Case report: Preemptive intervention for an infant with early signs of autism spectrum disorder during the first year of life.

Autism spectrum disorder (ASD) includes neurodevelopmental conditions traditionally considered to bring life long disabilities, severely impacting individuals and their families. Very early identification and intervention during the very first phases of life have shown to significantly diminish symptom severity and disability, and improve developmental trajectories. Here we report the case of a young child showing early behavioral signs of ASD during the first months of life, including diminished eye contact, reduced social reciprocity, repetitive movements. The child received a pre-emptive parent mediated intervention based on the Infant Start, an adaptation of the Early Start Denver Model (ESDM), specifically developed for children with ASD signs during the first year of life. The child here described received intervention from 6 to 32 months of age, in combination with educational services. Diagnostic evaluations performed at several time points (8, 14, 19, and 32 months) showed progressive improvements in his developmental level and ASD symptoms. Our case study supports the possibility of identifying ASD symptoms and providing services as soon as concerns emerge even during the first year of life. Our report, in combination with recent infant identification and intervention studies, suggests the need for very early screening and preemptive intervention to promote optimal outcomes.

Differences in clinical presentation, severity, and treatment of COVID-19 among individuals with Down syndrome from India and high-income countries: Data from the Trisomy 21 Research Society survey.

Background: People with Down syndrome (DS) are one of the highest risk groups for mortality associated with COVID-19, but outcomes may differ across countries due to different co-morbidity profiles, exposures, and societal practices, which could have implications for disease management. This study is designed to identify differences in clinical presentation, severity, and treatment of COVID-19 between India and several high-income countries (HICs). Methods: We used data from an international survey to examine the differences in disease manifestation and management for COVID-19 patients with DS from India vs HIC. De-identified survey data collected from April 2020 to August 2021 were analysed. Results: COVID-19 patients with DS from India were on average nine years younger than those from HICs. Comorbidities associated with a higher risk for severe COVID-19 were more frequent among the patients from India than from HICs. Hospitalizations were more frequent among patients from India as were COVID-19-related medical complications. Treatment strategies differed between India and HICs, with more frequent use of antibiotics in India. The average severity score of 3.31 was recorded for Indian DS in contrast to 2.3 for European and 2.04 for US cases. Conclusions: Presentation and outcomes of COVID-19 among individuals with DS were more severe for patients from India than for those from HIC. Global efforts should especially target vaccination campaigns and other risk-reducing interventions for individuals with DS from low-income countries.

Multidisciplinary early intervention in Down syndrome: a retrospective study.

BACKGROUND: Scientific community agrees on the importance of early, global multidisciplinary family-based care in the neuropsychological development of children with disabilities, including those with Down Syndrome (DS). This study aim to assess whether a structured, multidisciplinary early intervention carried out at the outpatient service of Stella Maris I.R.C.C.S. can lead to better outcomes in children with DS, in development and cognitive functioning, compared to conventional care provided by the local health centres (ASL). METHODS: We included in the study 20 children with DS. The experimental group received early treatment (0-36 months), while the control group only underwent cognitive assessments. In order to examine the outcome of long-term cognitive functioning, our study evaluated assessments of the children at 5 years of age, by administering the WPPSI-III scale. RESULTS: In our result we can confirm the typical profile of children with Down Syndrome described in the literature. Comparing the results obtained in both groups, we see that the mean scores obtained by the experimental group, in all three of the quotients examined, are higher than the mean scores obtained by the control group. CONCLUSIONS: This study makes it clear that early, structured, multidisciplinary interventions play a fundamental role in modifying neurocognitive outcomes in children with Down Syndrome. The results of this study thus confirm the usefulness of the outpatient service in the early management of individuals with DS, following a multidisciplinary, structured pathway focused on the child and his/her family.

COVID-19 Vaccination of Individuals with Down Syndrome-Data from the Trisomy 21 Research Society Survey on Safety, Efficacy, and Factors Associated with the Decision to Be Vaccinated.

Individuals with Down syndrome (DS) are among the groups with the highest risk for severe COVID-19. Better understanding of the efficacy and risks of COVID-19 vaccines for individuals with DS may help improve uptake of vaccination. The T21RS COVID-19 Initiative launched an international survey to obtain information on safety and efficacy of COVID-19 vaccines for individuals with DS. De-identified survey data collected between March and December 2021 were analyzed. Of 2172 individuals with DS, 1973 (91%) had received at least one vaccine dose (57% BNT162b2), 107 (5%) were unvaccinated by choice, and 92 (4%) were unvaccinated for other reasons. Most participants had either no side effects (54%) or mild ones such as pain at the injection site (29%), fatigue (12%), and fever (7%). Severe side effects occurred in <0.5% of participants. About 1% of the vaccinated individuals with DS contracted COVID-19 after vaccination, and all recovered. Individuals with DS who were unvaccinated by choice were more likely to be younger, previously recovered from COVID-19, and also unvaccinated against other recommended vaccines. COVID-19 vaccines have been shown to be safe for individuals with DS and effective in terms of resulting in minimal breakthrough infections and milder disease outcomes among fully vaccinated individuals with DS.

COVID-19 in Children with Down Syndrome: Data from the Trisomy 21 Research Society Survey.

Adults with Down Syndrome (DS) are at higher risk for severe outcomes of coronavirus disease 2019 (COVID-19) than the general population, but evidence is required to understand the risks for children with DS, which is necessary to inform COVID-19 shielding advice and vaccination priorities. We aimed to determine the epidemiological and clinical characteristics of COVID-19 in children with DS. Using data from an international survey obtained from a range of countries and control data from the United States, we compared the prevalence of symptoms and medical complications and risk factors for severe outcomes between DS and non-DS paediatric populations with COVID-19. Hospitalised COVID-19 patients <18 years with DS had a higher incidence of respiratory symptoms, fever, and several medical complications from COVID-19 than control patients without DS <18 years. Older age, obesity, and epilepsy were significant risk factors for hospitalisation among paediatric COVID-19 patients with DS, and age and thyroid disorder were significant risk factors for acute respiratory distress syndrome. Mortality rates were low in all paediatric COVID-19 patients (with and without DS), contrasting with previous findings in adults with DS (who exhibit higher mortality than those without DS). Children with DS are at increased risk for more severe presentations of COVID-19. Efforts should be made to ensure the comprehensive and early detection of COVID-19 in this population and to identify children with DS who present comorbidities that pose a risk for a severe course of COVID-19. Our results emphasize the importance of vaccinating children with DS as soon as they become eligible.

The Surplus Effect in Adaptive Behaviour in Down Syndrome: What Can Promote It?

BACKGROUND: In Down syndrome (DS), adaptive behaviour often shows a "surplus effect" (i.e., higher adaptive abilities than expected from cognitive skills). As inclusive schooling has become mandatory in Italy, we studied the impact of school inclusion on the surplus effect of adaptive behaviour in adult DS, considering potential confounding factors such as parental education. METHODS: All consecutive DS individuals from three different sites were queried prospectively regarding type of schooling (inclusive and non-inclusive). Demographic data were documented; cognitive abilities and adaptive behaviour were assessed (Coloured Progressive Matrices and Vineland Adaptive Behaviour Scales). The aim was to establish the presence of a surplus effect in adaptive behaviour, primarily in the overall level and secondarily in the main domains and subdomains. A multivariable-adjusted logistic regression model was used for the association of schooling, and parental education. RESULTS: The majority (65%) showed a surplus effect in adaptive behaviour and had attended inclusive schools (85%). Higher adaptive skills as well as early and longer functional treatment programmes were more readily available for younger individuals. In the group of inclusive schooling, the surplus effect on overall adaptive behaviour was present in 70% as opposed to 38% in the group without inclusive schooling, significant when adjusted for gender and maternal education. This was also observed in socialisation, written, and community, and after adjustment in playing and leisure time. CONCLUSIONS: Adaptive behaviour showed a surplus effect in the majority of DS adults, even more so after inclusive schooling. Younger adults showed higher adaptive skills. Moreover, female gender and higher maternal educational level significantly enhanced this surplus effect.

Medical vulnerability of individuals with Down syndrome to severe COVID-19-data from the Trisomy 21 Research Society and the UK ISARIC4C survey.

BACKGROUND: Health conditions, immune dysfunction, and premature aging associated with trisomy 21 (Down syndrome, DS) may impact the clinical course of COVID-19. METHODS: The T21RS COVID-19 Initiative launched an international survey for clinicians or caregivers on patients with COVID-19 and DS. Data collected between April and October 2020 (N=1046) were analysed and compared with the UK ISARIC4C survey of hospitalized COVID-19 patients with and without DS. FINDINGS: The mean age of COVID-19 patients with DS in the T21RS survey was 29 years (SD = 18). Similar to the general population, the most frequent signs and symptoms of COVID-19 were fever, cough, and shortness of breath. Joint/muscle pain and vomiting or nausea were less frequent (p < 0.01), whereas altered consciousness/confusion were more frequent (p < 0.01). Risk factors for hospitalization and mortality were similar to the general population with the addition of congenital heart defects as a risk factor for hospitalization. Mortality rates showed a rapid increase from age 40 and were higher in patients with DS (T21RS DS versus non-DS patients: risk ratio (RR) = 3.5 (95%-CI=2.6;4.4), ISARIC4C DS versus non-DS patients: RR = 2.9 (95%-CI=2.1;3.8)) even after adjusting for known risk factors for COVID-19 mortality. INTERPRETATION: Leading signs/symptoms of COVID-19 and risk factors for severe disease course are similar to the general population. However, individuals with DS present significantly higher rates of medical complications and mortality, especially from age 40. FUNDING: Down Syndrome Affiliates in Action, DSMIG-USA, GiGi's Playhouse, Jerome Lejeune Foundation, LuMind IDSC Foundation, The Matthew Foundation, NDSS, National Task Group on Intellectual Disabilities and Dementia Practices.

An international survey on the impact of COVID-19 in individuals with Down syndrome.

BACKGROUND: Health conditions and immune dysfunction associated with trisomy 21 (Down syndrome, DS) may impact the clinical course of COVID-19 once infected by SARS-CoV-2. METHODS: The T21RS COVID-19 Initiative launched an international survey for clinicians or caregivers/family members on patients with COVID-19 and DS (N=1046). De-identified survey data collected between April and October 2020 were analysed and compared with the UK ISARIC4C survey of hospitalized COVID-19 patients with and without DS. COVID-19 patients with DS from the ISARIC4C survey (ISARIC4C DS cases=100) were matched to a random set of patients without DS (ISARIC4C controls=400) and hospitalized DS cases in the T21RS survey (T21RS DS cases=100) based on age, gender, and ethnicity. FINDING: The mean age in the T21RS survey was 29 years (SD=18), 73% lived with their family. Similar to the general population, the most frequent signs and symptoms of COVID-19 were fever, cough, and shortness of breath. Pain and nausea were reported less frequently (p<0.01), whereas altered consciousness/confusion were reported more frequently (p<0.01). Risk factors for hospitalization and mortality were similar to the general population (age, male gender, diabetes, obesity, dementia) with the addition of congenital heart defects as a risk factor for hospitalization. Mortality rates showed a rapid increase from age 40 and were higher than for controls (T21RS DS versus controls: risk ratio (RR)=3.5 (95%-CI=2.6;4.4), ISARIC4C DS versus controls: RR=2.9 (95%-CI=2.1;3.8)) even after adjusting for known risk factors for COVID-19 mortality. INTERPRETATION: Leading signs/symptoms of COVID-19 and risk factors for severe disease course are similar to the general population. However, individuals with DS present significantly higher rates of mortality, especially from age 40. FUNDING: Down Syndrome Affiliates in Action, Down Syndrome Medical Interest Group-USA, GiGi's Playhouse, Jerome Lejeune Foundation, LuMind IDSC Foundation, Matthews Foundation, National Down Syndrome Society, National Task Group on Intellectual Disabilities and Dementia Practices.

Training RAN or reading? A telerehabilitation study on developmental dyslexia.

Rehabilitation procedures recommended for developmental dyslexia (DD) are still not fully defined, and only few studies directly compare different types of training. This study compared a training (Reading Trainer) working on the reading impairment with one (Run the RAN) working on the rapid automatized naming (RAN) impairment, one of the main cognitive deficits associated with DD. Two groups of DD children (N = 45) equivalent for age, sex, full IQ, and reading speed were trained either by Reading Trainer (n = 21) or by Run the RAN (n = 24); both trainings required an intensive home exercise, lasting 3 months. Both trainings showed significant improvements in reading speed and accuracy of passages and words. Bypassing the use of alphanumeric stimuli, but empowering the cognitive processes underlying reading, training RAN may be a valid tool in children with reading difficulties opening new perspectives for children with severe impairments or, even, at risk of reading difficulties.

Visual assessment in Down Syndrome: The relevance of early visual functions.

BACKGROUND: Children with Down Syndrome (DS) have a high prevalence of ocular disorders, and even when ophthalmological deficits (i.e. refractive errors or strabismus) are corrected, visual acuity seems to have a different developmental trend compared to typical children. Unfortunately, there is no consensus about the age at which it is fundamental to perform a first comprehensive visual assessment in this population. AIMS: We analyzed early visual functions in a sample of 42 Italian children with DS, in order to achieve new insights for early surveillance and intervention. MATERIAL AND METHODS: DS children were evaluated with the Early Neurovisual Assessment, including Teller Acuity Cards (at 6, 12 and 18 months of age) and the Pediatric Ophthalmological Examination (within the 36th months of age). RESULTS: Visual acuity in our sample was lower than findings reported in the literature on healthy Italian children, but the values were within the confidence interval reported in previous studies on DS children. Moderate or severe refractive errors (> 3diopters) were present in five children (four had hyperopia and one myopia). Abnormalities in ocular motility were observed in 15 children and pathological findings for fundus oculi or lens were found in another eight. Furthermore, ophthalmological findings correlated with visual acuity at 18 months of age. CONCLUSION: According to our results, the Early Neurovisual Assessment at 18 months of life is a reliable tool for early detection of visual disorders in children with DS and it is useful for programming early intervention to promote their neurodevelopment.

Telerehabilitation in developmental dyslexia: methods of implementation and expected results.

BACKGROUND: Developmental Dyslexia is a disorder, highly frequent in the school population, for which the recommended rehabilitation procedures are not well defined. This study aimed to automatize reading decoding skills by using an innovative system for rehabilitation, based on a telerehabilitation method. It requires an intensive home-exercise with the supervision, by web, of the clinician. The study had three main aims: to diffuse knowledge on new methods for rehabilitation of reading difficulties; to verify whether an intensive and simplified exercise, targeted to the automation of reading, is suitable for different subgroups of dyslexic children; to define the treatment effects on basic cognitive functions underlying reading. METHODS: Twenty-five children, grouped according to the neuropsychological and anamnestic profiles, took part to the treatment by the software Reading Trainer®. RESULTS: Both speed and accuracy of reading decoding increased significantly after treatment, independently from the functional neuropsychological profile or the history of oral language delay. These changes were specific to decoding and not associated with improvements in reading comprehension or spelling skills. However, there was a "cascade effect" of the treatment efficacy on those basic cognitive functions considered precursors of the ability to read, with significant improvements in rapid lexical access, phonological processing and visual attention. CONCLUSIONS: This study provides information on the efficacy of new tools for telerehabilitation of specific reading disorders.

Complex Phenotype of a Boy With De Novo 16p13.3-13.2 Interstitial Deletion.

Interstitial deletions encompassing chromosome 16p13.3-13.2 are rarely described in the literature, whereas terminal deletions or duplications involving this region are slightly more frequently described. The authors describe a boy harboring a de novo 16p13.3-13.2 interstitial deletion, with intellectual disability, verbal dyspraxia, epilepsy, and a distinctive brain magnetic resonance finding, namely a nodular heterotopia. The authors found partial genotype-phenotype correspondences regarding epilepsy and intellectual disability, which have been associated with 16p1 region. Conversely, nodular heterotopia and verbal dyspraxia have not been clearly related to this region. These data are in agreement with the emerging concept that similar copy number variants may be the general risk factors for distinct disorders. Verbal dyspraxia, which has not responded to speech therapy, is the child's most disabling trait. In view of the above, genetic studies should be appraised in cases of serious speech difficulties, especially if they are associated with intellectual disability and epilepsy.

Motion perception deficit in Down Syndrome.

It is a well established fact that Down Syndrome (DS) individuals have a tendency to develop Alzheimer's disease (AD) (Lott, I.T., Head, E., 2005. Alzheimer disease and Down syndrome: factors in pathogenesis. Neurobiol. Aging 26, 383-389). They have therefore been proposed as a model to study the pre-dementia stage of Alzheimer's (Mann, D.M., 1988. The pathological association between Down syndrome and Alzheimer disease. Mech. Ageing Dev. 43, 99-136). One of the specific deficits exhibited by AD patients is optic flow motion perception (Tetewsky, S.J., Duffy, C.J., 1999. Visual loss and getting lost in Alzheimer's disease. Neurology 52, 958-965), but there are no corresponding systematic studies in DS individuals. We performed sensitivity measurements to optic flow with Visual Evoked Potentials (VEP) and psychophysical techniques in a group of young DS participants with mild mental retardation and without significant Alzheimer's clinical symptoms. We found a significant reduction in direction discrimination sensitivity to optic flow (random dots moving in radial, rotational and translational trajectories) in DS participants compared to mental age-matched controls, while their sensitivity to direction of control moving stimuli (sinusoidal gratings) was similar to age-matched controls. Measurements of Visual Evoked Potentials (VEP) showed no response to optic flow, although the response to control stimuli (contrast-reversal checkerboard patterns) was significant. Overall, our results show a selective and substantial deficit in the perception of optic flow motion and a corresponding suppression of electroencephalographic activity in DS individuals, thus establishing a further common trait between Down Syndrome and Alzheimer's disease.

Vision problems in Down syndrome adults do not hamper communication, daily living skills and socialisation.

BACKGROUND: Down syndrome is the most commonly occurring chromosomal condition with a prevalence of 11.2-10000 life-births in Europe. The most important concern consists of various degrees of intellectual disability and sensory deficits. The overall prevalence of ophthalmologic abnormalities has been reported to be as high as 46-100%. Impairment of vision potentially hampers the capacity of learning and communication and thus of social integration. The aim of our study is to assess prospectively the occurrence of vision problems in patients with DS with special emphasis on adaptive behaviour and cognition. METHODS: Assessments included Hirschberg's corneal reflex method, eye alignment, cover test, Vineland Adaptive Behaviour Scales (VABS) for adaptive behaviour and Coloured Progressive Matrices (CPM) for cognitive abilities. RESULTS: We included prospectively 49 individuals from 19-52 years. Ophthalmologic problems were observed in 81.6% of our DS patients. The total number of visual disorders and symptoms was equally distributed with respect to ID-group and to levels of adaptive behaviour (p > 0.050). When comparing individuals matched for age, gender, cognitive skills and sociocultural background in a subset of individuals, vision problems did not decrease adaptive behaviour skills of our patients with visual disorders and daily living skills even fared better (p = 0.046). CONCLUSIONS: Effective early correction and intervention on visual-motor deficits seem to be important, but nevertheless personal autonomy is not seriously detained.

Effect of early multisensory massage intervention on visual functions in infants with Down syndrome.

BACKGROUND: Down syndrome is a frequent cause of intellectual disability, with severe impact on the quality of life of affected individuals and their families, and high social costs. Intervention programs should start soon after birth but no consensus exists on specific types and timing of early interventions in this population. AIM: This pilot study explores the effects of an early multi-sensory intervention, based on body massage, on the development of visual function in infants with Down syndrome. METHOD: Infants were randomly allocated to either a massage or a control group. Intervention consisted of only standard care (Control Group) or standard care plus infant massage (Massaged Group). Visual acuity was assessed by Teller Acuity Cards and stereopsis by the Frisby Stereopsis Screening Test at 5, 6, 9 and 12 months. RESULTS: Massaged Group Infants showed a significantly higher visual acuity at 6 months of age and an accelerated development up to at least 12 months; compared to Controls, stereopsis had an earlier onset in the Massaged Group followed by a faster maturation. CONCLUSION: Environmental enrichment, in the tested form of infant massage, seems to affect maturation of visual functions in human infants, also in the presence of a genetic disability, when applied during a period of high brain plasticity.

Benign and periodic movement disorders in 2 children with Down syndrome.

Children with Down syndrome show hypotonia and ligamentous laxity that are associated with motor development delay. Neurologic disorders are common in children with Down syndrome; however, in literature the presence of periodic movement disorders has not yet been described. We report 2 different types of periodic movement disorders in 2 infants with Down syndrome. In the first case, we described an 8-month-old girl with involuntary head nodding and absence of any other neurologic or ophthalmologic abnormalities. In the second case, we described a 6-month-old boy with abnormal but painless head rotation and inclination, alternating from side to side. Episodes of head tilting were often associated with a state of general uneasiness. Neurologic examination between attacks was normal. The aim of this paper is to provide practical information on recognition and management of movement disorders in Down syndrome.

The autistic phenotype in Down syndrome: differences in adaptive behaviour versus Down syndrome alone and autistic disorder alone.

The autistic phenotype in Down syndrome (DS) is marked by a characteristic pattern of stereotypies, anxiety and social withdrawal. Our aim was to study adaptive behaviour in DS with and without autistic comorbidity using the Vineland Adaptive Behaviour Scales (VABS), the Childhood Autism Rating Scales (CARS) and the DSM IV-TR criteria. We assessed 24 individuals and established three groups: Down syndrome (DS), DS and autistic disorder (DS-AD), and autistic disorder (AD). The DS and DS-AD groups showed statistically significantly similar strengths on the VABS (in receptive and domestic skills). The DS and DS-AD subjects also showed similar strengths on the CARS (in imitation and relating), differing significantly from the AD group. The profile of adaptive functioning and symptoms in DS-AD seemed to be more similar to that found in DS than to the profile emerging in AD. We suggest that the comorbidity of austistic symptoms in DS hampered the acquisition of adaptive skills more than did the presence of DS alone.

Adaptive behaviour in Down syndrome: a cross-sectional study from childhood to adulthood.

OBJECTIVE: Adaptive behaviour in Down syndrome is described to increase until middle childhood and to begin to decline in adolescence, whereas significant deterioration in middle adulthood has been attributed to early onset of dementia. Nevertheless, opinions diverge about when the slowing down of adaptive and cognitive abilities starts. Our aims were to describe the profile of adaptive behaviour in Down syndrome, the variability within different age-groups, age-related changes and the correlation to cognitive abilities. METHODS: In a prospective cross-sectional study, individuals with Down syndrome all living in the family and without signs of dementia in 4 Italian sites were included and performed a detailed medical and neuropsychiatric work-up, as well as cognitive testing and adaptive behaviour, using the Vineland Adaptive Behaviour Scales. RESULTS: Seventy-five individuals with Down syndrome from 4 to 52 years were included. Adults from 20 to 30 years showed the highest performance of all groups. The area of communication, always an area of strength, did not change over time, in childhood and especially in adolescence daily living skills (p = 0.012) and socialisation (p = 0.021) scored on average, whereas in young and middle adulthood performance in daily living skills and socialisation and were areas of strength. CONCLUSIONS: Individuals with DS continue to increase competence in adaptive behaviour until 30 years, even when cognitive abilities reach a plateau. We found no major decline in middle adulthood. This may be due to exposure to daily life, but needs to be supported by further studies.

Association of maternal polymorphisms in folate metabolizing genes with chromosome damage and risk of Down syndrome offspring.

We analyzed the role of six common polymorphisms in folate metabolizing genes as possible risk factors for having a child with Down syndrome (DS) in 94 Italian mothers of a DS child (MDS) and 113 matched control mothers, both aged less than 35 years at conception. Investigated polymorphisms include methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C, methionine synthase (MTR) 2756A>G, methionine synthase reductase (MTRR) 66A>G, and thymidylate synthase (TYMS) 28bp repeat and 1494del6. We also measured the amount of chromosome damage in peripheral blood lymphocytes of 42 MDS and 41 matched controls, by means of the micronucleus assay, and searched for association between this cytogenetic endpoint and any of the studied polymorphisms. Micronuclei in peripheral blood lymphocytes have been analyzed several years after conception: the mean age at sampling was 45.6+/-11.4 years for MDS and 47.95+/-6.9 years for controls. The combined MTHFR 677TT/MTR 2756AA genotype was associated with increased DS risk (P=0.034), and the combined MTHFR 1298AC/TYMS 2R/2R genotype with reduced risk (P=0.003). Moreover, we observed a significant increased frequency of micronucleated lymphocytes in MDS as compared to controls (P<0.0001) and, in the total population, a significant correlation between micronucleated cells and both MTHFR 677C>T (P=0.031) and 1298A>C (P=0.047) polymorphisms.

Polymorphisms in folate and homocysteine metabolizing genes and chromosome damage in mothers of Down syndrome children.

We recently observed an association between combinations of polymorphisms in the methylenetetrahydrofolate reductase (MTHFR 677C > T or 1298A > C) and reduced folate carrier (RFC-1 80G > A) genes and the risk of a Down syndrome (DS) pregnancy in young Italian women. Others have observed an association between a methionine synthase (MTR 2756A > G) gene polymorphism and the risk of a DS offspring in Italy. Moreover, in a separate study, we observed an increased frequency of both binucleated micronucleated cells (BNMN) and chromosome malsegregation events in peripheral lymphocytes of mothers of DS individuals aged less than 35 years at conception (MDS) in respect to controls. The aim of the present study was to evaluate chromosome damage, measured by means of the micronucleus assay, in peripheral lymphocytes of a group of women (n = 34) who had a DS child in young age (<35 years) and in a control group (n = 35), and to correlate them with MTHFR 677C > T and 1298A > C, RFC-1 80G > A and MTR 2756A > G polymorphisms. We observed an increased frequency of BNMN in the MDS group compared to the control group (17.13 +/- 8.31 per thousand vs. 10.28 +/- 4.53 per thousand; P < 0.001), and, in the general population, a correlation between years of age and BNMN frequency (P = 0.05). A significant correlation between the frequency of BNMN and the MTHFR 677C > T polymorphism (P = 0.038) was also found. Present results indicate that MDS are more prone to chromosome damage than control mothers; moreover the contribution of folate and homocysteine metabolizing gene polymorphisms seems to have an effect on the baseline frequency of BNMN lymphocytes.