Monica Forzan

p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas.

Analysis of 786 NF1 mutation-positive subjects with clinical diagnosis of neurofibromatosis type 1 (NF1) allowed to identify the heterozygous c.5425C>T missense variant (p.Arg1809Cys) in six (0.7%) unrelated probands (three familial and three sporadic cases), all exhibiting a mild form of disease. Detailed clinical characterization of these subjects and other eight affected relatives showed that all individuals had multiple cafè-au-lait spots, frequently associated with skinfold freckling, but absence of discrete cutaneous or plexiform neurofibromas, Lisch nodules, typical NF1 osseous lesions or symptomatic optic gliomas. Facial features in half of the individuals were suggestive of Noonan syndrome. Our finding and revision of the literature consistently indicate that the c.5425C>T change is associated with a distinctive, mild form of NF1, providing new data with direct impact on genetic counseling and patient management.

Association study of AMH and AMHRII polymorphisms with unexplained infertility.

OBJECTIVE To investigate the association of AMH and AMHRII polymorphisms with reproductive abilities in a sample of women with idiopathic infertility. DESIGN Case-control study. SETTING University Department of Obstetrics and Gynecology, and University Unit of Clinical Genetics. PATIENT(S) 76 women with idiopathic sterility and 100 fertile women as controls. INTERVENTION(S) Genotyping was performed by high-resolution melt analysis. MAIN OUTCOME MEASURE(S) Genotype distribution and allele frequency of AMH and AMHRII polymorphisms. Reconstruction of haplotype alleles to evaluate the linkage disequilibrium between single nucleotide polymorphisms. RESULT(S) Allele frequencies of -482 A>G, IVS 5-6 C>T, IVS 10+77 A>G, 146T>G polymorphisms are statistically significantly different in infertile patients compared with controls. CONCLUSION(S) Genetic variants of AMH and AMHRII genes seem to be associated with infertility, suggesting a role in the pathophysiology of normo-estrogenic and normo-ovulatory infertility. A clearer understanding of their function in ovarian physiology may help clinicians to find a role for antimüllerian hormone measurement in the field of reproductive medicine.

Catechol-O-methyltransferase genotype modifies executive functioning and prefrontal functional connectivity in women with anorexia nervosa

BACKGROUND Anorexia nervosa is characterized by high levels of perseveration and inflexibility, which interfere with successful treatments. Dopamine (DA) signalling seems to play a key role in modulating the prefrontal cortex, since both DA deficiency and excess nega tively influence the efficiency of cognitive functions. The present study explores the effect of a functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene on the set-shifting abilities and prefrontal functional connectivity of patients with anorexia nervosa. METHODS All participants performed the Wisconsin Card Sorting Task, and a subsample underwent resting-state functional magnetic resonance imaging. RESULTS We included 166 patients with DSM-IV lifetime anorexia nervosa and 140 healthy women in our study. Both underweight and weight-recovered patients with anorexia nervosa showed high levels of perseveration, but only in the underweight group did the Val158Met polymorphism affect cognitive performance, showing the U-shaped curve characteristic of increased DA signalling in the prefrontal cortex. Underweight patients with anorexia nervosa who are Met homozygotes had significantly higher levels of perseveration and increased prefrontal functional connectivity than underweight patients in the other genotype groups, indicating abnormal regional cortical processing. LIMITATIONS Although our data show that grey matter reduction in starving patients with anorexia nervosa did not explain our findings, the cross-sectional design of the present study did not allow us to distinguish between the effects of starvation and those of low estrogen levels. CONCLUSION Starvation affects DA release in the prefrontal cortex of patients with anorexia nervosa with different effects on executive functioning and prefrontal functional connectivity according to the COMT genotype. This observation has several therapeutic implications that need to be addressed by future studies.

No Difference in 5-HTTLPR and Stin2 Polymorphisms Frequency Between Premature Ejaculation Patients and Controls

INTRODUCTION Premature ejaculation (PE) is defined as the inability of men to control ejaculation and it is the most prevalent male sexual dysfunction. The neurobiogenesis of ejaculation is very complex and involves the serotoninergic (5-hydroxytryptamine [5-HT]) system. A genetic etiology of PE in humans was stated accounting for around 30%. Recently, genetic polymorphisms located on SLC6A4 gene codifying for 5-HT transporter (5-HTT or serotonin transporter [SERT]), the major regulator of serotonergic neurotransmission, have been linked with the pathogenesis of PE and associated with the clinical response to therapy with contrasting results. AIM In order to establish a possible pathogenetic link between PE and SLC6A4 polymorphisms, we analyzed the 5-HTT-linked polymorphic region (5-HTTLPR), rs25531, and STin2 polymorphisms in 121 patients affected by lifelong and acquired PE. METHODS Polymerase chain reaction (PCR)-based technology followed by restriction fragment length polymorphism (RFLP) analysis. MAIN OUTCOME MEASURES Intravaginal ejaculatory latency time was measured by stopwatch in order to diagnose PE, and the results of the SLC6A4 polymorphisms analysis in PE patients was compared with the control group. RESULTS Genotype frequencies for 5-HTTLPR, rs25531, and STin2 for both patients and controls showed no significant deviation from Hardy-Weinberg equilibrium. No statistically significant differences were found in the frequency of SLC6A4 gene polymorphisms in PE patients vs. controls, or in lifelong PE patients vs. controls, or acquired PE patients vs. controls, or lifelong PE vs. acquired PE patients. The obtained data were contrasting with three out of four previously published reports. CONCLUSIONS The present results indicate that no difference exists in SLC6A4 polymorphisms frequency between PE patients and controls. A comparison with the previously published reports on this field is reported.

Functional connectivity correlates of response inhibition impairment in anorexia nervosa

Anorexia nervosa (AN) is a disorder characterized by high levels of cognitive control and behavioral perseveration. The present study aims at exploring inhibitory control abilities and their functional connectivity correlates in patients with AN. Inhibitory control - an executive function that allows the realization of adaptive behavior according to environmental contingencies - has been assessed by means of the Stop-Signal paradigm. The study involved 155 patients with lifetime AN and 102 healthy women. A subsample underwent resting-state functional magnetic resonance imaging and was genotyped for COMT and 5-HTTLPR polymorphisms. AN patients showed an impaired response inhibition and a disruption of the functional connectivity of the ventral attention circuit, a neural network implicated in behavioral response when a stimulus occurs unexpected. The 5-HTTLPR genotype appears to significantly interact with the functional connectivity of ventral attention network in explaining task performance in both patients and controls, suggesting a role of the serotoninergic system in mechanisms of response selection. The disruption of the ventral attention network in patients with AN suggests lower efficiency of bottom-up signal filtering, which might be involved in difficulties to adapt behavioral responses to environmental needs. Our findings deserve further research to confirm their scientific and therapeutic implications.

Neural signatures of the interaction between the 5-HTTLPR genotype and stressful life events in healthy women

A change in neural connectivity of brain structures implicated in the memory of negative life events has been hypothesized to explain the enhancement of memory encoding during the processing of negative stimuli in depressed patients. Here, we investigated the effects of the interaction between negative life events and the 5-HTTLPR genotype - a polymorphism of the serotonin transporter gene - on the functional and structural connectivity of the hippocampal area in 34 healthy women. All participants were genotyped for the presence of the 5-HTTLPR short variant and for the A/G single-nucleotide polymorphism; they underwent clinical assessment including structured diagnostic interviews to exclude the presence of psychiatric disorders and to assess the presence of stressful life events. Resting state functional magnetic resonance imaging and diffusion tensor imaging scans were performed. We found significant interactions between stressful events and the 5-HTTLPR genotype in both the functional connectivity of the parahippocampus with the posterior cingulate cortex and the structural connectivity between the hippocampus and both the amygdala and the putamen. In addition, we found several genotype-related differences in the relationship between functional/structural connectivity of the hippocampal area and the ability to update expectations or stress-related phenotypes, such as anxiety symptoms. If confirmed by future studies, these mechanisms may clarify the role of the 5HTTLPR genotype as a risk factor for depression, in interaction with negative events.

ATXN2 trinucleotide repeat length correlates with risk of ALS

We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37–3.94]; p = 6 × 10−18), with an exponential relationship between repeat length and ALS risk for alleles of 29–32 repeats (R2 = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk.

Serotonin transporter gene polymorphism in eating disorders: Data from a new biobank and META-analysis of previous studies

Objectives Growing interest focuses on the association between 5-HTTLPR polymorphism and eating disorders (ED), but published findings have been conflicting. Methods The Italian BIO.VE.D.A. biobank provided 976 samples (735 ED patients and 241 controls) for genotyping. We conducted a literature search of studies published up to 1 April 2015, including studies reporting on 5HTTLPR genotype and allele frequencies in obesity and/or ED. We ran a meta-analysis, including data from BIO.VE.D.A. – comparing low and high-functioning genotype and allele frequencies in ED vs. controls. Results Data from 21 studies, plus BIO.VE.D.A., were extracted providing information from 3,736 patients and 2,707 controls. Neither low- nor high-functioning genotype frequencies in ED patients, with both bi- and tri-allelic models, differed from controls. Furthermore, neither low- nor high-functioning allele frequencies in ED or in BN, in both bi- and triallelic models, differed from control groups. After sensitivity analysis, results were the same in AN vs. controls. Results remained unaltered when investigating recessive and dominant models. Conclusions 5HTTLPR does not seem to be associated with ED in general, or with AN or BN in particular. Future studies in ED should explore the role of ethnicity and psychiatric comorbidity as a possible source of bias.

Neurofibromatosis type 1 in two siblings due to maternal germline mosaicism.

Neurofibromatosis type 1 (NF1) is caused by loss of function mutations of the NF1 gene, which are de novo in 50% of cases. Although this gene shows one of the highest mutation rates in the human genome, germline mosaicism is very rare in this condition. We describe the molecular analysis of a family in which neurofibromatosis type 1 occurred in two out of four siblings born to unaffected parents. Molecular analysis of the NF1 gene identified in both patients the same splicing mutation c.1392+1G>A, which was absent in parental lymphocytes. Microsatellite analysis showed that the two affected siblings shared the same maternal allele, however a specific PCR‐RFLP assay excluded the presence of the NF1 splicing mutation in multiple maternal tissues. Our molecular and clinical findings are consistent with a germline mosaicism for the NF1 splicing mutation. This is the first case of maternal germline mosaicism for a NF1 mutation characterized so far at the molecular level. Our data confirm that germline mosaicism is rare in neurofibromatosis 1, but it has important implications for genetic counseling.

Clinical and genetic correlates of decision making in anorexia nervosa

ABSTRACT Introduction: Decision-making (DM) abilities have been found to be impaired in anorexia nervosa (AN), but few data are available about the characteristics and correlates of this cognitive function. The aim of the present study was to provide data on DM functioning in AN using both veridical and adaptive paradigms. While in veridical DM tasks, the individual’s ability to predict a true/false response is measured, adaptive DM is the ability to consider both internal and external demands in order to make a good choice, in the absence of a single true “correct” answer. Method: The participants were 189 women, of whom 91 were eating-disordered patients with a lifetime diagnosis of anorexia nervosa, and 98 were healthy women. All the participants underwent clinical, neuropsychological, and genetic assessment. The cognitive evaluation included a set of neuropsychological tasks and two decision-making tests: The Iowa Gambling Task and the Cognitive Bias Task. Results: Anorexia nervosa patients showed significantly poorer performances on both decision-making tasks than healthy women. The Cognitive Bias Task revealed that anorexia nervosa patients employed significantly more context-independent decision-making strategies, which were independent from diagnostic subtype, handedness, education, and psychopathology. In the whole sample (patients and controls), Cognitive Bias Task performance was independently predicted by lifetime anorexia nervosa diagnosis, body mass index at assessment, and 5-HTTLPR genotype. Conclusions: Patients displayed poor decision-making functioning in both veridical and adaptive situations. The difficulties detected in anorexia nervosa individuals may affect not only the ability to consider the future outcomes of their actions (leading to “myopia for the future”), but also the capacity to update and review one’s own mindset according to new environmental stimuli.