Identical monochorionic twins with down syndrome and paternal origin of the extra chromosome 21.

UNLABELLED: Trisomy 21, the cause of Down syndrome (DS), is the most frequent trisomy in humans. The risk for DS increases with maternal age: mothers under 25 years of age are known to have an average risk of a DS pregnancy of 1: 1600, rising to 1: 350 at age 35 and to 1: 40 at 43, respectively. Twins with DS are rare. We report on monozygotic (MZ), monochorionic twin sisters with DS, whose parents are young (24 and 26 years old, respectively) and healthy. Family history is non contributory; pregnancy and delivery were uneventful. Both girls presented at birth with clinical manifestations of Down syndrome, that was confirmed cytogenetically (47XX,+21). Microsatellites analysis indicated that the twins are identical and that the extra chromosome 21 was of paternal origin. CONCLUSIONS: For practical purposes, the causative non disjunction should be considered a single sporadic event, with an empirical recurrence risk estimated at about 1%.

Trend of healthcare-associated infections in children: annual prevalence surveys in a research hospital in Italy, 2007-2010.

BACKGROUND: Annual prevalence surveys of healthcare-associated infections (HAIs) between 2007 and 2010 were conducted in the largest tertiary care children's hospital in Italy. During this period, actions to improve HAI prevention were implemented, including strengthened isolation measures; adoption of care bundles for invasive procedures; hand hygiene promotion using the World Health Organization multimodal strategy; and promotion of appropriate antimicrobial use. AIM: To determine the impact of these measures on HAI rates. METHODS: A total of 1506 patients were surveyed. Information on patient demographics, mechanical ventilation, central line and urinary catheterization in the preceding 48 h, and surgery in the previous 30 days were abstracted from medical charts. The type and date of onset of HAIs, and microbiological data were recorded. Univariate and multivariate logistic analysis were used to evaluate changes in HAI rates over time, and the influence of ward type and patient characteristics. FINDINGS: There were significant (P < 0.001) reductions in the prevalence of patients developing HAI (from 7.6% to 4.3%) and in the prevalence of total HAIs (from 8.6 to 4.3 per 100 patients). Factors independently associated with increased HAI risk were hospitalization in intensive care ward, length of stay >30 days, presence of invasive device, and age 6-11 years. CONCLUSION: This HAI prevention strategy was influential in decreasing infections among hospitalized children. Repeated prevalence surveys are an effective tool for monitoring HAI frequency, increasing awareness among the healthcare personnel, and contributing to the establishment of effective infection control.

The Simpson-Golabi-Behmel syndrome: A clinical case and a detective story.

The Simpson-Golabi-Behmel syndrome (SGBS) is an overgrowth condition comprising "coarseness" of facial traits, supernumerary nipples, congenital heart defects, polydactyly and fingernail hypoplasia, and an increased risk of neonatal death and later neoplasia. Psychomotor development is usually normal. The syndrome is caused by mutation/deletion of the X-linked gene GPC3. We describe a new case of SGBS, that led to the discovery of an extended family segregating a GPC3 mutation and, ultimately, of an affected relative forgotten, but not lost, in an anatomical museum, where he was classified as a macrosomic newborn, who was born probably around 1940 and died neonatally of unknown cause. This baby boy becomes the oldest case of SGBS on record.

Cardio-facio-cutaneous syndrome: phenotypic variability and differential diagnosis in 3 cases with de novo BRAF mutations.

Cardio-facio-cutaneous (CFC) syndrome is a developmental disorder causing mental retardation and multiple congenital anomalies, including craniofacial, ectodermal, cardiac and musculoskeletal defects. Mutation of several genes in the RAS/MAPK (mitogen activated protein kinase) signaling pathway, most commonly BRAF, results in CFC syndrome. In this study, we report 3 new patients with CFC syndrome caused by mutation of BRAF. These patients differed in neurological impairment, craniofacial features and cardiac defects, while they shared relatively similar ectodermal and skeletal anomalies. They also displayed some overlapping features with Costello syndrome, another RAS/MAPK pathway disorder. Our findings highlight the clinical variability of CFC syndrome, with respect to severity and pattern of the affected organs, as well as the phenotypic overlap with the Costello syndrome.

A case of CMT 1B due to Val 102/fs null mutation of the MPZ gene presenting as hyperCKemia.

Charcot-Marie-Tooth disease (CMT) is a group of clinically and genetically heterogeneous neuropathies classically divided into demyelinating (CMT1) and axonal forms (CMT2). The most common demyelinating form is CMT1A, due to a duplication in the gene encoding the peripheral myelin protein 22 (PMP22). Less frequently, mutations in the myelin protein zero gene (MPZ/P0) account for demyelinating CMT1B. Herein, we report a patient presenting with an isolated hyperCKemia in whom electrophysiological and pathological findings revealed a demyelinating and axonal neuropathy. Sequencing of the MPZ gene revealed a 306delA at codon 102 in the proband and in two relatives. This mutation has been already described in association with paucisymptomatic CMT without hyperCKemia.

Unexpected finding of a paternal premutation of the fragile X FMR1 gene in a female fetus of a premutation carrier mother.

We report on the fortuitous finding of a paternal premutation of the FMR1 gene during prenatal diagnosis in a female fetus whose mother was known to be a premutation carrier. Analysis of the DNA, extracted from cultured cells obtained by chorionic villus sampling, demonstrated the presence in the fetus of two FMR1 alleles of 23 and 71 CGG repeats, respectively. Chromosome analysis confirmed a normal female karyotype. The mother was known to be carrier of a normal allele of 23 repeats and a premutation of 79 repeats. Because the 23-CGG repeat allele is uncommon, we wanted to confirm its presence in the father, also given that a reduction in size from 79 to 71 repeats of the putative maternal allele is an unlikely event. Analysis of the father's DNA did in fact show that he is a carrier of a 69-CGG premutated allele. Therefore, the fetus inherited the normal 23-CGG allele from the mother and the 71-CGG allele from the father. Although a parental couple composed of two premutation carriers is rare, this case illustrates the importance of characterizing both parental genotypes when the results of prenatal diagnosis suggest an unusual segregation of the mutant and/or normal allele.

Pregabalin versus naltrexone in alcohol dependence: a randomised, double-blind, comparison trial.

Pregabalin (PRE) acts as a presynaptic inhibitor of the release of excessive levels of excitatory neurotransmitters by selectively binding to the alpha(2)-delta subunit of voltage-gated calcium channels. In this randomised, double-blind comparison trial with naltrexone (NAL), we aimed to investigate the efficacy of PRE on alcohol drinking indices. Craving reduction and improvement of psychiatric symptoms were the secondary endpoints. Seventy-one alcohol-dependent subjects were detoxified and subsequently randomised into two groups, receiving 50 mg of NAL or 150-450 mg of PRE. Craving (VAS; OCDS), withdrawal (CIWA-Ar) and psychiatric symptoms (SCL-90-R) rating scales were applied. Alcohol drinking indices and craving scores were not significantly different between groups. Compared with NAL, PRE resulted in greater improvement of specific symptoms in the areas of anxiety, hostility and psychoticism, and survival function (duration of abstinence from alcohol). PRE also resulted in better outcome in patients reporting a comorbid psychiatric disorder. Results from this study globally place PRE within the same range of efficacy as that of NAL. The mechanism involved in the efficacy of PRE in relapse prevention could be less related to alcohol craving and more associated with the treatment of the comorbid psychiatric symptomatology.

Fatty aspirin: a new perspective in the prevention of dementia of Alzheimer's type?

Alzheimer's disease (AD) leads to a dramatic decline in cognitive abilities and memory. A more modest disruption of memory often occurs in normal aging and the same circuits that are devastated through degeneration in AD are vulnerable to sub-lethal age-related changes that alter synaptic transmission. There are numerous indications that aberrant plasticity is critically involved in Alzheimer's. Is ageing itself the major risk factor for AD? Is AD an acceleration of normal ageing? We assume that the ability of the brain is to modify its own structural organization and functioning which is liable to become impaired in ageing until it becomes dramatically impaired in Alzheimer's. Moreover, ageing can compromise the conversion of dietary alpha-linolenic acid (ALA) to docosahexaenoic acid (DHA). DHA regulates synaptogenesis and affects the synaptic structure, and synapse density is reduced in ageing. DHA and newly identified DHA-derived messenger, neuroprotecting D1 (NPD1), protect synapses and decrease the number of activated microglia in the hippocampal system. Delaying AD onset by a few years would reduce the number of the cases of dementia in the community. DHA (and NPD1?) and aspirin induce brain-derived neurotrophic factor (BDNF) protein expression and this protein has a crucial role in neuronal survival. The authors--in view of the increased neuroinflammatory reaction frequently observed during normal brain ageing--suggest the long-term use of "fatty aspirin", an association of DHA and/or NPD1 and aspirin (or nitroaspirin), to postpone, or prevent, the structural neurodegeneration of the brain.

Psychiatric manifestations as a primary symptom in antiphospholipid syndrome.

Antiphospholipid syndrome is a disorder characterised by recurrent venous or arterial thrombosis and/or foetal losses associated with typical laboratory abnormalities. The initial manifestation of anthiphospholipid syndrome can involve many organ systems either singly or in combination. We describe the case of a 62 yr old female showing schizophrenia-like symptoms in which further evaluations allowed us to diagnose the antiphospolipid syndrome.

A truncating mutation in the IL1RAPL1 gene is responsible for X-linked mental retardation in the MRX21 family.

X-linked mental retardation (XLMR) is a genetically heterogeneous condition, due to mutations in at least 50 genes, involved in functioning of the central nervous system and located on the X chromosome. Nonspecific XLMR (MRX) is characterized essentially by mental retardation transmitted by X-linked inheritance. More than 80 extended MRX pedigrees have been reported to date, which have been distinguished exclusively by physical position of the corresponding gene on the X chromosome, established by linkage analysis. One such family, MRX21, which was described by us in 1993 and localized to Xp11.4-pter, has now been reanalyzed with additional markers and after one more affected individual had became available. This extra information allowed a significant reduction of the linkage interval and, eventually, identification of the mutant gene. A stop mutation in exon 10 of the IL1RAPL1 gene (in Xp21) was found in the four affected males and in obligate carriers, allowing conclusive counseling of other family members of uncertain carrier status. The W487X mutation results in the production of a truncated IL1RAPL protein, comprised of the extracellular Ig-like domain and transmembrane tract, but lacking the last 210 aminoacids of the cytoplasmic domain. MRX21 is the first extended MRX family with a point mutation in IL1RAPL1 and the second with a stop mutation, which had been previously found only in a small family. Our report confirms the role of the IL1RAPL1 gene in causing nonspecific mental retardation in males and underlines the importance of detailed linkage analysis before candidate gene mutational screening.

Assisted reproductive technology and congenital overgrowth: some speculations on a case of Pallister-Killian syndrome.

We report on a boy with Pallister-Killian syndrome (PKS) who was conceived by assisted reproductive technology (ART), specifically in vitro fertilization (IVF) with parents' gametes. A prenatal diagnosis performed elsewhere by CVS failed to detect the presence of the isochromosome 12p that was demonstrated postnatally in approximately 50% of cultured skin fibroblasts. Given that the patient did not show the congenital overgrowth typical of PKS, we speculate that ART might have restricted overgrowth in this particular case. More broadly, we hypothesize that overgrowth might protect from early demise fetuses conceived by ART, a technology known to cause low and very low birth weight.

Nonhomologous Robertsonian translocations (NHRTs) and uniparental disomy (UPD) risk: an Italian multicentric prenatal survey.

OBJECTIVES: The risk of uniparental disomy (UPD) occurrence associated with the prenatal finding of balanced nonhomologous Robertsonian translocations (NHRTs) has been estimated only on limited empirical data. The aim of the study was to verify the estimate of the general risk, to get narrower confidence intervals by cumulating the data and to obtain risk estimates for specific translocation types. METHODS: We tested for UPD 160 prenatal specimens referred to the participant centers after the cytogenetic finding of NHRT. RESULTS: One case of upd(14)mat was found, associated with a 45,XX,der(14;22)mat fetal karyotype. The general empirical risk of UPD occurrence in NHRT carrier fetuses, corrected for the actual number of chromosomes analyzed, was 0.76% (95% CI 0.02-4.25%). Cumulative data with previous studies gives a general risk of UPD associated with NHRT of 0.80% (95% CI 0.17-2.34%). The UPD risk for the specific NHRT der(13;14) did not significantly differ from that of the other NHRTs taken together. CONCLUSION: The present survey confirms the previously estimated risk of occurrence of UPD in offspring of NHRT carriers as a low, but not negligible risk, worth being investigated in prenatal diagnosis.

Concurrent lymph node metastases of medullary and papillary thyroid carcinoma in a case with RET oncogene germline mutation.

We report the case of a 72 yr-old woman who underwent total thyroidectomy and resection of neck lymph nodes because of a firm nodule in the right lobe, which was consistent with medullary thyroid carcinoma (MTC) on cytological examination. Histology showed multifocal bilateral MTC; a 2 mm papillary thyroid carcinoma (PTC) was also detected in the right lobe, next to a focus of MTC; five cervical lymph nodes contained MTC. In one right perithyroidal lymph node, concurrent metastases of MTC and PTC were demonstrated. DNA analysis showed a point mutation in exon 14 at codon 804 of the RET proto-oncogene locus, as frequently found in cases of familial MTC (FMTC). To our knowledge, this case represents the first documented case of concurrent lymph node metastases of MTC and PTC in a patient with RET proto-oncogene germline mutation. We report this unique case, discuss related thyroid malignancies, and suggest possible underlying pathogenetic mechanisms.

PTPN11 mutations are not responsible for the Cardiofaciocutaneous (CFC) syndrome.

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomalies/mental retardation syndrome characterized by congenital heart defects, characteristic facial appearance, short stature, ectodermal abnormalities and mental retardation. It was described in 1986, and to date is of unknown genetic etiology. All reported cases are sporadic, born to non-consanguineous parents and have apparently normal chromosomes. Noonan and Costello syndromes remain its main differential diagnosis. The recent finding of PTPN11 missense mutations in 45-50% of the Noonan patients studied with penetrance of almost 100% and the fact that in animals mutations of this gene cause defects of semilunar valvulogenesis, made PTPN11 mutation screening in CFC patients a matter of interest. We sequenced the entire coding region of the PTPN11 gene in ten well-characterised CFC patients and found no base changes. We also studied PTPN11 cDNA in our patients and demonstrated that there are no interstitial deletions either. The genetic cause of CFC syndrome remains unknown, and PTPN11 can be reasonably excluded as a candidate gene for the CFC syndrome, which we regard as molecular evidence that CFC and Noonan syndromes are distinct genetic entities.

[L-acetylcarnitine treatment on fragile X patients hyperactive behaviour]. / El tratamiento con L-acetilcarnitina del comportamiento hiperactivo de pacientes con el síndrome X frágil.

Hyperactivity is a significant problem for almost all young males affected by fragile X syndrome (FXS), the most common inherited disease causing mental retardation. Therapeutical approaches are actually based on Central Nervous System (CNS) stimulants lacking a well defined rationale and efficacy while they further decrease the patient's limited attention span. A pilot study on 17 fragile X male treated with L-acetylcarnitine (LAC) over one year, showed a significant reduction of their hyperactivity behaviour tested by the Conners Abbreviated Parent-Teacher Questionnaire. LAC use in FXS patients derives from the hypothesis that the biochemical and physiological properties this substance has may preserve brain activity. LAC is a small, hydrosoluble molecule that easily diffuses in the extracellular space and enters any cell in the nervous system through specific transporters. Different cerebral areas use this molecule differently to metabolize glucose and lipids to provide for ATP and neurotrasmitters synthesis. The acetyl group LAC carriers represents a key metabolic signaling element possibly mediating its effect in the CNS. The exogenous administration of LAC may affect brain activity in FXS by: I) modulation of fuel partitioning for energy production, which at the mithocondrial level is associated with the Kreb's cycle metabolic role in neurotransmitter synthesis; II) remodelling of lipid membrane in terms of LAC actively determining the production of polyunsaturated fatty acids; III) preferential effect on the attention component of the cholinergic system which relies on its peculiar modality of communication in the CNS. Based on the above premises an explorative, double-blind, placebo controlled, multicenter study is ongoing. A total population of 160 children from nine European centers will be enrolled. The objective of this study is to determine the effect of LAC on the hyperactive behaviour of FXS children as evaluated by the administration of the Conners Abbreviated Parent Questionnaire.

2,3-DPG-Hb complex: a hypothesis for an asymmetric binding.

This study was undertaken to test the symmetry of 2,3-diphosphoglycerate (2,3-DPG) binding site in hemoglobin (Hb). From Arnone's study [A. Arnone, Nature (London) 237 (1972) 146] the 2,3-DPG binding site is located at the top of the cavity, that runs through the center of the deoxy-Hb molecule. However, it is possible that this symmetry reported by Arnone, for crystals of 2,3-DPG-Hb complex, might not be conserved in solution. In this paper, we report the 31P nuclear magnetic resonances of the 2,3-DPG interaction with Hb. The 2,3-DPG chemical shifts of the P2 and P3 resonance are both pH- and hemoglobin-dependent [protein from man, polar bear (Ursus maritimus), Arctic fox (Alopex lagopus) and bovine]. 2,3-DPG binds tightly to deoxyhemoglobin and weakly, nevertheless significantly, to oxyhemoglobin. In particular, our results suggest similar spatial position of the binding site of 2,3-DPG in both forms of Hb in solutions. However, the most unexpected result was the apparent loss of symmetry in the binding site, which might correlate with the ability of the hemoglobin to modulate its functional behavior. The different interactions of the phosphate groups indicate small differences in the quaternary structure of the different deoxy forms of hemoglobin. Given the above structural perturbation an asymmetric binding in the complex could justify, at least in part, different physiological properties of Hb. Regardless, functionally relevant effects of 2,3-DPG seem to be measured and best elucidated through solution studies.

Inhibition of AChE: structure-activity relationship among conformational transition of Trp84 and biomolecular rate constant.

In this study the authors attempt to correlate kinetic constants for carbamylation of AChE, by a series of carbamate inhibitors, with the conformational positioning of Trp84 in transition state complexes of the same carbamates with Torpedo AChE, as obtained by computerized molecular modelling. They present evidence for changes in the distance of the carbamates from the center of the indole ring which can be correlated with the bimolecular rate constants for inhibition. As a result the greater the distance from Trp84, the smaller the bimolecular inhibition constant value, ki (= k2/Ka), becomes. In conclusion, the value of the bimolecular rate constant for selected AChE inhibitors (structural changes that have been hypothesised or natural alkaloids of unknown activity) which possess similar size and rigidity, can be obtained. Under these conditions energy minimization alone seems to be sufficient even to accurately predict protein-substrate interactions that actually occur. Modelling studies also suggest that conformational re-orientation of Trp84 in the transition state could produce an overall movement of the Cys67-Cys94 loop.

Synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of the FMR1 gene.

Most fragile X syndrome patients have expansion of a (CGG)(n)sequence with >200 repeats (full mutation) in the FMR1 gene responsible for this condition. Hypermethylation of the expanded repeat and of the FMR1 promoter is almost always present and apparently suppresses transcription, resulting in absence of the FMR1 protein. We recently showed that transcriptional reactivation of FMR1 full mutations can be achieved by inducing DNA demethylation with 5-azadeoxycytidine (5-azadC). The level of histone acetylation is another important factor in regulating gene expression; therefore, we treated lymphoblastoid cell lines of non-mosaic full mutation patients with three drugs capable of inducing histone hyperacetylation. We observed a consistent, although modest, reactivation of the FMR1 gene with 4-phenylbutyrate, sodium butyrate and trichostatin A, as shown by RT-PCR. However, we report that combining these drugs with 5-azadC results in a 2- to 5-fold increase in FMR1 mRNA levels obtained with 5-azadC alone, thus showing a marked synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of FMR1 full mutations.