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1.
Expert Opin Drug Metab Toxicol ; 16(12): 1187-1198, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32966143

RESUMO

INTRODUCTION: Obstetric history and maternal body composition and lifestyle may be associated with serious complications both for the mother, such as gestational diabetes mellitus (GDM), and for the fetus, including congenital malformations such as neural tube defects (NTDs). AREAS COVERED: In view of the recent knowledge, changes in nutritional and physical activity habits ameliorate glycemic control during pregnancy and in turn improve maternal and neonatal health outcomes. Recently, a series of small clinical and experimental studies indicated that supplemenation with inositols, a family of insulin sensitizers, was associated with beneficial impact for both GDM and NTDs. EXPERT OPINION: Herein, we discuss the most significant scientific evidence supporting myo-inositol administration as a prophylaxis for the above-mentioned conditions.

2.
Hum Mutat ; 40(9): 1557-1578, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31131967

RESUMO

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Biologia Computacional/métodos , Mutação de Sentido Incorreto , Neoplasias/diagnóstico , Processamento Alternativo , Detecção Precoce de Câncer , Feminino , Predisposição Genética para Doença , Humanos , Funções Verossimilhança , Masculino , Herança Multifatorial , Neoplasias/genética
3.
Int J Endocrinol ; 2018: 6050369, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30275827

RESUMO

[This corrects the article DOI: 10.1155/2017/5846286.].

4.
Artigo em Inglês | MEDLINE | ID: mdl-31517176

RESUMO

Purpose: To describe a snapshot of international genetic testing practices, specifically regarding the use of multigene panels, for hereditary breast/ovarian cancers. We conducted a survey through the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium, covering questions about 16 non-BRCA1/2 genes. Methods: Data were collected via in-person and paper/electronic surveys. ENIGMA members from around the world were invited to participate. Additional information was collected via country networks in the United Kingdom and in Italy. Results: Responses from 61 cancer genetics practices across 20 countries showed that 16 genes were tested by > 50% of the centers, but only six (PALB2, TP53, PTEN, CHEK2, ATM, and BRIP1) were tested regularly. US centers tested the genes most often, whereas United Kingdom and Italian centers with no direct ENIGMA affiliation at the time of the survey were the least likely to regularly test them. Most centers tested the 16 genes through multigene panels; some centers tested TP53, PTEN, and other cancer syndrome-associated genes individually. Most centers reported (likely) pathogenic variants to patients and would test family members for such variants. Gene-specific guidelines for breast and ovarian cancer risk management were limited and differed among countries, especially with regard to starting age and type of imaging and risk-reducing surgery recommendations. Conclusion: Currently, a small number of genes beyond BRCA1/2 are routinely analyzed worldwide, and management guidelines are limited and largely based on expert opinion. To attain clinical implementation of multigene panel testing through evidence-based management practices, it is paramount that clinicians (and patients) participate in international initiatives that share panel testing data, interpret sequence variants, and collect prospective data to underpin risk estimates and evaluate the outcome of risk intervention strategies.

5.
Int J Endocrinol ; 2017: 5846286, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28243254

RESUMO

The use of folic acid in the periconceptional period can prevent about 70% of neural tube defects (NTDs). In the remaining cases, no medical prevention is available, and those conditions should be defined as folate-resistant NTDs. Rodent models suggest that some folate-resistant NTDs can be prevented by inositol (myoinositol and chiroinositol) supplementation prior to pregnancy. Should folic acid be combined with myoinositol periconceptional supplementation to reduce the overall risk of NTDs even in humans? Hereafter, we discuss the results from the PONTI study that strongly support both the effectiveness and safety of myoinositol periconceptional supplementation in preventing human NTDs. We further report on the largest case series of pregnancies treated with myoinositol and folic acid. At our institution, a sequential study during 12 years involved mothers at risk of fetal NTDs, and 29 babies from 27 pregnancies were born after periconceptional combined myoinositol and folic acid supplementation. No case of NTDs was observed, despite the high recurrence risk in the mothers. Taken together, those data suggest that periconceptional folic acid plus myoinositol can reduce both the occurrence and recurrence risks of NTDs in a greater number of cases than folic acid alone.

6.
Eur J Obstet Gynecol Reprod Biol ; 195: 72-6, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26479434

RESUMO

In recent years, interest has been focused to the study of the two major inositol stereoisomers: myo-inositol (MI) and d-chiro-inositol (DCI), because of their involvement, as second messengers of insulin, in several insulin-dependent processes, such as metabolic syndrome and polycystic ovary syndrome. Although these molecules have different functions, very often their roles have been confused, while the meaning of several observations still needs to be interpreted under a more rigorous physiological framework. With the aim of clarifying this issue, the 2013 International Consensus Conference on MI and DCI in Obstetrics and Gynecology identified opinion leaders in all fields related to this area of research. They examined seminal experimental papers and randomized clinical trials reporting the role and the use of inositol(s) in clinical practice. The main topics were the relation between inositol(s) and metabolic syndrome, polycystic ovary syndrome (with a focus on both metabolic and reproductive aspects), congenital anomalies, gestational diabetes. Clinical trials demonstrated that inositol(s) supplementation could fruitfully affect different pathophysiological aspects of disorders pertaining Obstetrics and Gynecology. The treatment of PCOS women as well as the prevention of GDM seem those clinical conditions which take more advantages from MI supplementation, when used at a dose of 2g twice/day. The clinical experience with MI is largely superior to the one with DCI. However, the existence of tissue-specific ratios, namely in the ovary, has prompted researchers to recently develop a treatment based on both molecules in the proportion of 40 (MI) to 1 (DCI).


Assuntos
Anormalidades Congênitas/metabolismo , Diabetes Gestacional/metabolismo , Inositol/metabolismo , Resistência à Insulina , Síndrome Metabólica/metabolismo , Síndrome do Ovário Policístico/metabolismo , Feminino , Humanos , Inositol/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Gravidez , Estereoisomerismo , Complexo Vitamínico B/uso terapêutico
7.
Gynecol Endocrinol ; 31(6): 441-6, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26036719

RESUMO

A substantial body of research on mammalian gametogenesis and human reproduction has recently investigated the effect of myo-inositol (MyoIns) on oocyte and sperm cell quality, due to its possible application to medically assisted reproduction. With a growing number of both clinical and basic research papers, the meaning of several observations now needs to be interpreted under a solid and rigorous physiological framework. The 2013 Florence International Consensus Conference on Myo- and D-chiro-inositol in obstetrics and gynecology has answered a number of research questions concerning the use of the two stereoisomers in assisted reproductive technologies. Available clinical trials and studies on the physiological and pharmacological effects of these molecules have been surveyed. Specifically, the physiological involvement of MyoIns in oocyte maturation and sperm cell functions has been discussed, providing an answer to the following questions: (1) Are inositols physiologically involved in oocyte maturation? (2) Are inositols involved in the physiology of spermatozoa function? (3) Is treatment with inositols helpful within assisted reproduction technology cycles? (4) Are there any differences in clinical efficacy between MyoIns and D-chiro-inositol? The conclusions of this Conference, drawn depending on expert panel opinions and shared with all the participants, are summarized in this review paper.


Assuntos
Consenso , Inositol/fisiologia , Inositol/uso terapêutico , Oócitos/fisiologia , Técnicas de Reprodução Assistida/normas , Espermatozoides/fisiologia , Animais , Congressos como Assunto , Feminino , Humanos , Masculino
8.
Clin Case Rep ; 2(4): 156-8, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25356276

RESUMO

KEY CLINICAL MESSAGE: We report the case of a premature, very low birth weight, newborn with stigmata of Jeune syndrome, a rare skeletal dysplasia, and marked renal involvement (i.e. remarkable prenatal oligohydramnios, histologic nephronophthisis-like pattern, macroscopic renal cysts, and renal failure), expanding the phenotype consistent with the continuum of syndromic ciliopathies.

10.
Clin Genet ; 85(3): 267-72, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23711321

RESUMO

Proteolipid protein 1 (PLP1) gene-related disorders due to mutations in the PLP1 include a wide spectrum of X-linked disorders ranging from severe connatal Pelizaeus-Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). Duplications, deletions or point mutations in coding and noncoding regions of the PLP1 gene may occur. We report the clinical, neuroradiologic and molecular findings in six patients from two unrelated families. The affected males showed severe mental retardation, spastic tetraparesis, inability of walking and pes cavus at onset in early infancy. Brain magnetic resonance imaging (MRI) showed hypomyelination and brain atrophy. Nystagmus was never observed. The affected females showed adult-onset progressive spastic paraparesis leading to wheel-chair dependency and subtle white matter changes on brain MRI. Molecular studies in the two families identified two different intronic mutations, the novel c.622+2T>C and the known c.622+1G>A, leading to the skipping of PLP1-exon 4. The clinical presentation of the affected males did not consistently fit in any of the PLP1-related disorder subtypes (i.e., connatal or classic PMD, SPG2 and 'PLP1 null syndrome'), and in addition, the carrier females were symptomatic despite the severe clinical picture of their respective probands. This study provides new insight into the genotype-phenotype correlations of patients with PLP1 splice-site mutations.


Assuntos
Éxons , Estudos de Associação Genética , Mutação , Proteína Proteolipídica de Mielina/genética , Adulto , Encéfalo/patologia , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Doença de Pelizaeus-Merzbacher/diagnóstico , Doença de Pelizaeus-Merzbacher/genética , Mutação Puntual , Sítios de Splice de RNA , Adulto Jovem
11.
Mol Cytogenet ; 6(1): 45, 2013 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-24171812

RESUMO

BACKGROUND: Small supernumerary marker chromosomes (sSMCs) are additional, structurally abnormal chromosomes, generally smaller than chromosome 20 of the same metaphase spread. Due to their small size, they are difficult to characterize by conventional cytogenetics alone. In regard to their clinical effects, sSMCs are a heterogeneous group: in particular, sSMCs containing pericentromeric euchromatin are likely to be associated with abnormal outcomes, although exceptions have been reported. To improve characterization of the genetic content of sSMCs, several approaches might be applied based on different molecular and molecular-cytogenetic assays, e.g., fluorescent in situ hybridization (FISH), array-based comparative genomic hybridization (array CGH), and multiplex ligation-dependent probe amplification (MLPA).To provide a complementary tool for the characterization of sSMCs, we constructed and validated a new, FISH-based, pericentromeric Bacterial Artificial Chromosome (BAC) clone set that with a high resolution spans the most proximal euchromatic sequences of all human chromosome arms, excluding the acrocentric short arms. RESULTS: By FISH analysis, we assayed 561 pericentromeric BAC probes and excluded 75 that showed a wrong chromosomal localization. The remaining 486 probes were used to establish 43 BAC-based pericentromeric panels. Each panel consists of a core, which with a high resolution covers the most proximal euchromatic ~0.7 Mb (on average) of each chromosome arm and generally bridges the heterochromatin/euchromatin junction, as well as clones located proximally and distally to the core. The pericentromeric clone set was subsequently validated by the characterization of 19 sSMCs. Using the core probes, we could rapidly distinguish between heterochromatic (1/19) and euchromatic (11/19) sSMCs, and estimate the euchromatic DNA content, which ranged from approximately 0.13 to more than 10 Mb. The characterization was not completed for seven sSMCs due to a lack of information about the covered region in the reference sequence (1/19) or sample insufficiency (6/19). CONCLUSIONS: Our results demonstrate that this pericentromeric clone set is useful as an alternative tool for sSMC characterization, primarily in cases of very small SMCs that contain either heterochromatin exclusively or a tiny amount of euchromatic sequence, and also in cases of low-level or cryptic mosaicism. The resulting data will foster knowledge of human proximal euchromatic regions involved in chromosomal imbalances, thereby improving genotype-phenotype correlations.

12.
Clin Biochem ; 46(18): 1902-4, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24036223

RESUMO

OBJECTIVE: Canavan disease (OMIM 271900) is a severe autosomal recessive neurodegenerative disorder characterized by spongy degeneration of the brain and caused by mutations in the gene encoding for aspartoacylase (ASPA). The enzyme is responsible for the catalyses of the brain-specific compound N-acetylaspartate (NAA). DESIGN AND METHODS: We report the case of two Egyptian sibling patients suspected of Canavan disease (CD) showing clinical deterioration, white matter degeneration, megalencephaly and severe intellectual impairment. The patients underwent magnetic resonance imaging (MRI) and biochemical analysis of NAA in biological fluid samples (serum and urine). Subsequently, in order to determine the mutation responsible for CD in these two sibs, a molecular biological examination was performed. RESULTS: MRI findings and quantification of high NAA excretion (1378.5 and 680.1µmolNAA/mmolcreatinine in urine of 4months and 4years old patients, respectively) confirmed the diagnosis of CD and prompted a search for the responsible mutation. The molecular biological analysis revealed homozygosity for the substitution T530C (Ile177Thr) in the exon 4 of the ASPA gene in both sibs. A total loss of enzymatic activity was also recorded. CONCLUSIONS: The substitution T530C (Ile177Thr) results in a novel missense mutation causing a CD phenotype with severe clinical characteristics. This mutation was not previously described in the literature. In these two sibs, urinary concentration of NAA appears to correlate inversely to symptom severity and CD progression.


Assuntos
Amidoidrolases/genética , Ácido Aspártico/análogos & derivados , Doença de Canavan/enzimologia , Doença de Canavan/etiologia , Mutação de Sentido Incorreto , Ácido Aspártico/sangue , Ácido Aspártico/urina , Doença de Canavan/genética , Pré-Escolar , Homozigoto , Humanos , Lactente , Imagem por Ressonância Magnética
13.
Expert Rev Proteomics ; 10(2): 131-4, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23573780

RESUMO

Prenatal diagnosis is now offered to high-risk pregnancies, including advanced maternal age, ultrasound anomalies and positive Down's syndrome screening, and karyotype on cultured fetal material is the test of choice to screen these pregnancies. However, microscope analysis can only detect gross chromosome abnormalities, highlighting the need for more sensitive techniques. It has recently been established that the higher resolution of microarray-based platforms can increase the diagnostic yield, offering more information to couples, and it is being discussed as a replacement to the standard karyotype. Conversely, the very high sensitivity of microarray-based analysis allows us to detect small microdeletions/microduplications (copy number variations) with unknown functional role and difficult genotype/phenotype correlation. In addition, the new copy number variation syndromes are often associated with variable outcomes, ranging from normal to severely affected individuals. This means that the microarray-based analysis introduced routinely in prenatal diagnosis needs to answer the question: are laboratory staff, clinical geneticists and counselors really experienced enough to manage these new scenarios?

15.
Expert Opin Drug Deliv ; 9(9): 1033-9, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22724555

RESUMO

OBJECTIVE: Neural tube defects (NTDs) are classified as folate sensitive (about 70%) and folate resistant (about 30%); although folic acid is able to prevent the former, several data have shown that inositol may prevent the latter. It has recently been proposed that coffee intake might represent a risk factor for NTD, likely by interfering with the inositol signaling. In the present study, we tested the hypothesis that, beside affecting the inositol signaling pathway, coffee also interferes with inositol absorption. RESEARCH DESIGN AND METHODS: In order to evaluate coffee possible negative effects on inositol gastrointestinal absorption, a single-dose bioavailability trial was conducted. Pharmacokinetics (PK) parameters of myo-inositol (MI) powder and MI soft gelatin capsules swallowed with water and with a single 'espresso' were compared. PK profiles were obtained by analysis of MI plasma concentration, and the respective MI bioavailability was compared. RESULTS: Myo-inositol powder administration was negatively affected by coffee intake, thus suggesting an additional explanation to the interference between inositol deficiency and coffee consumption. On the contrary, the concomitant single 'espresso' consumption did not affect MI absorption following MI soft gelatin capsules administration. Furthermore, it was observed that MI soft gelatin capsule administration resulted in improved bioavailability compared to the MI powder form. CONCLUSIONS: Myo-inositol soft gelatin capsules should be considered for the preventive treatment of NTDs in folate-resistant subjects due to their higher bioavailability and to the capability to reduce espresso interference.


Assuntos
Café/efeitos adversos , Inositol/administração & dosagem , Defeitos do Tubo Neural/prevenção & controle , Complexo Vitamínico B/administração & dosagem , Adulto , Disponibilidade Biológica , Cápsulas , Feminino , Gelatina , Géis , Humanos , Inositol/farmacocinética , Absorção Intestinal , Defeitos do Tubo Neural/etiologia , Fatores de Risco , Complexo Vitamínico B/farmacocinética , Adulto Jovem
16.
Fetal Pediatr Pathol ; 31(6): 379-87, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22443204

RESUMO

Acrania may occur as a single isolated malformation or associated with extracranial defects. Hypospadias is one of the most common congenital abnormalities of the genitalia frequently missed on prenatal sonograms. Second trimester two- and three-dimensional ultrasound and MRI diagnosis with necropsy and folate metabolism pathway analysis. The mechanisms leading to closure of both neural and urethral tubes, are far from being demonstrated, and molecular studies of this very rare association are lacking although it might be based on a common genetic mechanism, leading to a disturbed development pathway at the molecular level.


Assuntos
Anencefalia/diagnóstico , Ácido Fólico/metabolismo , Hipospadia/diagnóstico , Imagem por Ressonância Magnética , Ultrassonografia Pré-Natal/métodos , Anormalidades Múltiplas , Aborto Eugênico , Adulto , Anencefalia/complicações , Anencefalia/metabolismo , Evolução Fatal , Feminino , Humanos , Hipospadia/complicações , Hipospadia/metabolismo , Masculino , Gravidez , Segundo Trimestre da Gravidez
17.
Birth Defects Res A Clin Mol Teratol ; 91(11): 962-5, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21956977

RESUMO

Neural tube defects (NTDs), most commonly spina bifida and anencephaly, can be prevented with periconceptional intake of folic acid in about 70% of cases. Recurrence of NTDs despite supplementation of high dose of folic acid further suggests that a proportion of NTD cases might be resistant to folic acid. Moreover, heterogeneity of NTDs has been suggested in animal studies, indicating that only some sub-type of NTDs should be considered sensitive to folate intake. Inositol isomers (particularly myo- and chiro-inositol) can prevent folate-resistant NTDs in the curly-tail mutant mouse, suggesting that some cases of human NTDs might benefit from inositol supplementation. In humans, lower inositol blood concentration was found in pregnant women carrying NTD fetuses, whereas a periconceptional combination therapy with folic acid associated with inositol has been linked to normal live births, despite high NTD recurrence risk. Fifteen pregnancies from 12 Caucasian women from different parts of Italy with at least one previous NTD-affected pregnancy underwent periconceptional combined myo-inositol and folic acid supplementation. Maternal serum α-feto-protein levels were found in the normal range, and normal results on ultrasound examination were found in all the pregnancies that followed. No collateral effects or intense uterine contractions were demonstrated in this pilot study in any of the pregnancies after inositol supplementation, and seventeen babies were born without any type of NTD.


Assuntos
Suplementos Nutricionais/estatística & dados numéricos , Ácido Fólico/uso terapêutico , Inositol/uso terapêutico , Defeitos do Tubo Neural/epidemiologia , Defeitos do Tubo Neural/prevenção & controle , Adulto , Estudos de Coortes , Feminino , Ácido Fólico/administração & dosagem , Heterozigoto , Humanos , Recém-Nascido , Inositol/administração & dosagem , Itália , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Projetos Piloto , Gravidez , Resultado da Gravidez , Resultado do Tratamento
20.
Mol Cytogenet ; 2: 19, 2009 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-19781104

RESUMO

BACKGROUND: Premature ovarian failure (POF) is a secondary hypergonadotrophic amenorrhea occurring before the age of 40 and affecting 1-3% of females. Chromosome anomalies account for 6-8% of POF cases, but only few cases are associated with translocations involving X and Y chromosomes.This study shows the cytogenetic and molecular analysis of a POF patient came to our attention as she developed a left ovary choriocarcinoma at the age of 10 and at 14 years of age she presented secondary amenorrhea with elevated levels of gonadotropins. RESULTS: Breakpoint position on X and Y chromosomes was investigated using Fluorescent In Situ Hybridisation (FISH) with a panel of specific BAC probes, microsatellite analysis and evaluation of copy number changes and loss of heterozigosity by Affymetrix(R) GeneChip platform (Santa Clara, CA, USA). Patient's karyotype resulted 46, X, der(Y)t(X;Y)(q13.1;q11.223). X inactivation study was assessed by RBA banding and showed preferential inactivation of derivative chromosome. The reciprocal spatial disposition of sexual chromosome territories was investigated using whole chromosome painting and centromeres probes: patient's results didn't show a significant difference in comparison to normal controls. CONCLUSION: The peculiar clinical case come to our attention highlighted the complexity of POF aetiology and of the translocation event, even if our results seem to exclude any effect on nuclear organisation. POF phenotype could be partially explained by skewed X chromosome inactivation that influences gene expression.

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