ETHICAL AND GENETIC ASPECTS REGARDING PRESYMPTOMATIC TESTING FOR NEURODEGENERATIVE DISEASES.

Neurodegenerative diseases, such as Alzheimer's dementia, Huntington's chorea, Parkinson's disease or spinocerebellar ataxia, manifests into adulthood with an insidious onset, slowly of progressive symptoms. All of these diseases are characterized by presimptomatic stages that preceded with many years of clinical debut. In Parkinson's disease, more than half of the dopaminergic neurons of the black substance are lost before the advent of motor characteristic manifestations. In Huntington's chorea, the progressive neurodegenerative disease could be diagnose prenatal and presymptomatic by analyse of the number of CAG repeats in exon 1 of the huntingtin gene. A similar mechanism represented by expansion of trinucleotide repeats during hereditary transmission from parents to children was identified in fragile X syndrome, spinocerebellar ataxia, spinal muscular and bulbar atrophy, or myotonic dystrophy. Presymptomatic diagnosis in all these progressive diseases raise many ethical issues, due to the psychological impact that can cause the prediction of a disease for which there is currently no curative treatment. Therefore, a positive result can produce serious psychological trauma and major changes in the lifestyle of the individual, instead, a negative result can bring joy and tranquillity. But the problem arises if presymptomatic testing in these neurodegenerative diseases brings greater benefits compared to the possible psychological damage, which can add the risk of stigmatization or discrimination.

Surgical Management of Type A Acute Aortic Dissection in Patients With Marfan Syndrome: A Single Center Experience.

Introduction: Acute aortic dissection is the most common cause of death in patients with Marfan syndrome and untreated aortic root enlargement. Emergency surgery for replacement of the ascending aorta has the potential of life saving procedure, but is associated with high morbidity and mortality. Long-term outcomes after surgical repair of acute aortic dissection type A in patients with Marfan syndrome are limited. Material and methods: We made a retrospective study concerning emergency surgical intervention for acute aortic dissection type A, by Bentall procedure, performed in Emergency Institute for Cardiovascular Diseases "Prof dr. C. C. Iliescu" Bucharest between January 2005 and July 2014. We included 332 patients with type a acute aortic dissection divided into two groups: group A - 16 patients with Marfan syndrome and group B - 316 patients with other etiologies. We analyzed differences between these two groups regarding perioperative characteristics, surgical technique and short and long-term morbidity and mortality. Results: The patients from group A were significantly younger than those in group B (35.1±12.7 years vs. 56.8±7.1 years; p<0.001). Arterial hypertension was three times more common in group B as compared to group A (p<0.001). The incidence of postoperative morbidity, and intraoperative and 30-days mortality death rates were similar between groups, but overall mortality at 10 years was lower in group A (31.3%) vs. group B (44.9 %). Conclusions: Emergency surgical in Marfan syndrome, by Bentall procedure could improve perioperative morbidity and mortality of patients with acute aortic dissection, but need an early diagnosis, proper medical therapy and imagistic surveillance.

Phenotypic variability in Patau syndrome.

UNLABELLED: Patau syndrome has an incidence of 1/10.000-20.000, the clinical diagnosis being suggested by the triad cleft lip and palate, microphthalmia/anophthalmia and postaxial polydactyly. Most frequent cytogenetic abnormality is free and homogeneous trisomy 13 (80.0%), rarely being detected trisomy mosaics or Robertsonian translocations. The objective of the study was to identify phenotypic features of trisomy 13. MATERIAL AND METHODS: The retrospective study was conducted on a trial group of 14 cases diagnosed cytogenetically with trisomy 13 between January 2000 and December 2012 at lasi Medical Genetics Centre. RESULTS: Of the 14 cases, 3 were evaluated pathologically (two aborted foetuses and one stillborn), 8 cases were detected in the neonatal period, and 3 in infancy. Clinical diagnosis was supported by the identification of a model of abnormal development, mainly characterized by: maxillary cleft (lip and palate--5 cases; lip--1 case), ocular abnormalities (microphthalmia/anophthalmia--7 cases; cyclopia--1 case), postaxial polydactyly (7 cases), scalp defects (6 cases), congenital heart anomalies (10 cases, 6 patients with atrial septal defect), complete holoprosencephaly (4 cases), ear abnormalities (11 cases), broad nasal root (10 cases). An important issue in confirming the phenotypic variability of Patau syndrome is that the classic clinical triad was identified only in one case. CONCLUSIONS: Patau syndrome is a disease with variable expression and is characterized by a pattern of abnormal prenatal development characterized by facial dysmorphia, polydactyly and severe birth defects (heart, brain) that generate an increased in utero and perinatal mortality.

Prenatal diagnosis of gonosomal anomalies: limitations of the FISH method and genetic counseling difficulties in 15 cases.

UNLABELLED: Prenatal diagnosis (PD) by FISH or cell culture is today an important tool for the prevention of chromosomal anomalies. A difficult issue is prenatal detection of gonosomal anomalies. Most gonosomal anomalies neither affect life expectancy nor cause psychomotor retardation, but sexualization disorders and the lack of reproductive potential are a constant finding. AIM: This study aimed at identifying the medical problems the specialists and the parental couple are faced with at the time of the diagnosis of fetal gonosomal anomalies. MATERIAL AND METHODS: This retrospective study (2004-2012) was conducted in the Prenatal Genetic Diagnosis Department of "CuzaVoda" Maternity by FISH technique in 1685 pregnancies. The AneuVysion probes were used for identifying and enumerating chromosomes 13, 18, 21, X, and Y via fluorescence in situ hybridization (FISH) in interphase nuclei obtained from amniotic fluid. RESULTS: Fifteen fetuses were selected in which we were faced with difficulties interpreting the number of gonosomes: monosomy X (5 cases), pseudomosaicism XX/XY (3), trisomy XXY (3 cases), trisomy XYY (1 case), 45,X/46.XX mosaicism (1 case) and triploidy XXX (2 cases). Later, by repeating the analysis, 2 cases with pseudomosaicism XX/XY were excluded. A case highlighting the limitations of the FISH test was that of a fetus in which the FISH test revealed trisomy XXY, while postnatal karyotyping showed a six cell line mosaicism (marker and ring X chromosomes). CONCLUSIONS: All parental couples received nondirective genetic counseling, respecting the individuals' dignity and rights of self-determination. Parents received information on the natural course of the disease, treatment options, and psychological support and were involved in their child's recovery.

Genotype- phenotype correlation in trisomy X: a retrospective study of a selected group of 36 patients and review of literature.

UNLABELLED: Trisomy X (47,XXX) is a gonosomal aneuploidy characterized by the presence of an extra X chromosome in a female person. Usually the diagnosis is established made postnatally by chromosome analysis in patients with suggestive clinical signs. Clinical signs vary by age. In prepubertal patients have a growth retardation associated with uncharacteristic facial dysmorphism, mild mental retardation with behavioral disorders, plus clinical signs of ovarian dysgenesis, postpubertal. AIM: We analyzed retrospectively the genotype - phenotype correlations for a selected group of 36 patients diagnosed with trisomy X (homogeneous or mosaic) by cytogenetic methods (X chromatin and karyotype). MATERIAL AND METHODS: Analysis of the clinical data of 36 patients diagnosed with trisomy X and correlation with the results of X chromatin and karyotype. RESULTS: Clinical signs detected in patients with homogeneous trisomy X 47,XXX (22.22%), mosaic 46,XX/47,XXX (16.66%) or 47,XXX/48,XXXX (5.55%) were prepubertal, growth retardation associated with dysmorphic facial (upslanted palpebral fissure, epichantus, thin lips) and postpubertal, signs of ovarian dysgenesis (secondary amenorrhea, early menopause). The phenotype of patients with different gonosomal mosaic corresponding to Turner syndrome, incorporating a cell line with trisomy X (55.55%) was variable, correlated with the type of chromosomal abnormalities detected. CONCLUSIONS: The results of our study are similar to those obtained in other studies and emphasizes that phenotypic variability of patients with trisomy X feature makes it difficult to genotype - phenotype correlations.

Inverted duplication deletion of 8P: characterization by standard cytogenetic and SNP array analyses.

Inverted 8p duplication deletions are recurrent chromosomal rearrangements that most often arise through non-allelic homologous recombination (NAHR) during maternal meiosis between segmental duplications made up of the olfactory receptor (OR) gene clusters. The presence of a paracentric inversion polymorphism in 8p23.1, found in approximately 26% of European population, may trigger meiotic misalignment and NAHR between the OR gene repeats. We report clinical, cytogenetic, and molecular findings in a 4 year 8 month-old female with concomitant inverted duplication and terminal deletion of chromosome 8p. The girl, the first child of unrelated parents, was born at term, by normal delivery, after an uneventful pregnancy. Clinical examination revealed dysmorphic features, pectus excavatum, hypertonia, severe developmental delay. Brain ultrasound and MRI showed agenesis of the corpus callosum without other abnormalities. Conventional cytogenetic analysis identified additional material on chromosome 8 at band p21. SNP array analysis further characterized the abnormality as a duplication of about 31.3 Mb, from 8p23.1 to 8p11.1, and additionally revealed a terminal deletion of about 6.8 Mb, from 8p23.3 to 8p23.1. Genomic microarray also identified a region of disomy between deletion and duplication. Chromosome analysis of both parents revealed normal results. Based on clinical examination, conventional cytogenetics and SNP array, we established the diagnosis of inverted duplication deletion of 8p. SNP array analysis precisely defined the breakpoints of rearrangement and, by identifying a region of disomy between the duplication and deletion, indicated that NAHR between segmental duplications was the most likely mechanism for this type of abnormality.

Hand, foot and mouth disease--outbreak in Romania?

Hand, foot and mouth disease (HFMD) is a viral illness usually occurring during the summer months in children younger than 5 years of age. In the North-East area of Romania the incidence is usually low, each dermatologist reporting 1-2 cases or even less per year. The diagnosis is usually based on the characteristic clinical aspect: vesicles and papules on the hands and feet and superficial oral ulcers. HFMD is typically a benign and self-limiting disease that resolves in approximately 7 days; in Asia there have been few reported severe cases that developed neurological complications and even death, while in certain areas of China this disease is a more and more serious public health problem. In the summer of 2012 in North-East Romania numerous cases of disease have been reported, some with atypical clinical manifestations and most of them with mild or moderate forms of disease. The present article is a discussion on one of these cases. The diagnosis was made based on lesions location and clinical appearance. An outbreak of HFMD should be confirmed by virology tests.

[Array CGH: technical considerations and applications]. / Hibridizarea genomica comparativa pe microretele: consideratii tehnice si aplicatii.

During the past ten years a particular molecular technology - array comparative genomic hybridization (aCGH)--has received a great deal of attention. Array CGH can detect simultaneously sub-microscopic copy number changes across the whole genome, thus overcoming the limitations of karyotyping or locus-specific techniques. Array CGH has become an important tool for clinical diagnostics and gene-identification studies and is having a great impact on the understanding of pathologies, the counselling of families and patient management. Different types of array CGH platforms at increasingly higher resolution have been developed, differing mainly in the type of the interrogating probes and in their coverage of the genome. Here, we review the array CGH methodology and its various applications in clinical diagnostics and research. Although it's an expensive technology and differentiating between pathogenic and benign copy number variations is a challenging task, array CGH is an efficient and robust method for assesing disease-causing genomic imbalances and will probably replace karyotype as the primary cytogenetic test.

[Improvement of genetic diagnostic strategy in velo-cardio-facial syndrome]. / Optimizarea strategiei de diagnostic genetic în sindromul velo-cardio-facial.

UNLABELLED: Velo-Cardio-Facial Syndrome (VCFS) is characterized by congenital heart defects (CHD), palatal abnormalities, facial dysmorphism, neonatal hypocalcemia, immune deficit, speech and learning disabilities. SVCF is caused by microdeletion 22q11.2. Microdeletion is detected by fluorescence in situ hybridization (FISH). The highly variable phenotype makes diagnosis and selection for FISH more difficult. AIM: To retrospectively analyze and compare the phenotype of children with a clinical diagnosis of VCFS with/without 22q11 deletion; to verify the validity of literature guidelines and to describe combinations of clinical features that should lead to molecular analysis. MATERIAL AND METHODS: The present study was performed in 21 patients with a clinical diagnosis of VCFS. Methaphase chromosome spreads were prepared from phytohaemagglutinin stimulated lymphocyte culture by standard methods before FISH. The patients were divided into two groups according to FISH test: positive and negative. RESULTS: The features commonly noticed in FISH positive patients were: palatal abnormalities/hypernasal speech, learning disabilities, facial dysmorphism, tapered fingers (6/6), CHD (5/6) and recurrent infections (2/6). In FISH negative patients the following were found: learning disabilities, CHD (12/15); facial dysmorphism (10/15), family history of CHD (7/15), short stature (6/15), hypocalcemia, tapered fingers (5/15), recurrent infections (3/15) and palatal cleft (2/15). In both groups, Tobias and McDonald-McGinn guidelines were positive. CONCLUSIONS: VCFS has a highly variable phenotype. Our study suggests that 22q11.2 deletion analysis by FISH should be performed in patients who have at least 2 (newborn)/3 (child, adult) specific criteria: CHD, hypocalcemia, palatal abnormalities, facial dysmorphism, learning disabilities, digital anomalies, and immune deficit.

[Research on the incidence and prevalence of congenital abnormalities in Iasi district and Iasi city, from 2001 to 2008]. / Cercetari pentru cunoasterea incidentei si prevalentei anomaliilor congenitale, în judetul si municipiul Iasi, in perioada 2001-2008.

UNLABELLED: Congenital abnormalities (CA) are deviations from the normal embryonic development that appear antenatal and they are characterized by the alteration of the morphology and function of an organ, system of organs or even of the entire body. MATERIAL AND METHOD: The study, on a period of eight years, included 1685 children with CA, from which 58% were males and 50% were from the country-side. RESULTS: It has been observed that 36% of the CA cases were premature births and 64% were normal term births. Also, 21% of the children with CA weighed less than 2700 grams at birth and 79% weighed more than 2700 grams at birth. The birth's APGAR score has been less than 7 in 30% of the cases and higher than 7 in 70% of the cases. 72% of the cases were natural births and 28% were caesarian births. 88% of the CA cases were singular congenital abnormalities and 12% were multiple congenital abnormalities. 24% of the CA were cardiac abnormalities and 21% were skeletal abnormalities. 3% of the subjects of the study have died, of which 69% died from cardiac abnormalities, 22% from hydrocephalus abnormalities, 7% from diaphragmatic hernia and 2% from renal congenital abnormalities.

[Chromosomal evaluation in couples with reproductive disorders--retrospective study of a selected group of 266 couples]. / Evaluarea cromozomiala a cuplurilor cu tulburari de reproducere--studiu retrospectiv pe un lot selectionat de 266 cupluri.

UNLABELLED: Reproductive Disorders (RD), manifested by the biological inability to conceive (primary sterility) or inability to carry a pregnancy to full-term (infertility), affect 10-15% of reproductive-aged couples. The genetic etiology of RD is represented, in the majority of cases, by the chromosomal abnormalities. AIM: To retrospectively analyze the karyotype results in a selected group of couples with RD. MATERIAL AND METHOD: The present study was performed in 266 couples with RD: 80 (30.07%) with primary sterility (ST), 149 (56.01%) with Recurrent Spontaneous Abortions (RSA) and 37 (13.90%) with Stillborn Children (SC). A GTG-banded karyotype was performed on both partners of each couple. RESULTS: We identified a chromosomal abnormality in 43 individuals (16.16%): 20 cases (7.51%) with ST, 13 cases (4.88%) with RSA and 10 cases (3.75%) with SC. The affected partner was female in 23 cases (8.64%) and male in 20 cases (7.51%). A X chromosome (numerical or structural) abnormality was detected in 18 cases (6.76%), most frequent X chromosome monosomy mosaicism in female and trisomy XXY in male; a balanced structural chromosomal abnormality (BSC) was detected in 23 couples (8.64%); in other two males with ST, the karyotype result was 46,XX. CONCLUSIONS: The results of our study are similar to other reported studies and underline the major etiologic role of chromosomal abnormalities in RD and the importance of chromosomal analysis for the etiologic diagnosis and genetic counseling of these patients.

[Clinical epidemiological retro prospective studies on the incidence and prevalence of cardiac congenital abnormalities in a group of 1570 children, born in Iasi between 2000-2009]. / Evaluari clinico-epidemiologice, retro-prospective asupra incidentei si prevalentei unor malformatii congenitale de cord, pe un lot de 1570 de copii, nascuti in judetul si in municipiul Iasi, in perioada 2000-2009.

MATERIAL AND METHOD: The study has been conducted on a period of ten years and it included 1570 children with congenital abnormalities (CA), of which 371 (24%) were cardiac abnormalities, 312 (20%) were skeletal abnormalities, 55 (3%) were Down Syndrome and 832 (53%) were other pathologies. RESULTS: 48% of the 371 children that were diagnosed with cardiac CA were males, while 52% were females; 52% of the children were from the city, while 48% were from the country-side; 42% of the children have been born prematurely, while 58% of them have been born at normal term. 38% of the children had an APGAR score lower than 7 and 62% of them had an APGAR score higher than 7. Of the total number of births, 72% were caesarian births and 28% were natural births. The different types of Cardiac CA that have been encountered in the study were atrioventricular canal (56%), transposition of the great vessels (18%), common arterial trunk (10%), atrial septal defect (8%), ventricular septal defect (5%) and tetralogy of Fallot (3%). 66% of the total number of deaths were represented by those with cardiac pathology, 21% were caused by hydrocephalus, 7% were caused by diaphragmatic hernia, 4% had renal CA, while 2% were caused by other pathologies.

[Idiopathic mental retardation--importance of clinical diagnostic scores for case selection]. / Retardul mental idiopatic--importanta scorurilor de diagnostic clinic pentru selectia cazurilor.

We present a retrospective study aimed to identify the correlation between de Vries clinical score and the detection of chromosomal abnormalities in mentally retarded (MR) children. We have used the score to identify patients who should be tested by karyotyping and subsequently MLPA (multiplex ligation dependent probe amplification) for subtelomeric rearrangements. Our group is formed of 36 children with variable MR associated with other anomalies. 18 children had chromosomal defects, whereas 18 had normal karyotypes. In the first group, total scores varied between 3 and 7. Chromosomal anomalies identified were: numerical (4) and structural (14). Chromosomes involved were: 1, 4, 5, 7, 8, 9, 17, X. Deletions were the most common and correlate with a greater score (> or = 4). Common clinical features were: short stature, microcephaly, nasal, ear and hand anomalies. In the second group the most frequent clinical feature was hand anomaly (61.2%) and cases with a high score have to be further tested (e.g. using MLPA) in order to identify minor defects. In our opinion a high score indicates the karyotype and then a MLPA testing. In conclusion, we present a retrospective study that proves the use of de Vries diagnostic score in the identification of chromosomal abnormalities in MR children.

Nutrigenomics in postgenomic era.

The last years modified major our conceptions about nutrition. These revolutionary changes were produced by implementation of new techniques of functional genomics. The nutrigenomics and nutrigenomics provide powerful approaches to unravel the complex relationships between bioactive molecules, genetic polymorphisms and biological system and can give rise to personalized nutrition and dietary recommendations. In monogenic diseases (phenylketonuria, galactosemia, lactose intolerance etc.) diet influence phenotypic expression and nutrigenomics will improve the prevention or treatment by the early identification of specific mutations or haplotype combinations that modulate dietary response in affected subjects. In the multifactor diseases, like cardiovascular diseases (CVD), obesity, type II diabetes mellitus or cancer, the nutrigenomics approach has begun to reveal that some of them are susceptible to dietary intervention and may modulate the onset and progression of disorders.

[Clinical, epidemiological and cytogenetic studies on 221 patients with Down syndrome]. / Studii clinice, epidemiologice si citogenetice pe un lot de 221 pacienti cu sindrom Down.

UNLABELLED: Down syndrome, determined by 21 trisomy, represents a major cause of infantile morbidity and mortality. AIM: The analysis of dysmorphic features in Down syndrome, incidence of major congenital abnormalities, of some epidemiological parameters and cytogenetic specifics. MATERIAL AND METHOD: Methods used were clinical, epidemiological and cytogenetical. We analysed 221 patients, from Iasi county, with clinical supposition of Down syndrome, identified in the first year of life, between 1985 and 1999. RESULTS: The majority of patients (67%) have more than 5 from 10 characteristics dysmorphic signs of Down syndrome in neonatal period. Visceral congenital abnormalities--82 cases (37.1%) were isolate (cardiac or digestive) or multiple. The presence of one visceral abnormality determined the death of patient in 30 cases (46.15% of death). Medium incidence of Down syndrome in Iasi county was 1.306 per thousand (1/769 new-born), with median value 1.091per thousand and corrected value related to the maternal age 1.056 per thousand. Cytogenetic analysis was performed at 101 patients, in 95 cases (94.05%) clinical suspicion of Down syndrome was correct, patients presenting 21 trisomy (in the majority of cases a homogenous free trisomy). CONCLUSION: The data obtained by us are concordant with the majority of literature studies, that a test the correctness of clinical trial and validate our results.

[FISH technique in aneuplodies prenatal diagnosis]. / Importanta tehnicii FISH in diagnosticul prenatal al aneuploidiilor.

UNLABELLED: Chromosomal disorders are severe and affect 0.9% of the newborns. In these conditions, prenatal diagnosis should be compulsory in every public medical system. MATERIAL AND METHOD: Our study is a retrospective analysis of pregnant women investigated by amniocentesis and FISH technique. RESULTS: We analyzed 233 samples collected between 2004 and 2007 at Iasi "Cuza-Voda" Obstetrics and Gynecology Hospital. The majority of cases were investigated between 16 and 24 weeks of pregnancy. Thirty-eight abnormal cases (16.30%) were identified: 17 cases with 21 trisomy, 16 cases with 18 trisomy, 3 cases with X monosomy, and 2 cases with 13 trisomy. The main reasons for amniocentesis were: advanced maternal age (12.5% abnormal cases) ultrasound abnormalities (26.15% abnormal cases), and biochemical abnormalities (7.14% abnormal cases). CONCLUSION: Our data are in agreement with other studies, and support our results.

[Importance of genetic factors in the pathogenesis of gonadal and postgonadal human infertility]. / Importanta factorilor genetici în patogenia sterilitatii umane periferice (gonadica si postgonadica).

The infertility is a important health problem, affecting about 10-15% of couples. The important role of genetic factors in pathogenesis of infertility is now increasingly recognized and our knowledge in this field are improved each day. For these reasons we review the most important genetic causes of infertility. In this paper we analyse the genetic implications in gonadal and postgonadal infertility. Gonadal infertility affects both sexes and are characterised by hypergonadotrophic hypogonadism. Gonadal infertility is produced by chromosomal or monogenic mutations. Chromosomal causes are represented by gonosomal aneuploidy and structural chromosomal abnormalities. The monogenic disorders are consequences of a recessive mutations of hormone, hormonal receptor or enzymes genes. Postgonadal infertility is present in men and is the result of some obstructive disorders.

[ The importance of genetic factors in pathogenesis of central infertility (hypothalamic and pituitary]. / Importanta factorilor genetici în patogenia sterilitatii umane centrale (hipotalamica si hipofizara).

The infertility is a important health problem, affecting about 10-15% of couples. The important role of genetic factors in pathogenesis of infertility is now increasingly recognized and our knowledges in this field are improved each day. For these reasons we review the most important genetic causes of infertility. In this paper we analyse the genetic implications in central infertility (hypothalamic and pituitary). These conditions affect both sexes and are characterised by hypogonadotrophic hypogonadism. In majority of cases central infertility is produced by recessive mutations of hormone or hormonal receptor genes. In some cases the infertility is a component of a specific syndrome.