Publications by authors named "Guido Cocchi"

55 Publications

Eating and Lifestyle Habits in Youth With Down Syndrome Attending a Care Program: An Exploratory Lesson for Future Improvements.

Front Nutr 2021 8;8:641112. Epub 2021 Sep 8.

Pediatrics, University of Bologna, Bologna, Italy.

Children with Down Syndrome (DS) have nutritional problems with unknown implications besides increased potential for obesity. Their food habits are unknown. We aim to delineate eating and lifestyle habits of DS children attending a multispecialist program to identify the challenges they face and the potential improvements. We interacted with 34 DS children (22 males, 12 females, 2-16 years old) and their families. Food habits, medical conditions and treatments, degrees of development and physical activity, anthropometric and laboratory data were recorded over 6 months and analyzed. A 3-day food diary and a 24-h recall food frequency questionnaire were administered. Twenty-nine (85%) children completed meals, only 11 (32%) received alternative food such as milk. Weaning regularly started in 25 (73%) children. Preschool children introduced adequate calories and nutrients. School children and adolescents did not reach recommendations. All age groups, as the general pediatric population, excessively ate protein and saturated fat, and preferred bread, pasta, fruit juices, meat and cold cuts. Peculiarly, pulses and fish were adequately assumed by preschool and school children, respectively. Five children (15%) were overweight/obese. Dietary excesses commonly found in the general pediatric population are also present in this DS group, proving a narrowing gap between the two. DS group performed better nutritionally in the early years and overweight/obesity occurrence seems contained. DS children may benefit from a practical yet professional care-program in which nutrition education may improve their growth, development and transition into adulthood.
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http://dx.doi.org/10.3389/fnut.2021.641112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455913PMC
September 2021

Is the Age of Developmental Milestones a Predictor for Future Development in Down Syndrome?

Brain Sci 2021 May 18;11(5). Epub 2021 May 18.

Department of Developmental Psychology and Socialization, University of Padova, via Venezia 8, 35131 Padova, Italy.

Down Syndrome (DS) is the most common genetic alteration responsible for intellectual disability, which refers to deficits in both intellectual and adaptive functioning. According to this, individuals with Down Syndrome (DS) reach developmental milestones (e.g., sitting, walking, and babbling) in the same order as their typically developing peers, but later in life. Since developmental milestones are the first blocks on which development builds, the aims of the current study are to: (i) expand the knowledge of developmental milestone acquisition; and (ii) explore the relationship between developmental milestone acquisition and later development. For this purpose 105 children/adolescents with DS were involved in this study, divided in two groups, Preschoolers ( = 39) and School-age participants ( = 66). Information on the age of acquisition of and was collected, together with cognitive, motor, and adaptive functioning. predicted later motor development, but, with age, it became less important in predicting motor development in everyday life. predicted later language development in older children. Finally, emerged as the strongest predictor of motor, cognitive, language, and adaptive skills, with its role being more evident with increasing age. Our data suggest that the age of reaching the milestones considered in the study has an influence on successive development, a role that can be due to common neural substrates, the environment, and the developmental cascade effect.
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http://dx.doi.org/10.3390/brainsci11050655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157296PMC
May 2021

The transcriptome profile of human trisomy 21 blood cells.

Hum Genomics 2021 05 1;15(1):25. Epub 2021 May 1.

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, BO, Italy.

Background: Trisomy 21 (T21) is a genetic alteration characterised by the presence of an extra full or partial human chromosome 21 (Hsa21) leading to Down syndrome (DS), the most common form of intellectual disability (ID). It is broadly agreed that the presence of extra genetic material in T21 gives origin to an altered expression of genes located on Hsa21 leading to DS phenotype. The aim of this study was to analyse T21 and normal control blood cell gene expression profiles obtained by total RNA sequencing (RNA-Seq).

Results: The results were elaborated by the TRAM (Transcriptome Mapper) software which generated a differential transcriptome map between human T21 and normal control blood cells providing the gene expression ratios for 17,867 loci. The obtained gene expression profiles were validated through real-time reverse transcription polymerase chain reaction (RT-PCR) assay and compared with previously published data. A post-analysis through transcriptome mapping allowed the identification of the segmental (regional) variation of the expression level across the whole genome (segment-based analysis of expression). Interestingly, the most over-expressed genes encode for interferon-induced proteins, two of them (MX1 and MX2 genes) mapping on Hsa21 (21q22.3). The altered expression of genes involved in mitochondrial translation and energy production also emerged, followed by the altered expression of genes encoding for the folate cycle enzyme, GART, and the folate transporter, SLC19A1.

Conclusions: The alteration of these pathways might be linked and involved in the manifestation of ID in DS.
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http://dx.doi.org/10.1186/s40246-021-00325-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088681PMC
May 2021

One-carbon pathway and cognitive skills in children with Down syndrome.

Sci Rep 2021 Feb 19;11(1):4225. Epub 2021 Feb 19.

Department of Experimental, Diagnostic and Specialty Medicine, (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, BO, Italy.

This work investigates the role of metabolite levels in the intellectual impairment of subjects with Down syndrome (DS). Homocysteine, folate, vitamin B12, uric acid (UA), creatinine levels and MTHFR C677T genotype were analyzed in 147 subjects with DS. For 77 subjects, metabolite levels were correlated with cognitive tests. Griffiths-III test was administered to 28 subjects (3.08-6.16 years) and WPPSI-III test was administered to 49 subjects (7.08-16.08 years). Significant correlations were found among some metabolite levels and between homocysteine levels and MTHFR C677T genotype. Moreover, homocysteine, UA and creatinine levels resulted increased with age. We did not find any correlation between metabolites and cognitive test score in the younger group. Homocysteine showed statistically significant correlation with WPPSI-III subtest scores when its level is ≥ 7.35 µmol/L, remaining correlated in higher thresholds only for non-verbal area scores. Vitamin B12 showed correlations with all WPPSI-III subtest scores when its level is < 442 pg/mL. The relevance of the present findings is the detection of a specific metabolite threshold related with a better or worse cognitive score, suggesting that vitamin B12 and homocysteine may have a role in cognitive development in children with DS.
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http://dx.doi.org/10.1038/s41598-021-83379-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895965PMC
February 2021

Plasma metabolome and cognitive skills in Down syndrome.

Sci Rep 2020 06 26;10(1):10491. Epub 2020 Jun 26.

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, BO, Italy.

Trisomy 21 (Down syndrome, DS) is the main human genetic cause of intellectual disability (ID). Lejeune hypothesized that DS could be considered a metabolic disease, and we found that subjects with DS have a specific plasma and urinary metabolomic profile. In this work we confirmed the alteration of mitochondrial metabolism in DS and also investigated if metabolite levels are related to cognitive aspects of DS. We analyzed the metabolomic profiles of plasma samples from 129 subjects with DS and 46 healthy control (CTRL) subjects by H Nuclear Magnetic Resonance (NMR). Multivariate analysis of the NMR metabolomic profiles showed a clear discrimination (up to 94% accuracy) between the two groups. The univariate analysis revealed a significant alteration in 7 metabolites out of 28 assigned unambiguously. Correlations among the metabolite levels in DS and CTRL groups were separately investigated and statistically significant relationships appeared. On the contrary, statistically significant correlations among the NMR-detectable part of DS plasma metabolome and the different intelligence quotient ranges obtained by Griffiths-III or WPPSI-III tests were not found. Even if metabolic imbalance provides a clear discrimination between DS and CTRL groups, it appears that the investigated metabolomic profiles cannot be associated with the degree of ID.
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http://dx.doi.org/10.1038/s41598-020-67195-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319960PMC
June 2020

Disseminate Recurrent Folliculitis and Hidradenitis Suppurativa Are Associated Conditions: Results From a Retrospective Study of 131 Patients With Down Syndrome and a Cohort of 12,351 Pediatric Controls.

Dermatol Pract Concept 2019 Jul 31;9(3):187-194. Epub 2019 Jul 31.

Division of Dermatology, Sant'Orsola-Malpighi Polyclinic, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy.

Background: Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent skin disease of the pilosebaceous unit characterized by protean manifestations. Several studies have found an increased incidence and earlier presentation of this disease in patients carrying trisomy 21. Patients with Down syndrome (DS) have a higher risk of developing a wide range of cutaneous manifestations, including HS and chronic folliculitis. Recently, disseminate recurrent folliculitis (DRF) has been reported as an atypical monosymptomatic feature of HS at its onset.

Objective: To assess the prevalence of HS and DRF by comparing a cohort of patients carrying trisomy 21 vs pediatric controls.

Methods: A retrospective 2-year monocentric clinical study was performed by collecting clinical data of 131 patients with DS, aged 4-36 years, followed at the Dermatology Unit and Down Syndrome Regional Center of Bologna University. Data were matched with those coming from 12,351 pediatric controls.

Results: In DS patients, DRF and HS showed a prevalence of, respectively, 6.8% and 24.4%, while 5.3% of patients presented both diseases. In the control group the prevalence for HS+ and DRF+ was 0.5% and 1.2%, respectively, with a 0.14% of overlap cases. The association between HS and DRF proved to be statistically significant in both groups (P < 0.05). In the DS cohort the mean age of symptoms onset was 15.67 (SD: 2.29) years for HS and 13.11 (SD: 4.93) years for DRF. Buttocks were the most frequently affected body area for DRF followed by the inguinocrural area, while in HS buttocks were less frequently involved than groins and upper thighs.

Conclusions: Because of the later onset of HS, patients with DRF at an early age should be monitored for the possible onset of HS in the apocrine-bearing areas.
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http://dx.doi.org/10.5826/dpc.0903a03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659610PMC
July 2019

Prenatal diagnosis and prevalence of critical congenital heart defects: an international retrospective cohort study.

BMJ Open 2019 07 2;9(7):e028139. Epub 2019 Jul 2.

Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.

Objectives: To assess international trends and patterns of prenatal diagnosis of critical congenital heart defects (CCHDs) and their relation to total and live birth CCHD prevalence and mortality.

Setting: Fifteen birth defect surveillance programmes that participate in the International Clearinghouse for Birth Defects Surveillance and Research from 12 countries in Europe, North and South America and Asia.

Participants: Live births, stillbirths and elective terminations of pregnancy for fetal anomaly diagnosed with 1 of 12 selected CCHD, ascertained by the 15 programmes for delivery years 2000 to 2014.

Results: 18 243 CCHD cases were reported among 8 847 081 births. The median total prevalence was 19.1 per 10 000 births but varied threefold between programmes from 10.1 to 31.0 per 10 000. CCHD were prenatally detected for at least 50% of the cases in one-third of the programmes. However, prenatal detection varied from 13% in Slovak Republic to 87% in some areas in France. Prenatal detection was consistently high for hypoplastic left heart syndrome (64% overall) and was lowest for total anomalous pulmonary venous return (28% overall). Surveillance programmes in countries that do not legally permit terminations of pregnancy tended to have higher live birth prevalence of CCHD. Most programmes showed an increasing trend in prenatally diagnosed CCHD cases.

Discussion And Conclusions: Prenatal detection already accounts for 50% or more of CCHD detected in many programmes and is increasing. Local policies and access likely account for the wide variability of reported occurrence and prenatal diagnosis. Detection rates are high especially for CCHD that are more easily diagnosed on a standard obstetric four-chamber ultrasound or for fetuses that have extracardiac anomalies. These ongoing trends in prenatal diagnosis, potentially in combination with newborn pulse oximetry, are likely to modify the epidemiology and clinical outcomes of CCHD in the near future.
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http://dx.doi.org/10.1136/bmjopen-2018-028139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609145PMC
July 2019

Partial trisomy 21 map: Ten cases further supporting the highly restricted Down syndrome critical region (HR-DSCR) on human chromosome 21.

Mol Genet Genomic Med 2019 08 25;7(8):e797. Epub 2019 Jun 25.

Neonatology Unit, Department of Medical and Surgical Sciences (DIMEC), St. Orsola-Malpighi Polyclinic, University of Bologna, Bologna (BO), Italy.

Background: Down syndrome (DS) is characterized by the presence of an extra full or partial human chromosome 21 (Hsa21). An invaluable model to define genotype-phenotype correlations in DS is the study of the extremely rare cases of partial (segmental) trisomy 21 (PT21), the duplication of only a delimited region of Hsa21 associated or not to DS. A systematic retrospective reanalysis of 125 PT21 cases described up to 2015 allowed the creation of the most comprehensive PT21 map and the identification of a 34-kb highly restricted DS critical region (HR-DSCR) as the minimal region whose duplication is shared by all PT21 subjects diagnosed with DS. We reanalyzed at higher resolution three cases previously published and we accurately searched for any new PT21 reports in order to verify whether HR-DSCR limits could prospectively be confirmed and possibly refined.

Methods: Hsa21 partial duplications of three PT21 subjects were refined by adding array-based comparative genomic hybridization data. Seven newly described PT21 cases fulfilling stringent cytogenetic and clinical criteria have been incorporated into the PT21 integrated map.

Results: The PT21 map now integrates fine structure of Hsa21 sequence intervals of 132 subjects onto a common framework fully consistent with the presence of a duplicated HR-DSCR, on distal 21q22.13 sub-band, only in DS subjects and not in non-DS individuals. No documented exception to the HR-DSCR model was found.

Conclusions: The findings presented here further support the association of the HR-DSCR with the diagnosis of DS, representing an unbiased validation of the original model. Further studies are needed to identify and characterize genetic determinants presumably located in the HR-DSCR and functionally associated to the critical manifestations of DS.
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http://dx.doi.org/10.1002/mgg3.797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687668PMC
August 2019

Myoclonic epilepsy with photosensitivity in infants with Pallister-Killian Syndrome.

Eur J Paediatr Neurol 2019 Jul 25;23(4):653-656. Epub 2019 May 25.

Child Neurology and Psychiatry Unit, Department of Medical and Surgical Sciences (DIMEC), S. Orsola Hospital, University of Bologna, Bologna, Italy. Electronic address:

Introduction: Pallister-Killian Syndrome (PKS) (OMIM #601803) is a rare genetic disorder caused by a mosaic tetrasomy of the short arm of chromosome 12. Epilepsy is a frequent concern in PKS patients.

Methods: we report 3 PKS patients, with early-onset myoclonic epilepsy and photosensitivity. In these children, we analysed epileptic history and the EEG phenotype.

Results: Epilepsy onset was in the first 2 years of life in all patients and in 2 of them myoclonic seizures were the only seizure type. In all children photosensitivity was observed and myoclonic seizures were mainly related to low-frequency (1-6 Hz) intermittent photic stimulation. Levetiracetam was effective and well tolerated in the 2 treated patients.

Conclusions: early-onset myoclonic epilepsy is a possible clinical manifestation of PKS. Low-frequency photosensitivity is a peculiar bioelectrical marker in these children.
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http://dx.doi.org/10.1016/j.ejpn.2019.05.012DOI Listing
July 2019

[Corrigendum] Analysis of a nanoparticle‑enriched fraction of plasma reveals miRNA candidates for Down syndrome pathogenesis.

Int J Mol Med 2019 08 30;44(2):768. Epub 2019 May 30.

Department of Molecular and Translational Medicine, University of Brescia, I‑25123 Brescia, Italy.

After the publication of the above paper, the authors noted that the names of a couple of the authors listed on the paper were associated with the wrong affliation: Specifically, the eighth and ninth listed authors, Francesca Antonaros and Allison Piovesan, are located at DIMES at the University of Florence (fourth affiliation address), not at CSGI, the Research Center for Colloids and Nanoscience in Florence (third affliation address). Therefore, the author and affiliation details for this paper should have been presented as follows: ALESSANDRO SALVI1, MARIKA VEZZOLI2, SARA BUSATTO1, LUCIA PAOLINI1,3, TERESA FARANDA1, EDOARDO ABENI1, MARIA CARACAUSI4, FRANCESCA ANTONAROS4, ALLISON PIOVESAN4, CHIARA LOCATELLI5, GUIDO COCCHI5,6, GUALTIERO ALVISI7, GIUSEPPINA DE PETRO1, DORIS RICOTTA1, PAOLO BERGESE1,3 and ANNALISA RADEGHIERI1,3. 1Department of Molecular and Translational Medicine, University of Brescia; 2Unit of Biostatistics, Department of Molecular and Translational Medicine, University of Brescia, I‑25123 Brescia; 3CSGI, Research Center for Colloids and Nanoscience, Sesto Fiorentino, I‑50019 Florence; 4Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna; 5Neonatology Unit, St. Orsola‑Malpighi Polyclinic; 6Department of Medical and Surgical Sciences (DIMEC), University of Bologna, I‑40138 Bologna; 7Department of Molecular Medicine, University of Padua, I‑35121 Padua, Italy. The authors regret that this error with the author affiliations for Francesca Antonaros and Allison Piovesan was not noticed prior to the publication of their paper, and apologize for any inconvenience caused. [the original article was published in International Journal of Molecular Medicine 43: 2303‑2318, 2018; DOI: 10.3892/ijmm.2019.4158].
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http://dx.doi.org/10.3892/ijmm.2019.4222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605711PMC
August 2019

Analysis of a nanoparticle‑enriched fraction of plasma reveals miRNA candidates for Down syndrome pathogenesis.

Int J Mol Med 2019 Jun 9;43(6):2303-2318. Epub 2019 Apr 9.

Department of Molecular and Translational Medicine, University of Brescia, I‑25123 Brescia, Italy.

Down syndrome (DS) is caused by the presence of part or all of a third copy of chromosome 21. DS is associated with several phenotypes, including intellectual disability, congenital heart disease, childhood leukemia and immune defects. Specific microRNAs (miRNAs/miR) have been described to be associated with DS, although none of them so far have been unequivocally linked to the pathology. The present study focuses to the best of our knowledge for the first time on the miRNAs contained in nanosized RNA carriers circulating in the blood. Fractions enriched in nanosized RNA‑carriers were separated from the plasma of young participants with DS and their non‑trisomic siblings and miRNAs were extracted. A microarray‑based analysis on a small cohort of samples led to the identification of the three most abundant miRNAs, namely miR‑16‑5p, miR‑99b‑5p and miR‑144‑3p. These miRNAs were then profiled for 15 pairs of DS and non‑trisomic sibling couples by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). Results identified a clear differential expression trend of these miRNAs in DS with respect to their non‑trisomic siblings and gene ontology analysis pointed to their potential role in a number of typical DS features, including 'nervous system development', 'neuronal cell body' and certain forms of 'leukemia'. Finally, these expression levels were associated with certain typical quantitative and qualitative clinical features of DS. These results contribute to the efforts in defining the DS‑associated pathogenic mechanisms and emphasize the importance of properly stratifying the miRNA fluid vehicles in order to probe biomolecules that are otherwise hidden and/or not accessible to (standard) analysis.
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http://dx.doi.org/10.3892/ijmm.2019.4158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488180PMC
June 2019

MTHFR C677T polymorphism analysis: A simple, effective restriction enzyme-based method improving previous protocols.

Mol Genet Genomic Med 2019 05 13;7(5):e628. Epub 2019 Mar 13.

Unit of Histology, Embryology and Applied Biology, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.

Background: 5,10-Methylentetrahydrofolate reductase (MTHFR) C677T polymorphism is one of the most studied genetic variations in the human genome. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) is one of the most used techniques to characterize the point mutations in genomic sequences because of its suitability and low cost. The most widely used method for the MTHFR C677T polymorphism characterization was developed by Frosst et al. (1995) but appears to have some technical limitations. The aim of this study was to propose a novel PCR-RFLP method for the detection of this polymorphism.

Methods: In order to retrieve all published articles possibly describing any PCR-RFLP methods useful to analyze MTHFR C677T polymorphism, we performed systematic queries on PubMed, using a combination of Boolean operators (AND/OR) and MeSH terms. Amplify software was used in order to design a new primer pair following the optimal standard criteria. Primer-BLAST software was used to check primer pair's biological specificity.

Results: The analysis of previous literature showed that PCR-RFLP method remains the most used technique. None of the 108 primer pairs described was ideal with regard to main accepted primer pair biochemical technical parameters. The new primer pair amplifies a DNA-fragment of 513 base pair (bp) that, in the presence of the polymorphism, is cut by Hinf I enzyme in two pieces of 146 bp and 367 bp and clearly visible on 2% agarose gel. The level of expertise and the materials required are minimal and the protocol takes one day to carry out.

Conclusion: Our original PCR-RFLP strategy, specifically designed to make the analysis optimal with respect to PCR primers and gel analysis, fits the ideal criteria compared to the widely used strategy by Frosst et al (1995) as well as any other PCR-RFLP strategies proposed for MTHFR C677T polymorphism genotyping to date.
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http://dx.doi.org/10.1002/mgg3.628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503068PMC
May 2019

Human trisomy 21 fibroblasts rescue methotrexate toxic effect after treatment with 5-methyl-tetrahydrofolate and 5-formyl-tetrahydrofolate.

J Cell Physiol 2019 Jan 22. Epub 2019 Jan 22.

Unit of Histology, Embryology and Applied Biology, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.

Trisomy 21 causes Down syndrome (DS), the most common human genetic disorder and the leading genetic cause of intellectual disability. The alteration of one-carbon metabolism was described as the possible metabolic cause of the intellectual disability development in subjects with DS. One of the biochemical pathways involved in the one-carbon group transfer is the folate cycle. The cytotoxic drug methotrexate (MTX) is a folic acid (FA) analogue which inhibits the activity of dihydrofolate reductase enzyme involved in the one-carbon metabolic cycle. Trisomy 21 cells are more sensitive to the MTX effect than euploid cells, and in 1986 Jérôme Lejeune and Coll. demonstrated that MTX was twice as toxic in trisomy 21 lymphocytes than in control cells. In the present work, the rescue effect on MTX toxicity mediated by FA and some of its derivatives, tetrahydrofolate (THF), 5-formyl-THF, and 5-methyl-THF, in both normal and trisomy 21 skin fibroblast cells, was evaluated. A statistically significant rescue effect was obtained by 5-formyl-THF, 5-methyl-THF, and their combination, administered together with MTX. In conclusion, trisomy 21 fibroblast cell lines showed a good response to the rescue effects of 5-formyl-THF and 5-methyl-THF on the MTX toxicity almost as normal cell lines.
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http://dx.doi.org/10.1002/jcp.28140DOI Listing
January 2019

Integrated Quantitative Transcriptome Maps of Human Trisomy 21 Tissues and Cells.

Front Genet 2018 24;9:125. Epub 2018 Apr 24.

Department of Experimental, Diagnostic and Specialty Medicine, Unit of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy.

Down syndrome (DS) is due to the presence of an extra full or partial chromosome 21 (Hsa21). The identification of genes contributing to DS pathogenesis could be the key to any rational therapy of the associated intellectual disability. We aim at generating quantitative transcriptome maps in DS integrating all gene expression profile datasets available for any cell type or tissue, to obtain a complete model of the transcriptome in terms of both expression values for each gene and segmental trend of gene expression along each chromosome. We used the TRAM (Transcriptome Mapper) software for this meta-analysis, comparing transcript expression levels and profiles between DS and normal brain, lymphoblastoid cell lines, blood cells, fibroblasts, thymus and induced pluripotent stem cells, respectively. TRAM combined, normalized, and integrated datasets from different sources and across diverse experimental platforms. The main output was a linear expression value that may be used as a reference for each of up to 37,181 mapped transcripts analyzed, related to both known genes and expression sequence tag (EST) clusters. An independent example validation of fibroblast transcriptome map data was performed through "Real-Time" reverse transcription polymerase chain reaction showing an excellent correlation coefficient ( = 0.93, < 0.0001) with data obtained . The availability of linear expression values for each gene allowed the testing of the gene dosage hypothesis of the expected 3:2 DS/normal ratio for Hsa21 as well as other human genes in DS, in addition to listing genes differentially expressed with statistical significance. Although a fraction of Hsa21 genes escapes dosage effects, Hsa21 genes are selectively over-expressed in DS samples compared to genes from other chromosomes, reflecting a decisive role in the pathogenesis of the syndrome. Finally, the analysis of chromosomal segments reveals a high prevalence of Hsa21 over-expressed segments over the other genomic regions, suggesting, in particular, a specific region on Hsa21 that appears to be frequently over-expressed (21q22). Our complete datasets are released as a new framework to investigate transcription in DS for individual genes as well as chromosomal segments in different cell types and tissues.
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http://dx.doi.org/10.3389/fgene.2018.00125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928158PMC
April 2018

Emilia-Romagna Study on Pregnancy and Exposure to Antiepileptic drugs (ESPEA): a population-based study on prescription patterns, pregnancy outcomes and fetal health.

J Neurol Neurosurg Psychiatry 2018 09 16;89(9):983-988. Epub 2018 Mar 16.

Institute of Neurological Sciences of Bologna, Bologna, Italy.

Objectives: To assess the prevalence of antiepileptic drug (AED) exposure in pregnant women and the comparative risk of terminations of pregnancy (TOPs), spontaneous abortions, stillbirths, major birth defects (MBDs), neonatal distress and small for gestational age (SGA) infants following intrauterine AED exposure in the Emilia Romagna region, Italy (4 459 246 inhabitants on 31 December 2011).

Methods: We identified all deliveries and hospitalised abortions in Emilia Romagna in the period 2009-2011 from the certificate of delivery assistance registry (Certificato di Assistenza al Parto- CedAP) and the hospital discharge card registry, exposure to AEDs from the reimbursed drug prescription registries, MBDs from the regional registry of congenital malformations, and Apgar scores and cases of SGA from the CedAP. Records from different registries were linked.

Results: We identified 145 243 pregnancies: 111 284 deliveries, 16 408 spontaneous abortions and 17 551 TOPs. Six hundred and eleven pregnancies (0.42%; 95% Cl 0.39 to 0.46) were exposed to AEDs. In the AED-exposed group 21% of pregnancies ended in TOPs vs 12% in the non-exposed women (OR: 2.24; 95% CI 1.41 to 3.56). Rates of spontaneous abortions, stillbirths, neonatal distress and SGA were comparable. Three hundred and fifty-three babies (0.31%; 95% CI 0.28 to 0.35) were exposed to AEDs during the first trimester. MBD rates were 2.3% in the exposed vs 2.0% in the non-exposed pregnancies (OR: 1.12, 95% CI 0.55 to 2.55).

Conclusion: The Emilia Romagna prevalence of AED exposure in pregnancy was 0.42%, comparable with previous European studies. Rates of spontaneous abortions, stillbirths, neonatal distress, SGA and MBDs following AED exposure were not significantly increased. The rate of TOPs was significantly higher in the AED-exposed women.
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http://dx.doi.org/10.1136/jnnp-2017-317833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109238PMC
September 2018

Plasma and urinary metabolomic profiles of Down syndrome correlate with alteration of mitochondrial metabolism.

Sci Rep 2018 02 14;8(1):2977. Epub 2018 Feb 14.

Neonatology Unit, St. Orsola-Malpighi Polyclinic, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138, Bologna, BO, Italy.

Down syndrome (DS) is caused by the presence of a supernumerary copy of the human chromosome 21 (Hsa21) and is the most frequent genetic cause of intellectual disability (ID). Key traits of DS are the distinctive facies and cognitive impairment. We conducted for the first time an analysis of the Nuclear Magnetic Resonance (NMR)-detectable part of the metabolome in plasma and urine samples, studying 67 subjects with DS and 29 normal subjects as controls selected among DS siblings. Multivariate analysis of the NMR metabolomic profiles showed a clear discrimination (up to of 80% accuracy) between the DS and the control groups. The univariate analysis of plasma and urine revealed a significant alteration for some interesting metabolites. Remarkably, most of the altered concentrations were consistent with the 3:2 gene dosage model, suggesting effects caused by the presence of three copies of Hsa21 rather than two: DS/normal ratio in plasma was 1.23 (pyruvate), 1.47 (succinate), 1.39 (fumarate), 1.33 (lactate), 1.4 (formate). Several significantly altered metabolites are produced at the beginning or during the Krebs cycle. Accounting for sex, age and fasting state did not significantly affect the main result of both multivariate and univariate analysis.
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http://dx.doi.org/10.1038/s41598-018-20834-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813015PMC
February 2018

Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes.

Am J Hum Genet 2018 02 25;102(2):309-320. Epub 2018 Jan 25.

GeneDX, Gaithersburg, MD 20877, USA.

Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in vitro, and in vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation.
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http://dx.doi.org/10.1016/j.ajhg.2017.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985417PMC
February 2018

Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement.

Nat Rev Endocrinol 2018 04 29;14(4):229-249. Epub 2018 Jan 29.

South West Thames Regional Genetics Service and St George's University of London and Institute of Cancer Research, London, SW17 0RE, UK.

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.
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http://dx.doi.org/10.1038/nrendo.2017.166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022848PMC
April 2018

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care.

Genet Med 2018 09 4;20(9):965-975. Epub 2018 Jan 4.

Neuropsychiatric Department, Spedali Civili Brescia, Brescia, Italy.

Purpose: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.

Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.

Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.

Conclusion: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.
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http://dx.doi.org/10.1038/gim.2017.221DOI Listing
September 2018

Adverse pregnancy outcomes in women exposed to gabapentin and pregabalin: data from a population-based study.

J Neurol Neurosurg Psychiatry 2018 02 17;89(2):223-224. Epub 2017 Jul 17.

IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1136/jnnp-2017-316143DOI Listing
February 2018

Genotype-phenotype correlation for congenital heart disease in Down syndrome through analysis of partial trisomy 21 cases.

Genomics 2017 10 23;109(5-6):391-400. Epub 2017 Jun 23.

Neonatology Unit, St. Orsola-Malpighi Polyclinic, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna (BO), Italy.

Among Down syndrome (DS) children, 40-50% have congenital heart disease (CHD). Although trisomy 21 is not sufficient to cause CHD, three copies of at least part of chromosome 21 (Hsa21) increases the risk for CHD. In order to establish a genotype-phenotype correlation for CHD in DS, we built an integrated Hsa21 map of all described partial trisomy 21 (PT21) cases with sufficient indications regarding presence or absence of CHD (n=107), focusing on DS PT21 cases. We suggest a DS CHD candidate region on 21q22.2 (0.96Mb), being shared by most PT21 cases with CHD and containing three known protein-coding genes (DSCAM, BACE2, PLAC4) and four known non-coding RNAs (DSCAM-AS1, DSCAM-IT1, LINC00323, MIR3197). The characterization of a DS CHD candidate region provides a useful approach to identify specific genes contributing to the pathology and to orient further investigations and possibly more effective therapy in relation to the multifactorial pathogenesis of CHD.
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http://dx.doi.org/10.1016/j.ygeno.2017.06.004DOI Listing
October 2017

Neuroimaging findings in Mowat-Wilson syndrome: a study of 54 patients.

Genet Med 2017 06 10;19(6):691-700. Epub 2016 Nov 10.

Neuroradiology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.

Purpose: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined.

Methods: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations.

Results: Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis.

Conclusion: This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.
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http://dx.doi.org/10.1038/gim.2016.176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438871PMC
June 2017

Oro-dental features of Pallister-Killian syndrome: Evaluation of 21 European probands.

Am J Med Genet A 2016 09 29;170(9):2357-64. Epub 2016 Jun 29.

Department of Biomedical and NeuroMotor Sciences (DiBiNeM), Unit of Dental Care for Special Needs Patients and Paediatric Dentistry, University of Bologna, Bologna, Italy.

Pallister-Killian syndrome (PKS) is a rare sporadic multi-systemic developmental disorder caused by a mosaic tetrasomy of the short arm of chromosome 12. A wide range of clinical characteristics including intellectual disability, seizures, and congenital malformations has previously been described. Individuals with PKS show a characteristic facial phenotype with frontal bossing, alopecia, sparse eyebrows, depressed nasal bridge, long philtrum, telecanthus, and posteriorly rotated ears. Oro-dental features, such as "Pallister lip," macroglossia, delayed eruption of primary teeth, high arched-palate, prognathism, and cleft palate have been occasionally reported in the medical literature. The aim of the study was to assess the oro-dental phenotype of PKS and to describe the oral health status in a cohort participating in the First European Workshop on PKS. A clinical dental examination was performed in 21 Caucasian probands and data regarding medical and dental history collected. Twelve probands (57%) showed an atypical dental pattern, with multiple missing teeth (primarily the first permanent molars) and 2 (10%) a double teeth. The severity of gingivitis and dental caries increased with age and gingival overgrowth was a common finding. A characteristic occlusive phenotype was found: a high-arched palate with mandibular prognathism associated with an anterior openbite and crossbite and with posterior crossbite (unilateral or bilateral). The prevalence of oral habits (non-nutritive sucking, mouth breathing, bruxism) was high, even in older probands. This study suggests that individuals affected by PKS should be observed closely for oro-dental diseases and a multidisciplinary approach is needed to implement the right preventive measures. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37815DOI Listing
September 2016

Systematic reanalysis of partial trisomy 21 cases with or without Down syndrome suggests a small region on 21q22.13 as critical to the phenotype.

Hum Mol Genet 2016 06 22;25(12):2525-2538. Epub 2016 Apr 22.

Neonatology Unit, St. Orsola-Malpighi Polyclinic, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, BO, Italy.

A 'Down Syndrome critical region' (DSCR) sufficient to induce the most constant phenotypes of Down syndrome (DS) had been identified by studying partial (segmental) trisomy 21 (PT21) as an interval of 0.6-8.3 Mb within human chromosome 21 (Hsa21), although its existence was later questioned. We propose an innovative, systematic reanalysis of all described PT21 cases (from 1973 to 2015). In particular, we built an integrated, comparative map from 125 cases with or without DS fulfilling stringent cytogenetic and clinical criteria. The map allowed to define or exclude as candidates for DS fine Hsa21 sequence intervals, also integrating duplication copy number variants (CNVs) data. A highly restricted DSCR (HR-DSCR) of only 34 kb on distal 21q22.13 has been identified as the minimal region whose duplication is shared by all DS subjects and is absent in all non-DS subjects. Also being spared by any duplication CNV in healthy subjects, HR-DSCR is proposed as a candidate for the typical DS features, the intellectual disability and some facial phenotypes. HR-DSCR contains no known gene and has relevant homology only to the chimpanzee genome. Searching for HR-DSCR functional loci might become a priority for understanding the fundamental genotype-phenotype relationships in DS.
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http://dx.doi.org/10.1093/hmg/ddw116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5181629PMC
June 2016

Recommendations of the Scientific Committee of the Italian Beckwith-Wiedemann Syndrome Association on the diagnosis, management and follow-up of the syndrome.

Eur J Med Genet 2016 Jan 22;59(1):52-64. Epub 2015 Nov 22.

Department of Public Health and Pediatric Sciences, University of Torino, Torino, Italy. Electronic address:

Unlabelled: Beckwith-Wiedemann syndrome (BWS) is the most common (epi)genetic overgrowth-cancer predisposition disorder. Given the absence of consensual recommendations or international guidelines, the Scientific Committee of the Italian BWS Association (www.aibws.org) proposed these recommendations for the diagnosis, molecular testing, clinical management, follow-up and tumor surveillance of patients with BWS. The recommendations are intended to allow a timely and appropriate diagnosis of the disorder, to assist patients and their families, to provide clinicians and caregivers optimal strategies for an adequate and satisfactory care, aiming also at standardizing clinical practice as a national uniform approach. They also highlight the direction of future research studies in this setting. With recent advances in understanding the disease (epi)genetic mechanisms and in describing large cohorts of BWS patients, the natural history of the disease will be dissected. In the era of personalized medicine, the emergence of specific (epi)genotype-phenotype correlations in BWS will likely lead to differentiated follow-up approaches for the molecular subgroups, to the development of novel tools to evaluate the likelihood of cancer development and to the refinement and optimization of current tumor screening strategies.

Conclusions: In this article, we provide the first comprehensive recommendations on the complex management of patients with Beckwith-Wiedemann syndrome.
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http://dx.doi.org/10.1016/j.ejmg.2015.11.008DOI Listing
January 2016

Identification of a DNA methylation signature in blood cells from persons with Down Syndrome.

Aging (Albany NY) 2015 Feb;7(2):82-96

Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum-University of Bologna, Bologna 40138, Italy.

Down Syndrome (DS) is characterized by a wide spectrum of clinical signs, which include segmental premature aging of central nervous and immune systems. Although it is well established that the causative defect of DS is the trisomy of chromosome 21, the molecular bases of its phenotype are still largely unknown. We used the Infinium HumanMethylation450 BeadChip to investigate DNA methylation patterns in whole blood from 29 DS persons, using their relatives (mothers and unaffected siblings) as controls. This family-based model allowed us to monitor possible confounding effects on DNA methylation patterns deriving from genetic and environmental factors. Although differentially methylated regions (DMRs) displayed a genome-wide distribution, they were enriched on chromosome 21. DMRs mapped in genes involved in developmental functions, including embryonic development (HOXA family) and haematological (RUNX1 and EBF4) and neuronal (NCAM1) development. Moreover, genes involved in the regulation of chromatin structure (PRMD8, KDM2B, TET1) showed altered methylation. The data also showed that several pathways are affected in DS, including PI3K-Akt signaling. In conclusion, we identified an epigenetic signature of DS that sustains a link between developmental defects and disease phenotype, including segmental premature aging.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359691PMC
http://dx.doi.org/10.18632/aging.100715DOI Listing
February 2015

Prenatal diagnosis of open spina bifida in Emilia-Romagna.

Fetal Diagn Ther 2015 21;37(4):301-4. Epub 2015 Jan 21.

Department of Obstetrics and Gynecology, Sant'Orsola Malpighi University Hospital, Bologna, Italy.

Objective: To report recent data on the epidemiology of pregnancies affected by open spina bifida in the Emilia-Romagna region of Italy.

Methods: All cases of open spina bifida diagnosed in the Emilia-Romagna region between 2001 and 2011 and reported to the IMER regional registry were included in the study group. The pregnancy outcome was retrospectively assessed.

Results: In the study period out of 390,978 babies born in Emilia-Romagna 126 cases of open spina bifida were reported to the IMER registry, resulting in a global prevalence of 3.2 per 10,000 births. Prenatal diagnosis was achieved in the vast majority of these cases (105/126; 83.3%) and in a great proportion of those women (85/105; 80.9%) who opted for termination of pregnancy.

Conclusions: In a wide region of northern Italy where ultrasound anomaly scan is routinely offered to the general population, the vast majority of cases of open spina bifida are diagnosed antenatally and terminated electively.
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http://dx.doi.org/10.1159/000366158DOI Listing
February 2016

Age-related changes of adaptive and neuropsychological features in persons with Down Syndrome.

PLoS One 2014 24;9(11):e113111. Epub 2014 Nov 24.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy; Interdepartmental Centre "L. Galvani" - CIG, University of Bologna, Bologna, Italy; IRCCS Institute of Neurological Sciences, Bologna, Italy; National Research Council of Italy, CNR, Institute for Organic Synthesis and Photoreactivity (ISOF), Bologna, Italy; National Research Council of Italy, CNR, Institute of Molecular Genetics, Unit of Bologna, Bologna, Italy.

Down Syndrome (DS) is characterised by premature aging and an accelerated decline of cognitive functions in the vast majority of cases. As the life expectancy of DS persons is rapidly increasing, this decline is becoming a dramatic health problem. The aim of this study was to thoroughly evaluate a group of 67 non-demented persons with DS of different ages (11 to 66 years), from a neuropsychological, neuropsychiatric and psychomotor point of view in order to evaluate in a cross-sectional study the age-related adaptive and neuropsychological features, and to possibly identify early signs predictive of cognitive decline. The main finding of this study is that both neuropsychological functions and adaptive skills are lower in adult DS persons over 40 years old, compared to younger ones. In particular, language and short memory skills, frontal lobe functions, visuo-spatial abilities and adaptive behaviour appear to be the more affected domains. A growing deficit in verbal comprehension, along with social isolation, loss of interest and greater fatigue in daily tasks, are the main features found in older, non demented DS persons evaluated in our study. It is proposed that these signs can be alarm bells for incipient dementia, and that neuro-cognitive rehabilitation and psycho-pharmacological interventions must start as soon as the fourth decade (or even earlier) in DS persons, i.e. at an age where interventions can have the greatest efficacy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0113111PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4242614PMC
July 2015

CHARGE-like presentation, craniosynostosis and mild Mowat-Wilson Syndrome diagnosed by recognition of the distinctive facial gestalt in a cohort of 28 new cases.

Am J Med Genet A 2014 Oct 14;164A(10):2557-66. Epub 2014 Aug 14.

Division of Craniofacial Medicine, Seattle Children's Hospital, Seattle, WA.

Mowat-Wilson syndrome (MWS) is characterized by moderate to severe intellectual disability and distinctive facial features in association with variable structural congenital anomalies/clinical features including congenital heart disease, Hirschsprung disease, hypospadias, agenesis of the corpus callosum, short stature, epilepsy, and microcephaly. Less common clinical features include ocular anomalies, craniosynostosis, mild intellectual disability, and choanal atresia. These cases may be more difficult to diagnose. In this report, we add 28 MWS patients with molecular confirmation of ZEB2 mutation, including seven with an uncommon presenting feature. Among the "unusual" patients, two patients had clinical features of charge syndrome including choanal atresia, coloboma, cardiac defects, genitourinary anomaly (1/2), and severe intellectual disability; two patients had craniosynostosis; and three patients had mild intellectual disability. Sixteen patients have previously-unreported mutations in ZEB2. Genotype-phenotype correlations were suggested in those with mild intellectual disability (two had a novel missense mutation in ZEB2, one with novel splice site mutation). This report increases the number of reported patients with MWS with unusual features, and is the first report of MWS in children previously thought to have CHARGE syndrome. These patients highlight the importance of facial gestalt in the accurate identification of MWS when less common features are present.
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http://dx.doi.org/10.1002/ajmg.a.36696DOI Listing
October 2014
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