q14‐21) is a non‐random translocation that results in the fusion of CALM gene on chromosome 11 with AF10 gene on chromosome 10. This translocation is observed in acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoblastic lymphoma. Here we report a patient with t(10;11) who was diagnosed with AML‐M4. Reverse transcriptase‐polymerase chain reaction (RT‐PCR) assay revealed one type of CALM/AF10 and three types of AF10/CALM fusion transcripts. Sequencing analysis for these RT‐PCR products determined the breakpoint in CALM at nucleotide (nt) 1926–1927 and in AF10 at nt 423–424. The latter breakpoint was the same as that identified in three monocytic cell lines carrying t(10;11). After achieving complete remission, the patient developed mediastinal emphysema during the course of consolidation therapy, possibly due to the necrosis of his mediastinal mass. Monocytic leukemias with CALM/AF10 fusion are frequently associated with mediastinal invasion. We need to pay special attention to such a complication, even if the chest X‐ray is normal at presentation. Am. J. Hematol. 72:138–142, 2003. © 2003 Wiley‐Liss, Inc.
Successful engraftment and stable full donor chimerism after myeloablation with thiotepa, fludarabine, and melphalan and CD34‐selected peripheral allogeneic stem cell transplantation in hemophagocytic lymphohistiocytosis
Authors: Cesaro Simone , Gazzola Maria Vittoria , Marson Piero , Calore Elisabetta , Caenazzo Luciana , Destro Roberta , De Silvestro Giustina , Varotto Stefania , Pillon Marta , Zanesco Luigi , Messina Chiara
Published: January 2003

Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only curative option for primary hemophagocytic lymphohistiocytosis (HLH), a rare disease of infants and young children, characterized by recurrent fever, hepatosplenomegaly, and cytopenia. We report a case of successful engraftment and stable full‐donor chimerism in a patient with HLH who underwent peripheral allogeneic CD34‐selected HSCT. The donor was his 1‐antigen‐HLA‐mismatched grandmother. After a conditioning regimen based on the combination of thiotepa, fludarabine, melphalan, and rabbit antilymphocyte serum, the patient received a megadose of 26.3 × 106/kg of CD34+ peripheral blood cells. Neutrophil (>0.5 × 109/L) and platelet (>50 × 109/L) engraftment was observed on days +16 and +12, respectively, and the patient was discharged home on day +24. No acute or chronic GVHD was observed. Infectious complications were the main causes of re‐hospitalization in the first year after transplantation, but no significant morbidity was observed thereafter. Thirty‐two months after HSCT, the patient is alive and well, still in complete clinical remission of his underlying disease with a durable engraftment, normal NK activity and full donor chimerism. This case suggests that a fludarabine‐based conditioning regimen and CD34‐selected peripheral allogeneic HSCT may be a feasible option in case of unavailability of a fully HLA‐matched related or unrelated donor. Am. J. Hematol. 72:143–146, 2003. © 2003 Wiley‐Liss, Inc.
Thromboembolism preceding cancer: A correlation study
Authors: Saba Hussain I. , Khalil Farrah K. , Morelli Genevieve A. , Foulis Philip R.
Published: January 2003

Thromboembolic (TE) events preceding cancer have been observed. Some studies failed to find this correlation. We retrospectively examined the cancer incidence following thromboembolic events in patients at our medical center. Medical records of 183 patients with established thromboembolic events documented in their records were selected and reviewed. Time interval between primary, secondary, and recurrent TE events preceding cancer diagnosis was analyzed. Two hundred age‐ and sex‐matched controls seen during the same period and without any evidence of TE were randomly selected and charts reviewed for malignancy. Cancer occurred after TE in 48 of 183 patients (26.2%). In controls, cancer was diagnosed in 23 (11.5%). This was statistically significant with an odds ratio of 2.736 (1.586, 4.720). In the 64 primary TE patients, the cancer incidence was 37.5%. The 63 patients with recurrent TE had an incidence of 35.4%, and 56 secondary TE patients had an incidence of 27.1%. Time between initial TE and cancer diagnosis was <6 months in 27 (56.3%) patients, between 6 months and 1 year in 12 (25.0%), 1–5 years in 5 (10.4%), and >5 years in 4 (8.3%). Fourteen (31.1%) TE patients presented with metastatic cancer. This study indicates that thromboembolic events are important predictors of cancer. Cancer in this population occurs within a year in the majority of patients. Cancer screening in patients without identifiable risk factors for thrombosis could be helpful for early detection, diagnosis, and management of cancer. Am. J. Hematol. 72:109–114, 2003. © 2003 Wiley‐Liss, Inc.
Ethnicity and prognosis in acute myeloid leukemia
Authors: Alcalai Ronny , Ben‐Yehuda Dina , Ronen Ilana , Paltiel Ora
Published: January 2003

Ethnicity has been described as a prognostic factor in breast cancer and in childhood acute lymphocytic leukemia but not in adult acute myeloid leukemia (AML). We reviewed the records of 225 consecutive AML patients who were diagnosed and treated between 1983 and 1995. Data were collected concerning demographic factors, presenting clinical features, and treatment protocols. We categorized ethnicity as follows: European Jews, non‐European Jews, and Arabs. We assessed the role of ethnicity controlling for other known prognostic factors on treatment outcome and survival in this population. Older age, high leukocyte count at diagnosis, and high‐risk chromosomal aberrations were significantly associated with overall survival in univariate analysis. In multivariate analysis high leukocyte count and high‐risk chromosomal aberrations exerted an independent negative effect on survival. European origin was associated with longer event‐free survival in univariate analysis (P= 0.024) and longer overall (P< 0.01) and event‐free (P< 0.01) survival but not with a higher remission rate in multivariate analysis. For AML patients who achieved remission after induction chemotherapy and survived its complications, European origin is an independent favorable prognostic factor for long‐term remission and survival in Israel. These findings may reflect better socioeconomic status, social support, increased compliance with treatment protocols, or better psychological coping mechanisms with malignancy. Am. J. Hematol. 72:127–134, 2003. © 2003 Wiley‐Liss, Inc.
Access to stem cell transplantation: Do women fare as well as men?
Authors: Mehta Paulette , Pollock Brad H. , Nugent Melodee , Horowitz Mary , Wingard John R.
Published: January 2003

Women have less access to certain types of expensive treatments including renal transplantation, cardiac catheterization and diagnostic studies for lung cancer. Whether women have less access to stem cell transplantation (SCT) is not known. We evaluated allogeneic SCT data from the International Bone Marrow Transplant Registry (IBMTR) and compared them with disease incidence data from the Surveillance and Epidemiologic End Results (SEER) database. We estimated the ratio of males to females among transplanted patients with acute lymphoblastic (ALL), acute myelogenous (AML) and chronic myelogenous (CML) leukemia, diseases for which SCT is often done and compared them to male/female ratios of disease incidence. The association between gender and SCT was estimated as odds ratios (OR) with 95% confidence intervals (CI). There was no association between gender (male vs female) and the rates of SCT for individuals with AML (OR = 0.95, 95% CI = 0.89−1.02), or CML (OR = 1.0; CI = 0.90−1.1). Among patients with newly diagnosed ALL, more males underwent SCT than females (OR = 1.30, CI = 1.18−1.44). Because children with newly diagnosed ALL usually have a favorable prognosis, SCT is not generally a frontline therapy. Therefore, when we compared SCT rates to a population of children with relapsed ALL, the gender differences disappeared (OR = 1.09, CI = 0.94−1.25). We conclude that for the diagnoses where SCT is commonly used, there is no significant bias towards use in males compared to females. While boys with ALL appear to receive SCT at a higher rate, this difference is likely attributable to biological rather than social reasons. Am. J. Hematol. 72:99–102, 2003. © 2003 Wiley‐Liss, Inc.
CTLA‐4 exon 1 polymorphism in patients with autoimmune blood disorders
Authors: Pavkovic Marica , Georgievski Borce , Cevreska Lidija , Spiroski Mirko , Efremov Dimitar G.
Published: January 2003

CTLA‐4 is a CD28 homologue that plays an important role in negative regulation of T‐cell responses. Its transient expression on the surface of activated T cells antagonizes the activating signals and terminates the T‐cell response. An A to G polymorphism at position 49 of the CTLA‐4 first exon has recently been associated with several autoimmune disorders. In the present study we have examined the prevalence of the A and G alleles of the CTLA‐4 gene in 50 patients with autoimmune hemolytic anemia (AIHA), of which 20 had idiopathic AIHA and 30 had AIHA and chronic lymphocytic leukemia (CLL), and in 60 patients with immune thrombocytopenic purpura (ITP). Control subjects were 100 healthy individuals and 100 CLL patients without clinical evidence for an autoimmune disease. The G allele was present at a significantly higher frequency among the patients with AIHA (P = 0.003), whereas no difference was observed between patients with ITP and controls. The G allele frequency was highest among CLL patients who had developed AIHA. The obtained data indicate that the G allele of CTLA‐4 predisposes to the development of AIHA, particularly among patients with CLL. Am. J. Hematol. 72:147–149, 2003. © 2003 Wiley‐Liss, Inc.
Acquired activated protein C resistance, high tissue factor expression, and hyper‐homocysteinemia in systemic lupus erythematosus
Authors: Oh D. , Kim S.H. , Kang M.S. , Kim N.K. , Chang N.S. , Na B.W. , Chung S.Y. , Park S. , Cho C.S.
Published: January 2003

Activated protein C resistance (APCR), high tissue factor (TF) expression, and hyper‐homocysteinemia are associated with thromboembolic diseases. Thromboembolism is a frequent complication of systemic lupus erythematosus (SLE). In this study, we evaluated the prevalence of APCR, high TF, and homocysteine with correlation of the thrombotic tendency in SLE. Ninety‐four SLE patients and 28 normal controls were included. APC ratio and TF antigen were measured using commercial kits. Plasma homocysteine level was measured using HPLC. The prevalence of APCR, high TF antigen level, and hyper‐homocysteinemia in our SLE patients were 21.3%, 66.0%, and 23.4%, respectively. The median plasma level of TF antigen in SLE patients was 145.23 pg/mL (range, 31.00–778.50 pg/mL), which was significantly higher than the control value of 39.83 pg/mL (range, 1.55–168.50 pg/mL). The median APC ratio in SLE patients was 2.76 (range, 1.48–13.47), which was significantly lower than the control value of 3.59 (range, 0.26–5.66). The plasma level of homocysteine was not significantly different from that of control. A significant association was observed between the presence of APCR (OR = 8.59, P < 0.0001) but not with the presence of high plasma TF antigen level (OR = 1.24, P = 0.67) and thrombotic complications in SLE patients. In conclusion, APCR and high plasma TF levels are common in SLE, but a significant association was observed only between the presence of APCR and thrombosis in SLE patients. Am. J. Hematol. 72:103–108, 2003. © 2003 Wiley‐Liss, Inc.
Thromboxane synthesis is increased by upregulation of cytosolic phospholipase A2 and cyclooxygenase‐2 in peripheral polymorphonuclear leukocytes during bacterial infection in childhood
Authors: Zaitsu Masafumi , Hamasaki Yuhei , Nishimura Shinji , Matsuo Muneaki , Fujita Ichiro , Ishii Eiichi
Published: January 2003

Prostaglandins (PGs) and thromboxane (TX) are important mediators of inflammation. Recent studies revealed that PG and TX synthesis is controlled by the regulation of PG‐ and TX‐synthesizing enzymes. In this study, we examined the TX synthesis and the expression of TX‐synthesizing enzymes in activated peripheral polymorphonuclear leukocytes (PMNs) obtained from children with bacterial infection. Blood samples were obtained from controls and patients with bacterial infection. A23187‐stimulated production of TXB2, a stable metabolite of TXA2 in PMNs, was measured by a specific radioimmunoassay. The mRNA expression of cytosolic phospholipase A2 (cPLA2), cyclooxygenase (COX)‐1, COX‐2, and TXA2 synthase was determined by RT‐PCR. The synthesis of TXB2 in PMNs was significantly increased in the patients [925.0 (550.0–1100.0) pg/106 cells], compared with the controls [550.0 (450.0–775.0) pg/106 cells]. The mRNA expression for cPLA2 and COX‐2 in PMNs was also enhanced in the patients. The results indicate that TX production in PMNs is significantly increased through possible transcriptional mechanisms of cPLA2 and COX‐2 during bacterial infection in children. The upregulation of TXA2 synthesis may contribute to the process of acute inflammatory reaction caused by bacterial infection. Am. J. Hematol. 72:115–120, 2003. © 2003 Wiley‐Liss, Inc.
An investigation of the 5‐HT2C receptor gene as a migraine candidate gene
Authors: Johnson Matthew P. , Lea Rod A. , Curtain Robert P. , MacMillan John C. , Griffiths Lyn R.
Published: January 2003

Migraine is a common complex disorder, currently classified into two main subtypes, migraine with aura (MA) and migraine without aura (MO). The strong preponderance of females to males suggests an X‐linked genetic component. Recent studies have identified an X chromosomal susceptibility region (Xq24–q28) in two typical migraine pedigrees. This region harbours a potential candidate gene for the disorder, the serotonin receptor 2C (5‐HT2C) gene. This study involved a linkage and association approach to investigate two single nucleotide variants in the 5‐HT2C gene. In addition, exonic coding regions of the 5‐HT2C gene were also sequenced for mutations in X‐linked migraine pedigrees. Results of this study did not detect any linkage or association, and no disease causing mutations were identified. Hence, results for this study do not support a significant role of the 5‐HT2C gene in migraine predisposition. © 2003 Wiley‐Liss, Inc.
Association study between dopamine D3 receptor gene variant and personality traits
Authors: Jönsson Erik G. , Burgert Edgar , Crocq Marc‐Antoine , Gustavsson J Petter , Forslund Kaj , Mattila‐Evenden Marja , Rylander Gunnar , Flyckt Lena K. , Bjerkenstedt Lars , Wiesel Frits‐Axel , Åsberg Marie , Bergman Hans
Published: January 2003

Dopamine receptor gene variation has been hypothesized to influence personality traits characterized by novelty seeking and related traits. We analyzed a dopamine D3 receptor gene (DRD3) variant in a Swedish population (n = 373) investigated with one or more of several personality questionnaires. No significant relationships were found between DRD3 genotypes and any of the 15 Karolinska Scales of Personality (KSP) and five Health‐relevant Personality 5 factor inventory (HP5i) scales. The DRD3 variant was associated with some scales related to novelty seeking: the Swedish universities Scales of Personality (SSP) Adventure Seeking and the revised NEO personality inventory (NEO‐PI‐R) Fantasy (O1) and Order (C2) scales. There were also associations with the Temperament and Character Inventory (TCI) Cooperativeness and Compassion (C4) scales. After correction for multiple testing, however, no significant difference remained. We conclude that the investigated DRD3 polymorphism does not have a major impact on personality in the investigated population. © 2003 Wiley‐Liss, Inc.
Dopamine Beta‐Hydroxylase (DBH) gene and schizophrenia phenotypic variability: A genetic association study
Authors: Yamamoto Kenji , Cubells Joseph F. , Gelernter Joel , Benkelfat Chawki , Lalonde Pierre , Bloom David , Lal Samarthji , Labelle Alain , Turecki Gustavo , Rouleau Guy A. , Joober Ridha
Published: January 2003

Recently, two polymorphisms (DBH5′‐Ins/del and DBH 444 g/a) of the Dopamine Beta Hydroxylase (DBH) gene were isolated, and one haplotype (Del‐a) was found to be associated with low DBH activity and cocaine‐induced paranoia. The purpose of this study is to test for association between these two polymorphisms and schizophrenia or its phenotypic variability with respect to neuroleptic therapeutic response and symptom profile. Allelic and haplotype distributions of these two polymorphisms were compared between two groups of schizophrenic patients (excellent neuroleptic‐responders; R, n = 42 and non‐responders; NR, n = 64), and one group of healthy volunteers (n = 120). The “Del” and “a” alleles were in positive linkage disequilibrium. No allelic or genotype differences in the distribution of these two polymorphisms were observed between patients and controls. However, The Del‐a haplotype was significantly more common in NR patients, and the mean total BPRS score was significantly higher in the group of patients with the Del‐a compared to those without the Del‐a haplotype. These results suggest that the DBH gene is not a causative factor in schizophrenia but that it may be a modulator of psychotic symptoms, severity of the disorder and therapeutic response to neuroleptic drugs. © 2003 Wiley‐Liss, Inc.
Association of a MAOA gene variant with generalized anxiety disorder, but not with panic disorder or major depression
Authors: Tadic A. , Rujescu D. , Szegedi A. , Giegling I. , Singer P. , Möller H.‐J. , Dahmen N.
Published: January 2003

This study was conducted to detect a possible association of a T941G single nucleotide polymorphism (SNP) in the monoamine oxidase A (MAOA) gene with generalized anxiety disorder (GAD), panic disorder (PD), or major depression (MD). Fifty GAD patients (34 females and 16 males), 38 PD patients (21 females and 17 males), and 108 MD patients (80 females and 28 males) were included. The comparison group consisted of 276 (132 females and 144 males) unrelated healthy individuals. The 941T allele was over‐represented in patients suffering from GAD (χ2 = 6.757; df = 1; P < 0.01, not corrected for multiple testing) when compared to healthy volunteers. No association was observed in MD or PD. This is the first study specifically analyzing the MAOA G941T polymorphism in GAD and thus needs to be replicated in an independent sample. However, the results are in line with previous data suggesting an association between the MAOA locus and regulation of complex human behavior. © 2003 Wiley‐Liss, Inc.
Role of elastin polymorphisms in panic disorder
Authors: Philibert Robert A. , Nelson Jeffrey J. , Bedell Bruce , Goedken Rhinda , Sandhu Harinder K. , Noyes Russell , Crowe Raymond R.
Published: January 2003

Panic disorder (PD) is a complex neuropsychiatric disorder that has been associated with an increased frequency of mitral valve prolapse. Elastin is a prominent component of mitral valves and, in a genome screen of 23 pedigrees with PD, we found evidence of linkage to the region of chromosome 7 that contains the elastin gene (ELN). Therefore, we examined the minimal essential promoter and coding regions of ELN in 23 independent probands from the families in our linkage studies using single strand conformational polymorphism analysis. We found three polymorphisms including one that coded for a non‐conservative amino acid change. However, none of these polymorphisms were associated with panic disorder in a case‐control analysis or linked to it in multiplex pedigrees. In our pedigrees, exonic polymorphisms in ELN do not play a major role in the genetic vulnerability to PD. © 2003 Wiley‐Liss, Inc.
Association of an exonic LDHA polymorphism with altered respiratory response in probands at high risk for panic disorder
Authors: Philibert Robert A. , Nelson Jeffrey J. , Sandhu Harinder K. , Crowe Raymond R. , Coryell William H.
Published: January 2003

Panic disorder (PD) is a clinical syndrome characterized by recurrent discrete episodes of fear accompanied by a variety of physiological and psychological symptoms, often with prominent respiratory components. A series of clinical observations has led some investigators to hypothesize that subtle alterations in ventilatory regulation are integral to at least a subtype of PD. In order to identify genetic factors that might predispose individuals to these alterations in ventilatory response, we conducted single stranded conformation polymorphism analysis across the exons of the lactate dehydrogenase A and B genes (LDHA and LDHB) using DNA prepared from 86 subjects previously characterized by respiratory response to a CO2 challenge with a variable genetic loading for PD. Remarkably, a single conserved LDHA exon 5 haplotype conferred increased risk for a paradoxical ventilatory response pattern to CO2 inhalation which robustly separated well subjects at high risk for PD from low‐risk control subjects. But, comparison of LDHA exon 5 genotypes in PD probands (n = 25) to that of random newborn controls (n = 182) did not demonstrate any significant differences. Given the pivotal role of LDH in the metabolism of lactate, a known inducer of panic attacks, and the dependence of LDH activity on cell pH, we suggest that LDHA polymorphisms may contribute to the variability to CO2 respiratory challenge. © 2003 Wiley‐Liss, Inc.
Absence of MeCP2 mutations in patients from the South Carolina autism project
Authors: Lobo‐Menendez Fe , Sossey‐Alaoui Khalid , Bell Jennifer M. , Copeland‐Yates Susan A. , Plank Sara M. , Sanford Stewart O. , Skinner Cindy , Simensen Richard J. , Schroer Richard J. , Michaelis Ron C.
Published: January 2003

The methyl‐CpG binding protein 2 (MeCP2) gene has recently been identified as the gene responsible for Rett syndrome (RS), a pervasive developmental disorder considered by many to be one of the autism spectrum disorders. Most female patients with MeCP2 mutations exhibit the classic features of RS, including autistic behaviors. Most male patients with MeCP2 mutations exhibit moderate to severe developmental delay/mental retardation. Ninety nine patients from the South Carolina autism project (SCAP) were screened for MeCP2 mutations, including all 41 female patients from whom DNA samples were available plus the 58 male patients with the lowest scores on standard IQ tests and/or the Vineland Adaptive Behavior Scale. No pathogenic mutations were observed in these patients. One patient had the C582T variant, previously reported in the unaffected father of an RS patient. Two other patients had single nucleotide polymorphisms in the 3′ UTR of the gene, G1470A and C1516G. These variants were seen in 12/82 and 1/178 phenotypically normal male controls, respectively. The findings from this and other studies suggest that mutations in the coding sequence of the MeCP2 gene are not a significant etiological factor in autism. © 2003 Wiley‐Liss, Inc.
Functional variation in promoter region of monoamine oxidase A and subtypes of alcoholism: Haplotype analysis
Authors: Parsian Abbas , Cloninger C. Robert , Sinha Rashmi , Zhang Zhen Hua
Published: January 2003

Monoamine oxidase (MAO) is a mitochondrial enzyme involved in the degradation of certain neurotransmitter amines. MAO‐A, due to its function in central nervous system, has been one of the important candidate genes involved in the development of neuropsychiatric disorders. A functional polymorphism in the promoter region of the MAO‐A gene has been identified. This variation affects the transcriptional efficiency of the gene. To determine the role of this MAO‐A functional polymorphism in the development of subtypes of alcoholism, a sample of alcoholics and normal controls were screened with this marker. The allele frequency differences between total alcoholics, Types I and II alcoholics, and normal controls was not significant. Comparison of male alcoholics to male normal controls for the frequencies of two‐loci and three‐loci haplotypes was statistically significant. After Bonferroni's correction for multiple tests none of the results remained significant at P < 0.05. Our results indicate that MAO‐A may play a role in the development of alcoholism but the gene effect is very small. © 2003 Wiley‐Liss, Inc.
Human nuclear transcription factor gene CREM: Genomic organization, mutation screening, and association analysis in panic disorder
Authors: Domschke K. , Kuhlenbäumer G. , Schirmacher A. , Lorenzi C. , Armengol L. , DiBella D. , Gratacos M. , Garritsen H.S. , Nöthen M.M. , Franke P. , Sand P. , Fritze J. , Perez G. , Maier W. , Sibrowski W. , Estivill X. , Bellodi L. , Ringelstein E.B. , Arolt V. , Martin‐Santos R. , Catalano M. , Stögbauer F. , Deckert J.
Published: January 2003

Panic disorder is an anxiety disorder with an estimated heritability of 48%. Variation in the gene of the nuclear transcription factor “cAMP‐responsive element modulator” (CREM) might contribute to its pathogenesis. CREM knock‐out mice exhibit significantly less anxiety behavior than wild‐type mice and the alternative CREM gene product “inducible cAMP early repressor” (ICER) plays a pivotal role in the hypothalamo‐pituitary‐adrenal (HPA) axis, which is disturbed in panic disorder. We characterized the genomic organization of the human CREM gene and performed a systematic mutation screening by means of single stranded conformational analysis (SSCA) in a sample of 40 German patients with panic disorder (DSM‐III‐R). Four novel single nucleotide polymorphisms in CREM promoters P 1 and P 4, one trinucleotide (ATT)‐repeat polymorphism in CREM promoter P 2—generating the ICER isoform—and a rare amino acid substitution in CREM exon glut 2 were identified. Association analysis in an extended sample of German patients (n = 88) revealed a significant excess of the shorter CREM P 2 promoter eight‐repeat trinucleotide allele and of genotypes containing the eight‐repeat trinucleotide allele in panic disorder (P = 0.02), in particular in panic disorder without agoraphobia (P = 0.001). A replication study in independent Italian (n = 76) and Spanish (n = 62) samples, however, failed to confirm this observation. This suggests that the CREM P 2 promoter trinucleotide polymorphism is not a major susceptibility factor in the pathogenesis of panic disorder. Functional analysis of the observed CREM P 2 promoter polymorphism as well as studies in independent panic disorder samples are necessary. © 2003 Wiley‐Liss, Inc.
Association of GABAA receptors and alcohol dependence and the effects of genetic imprinting
Authors: Song Jiuzhou , Koller Daniel L. , Foroud Tatiana , Carr Kristie , Zhao Jinghua , Rice John , Nurnberger John I. , Begleiter Henri , Porjesz Bernice , Smith Tom L. , Schuckit Marc A. , Edenberg Howard J.
Published: January 2003

GABA receptor genes have been postulated as candidates affecting the risk for alcoholism. The potential association between genes encoding five subunits of the GABAA receptors and alcoholism (alcohol dependence) was analyzed in the multiplex alcoholic pedigrees collected by the Collaborative Study on the Genetics of Alcoholism (COGA) using family‐based association tests. We found consistent, although weak, linkage disequilibrium between GABRB1 (located on chromosome 4) and alcoholism (P < 0.03). Genes encoding GABRA1 and GABRA6, on chromosome 5, did not provide evidence for association with alcoholism. GABRA5 and GABRB3, on chromosome 15, were reported to be expressed uniparentally from the paternal chromosome. Analyses of paternal transmission of alleles of GABRA5 provided evidence for association with alcoholism, particularly in the Caucasian population and with the stricter ICD‐10 definition of alcoholism (P < 0.004). Evidence of association was also observed during paternal transmission with GABRB3 in the Caucasian population (P < 0.007). Maternal transmissions provided no evidence for association. These data are consistent with an association between the expressed alleles in the GABAA‐gene cluster on chromosome 15 and alcoholism that is modulated by genetic imprinting. © 2003 Wiley‐Liss, Inc.
Genetic refinement and physical mapping of a 2.3 Mb probable disease region associated with a bipolar affective disorder susceptibility locus on chromosome 4q35
Authors: Badenhop Renee F. , Moses Melissa J. , Scimone Anna , Adams Linda J. , Kwok John B.J. , Jones Anne‐Marie , Davison Gail , Evans Mary R. , Kirkby Kenneth C. , Hewitt Jane E. , Donald Jennifer A. , Mitchell Philip B. , Schofield Peter R.
Published: January 2003

A susceptibility locus for bipolar affective disorder has been mapped to chromosome 4q35 in a large multigenerational pedigree. We have expanded this analysis to include 55 pedigrees (674 individuals, 214 affecteds). The evidence for linkage to 4q35 was strengthened in this larger cohort, with a maximum two‐point LOD score of 3.2 for marker D4S1652. Several other markers in the region gave LOD scores greater than 1.5. Non‐parametric analysis provided additional support for linkage to the 4q35 region. To further refine this region, haplotype analysis was carried out in 16 of the 55 pedigrees that showed evidence of linkage. As there is no evidence for an ancestral haplotype, nor a one‐to‐one correspondence between the disease and putative disease haplotype, we undertook an analysis based on pedigree‐specific, identical‐by‐descent allele‐sharing in order to define a probable disease region. This analysis indicated that the percentage sharing of alleles, identical‐by‐descent, in affecteds of all linked pedigrees increases from 60% at the centromeric markers to 75% for markers at the telomere. Maximal allele sharing occurred between markers D4S3051 and 4qTEL13 with this 24 cM region defining a probable disease region. We have constructed a physical map of the 4q35 interval consisting of a YAC contig and BAC clones. Based on this map the probable disease region between D4S3051 and 4qTEL13 corresponds to only 2.3 Mb. This region is very gene poor with only three known genes indicated from the YAC/BAC map. The small number of genes will facilitate systematic screening for variations associated with bipolar disorder. © 2003 Wiley‐Liss, Inc.
Heritability of attention problems in children: I. cross‐sectional results from a study of twins, age 3–12 years
Authors: Rietveld M.J.H. , Hudziak J.J. , Bartels M. , van Beijsterveldt C.E.M. , Boomsma D.I.
Published: January 2003

Multiple twin studies of attention problems (AP) from the Child Behavior Checklist or ADHD from the DSM criteria have reported on the genetic and environmental influences on these behaviors. The majority of these have studied AP and ADHD symptoms in twin samples combined across wide age spans, combined rater information and both genders. Thus, it is possible that the results are complicated by developmental, informant, and gender differences. The purpose of this study was to assess for the genetic and environmental contributions to overactive behavior (a syndrome highly related to AP in 7‐, 10‐, and 12‐years olds) in 3‐years olds (3,671 twin pairs), and attention problems in 7‐ (3,373 twin pairs), 10‐ (2,485 twin pairs), and 12‐years olds (1,305 twin pairs) while controlling for developmental, gender and rater contrast contributions. Using a cross‐sectional twin design, contributions from genetic additive, genetic dominance, unique environmental and rater contrast effects were estimated for CBCL maternal reports. We found that genetic influences on overactive behavior and attention problems are high across an age span that covers pre‐school and elementary school age. Although girls display less problem behavior compared to boys, heritability estimates were found equal for both genders at each age. Environmental experiences that are unique to the individual accounted for the remaining influence. At the age of 3 years, a rater contrast effect was detected. We hypothesize that the contrast effect represents a maternal rater bias effect that is dependent on the age of the twins. The implications of these findings are discussed with reference to the clinical setting and in the context of future research. © 2003 Wiley‐Liss, Inc.
Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome
Authors: Mihara Kazuo , Kondo Tsuyoshi , Suzuki Akihito , Yasui‐Furukori Norio , Ono Shingo , Sano Akira , Koshiro Kazuko , Otani Koichi , Kaneko Sunao
Published: January 2003

Our previous study has suggested that the TaqI A polymorphism of dopamine D2 receptor gene (DRD2) is associated with the predisposition to neuroleptic malignant syndrome (NMS). However, the specificity of this polymorphism as a predictor of NMS dose not seem to be sufficient enough. Meanwhile, it has been shown that the non‐carriers of Del allele of the −141C Ins/Del polymorphism in the promoter region of DRD2 have lower dopamine D2 receptor in the brain than the carriers. In addition, dopamine D3 receptor gene has a Ser9Gly polymorphism, which may alter the receptor function. The present study examined the association between these three polymorphisms and the development of NMS to investigate if a combination of these polymorphisms could increase the specificity as markers for NMS. The subjects were 17 psychiatric patients who had developed NMS (13 patients with schizophrenia, 3 with major depression, and 1 with dementia of the Alzheimer's type) and 163 schizophrenic patients who had never developed this syndrome. The frequency of the A1 allele was significantly (P = 0.012) higher in the patients who had developed NMS (59%) than in the patients who had not (35%). The proportion of the A1 carriers was significantly (P = 0.003) higher in the patients with NMS (16/17: 94%) than in those without the syndrome (93/163: 57%). However, no significant differences were found in the allele and genotype frequencies of the other two polymorphisms between the two groups. The present study suggests that only the TaqI A polymorphism is at least partly useful as a predictor of NMS, but the −141 C Ins/Del and Ser9Gly polymorphisms are not. © 2003 Wiley‐Liss, Inc.
Association of the 3′ UTR transcription factor LBP‐1c/CP2/LSF polymorphism with late‐onset Alzheimer's disease
Authors: Luedecking‐Zimmer Erin , DeKosky Steven T. , Nebes Robert , Kamboh M. Ilyas
Published: January 2003

Alzheimer's disease (AD) is a genetically heterogeneous neurodegenerative disorder. To date, apolipoprotein E (apoE) is the only established susceptibility gene for late‐onset AD. ApoE accounts for less than 50% of the risk of AD, indicating the presence of other unknown susceptibility loci. Linkage studies have indicated chromosome 12 as the most likely location for another late‐onset AD locus. We examined seven polymorphisms in five candidate genes located in and around the linkage peaks on chromosome 12 in 564 cases and 523 controls. The genes included complement component 1R (C1R), vitamin D receptor (VDR), scavenger‐receptor B1 (SR‐B1), low‐density lipoprotein receptor related protein 1 (LRP1), and transcription factor LBP‐1c/CP2/LSF. We found no association with C1R, VDR, SR‐B1, and LRP1 polymorphisms. However, the frequency of the A allele of the 3′ (untranslated region) UTR LBP‐1c/CP2/LSF polymorphism was higher in controls than cases (0.071 vs. 0.051; P = 0.042) with an adjusted odds ratio (OR) of 0.65 (95% confidence interval [CI]: 0.43–0.96; P = 0.0498). Our data suggest that the LBP‐1c/CP2/LSF polymorphism may have a moderate protective effect against the risk of AD. © 2003 Wiley‐Liss, Inc.
Testing the test—why pursue a better test for Huntington disease?
Authors: Timman Reinier , Maat‐Kievit Anneke , Brouwer‐DudokdeWit Christine , Zoeteweij Moniek , Breuning Martijn H. , Tibben Aad
Published: January 2003

In 1993, the gene mutation for Huntington disease (HD) was identified and testing became possible with a reliability of >99%, without the need for co‐operation of relatives. In 1997, a systematic information program offered the mutation retest to individuals who had earlier received a linkage test result for HD, which has a residual uncertainty of 1–9%. The characteristics of 129 individuals tested by linkage analysis for HD are reported on, as well as the reasons for their reassessment by mutation testing. Three groups were compared: (1) people who were retested between 1993 and 1997, before this study had started, (2) people who were retested after we provided information, and (3) persons who refrained from retesting. Nearly half of the linkage‐tested individuals were retested, with the exception of noncarriers with a residual risk of 1 or 2%. Of them, less than one out of five were retested. Carriers with a hopeful view on the future (BHS) and a better sense of well‐being (GHQ) were more likely to have the retest. Female carriers were also more likely to have the retest before we contacted them. Noncarriers who were retested were more anxious (HADS) than noncarriers who refrained from the retest. Retestees were younger at the time of testing. No risk reversals were revealed by this study. © 2003 Wiley‐Liss, Inc.
Tridimensional personality questionnaire trait of harm avoidance (anxiety proneness) is linked to a locus on chromosome 8p21
Authors: Zohar Ada H. , Dina Christian , Rosolio Naama , Osher Yamima , Gritsenko Inga , Bachner‐Melman Rachel , Benjamin Jonathan , Belmaker Robert H. , Ebstein Richard P.
Published: January 2003

Human personality traits are moderately heritable but only recently have specific polymorphisms been associated with particular personality dimensions especially anxiety‐related and novelty‐seeking traits. The first genome‐wide scan for personality traits was recently carried out by Cloninger et al. [1998: Am J Med Genet 81:313–317] and his colleagues and they reported that a region on 8p21 showed linkage to TPQ Harm Avoidance, an anxiety‐related personality trait. Towards replicating and extending these results, we examined both 8p21 and two additional chromosomal regions (1q21–24 and 22q12–13) for linkage to TPQ personality traits by genotyping at least three microsatellite markers in each region in a group of 384 sibling pairs. We found evidence for linkage to TPQ HA at 8p21–23 (Lod score = 2.907) confirming in an independent sample the initial findings by Cloninger and his colleagues. © 2003 Wiley‐Liss, Inc.