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.

Candidate genes for association studies in panic disorder are often selected on the basis of molecular mechanisms of drugs utilized in challenge tests such as m-chlorophenylpiperazine (mCPP), a non-selective 5-HT2C receptor agonist. Two novel, adjacent polymorphisms [(GT)12-18 and (CT)4-5] in the 5'-regulatory region of the X-chromosomal 5-HT2C receptor gene have recently been reported. We determined the allele frequency of long vs. short polymorphism haplotypes in a German and an Italian sample (combined n = 211) of panic disorder patients (DSM-III-R) and compared it with allele frequencies in two ethnically matched control samples (combined n = 226). In the German sample, a comparison of female genotypes containing the short haplotype vs. female genotypes containing only long haplotypes showed a significant difference (p = 0.01, ?2 analysis). In the Italian sample, however, this observation could not be replicated (p = 0.54, ?2 analysis). This argues against a major role for these promoter-associated 5-HT2C receptor gene length polymorphisms in the aetiopathogenesis of panic disorder.

Clinical GeneticsVolume 52, Issue 3 p. 194-195 Intragenic tetranucleotide repeat polymorphism at the human histidase (HAL) locus Piermario Maffei, Piermario Maffei Istituto di Ricovero e Cura a Carattere Scientifico H San Raffaele, Department of Neuropsychiatry Sciences and University of Milan, School of Medicine, Milan, ItalySearch for more papers by this authorMaria Nobile, Maria Nobile Istituto di Ricovero e Cura a Carattere Scientifico H San Raffaele, Department of Neuropsychiatry Sciences and University of Milan, School of Medicine, Milan, ItalySearch for more papers by this authorDaniela Di Bella, Daniela Di Bella Istituto di Ricovero e Cura a Carattere Scientifico H San Raffaele, Department of Neuropsychiatry Sciences and University of Milan, School of Medicine, Milan, ItalySearch for more papers by this authorEmanuela Novelli, Emanuela Novelli Istituto di Ricovero e Cura a Carattere Scientifico H San Raffaele, Department of Neuropsychiatry Sciences and University of Milan, School of Medicine, Milan, ItalySearch for more papers by this authorEnrico Smeraldi, Enrico Smeraldi Istituto di Ricovero e Cura a Carattere Scientifico H San Raffaele, Department of Neuropsychiatry Sciences and University of Milan, School of Medicine, Milan, ItalySearch for more papers by this authorMarco Catalano, Corresponding Author Marco Catalano Istituto di Ricovero e Cura a Carattere Scientifico H San Raffaele, Department of Neuropsychiatry Sciences and University of Milan, School of Medicine, Milan, ItalyIRCCS HSR, DSNP, Via Prinetti 29, 20127 Milan, ItalySearch for more papers by this author Piermario Maffei, Piermario Maffei Istituto di Ricovero e Cura a Carattere Scientifico H San Raffaele, Department of Neuropsychiatry Sciences and University of Milan, School of Medicine, Milan, ItalySearch for more papers by this authorMaria Nobile, Maria Nobile Istituto di Ricovero e Cura a Carattere Scientifico H San Raffaele, Department of Neuropsychiatry Sciences and University of Milan, School of Medicine, Milan, ItalySearch for more papers by this authorDaniela Di Bella, Daniela Di Bella Istituto di Ricovero e Cura a Carattere Scientifico H San Raffaele, Department of Neuropsychiatry Sciences and University of Milan, School of Medicine, Milan, ItalySearch for more papers by this authorEmanuela Novelli, Emanuela Novelli Istituto di Ricovero e Cura a Carattere Scientifico H San Raffaele, Department of Neuropsychiatry Sciences and University of Milan, School of Medicine, Milan, ItalySearch for more papers by this authorEnrico Smeraldi, Enrico Smeraldi Istituto di Ricovero e Cura a Carattere Scientifico H San Raffaele, Department of Neuropsychiatry Sciences and University of Milan, School of Medicine, Milan, ItalySearch for more papers by this authorMarco Catalano, Corresponding Author Marco Catalano Istituto di Ricovero e Cura a Carattere Scientifico H San Raffaele, Department of Neuropsychiatry Sciences and University of Milan, School of Medicine, Milan, ItalyIRCCS HSR, DSNP, Via Prinetti 29, 20127 Milan, ItalySearch for more papers by this author First published: 28 June 2008 https://doi.org/10.1111/j.1399-0004.1997.tb02545.xCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References Lucca A, Catalano M, Valsasina R, Fara C, Smeraldi E. Biochemical investigation of histidinemia in schizophrenic patients. Biol Psychiatr 1990: 27: 69–75. 10.1016/0006-3223(90)90021-S CASPubMedWeb of Science®Google Scholar Soto D, Sukumar S. Improved detection of mutations in the p53 gene in human tumors as single-stranded conformation polymorphs and double-stranded heteroduplex DNA. PCR Methods Applic 1992: 2: 96–98. 10.1101/gr.2.1.96 CASPubMedGoogle Scholar Suchi M, Harada N, Wada Y, Takagi Y. Molecular cloning of a cDNA encoding human histidase. Biochim Biophys Acta 1993: 1216: 293–295. 10.1016/0167-4781(93)90157-9 CASPubMedWeb of Science®Google Scholar Suchi M, Sano H, Mizuno H, Wada Y. Molecular cloning and structural characterisation of the human histidase gene (HAL). Genomics 1995: 29: 98–104. 10.1006/geno.1995.1219 CASPubMedWeb of Science®Google Scholar Taylor RG, Levy HL, McInnes RR. Histidase and histidinemia: clinical and molecular considerations. Mol Biol Med 1991a: 8: 101–116. CASPubMedWeb of Science®Google Scholar Taylor RG, Garcia-Haras J, Sadler SJ, Lafreniere RG, Willard HF, Ledbetter DH, Mclnnes RR. Localisation of histidase to human chromosome region 12q22-q24.1 and mouse chromosome region 10C2-D1. Cytogenet Cell Genet 1991b: 56: 178–181. 10.1159/000133082 CASPubMedWeb of Science®Google Scholar Citing Literature Volume52, Issue3September 1997Pages 194-195 ReferencesRelatedInformation

BACKGROUND Liver involvement and cholelithiasis are common complications of sickle-cell disease. The incidence of clinically evident hepatic damage reported in the literature for black people varies from 15% to 30%, while no data are reported for white people. OBJECTIVE To evaluate the liver involvement in 40 patients with homozygous sickle cell anemia (the beta 5 beta 5 form of sickle-cell disease) and 102 patients with double-heterozygous hemoglobin S and beta-thalassemia (65 with the beta 5 beta 0th and 37 with the beta 5 beta +th form of sickle-cell disease). SETTING The Department of Pediatric Hematology and Oncology, University of Catania, Catania, Italy. PATIENTS Outpatients with sickle-cell disease. RESULTS We found that, in our patients, liver disease seems to be clinically irrelevant: only 2 of the 142 patients examined had notable alterations in hepatic function. Cholelithiasis was found in 42.1% of the subjects with the beta 5 beta 5 form of sickle-cell disease and in 26.8% of the subjects with the beta 5 beta th form. Age-related analysis revealed a greater incidence of cholelithiasis during the first years of life in the patients with the beta 5 beta 5 form of the disease than in patients with the beta 5 beta th form. CONCLUSION Our data showed that liver involvement in sickle-cell disease is clinically irrelevant, reflecting the fact that the clinical expression of sickle-cell disease in Sicilian patients is moderate.

The serotonin transporter (5-HTT) is a candidate locus for aetiological involvement in affective disorders. Biochemical studies in suicides and depressed patients suggest that 5-HT uptake function is frequently reduced in affective illness. Furthermore, 5-HTT is targeted by widely used antidepressant drugs such as fluoxetine. We have performed an association study of a short variant of the 5-HTT-linked polymorphic region (5-HTTLPR), which restricts transcriptional activity of the 5-HTT promoter leading to low functional expression of the 5-HTT, in 454 patients with bipolar or unipolar affective disorder and 570 controls, derived from three European Centres (London, Milan and Würzburg). In all three centres, the frequency of the low activity allele was higher in patients than in controls (50% vs 45% in London, 45% vs 43% in Milan, 47% vs 40% in Würzburg). Although these differences were not individually significant, a stratified analysis of all three samples gave a significant overall odds ratio of 1.23 (95% confidence interval 1.02-1.49, P = 0.03). The excess of the homozygous low-activity genotype among the patients was even greater (odds ratio 1.53, 95% confidence interval 1.04-2.23, P = 0.02), suggesting partial recessively of the low-activity allele. Given the functional role of 5-HTT, our findings suggest that 5-HTTLPR-dependent variation in functional 5-HTT expression is a potential genetic susceptibility factor for affective disorders. If this finding is replicated, further work on genetic variants with low 5-HTT activity may facilitate the differential diagnosis of affective disorders, the assessment of suicidal behaviour, and the prediction of good clinical response to antidepressants.

We report two novel polymorphisms and a rare deletion variant in the human dopaine D4 receptor gene. The two polymorphisms are characterized by single base pair substitutions, namely a G-->C transversion changing codon 11 from GGG (encoding Gly) to CGG (encoding Arg) and a C-->T transition in position -11 upstream from the start codon. The Arg11 variant occurs at a frequency of about 1% and the C-->T transition at a frequency of about 7% in German control subjects (n = 148). Allele frequencies observed in patients suffering from schizophrenia (n = 256) and bipolar affective disorder (n = 99) were similar. The deletion variant is characterized by a 21 bp deletion affecting codons 36 to 42 coding for amino acids Ala-Ala-Leu-Val-Gly-Gly-Val located in the first transmembrane domain of the dopamine D4 receptor. The mutation was identified in a single individual suffering from obsessive-compulsive disorder and panic disorder. We were unable to detect the deletion in patients with schizophrenia and bipolar affective disorder, nor in healthy controls.

Controversial results possibly suggesting an association between Tourette's Syndrome (TS) and excess of homozygosity at a Msc I polymorphism in the Dopamine D3 receptor (DRD3) gene have recently been reported. Since a relationship between Obsessive-Compulsive Disorder (OCD) and Tourette's Syndrome (TS) has been suggested, in this study we assessed the frequency of this 2-allele polymorphism in a sample of 97 OCD patients and in 97 control subjects. No statistically significant differences in allele or genotype frequencies were found. Thus this mutation in the coding sequence of the DRD3 gene is unlikely to confer susceptibility to OCD.

Cardiological examination, chest teleradiotherapy, electrocardiography and echocardiography were performed in 81 Sicilian patients affected by drepanocytosis (30 had genotype betas betas, 36 had betas betath0 and 15 betas betath +).The series was considered globally as no significant variations were observed in the three groups studied.Cardiac ascultation revealed functional systolic murmur (2-3/6 Levine) in 44.4% of the patients. A slight increase in heart rate was observed in 4.9%, while diastolic arterial pressure was reduced (between 10th e 5th percentile of normal age levels) in all subjects.Radiographic examination revealed a cardiothoracic index above 0.50 in 67.9% of the cases and electrocardiography showed slight non specific ventricular ripolarization disorders in 2.4%. Mono and bidimensional echocardiography revealed no right heart alterations but showed increased left ventricular telediastolic diameter in 77.7% and augmented left ventricular telediastolic and telesystolic diameter in 58.02%. These two parameters were inversely correlated with hemoglobin values. Left ventricle fractional shortening and ejection fraction were normal in all patients.Our echocardiological findings agree with most reports in the literature on black populations. They demonstrate that the left ventricle of Sicilian patients with sickle cell anemia mantains its correct functions, in spite of the increased heart size in patients with this disease.

Jarcho‐Levin syndrome is a variety of autosomal recessive spondylocostal dysostosis characterized by severe deformity of the thoracic cage, leading to respiratory failure and early death. There are often associated dysmorphic features. The disease is more frequent in Puerto Ricans and rare in Europe. A Sicilian family with four affected individuals in two interrelated sibships is reported.

Prophylactic cranial irradiation in acute lymphoblastic leukemia (ALL) has been held responsible for long-term neuropsychological sequelae. This study evaluates the activity of monoamine oxidase (MAO) in children with ALL in first complete remission both before and after cranial irradiation, given to prevent central nervous system involvement. There was a significant decrease (p less than 0.025) in platelet MAO activity shortly after cranial irradiation. MAO activity values were in the normal range in patients investigated 3 months or more after the radiation treatment was completed. The pathogenesis and clinical relevance of this decrease are discussed.