Quantitative 3D evaluation of step ascent and descent in individuals with Down syndrome--analysis of a daily challenging task.

BACKGROUND: Step ascent and descent can perturb stability increasing the incidence of falls, especially in older individuals with functional limitations and intellectual disabilities, such as those with Down syndrome (DS). The aim of this study was to investigate the biomechanics and motor coordination of step ascent and descent in adults with DS and compare them with a group of healthy individuals, considering movement kinematics and kinetics. METHOD: Fourteen adults with DS and 12 similarly aged adults without DS who were free of known motor problems were quantitatively assessed during ascending and descending a step using an optoelectronic system (BTS SMART-D), force platforms and video recording. Kinematic and kinetic parameters were identified and calculated for each study participant and comparisons were made between the DS and a control group (CG). RESULTS: Despite similar age ranges, subjects in the DS group performed the step ascent and descent movements slower, with longer duration and with a more accentuated range of motion of the trunk and of the ankle joint than those in the CG. Additionally, the double stance phase on the step was substantially longer in the DS group when represented as a percentage of the entire stepping sequence (ascent, double stance on the step and descent). In terms of kinetics, ground force platform data revealed that the DS subjects showed higher instability in the medio-lateral direction during double support phase than similarly aged CG subjects and cannot be attributed to age-associated changes in stability. CONCLUSIONS: These findings help to elucidate the complex biomechanical strategy of people with DS during a step ascent and descent movement task and may have a major role in the multidimensional evaluation and tailored management for them.

A complex mutable polymorphism located within the fragile X gene.

While studying founder chromosomes in the fragile X syndrome, we have unexpectedly found linkage equilibrium to FRAXAC2, an Alu-associated microsatellite within the defective gene, FMR-1. DNA sequencing of 265 chromosomes revealed 39 alleles and a complex microsatellite of form (GT)x-C-(TA)y-(T)z. A mutation rate of 3.3% was observed but only among fragile X maternally derived meioses. Finding a second mutable locus within FMR-1 suggests that the target for tandem repeat instability may not be confined to the (CGG)n repeat alone and raises the possibility of an FMR-1 mutation mechanism involving microsatellites.

Evidence of founder chromosomes in fragile X syndrome.

The mutation responsible for fragile X syndrome and myotonic dystrophy involves the amplification of a simple trinucleotide repeat sequence, which increases in successive generations of affected pedigrees accounting for increasing penetrance of both disorders. This common molecular basis suggests that the two diseases may share other genetic features, but whereas myotonic dystrophy exhibits a significant founder chromosome effect, fragile X syndrome apparently has a very high mutation frequency. By haplotype analysis of microsatellite markers which flank the fragile X unstable element, we have uncovered evidence of founder chromosomes of the fragile X 'mutation'. Disorders caused by heritable unstable elements may therefore exhibit common genetic properties including anticipation and founder chromosomes.

Autism severity is associated with child and maternal MAOA genotypes.

Autism severity is associated with child and maternal MAOA genotypes. We replicated and extended a previously reported association between autism severity and a functional polymorphism in the monoamine oxidase A (MAOA) promoter region, MAOA-uVNTR, in a sample of 119 males, aged 2-13 years, with autism spectrum disorder from simplex families. We demonstrated that (i) boys with the low activity 3-repeat MAOA allele had more severe sensory behaviors, arousal regulation problems, and aggression, and worse social communication skills than males with the high activity allele; and (ii) problems with aggression, as well as with fears and rituals, were modified by the mothers' genotype. Boys with the 4-repeat high activity allele who had homozygous 4-repeat mothers showed increased severity of these behaviors relative to those born to heterozygous mothers. These findings indicate the importance of considering maternal genotype in examining associations of MAOA and other genes with behavior in male offspring.

Association of aggressive behaviours with psychiatric disorders, age, sex and degree of intellectual disability: a large-scale survey.

BACKGROUND: The link between aggression and mental disorders has been the focus of diverse studies in persons with and without intellectual disabilities (ID). Because of discrepancies in the finding of studies in persons with ID to date, and because of differences in research design, instruments used and the population studied, more research is needed. The purpose of this study was to delineate any significant association between certain psychiatric disorders and specific domains of aggressive behaviours in a large sample of persons with ID controlling for sex, age, autism and degree of ID. METHOD: Data from the present study were obtained from 47% of all persons with ID receiving services from New York State agencies, using the Institute for Basic Research - Modified Overt Aggression Scale (IBR-MOAS between 2006 and 2007). The IBR-MOAS was completed by the chief psychologists of 14 agencies based on information from the participants' files. Demographic information obtained included the psychiatric diagnosis made by the treating psychiatrist as well as information on age, sex and degree of ID. Data from 4069 participants were analysed. RESULTS: Impulse control disorder and bipolar disorder were strongly associated with all five domains of aggressive behaviour in the IBR-MOAS. Psychotic disorder was highly associated with four domains except for physical aggression against self (PASLF), which was of borderline significance. Anxiety was most associated with PASLF and verbal aggression against self (VASLF); depression with VASLF; obsessive compulsive disorder with physical aggression against objects (PAOBJ); personality disorders with verbal aggression against others (VAOTH), VASLF and PASLF; and autism with physical aggression against others (PAOTH), PAOBJ and PASLF. Mild to moderate ID was associated with VAOTH and VASLF and severe to profound ID with PAOBJ and PASLF. Female sex was most associated with VASLF. CONCLUSIONS: Impulse control, mood dysregulation and perceived threat appear to underlie most of the aggressive behaviours reported. Psychosis and depression appeared to have been over-diagnosed in persons with mild to moderate ID and under-diagnosed in persons with severe and profound ID. These findings replicate and extend findings from previous studies. The pattern of associations reported can be used as helpful indicators by professionals involved in the treatment of aggressive behaviours in persons with ID.

Genetic analysis of first-trimester miscarriages with a combination of cytogenetic karyotyping, microsatellite genotyping and arrayCGH.

Miscarriage is the spontaneous loss of an embryo or fetus before the 20th week of pregnancy. Most miscarriages occur before the end of the first trimester (<13 weeks). Although many risk factors relate to this occurrence, genetic factors play the most important role. Chromosomal abnormalities, including both numerical and structural anomalies, underlie the majority of miscarriages. In this study, we employed a comprehensive approach using cytogenetic karyotyping, polymerase chain reaction (PCR)-based genotyping, and microarray-based comparative genomic hybridization (arrayCGH) in combination to analyze chromosomal profiles of 115 first-trimester miscarriages of Chinese women. Seventy cases (61%) were found to have chromosomal anomalies, of which 90% were numerical and 10% were structural. Cytogenetic karyotyping identified 78.6% (55/70), PCR assays 2.9% (2 triploids), and arrayCGH 18.6% (13/70) of the anomalies. In this study, a microdeletion of 108 kb and four microduplications sizing from 300 to 1460 kb were observed. An advantage of using this combination approach is that microsatellite genotyping and arrayCGH can be accomplished in spite of culture failure and maternal cell contamination. In addition, arrayCGH can detect submicroscopic chromosomal anomalies and gene dosage alterations.

Psychotic manifestations in a patient with mental retardation and a 6.2 megabase deletion at the distal short arm of chromosome 12.

Genetic factors are known to contribute to the development of schizophrenia and related psychoses. Cytogenetic abnormalities have been occasionally found in patients with psychotic disorders and, thus, have helped identify candidate gene contributors for these conditions. The individual described here first presented with mental retardation and anxiety disorder in his mid-childhood. In his early 20s, the patient started exhibiting various psychotic manifestations, including delusions and hallucinations. His psychotic symptoms were difficult to control with psychotropic medications. The family history was negative for psychiatric disorders. This patient was found to have a 6.2 megabase deletion of the terminal portion of the short arm of chromosome 12 that was characterized using fluorescence in situ hybridization and microarray comparative genomic hybridization analysis. The maternal chromosomes were normal, but the paternal chromosomes could not be tested. To-date such a chromosomal abnormality has not been described in association with schizophrenia/psychosis. This case suggests that psychosis-associated gene(s) may be located in the terminal region of the short arm of chromosome 12.

Relation between clinical features of the mitral prolapse syndrome and echocardiographically documented mitral valve prolapse.

Mitral valve prolapse, the most common inherited cardiovascular condition, has been associated with a variety of signs, symptoms and electrocardiographic abnormalities, but the true spectrum of the mitral prolapse syndrome remains in doubt because clinical findings often contribute to patient identification and their prevalence in patient groups may be overstated because of ascertainment bias. Accordingly, clinical findings in 88 patients with echocardiographic mitral prolapse were compared with those in 81 of their adult first degree relatives with mitral prolapse (a group free of ascertainment bias) and in two control groups without mitral prolapse: 172 first degree relatives and 60 spouses. Comparison of relatives with and without mitral prolapse demonstrated true associations between mitral prolapse and clicks or murmurs, or both (67 versus 9%, p less than 0.001), thoracic bony abnormalities (41 versus 16%, p less than 0.001), systolic blood pressure less than 120 mm Hg (53 versus 31%, p less than 0.001), body weight 90% or less of ideal (31 versus 14%, p less than 0.005) and palpitation (40 versus 24%, p less than 0.01). In contrast, relatives with mitral prolapse showed no significant increase over normal relatives or spouses without mitral prolapse in prevalence of chest pain, dyspnea, panic attacks, high anxiety or repolarization abnormalities, but these features were all more common in women than in men (p less than 0.01 to less than 0.001). Thus, the true spectrum of the mitral prolapse syndrome encompasses a midsystolic click and late systolic murmur, thoracic bony abnormalities, low body weight and blood pressure and palpitation. Other suggested clinical features, including nonanginal chest pain, dyspnea, panic attacks and electrocardiographic abnormalities, have appeared to be associated with mitral valve prolapse because of ascertainment bias and an erroneous classification of differences between men and women as being due to mitral valve prolapse.

Genome-wide differential expression of synaptic long noncoding RNAs in autism spectrum disorder.

A genome-wide differential expression of long noncoding RNAs (lncRNAs) was identified in blood specimens of autism spectrum disorder (ASD). A total of 3929 lncRNAs were found to be differentially expressed in ASD peripheral leukocytes, including 2407 that were upregulated and 1522 that were downregulated. Simultaneously, 2591 messenger RNAs (mRNAs), including 1789 upregulated and 821 downregulated, were also identified in ASD leukocytes. Functional pathway analysis of these lncRNAs revealed neurological pathways of the synaptic vesicle cycling, long-term depression and long-term potentiation to be primarily involved. Thirteen synaptic lncRNAs, including nine upregulated and four downregulated, and 19 synaptic mRNAs, including 12 upregulated and seven downregulated, were identified as being differentially expressed in ASD. Our identification of differential expression of synaptic lncRNAs and mRNAs suggested that synaptic vesicle transportation and cycling are important for the delivery of synaptosomal protein(s) between presynaptic and postsynaptic membranes in ASD. Finding of 19 lncRNAs, which are the antisense, bi-directional and intergenic, of HOX genes may lead us to investigate the role of HOX genes involved in the development of ASD. Discovery of the lncRNAs of SHANK2-AS and BDNF-AS, the natural antisense of genes SHANK2 and BDNF, respectively, indicates that in addition to gene mutations, deregulation of lncRNAs on ASD-causing gene loci presents a new approach for exploring possible epigenetic mechanisms underlying ASD. Our study also opened a new avenue for exploring the use of lncRNA(s) as biomarker(s) for the early detection of ASD.

Autism and the fragile X syndrome.

The fragile X chromosome is an important factor in inherited mental retardation in males. It has also been reported that infantile autism is associated with fragile X. Recently, an article reported an examination of a small sample of autistic children in whom the fragile X chromosome was not found. Its authors concluded that if an association between fragile X and autism exists, it is infrequent. In the present study of 144 autistic male subjects, 18 were found to have the fragile X chromosome, supporting other (epidemiological) findings that the association between fragile X and autism occurs relatively frequently.

Progeria: a human-disease model of accelerated aging.

Progeria is a rare genetic disease with striking features that resemble accelerated aging. The inheritance pattern, paternal age effect, and lack of consanguinity argue that it is due to a sporadic dominant mutation. We have observed elevated levels of hyaluronic acid (HA) excretion in progeria patients. In several progeria patients we observed normal levels of growth hormone (GH) but very low levels of insulin-like growth factor I along with very high basal metabolic rates (BMRs). A trial of GH treatment was begun, which resulted in a marked increase in linear growth and a paradoxical drop in BMRs in these two patients. We hypothesize that the failure of patients with progeria to thrive may be due to a bioinactive form of GH and a lack of vasculogenesis caused by excess HA. An understanding of the progeria genetic mutation may define a key gene with a major effect on normal aging.

Human mutations affecting aging--a review.

A review of human genetic mutations that affect aging and their potential contribution to help understand normal aging processes is presented. The lifespans of most animal species, including man, have a genetically determined maximum. The lifespan of man appears to have evolved exceedingly rapidly, which suggests that relatively few genes may determine longevity. Analysis of biochemical evolution suggests that the regulation of enzyme levels may underlie most evolutionary changes. There is a wide spectrum of human genetic mutations. Some, such as progeria and Werner's syndrome, produce a phenotype resembling premature aging and may involve genes related to the aging process. Certain human chromosomal abnormalities, such as Down's syndrome, produce an appearance of premature aging and may be due to abnormal gene regulatory mechanisms. Progress in understanding the genetic mechanisms underlying aging is likely to come from elucidation of the molecular defects that result in the premature aging syndromes and from insights gained regarding the regulatory mechanisms governing eukaryotic genetic expression.

Urinary hyaluronic acid elevation in Hutchinson-Gilford progeria syndrome.

The basic genetic defect in the Hutchinson-Gilford Progeria Syndrome (progeria), a premature aging syndrome, is unknown. To investigate possible defects in hyaluronic acid (HA) metabolism in this disease, the urinary excretion of HA was studied. Urine specimens from 11 patients with this disorder were examined for HA by a novel high performance liquid chromatography (HPLC) technique. In patients with progeria, HA excretion ranged from 169 micrograms HA/g creatinine to 1440 micrograms HA/g creatinine. In normal age-matched controls, HA excreted ranged from 0 to 77 micrograms HA/g creatinine. In all, a mean 17-fold increase in HA excretion was observed in patients with progeria when compared with age-matched normal controls. Total glycosaminoglycan (GAG) excretion was not elevated. Amongst normal controls, a modest age-related increase in HA excretion was observed. These results suggest that urinary HA levels are abnormally elevated in progeria.

Clinical and molecular genetic study of a large German kindred with Gerstmann-Sträussler-Scheinker syndrome.

We have verified, by full open reading frame sequencing, the presence of an amino-acid-altering mutation in codon 102 of the scrapie amyloid protein gene in three affected members of a large and well-documented German family with experimentally transmitted Gerstmann-Sträussler-Scheinker syndrome. In addition, we identified the mutation by partial sequencing or DNA restriction enzyme analysis in three of 12 presently healthy family members with an affected parent, and none of 12 members without an affected parent. Thus, a total of six of 15 family members at risk for the disease (including the three established cases) had the same codon 102 mutation, a proportion consistent with the autosomal dominant inheritance pattern of disease expression. It is undetermined whether the mutation influences susceptibility to infection by an exogenous agent or is itself a proximate cause of disease.

A profile of cognitive deficit in females from fragile X families.

Fragile X, a recently discovered X-linked syndrome, is usually associated with mental retardation in affected males. Less consistent findings have been described for females. neuropsychological evaluation of seven nonretarded females from fragile X families suggested a characteristic profile: on Wechsler IQ tests, a positive Verbal-Performance score difference and lower subtest scaled scores on Arithmetic, Digit Span, Block Design, and Object Assembly; on the Wide Range Achievement Test, a lower score on Arithmetic than on Reading or Spelling; and on the Benton Visual Retention Test, defective recall. These results suggest the existence of X-linked learning disability in females.

Fmr1 knockout mouse has a distinctive strain-specific learning impairment.

The Fmr1 gene knockout mouse is a model for the human Fragile X mental retardation syndrome. Fmr1 knockout mice with a C57BL/6-129/OlaHsd hybrid background have been reported to have only a very mild deficiency in learning the Morris water maze task. We compared the effect of this knockout mutation on learning in mice with either an FVB/N-129/OlaHsd hybrid background or a C57BL/6 background. When FVB-129 mice were tested in a cross-shaped water maze task, the knockout mice showed a pronounced deficiency in their ability to learn the position of a hidden escape platform in comparison to normal littermates. In contrast, knockout mice with a C57BL/6 background learned the maze just as well as their normal littermates. Fear conditioning did not reveal differences between knockout and normal mice in either background. These results show that silencing the Fmr1 gene clearly interfered with learning a specific visuospatial task in FVB/N-129 hybrid mice but not in C57BL/6 mice. The strain dependence may model the influence of genetic background in the human Fragile X syndrome.

Changing manifestations of brown tumors on bone scan in renal osteodystrophy.

In a patient with chronic renal failure and secondary hyperparathyroidism, brown tumors, visualized initially as photon-deficient areas on bone scintigraphy, reverted to areas of abnormally increased activity following parathyroidectomy. This dual appearance on bone scan paralleled the functional state of the parathyroid gland. The possible relationship of hyperhosphatemia to the increased bone-scan activity noted in the calvarium, mandible, and facial bones is discussed.

Lack of association between dermal arches and mitral valve prolapse: relation to anxiety.

Mitral valve prolapse (MVP) has been reported to be associated with an increased frequency of dermal arches. To determine whether dermal arches are associated with MVP, 42 patients with echocardiographic (echo) MVP (probands) and 140 first-degree relatives in their families, including 48 with and 92 without MVP, were studied. Seventy-five, subjects with neither MVP nor blood relation to probands served as control subjects. Among the female probands, 6.9% had arches and among the males, 3.8% had arches. The proportion of arches was lower among female control subjects (4.0%) but higher among male control subjects (7.9%) (neither difference being significant [NS]). Among the relatives, 7.1% of the women with MPV and 4.6% of the women without MVP had arches (NS). Five percent of the men with MVP and 6.3% without MVP had arches (NS). No association existed between the occurrence of cardiovascular symptoms in patients and family members with MVP and presence of dermal arches, but a high proportion of probands with elevated trait anxiety without panic disorder had 4 or more dermal arches. These findings do not support a direct association of dermal arches with MVP.

Pulsed-field gradient-gel studies around the fragile site.

Using pulsed-field gradient-gel electrophoresis (PFGE) we compared two fragile X (fra(X] chromosomes from individuals in families that exhibit linkage heterogeneity between fra(X) and coagulation factor IX (F9). The analysis of very large restriction fragments indicated that there is a structural difference in the interval between fra(X) and F9 near the locus DXS105. Differences were observed in the Sfi I partial digestion analysis and in the Mlu I pattern of the DXS105 region. Digestion with Nru I and Sst II also showed differences between these alleles. The analyses suggest that the alleles differ in a region of greater than 200 kb. Analysis of other normal and fra(X) chromosomes will be necessary to determine whether the observed difference is a normal population variant or if it may be responsible for the linkage heterogeneity observed between these loci.

KH domain-containing proteins of yeast: absence of a fragile X gene homologue.

The KH domain is a region defined by its homology to the RNA-binding domains of the heterogeneous nuclear ribonucleoprotein K (hnRNPK). There are two such domains in the FMR1 protein which is underexpressed in the fragile X syndrome. We developed a computer method to search the S. cerevisiae protein sequences as they became available for the KH domain of the FMR1 protein. Using our motif and FINDPATTERNS of the Wisconsin Package of GCG, nine proteins were identified in the completed yeast ORF database that contain KH domains. Five proteins have known or predicted functions; four await functional analysis. Using GeneWorks and GeneJockeyII alignments, we found that the yeast protein KH domain showing the most similarity to either FMR1P KH domain was a KH domain in HX/SCP160. Its sequence is 50% identical to the second KH domain of FMR1P. However, SCP160 contains eight conserved and six degenerate KH domains. Further analysis showed that SCP160 is a better match overall to the vertebrate and C. elegans protein Vigilin, which also contains 14 KH domains. The next most similar yeast KH domain was found in YB83, a protein shorter than FMR1P and containing three KH domains, one of which shares 45% identity with the second KH domain in FMR1P. There is no significant overall sequence similarity between this yeast protein and FMR1P. Thus, while several proteins in yeast contain KH domains, no apparent yeast homologue exists for the FMR1 protein of the fragile X gene family.