Grandmaternal age in children with Down syndrome in St. Petersburg

Advanced maternal age is a well-established factor of DS occurrence. However the majority of DS cases are born to young couples. Some studies suggested that the risk for Down syndrome may be related to an aging grandmother. We obtained data on grandmaternal ages in 243 families of DS and 330 families of healthy children born in 1990-1999. The data were analyzed according to two categories of maternal ages, <30 yr and > or =30 yr. We did not find systematic differences in grandparental age distribution between the studied groups. Specifically, in 102 young couples with DS, medians for both maternal and paternal grandmother's age appeared to be equal (26 yr). Similar figures were observed in 284 young controls (27 yr). There was no difference in age distribution between 141 older couples with DS and 104 control couples. Therefore we failed to support the suggestion that advanced age of the DS grandmother is responsible for meiotic disturbance in her daughter. Neither the hypothesis suggesting a significant contribution of parentally transmitted trisomy 21 to DS population rate has been confirmed.     

Pedometer-determined physical activity levels of healthy children and children with Down’s syndrome

Purpose: Children with Down’s syndrome (DS) are considered sedentary and less engaged in recommended physical activity (PA) levels. This study compared the PA levels between children with DS and healthy children in Saudi Arabia.

Methods: The study included 85 children divided into two groups. The DS group comprised 37 children with DS aged 8–12?years recruited from the Down Syndrome Charitable Association and Al-Nahda Schools for DS. The healthy group comprised 41 healthy children aged 8–12?years recruited from regular schools in the same region. PA levels were measured over 7?days using a pedometer.

Results: The healthy group was more active than the DS group (p?p?p?Conclusions: The DS group had a high body mass index and physical inactivity compared with the second group. Obesity and physical inactivity among Saudi Arabian children with and without DS are major health concerns. Therefore, concerted efforts are needed to combat childhood obesity, promote PA, improve patient quality of life, and reduce the sedentary lifestyle among Saudi children and adolescents.     

Fecundity of Paternal and Maternal Non-Parental Female Relatives of Homosexual and Heterosexual Men

A variety of social, developmental, biological and genetic factors influence sexual orientation in males. Thus, several hypotheses have attempted to explain the sustenance of genetic factors that influence male homosexuality, despite decreased fecundity within the homosexuals. Kin selection, the existence of maternal effects and two forms of balancing selection, sexually antagonistic selection and overdominance, have been proposed as compensatory mechanisms for reduced homosexual fecundity. Here, we suggest that the empirical support for kin selection and maternal effects cannot account for the low universal frequency and stability of the distribution of homosexuals. To identify the responsible compensatory mechanism, we analyzed fecundity in 2,100 European female relatives, i.e., aunts and grandmothers, of either homosexual or heterosexual probands who were matched in terms of age, culture and sampling strategy. Female relatives were chosen to avoid the sampling bias of the fraternal birth order effect, which occurs when indirectly sampling mothers though their homosexual sons. We observed that the maternal aunts and grandmothers of homosexual probands were significantly more fecund compared with the maternal aunts and maternal grandmothers of the heterosexual probands. No difference in fecundity was observed in the paternal female lines (grandmothers or aunts) from either of the two proband groups. Moreover, due to the selective increase in maternal female fecundity, the total female fecundity was significantly higher in homosexual than heterosexual probands, thus compensating for the reduced fecundity of homosexuals. Altogether, these data support an X-linked multi-locus sexually antagonistic hypothesis rather than an autosomal multi-locus overdominance hypothesis.     

Altered serum pro-inflammatory cytokines in children with Down's syndrome

There are reports showing that pro-inflammatory cytokines are dysregulated in patients with Down's syndrome (DS). However, most of these reports concern adults. We analyzed cytokine levels in serum samples from children with DS, and compared them with samples from intellectually disabled (ID), and healthy, control children. Blood samples were collected from 24 DS, 24 age-/sex-matched ID, and 24 age-/sex-matched healthy, control children. Serum levels of the cytokines IL-5, IL-10, IL-13, IFN-γ, and TNF-α were measured using a sandwich ELISA method, . The age range of the children was 1-15 years, with a mean ± SD of 5.75 ± 4.36 years. TNF-α levels were significantly higher in the DS and ID groups compared with those found in healthy, control children (P<0.05). The DS and ID groups had significantly higher IFN-γ levels compared with healthy, control children (P = 0.0002 and P<0.01, respectively), with significant higher levels in the DS than the ID group (P<0.05). Serum from the ID group showed significantly higher IL-10 levels compared with those from the DS group (P<0.05), but not the healthy, control group. Significant correlations were found between the differences in TNF-α and IFN-γ levels, in both ID (rs = 0.558; P = 0.005) and DS children (rs = 0.405; P<0.05). There were no significant differences found in serum levels of IL-13 between the groups, and IL-5 was not detectable in any of the serum samples. Levels of TNF-α and IFN-γ were increased, and IL-10 decreased in serum from children with DS. It may be that these differences contribute to the clinical symptoms seen in DS: consequently, these pro-inflammatory cytokines might be useful as early biomarkers of the disorders associated with DS.     

Age and chromosome nondisjunction]

The parental age in 77 families of Down syndrome (DS) children with the known origin of extra chromosome 21 and in 12 families of DS children resulting from de novo translocation (more probable than not in 2 meiotic division) was studied. It was shown that when nondisjunction occurred in the 1st meiotic division, both in oogenesis (n = 30) and spermatogenesis (n = 12), mean parental ages and age distributions were different from that of control (400 couples with normal children). The mean age and age distribution were found to differ from control when nondisjunction occurred in the 2nd meiotic division of oogenesis (n = 19). On the basis of our information and the previously published data, lack of the effect of parental age on chromosome segregation in the Ist meiosis may be inferred. It is chromatid disjunction in the 2nd meiosis which is more probably age-dependent. The reasons preventing elucidation of real associations are under debate.     

Clinical and genealogical characteristics in families with Nijmegen breakage syndrome

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, immunodeficiency and high predisposition for malignancies, particularly B-lymphoma. Clinical and genealogical analysis has been conducted in 7 families with NBS. Eight children with NBS (5 boys and 3 girls) were observed at the age from 7 months to 11 years. All the children were homozygous carriers for mutation 657del5. Oncohematological complications developed in 5 cases (4 cases of lymphoma and one case of lymphohystiocytosis) at the age of 6-12 years. NBS in probands is often accompanied with birth defects, especially with kidney pathologies. Considerable reproductive losts in the families with NBS were noted mainly among males who died at the age less than one year (4-6 events in the families). The cases of digestive system cancers (stomach, rectum, duodenum) were revieled in the family-trees. Consanguineous couple was observed in 1 case (marriage between third cousins) and 2 children had developed NBS in this family. Genealogical analysis seems to be very informative to predict somatic and reproductive disturbances in NBS families.     

Nephelometry determined serum immunoglobulin isotypes in healthy Thai children aged 2-15 years

Knowledge of what constitute normal serum immunoglobulin (Ig) concentrations are important for the diagnosis of immunologic disorders. Data on normal Ig evaluated by nephelometry are limited in healthy Asian children, none being available for Thai children. One hundred and forty-eight healthy Thai children aged 2-15 years were tested for serum immunoglobulins G, A, M, G1, G2, G3, and G4 (Ig G, A, M, G1, G2, G3, and G4) by nephelometry. Sixty-three percent were girls of median interquartile range age 6.9 (4.8-9.7) years. The geometric means for each Ig were summarized and categorized by age. Statistical analyses were used to compare Igs between sexes and age groups, and to compare IgG in this study with data from other published studies. The average ratios of IgG subclasses/IgG for Ig G1:2:3:4 were 66:22:5:7%. IgG, IgA, IgG2, and IgG3 concentrations showed a gradual increase with increasing age. There were no significant sex differences for any immunoglobulin isotype (P= 0.971). Our mean IgG concentration was lower than that measured by the radial diffusion method in healthy Thai children (P < 0.05). In all age groups, the mean IgG concentration in our study was significantly higher than that reported in Turkish and USA children, evaluated by the nephelometric and radial diffusion techniques, respectively (both P < 0.001). This study provides information about normal Ig concentrations measured by nephelometry in healthy Asian children and illustrates the importance of ascertaining normal Ig values for age- and ethnic-matched controls using the same assay to diagnose immunologic disorders correctly.     

HLA and trisomy 21. Confirmation of a trend of restricted HLA heterogeneity in parents of Down syndrome children

As the HLA system could play a role in the in utero selection process against abnormal fetuses, HLA-A and -B antigens were evidenced in 30 children with trisomy 21 and in their parents, using a standard microlymphocytotoxicity test. The comparison group included 60 families among whom 39 had HLA typing for paternity exclusion and 21 had been previously selected for a segregation study. Both groups consisted of nonconsanguineous Caucasians from the same geographical area. The Down syndrome (DS) children did not show a significant association with a specific HLA antigen. However, six out of 30 couples having a DS child showed two antigens shared at the A and/or B locus, compared to seven out of 60 control couples. The shared parental antigens were not selectively inherited, and the proportion of homozygote children at one locus was lower for DS (5/30) than for controls (13/60). These findings demonstrate the same trend as previously published but need to be confirmed by other investigators. Perhaps a strong selective pressure in favor of heterozygotes contributes to a better survival rate, as suggested from histocompatibility studies in animals.     

The occurrence of new mutants in the X-linked recessive Lesch-Nyhan disease.

In a population at equilibrium for a sex-linked lethal, one-third of the genes for that lethal must arise anew each generation. Therefore, one-third of all cases of Lesch-Nyhan disease, a severe X-linked recessive lethal disorder, should be new mutants. To test this hypothesis, we have collected 47 families, 20 with a single proband and 27 with multiple affected males in which the patients' mothers and other female relatives had been studied for heterozygosity. Available carrier detection tests identify heterozygous for HPRT deficiency in hair roots and skin fibroblasts. Only four mothers were found not to be carriers. This result deviates significantly from expected (P less than .001). Statistical tests for ascertainment effects indicated absence of bias for multiple proband families but strong bias in favor of families with many heterozygous females. When the analysis was limited to single proband families, the deviation from expected was still significant (P less than .01). The incidence of new mutants among the heterozygous mothers, as determined by the ratio of +/+ to +/- maternal grandmothers, should be one-half (see Appendix). Of all 20 maternal grandmothers studied, five were +/+ and 15 were +/- (P less than .05). Considering only the single proband families, the ratio of 5 +/+ to 8 +/- was not significantly different from expected. In four of the five cases in which the heterozygous mother of an affected individual was a new mutation, the age of her parents was considerably higher than the mean parental age in the population. This raises the possibility of a paternal age effect on X-linked mutations. There appears to be a true deficiency of new mutatnts among males but not among females. Data on additional Lesch-Nyhan families are needed before conclusions regarding a possible higher mutation rate in males can be drawn.     

Analysis of genetic heterogeneity of bronchial asthma in relation with the age at the onset of disease

Earlier, the distribution of bronchial asthma (BA) morbidity with respect to the age of onset (AO) in the Moscow population was found to be bimodal. The distribution had two peaks (before and after 25 years of age) and a significant (P < 0.001) minimum between them. Based on these data, genetic heterogeneity of BA with respect to AO was hypothesized. The purpose of this study was to test this hypothesis via analysis of BA morbidity in families of probands with different AOs. The BA morbidity at different ages and the total recurrent risk of BA were estimated in 1518 relatives of 815 BA probands registered in several district outpatient clinics of Moscow. Based on the data obtained, phenotypic between relatives and correlation by genotype between early-onset and late-onset BA cases (with AOs under and over 25 years, respectively) were estimated. It was demonstrated for the first time that the age distribution of BA morbidity in families of probands was also bimodal. Moreover, when probands with early and late AOs were analyzed separately, proband relatives in each of the two groups exhibited these two peaks of morbidity. This suggests that BA that begins in adolescence and BA of adults are not genetically independent forms of the disease. This agrees with the data on the correlation by genotype between the "forms" with the early and late AOs, which does not significantly differ from 1. However, the prevalence of BA was higher in relatives of those probands who developed BA under the age of 25 compared to relatives of those who developed BA over the age of 25 (11.28 and 7.31%, respectively; P < 0.05). Therefore, patients with early-onset BA are more "burdened" genetically with respect to this disease. Since the BA genetic heterogeneity connected with AO has not been confirmed in this study, it is assumed that the observed bimodal distribution of BA morbidity with respect to age is accounted for by the effect of age itself. In other words, it is hypothesized that ontogenetic factors affect susceptibility to BA so that the susceptibility threshold varies with age.     

Healthy growth in children with Down syndrome

Objective

To provide cross-sectional height and head circumference (HC) references for healthy Dutch children with Down syndrome (DS), while considering the influence of concomitant disorders on their growth, and to compare growth between children with DS and children from the general population.

Study design

Longitudinal growth and medical data were retrospectively collected from medical records in 25 of the 30 regional hospital-based outpatient clinics for children with DS in the Netherlands. Children with Trisomy 21 karyotype of Dutch descent born after 1982 were included. The LMS method was applied to fit growth references.

Results

We enrolled 1,596 children, and collected 10,558 measurements for height and 1,778 for HC. Children with DS without concomitant disorders (otherwise healthy children) and those suffering only from mild congenital heart defects showed similar growth patterns. The established growth charts, based on all measurements of these two groups, demonstrate the three age periods when height differences between children with and without DS increase: during pregnancy, during the first three years of life, and during puberty. This growth pattern results in a mean final height of 163.4 cm in boys and 151.8 cm in girls (−2.9 standard deviation (SD) and −3.0 SD on general Dutch charts, respectively). Mean HC (0 to 15 months) was 2 SD less than in the general Dutch population. The charts are available at www.tno.nl/growth.

Conclusions

Height and HC references showed that growth retardation in otherwise healthy children with DS meanly occurs in three critical periods of growth, resulting in shorter final stature and smaller HC than the general Dutch population shows. With these references, health care professionals can optimize their preventive care: monitoring growth of individual children with DS optimal, so that growth retarding comorbidities can be identified early, and focusing on the critical age periods to establish ways to optimize growth.     

Will granny save me? Birth status,survival, and the role of grandmothers in historical Finland

Grandmothers play a crucial role in families enhancing grandchild wellbeing and survival but their effects can be context-dependent, and the children born in poor conditions are most likely to benefit from the investments made by helping grandmothers. In this study, we examined, for the first time, whether grandmothers' presence modified associations between adverse birth status and survival up to 5 years of age. In detail, we verified, whether (i) firstborns, (ii) twins, (iii) children born within 24 months after their sibling, and (iv) children followed by short interval (i.e. their younger sibling was born within 24 months) survived better when either their maternal, paternal, or both grandmothers were present. Moreover, we evaluated whether illegitimate children survived better when the maternal grandmother was present. We used an extensive and largely pre-industrial demographic dataset collected from parish population registers kept by the Lutheran Church of Finland from years 1730–1895. We show that although grandmother presence cannot mitigate adverse effects of many poorer birth conditions, grandchildren whose next sibling was born after a short interval survived better when the maternal grandmother was present. Taken together, these findings highlight an important role of grandmothers in compensating the mother's investment in the new baby, thus enabling overall faster successful reproductive rate of mothers. Whilst the opportunity for grandmothers to mitigate the risks of adverse birth statuses is limited, this study does show - through the beneficial effect on survival for those with a short subsequent birth interval - that grandmothers can increase their daughters' and their own reproductive success.     

HLA haplotype segregation in families of type 1 diabetics

The hypothesis of linkage between HLA and a disease susceptibility (DS) locus (or loci) for type 1 diabetes was tested. HLA segregation was random among 57 non-diabetic sibs but not among 39 diabetic sibs, suggesting that susceptibility to type 1 diabetes may be due to an HLA-linked gene(s). The data did not fit a genetic model involving either a single recessive or dominant gene. The excess of HLA-identical diabetic sibs and the reduced number who were HLA-discordant compared to expected numbers indicated that factors from both paternal and maternal haplotypes were necessary for DS. In 1 of the 3 families with a diabetic parent and more than one diabetic sib, the diabetic sibs inherited different haplotypes from the affected parent, suggesting that either of these haplotypes conferred DS. HLAB 8, B 18 and B 40 were increased in frequency among 97 unrelated type 1 diabetics compared with 238 controls, especially among those with onset age less than 10 years. This early onset group may represent a subtype of type 1 diabetes.     

Development of Overweight in Children in Relation to Parental Weight and Socioeconomic Status

The purpose of the study was to test the hypothesis that socioeconomic status (SES) moderates the association between parental weight and changes in BMI from childhood to early adolescence. Participants included 428 twin children from 100 families with obese parents (“obese families”) and 114 sociodemographically matched families with normal‐weight parents (“lean families”) who were assessed in their homes (age = 4.4). Follow‐up study was conducted 7 years later (age = 11.2) on 346 children (81%). Complete data were available for 333 children. Family SES was indexed with maternal education. Children's weights and heights were measured to calculate BMI s.d. scores based on 1990 British norms. Overweight was defined as >91st BMI centile. In children with obese parents, BMI s.d. scores increased from 0.51 at age 4 to 1.06 at age 11. In children with lean parents, BMI s.d. scores decreased from 0.11 to 0.05. Prevalence of overweight remained stable from age 4 to 11 in children with lean parents (8% to 9%), but it more than doubled in children with obese parents (17% to 45%). There was a significant interaction between parental weight and family SES (P < 0.01), so that in children with lean parents there was no SES difference in the BMI status from age 4 to 11; however, in children with obese parents, the increase in adiposity was significantly greater in lower SES families. These results suggest that parental leanness confers significant protection against development of overweight in children regardless of family SES, while parental obesity is an adverse prognostic sign, especially in lower SES families.     

Case-control study of whether subfertility in men is familial.

OBJECTIVE--To test the hypothesis that subfertility in men is familial and to examine the distribution of subfertility within families for consistency with a genetic cause. DESIGN--Case-control study and segregation analysis. SETTING--Two teaching hospitals in Leeds. SUBJECTS--Cases (probands) were men with an abnormal sperm count who attended a subfertility clinic and whose partners had no major factor contravening fertility. Controls were fathers of two or more children recruited through vasectomy clinics or a maternity department. MAIN OUTCOME MEASURES--The incidence of involuntary childlessness among brothers with partners and among sisters and second and third degree male relatives. When possible clinical and laboratory details were obtained from involuntarily childless brothers. RESULTS--Seventeen of the 148 (11.5%) brothers of probands but none of the 169 brothers of controls had sought medical advice for childlessness (P < 0.0005). Four probands had more than one involuntarily childless brother. There were six further brothers whose childlessness was thought to be involuntary bringing the total prevalence of subfertility among brothers of probands to 16%. Segregation analysis was consistent with an autosomal recessive mode of inheritance accounting for 60% of subfertility in men. Seventeen of the 346 (4.9%) uncles of probands and 10 of 420 (2.8%) uncles of controls were reported to be involuntarily childless (P = 0.09), but there was no difference in childlessness among sisters. In three families sperm counts from "affected" brothers confirmed the diagnosis and showed considerable similarities within but not between families. CONCLUSION--Subfertility in men has a familial component, and the observations are consistent with an autosomal recessive mode of inheritance in over half the cases. Several different genes are probably involved.     

Complex segregation analysis of obsessive-compulsive disorder in families with pediatric probands

OBJECTIVE: The purpose of this study was to assess the mode of inheritance for obsessive-compulsive disorder (OCD) in families ascertained through pediatric probands. METHODS: We ascertained 52 families (35 case and 17 control families) through probands between the ages of 10 and 17 years. Direct interviews were completed with 215 individuals. Family informant data were collected on another 450 individuals without direct interviews, forming two data sets with one contained within the other. Complex segregation analyses were performed using regressive models as programmed in REGTL in the S.A.G.E. package.All models used in the analyses included sex-specific age and type parameters. RESULTS: All models that excluded a residual effect of an affected parent were rejected. With that parameter included, the environmental and sporadic models were rejected in comparisons with the most general model in both data sets (all p < 0.005). With the direct interview data, the general codominant Mendelian model was not rejected when compared with the most general model (p = 0.140). We could not distinguish between any of the simple Mendelian models using either data set. However, the dominant Mendelian model provided a somewhat better fit than the other Mendelian models to the direct interview data. CONCLUSIONS: The results provide evidence for a major susceptibility locus in families with OCD when age at onset is incorporated into the model. Mendelian factors at most partially explained the familial aggregation of the phenotype, and residual familial effects were necessary to fit the data adequately. The results support the importance of linkage efforts by suggesting that a major locus is segregating within a proportion of families with OCD ascertained through pediatric probands.     

Proguanylin: development, analytical characterization, and clinical testing of a new ELISA

The aim of our work was to develop an assay for the determination of proguanylin in human blood, and investigate its levels in healthy volunteers and donors suffer from hypertension often accompanied by body sodium accumulation and plasma volume expansion. We developed and evaluated the sandwich ELISA method for the quantitative determination of human proguanylin in serum samples. We conducted also the pilot study on individuals with hypertension and oh healthy probands and measured proguanylin serum levels, serum and urine sodium and creatinine levels. In the study on 256 healthy volunteers we demonstrated that women have significantly higher values of proguanylin than men (medians 12.7 vs. 9.6 ng/ml, p < 0.01) and proguanylin values increased with age of individuals (p < 0.01). Futhermore, we tested 17 individuals with hypertension and found that probands with anamnesi of hypertension had higher proguanylin values than healthy individuals from the first study (medians 16.2 vs. 11.3 ng/ml, p < 0.01). Both of groups did not differ in sex or age. Proguanylin values correlated with the systolic blood pressure (r = 0.41, p < 0.01), sodium fraction excretion (r = 0.72, p < 0.01) and serum sodium (r = -0.39, p < 0.01). No significant correlation we found with serum proguanylin and creatinine. In the group of 9 healthy probands we demonstrated the existence of a diurnal rhythm of proguanylin with its maximum in the evening hours (between 6-10 p.m.). The pilot study supports the hypothesis about the role of proguanylin in sodium metabolism and its possible importance for hypertension disorder. Further research is necessary to confirm our findings in individuals with hypertension with different medication in order to assess proguanylin value as a risk predictor of accelerated hypertension, and to classify individuals with hypertension for variuos types of diuretic therapy.     

Antioxidant system in Down syndrome: a possible role in cataractogenesis

Recent studies show a relationship between oxidants, antioxidants, and degenerative disease of aging like cataract formation. Focal lens cortical changes and cortical liquification have been reported in patients with Down syndrome (DS) over 14 years. There is evidence supporting the hypothesis that trisomy 21 patients have an increase in free radical reactions. These changes in antioxidant system may play a role in cataractogenesis in Down syndrome. We screened serum samples from 12 patients with DS and cataract: and 12 healthy age and sex-matched persons. We evaluated the antioxidant enzyme activities of superoxide dismutase (SOD), glutathione peroxidase (GSHPx), glutathione-S-transferase (GST) and reduced glutathione (GSH) in erythrocytes. SOD and GSHPx levels of patients with DS were significantly higher than the control group. No significant changes were observed in GST and GSH levels between the DS and control groups. These findings suggest impairment in antioxidant system, which may be a possible mechanism for early cataract formation in DS.     

Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations

Autosomal dominant parkinsonism has been attributed to pathogenic amino acid substitutions in leucine-rich repeat kinase 2 (LRRK2). By sequencing multiplex families consistent with a PARK8 assignment, we identified a novel heterozygous LRRK2 mutation. A referral sample of 248 affected probands from families with autosomal dominant parkinsonism was subsequently assessed; 7 (2.8%) were found to carry a heterozygous LRRK2 6055G-->A transition (G2019S). These seven patients originate from the United States, Norway, Ireland, and Poland. In samples of patients with idiopathic Parkinson disease (PD) from the same populations, further screening identified six more patients with LRRK2 G2019S; no mutations were found in matched control individuals. Subsequently, 42 family members of the 13 probands were examined; 22 have an LRRK2 G2019S substitution, 7 with a diagnosis of PD. Of note, all patients share an ancestral haplotype indicative of a common founder, and, within families, LRRK2 G2019S segregates with disease (multipoint LOD score 2.41). Penetrance is age dependent, increasing from 17% at age 50 years to 85% at age 70 years. In summary, our study demonstrates that LRRK2 G2019S accounts for parkinsonism in several families within Europe and North America. Our work highlights the fact that a proportion of clinically typical, late-onset PD cases have a genetic basis.