SEARCH · PubMed Health

Results for “Neurodevelopmental Disorders”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 919 records · Page 51Linked to original sources

PubMed2005

Dissecting MECP2 function in the central nervous system.

Rett syndrome is a neurodevelopmental disorder and an important cause of mental retardation and autistic behavior in girls and in a small group of boys. In 1999, mutation of the methyl-CpG binding protein 2 (MECP2) gene encoding a transcriptional repressor on the X chromosome was found to cause Rett syndrome. Since this discovery, significant research has focused on the elucidation of its specific role in the central nervous system. Recent studies revealed that MECP2 is expressed in more differentiated neurons rather than in less differentiated neuroblasts and that MECP2 is involved in the maturation and maintenance of neurons, including dendritic arborization and axonal projections, rather than in early cell fate decisions in the mammalian brain. In this review, we summarize recent findings regarding regional, temporal, and cell type-specific MECP2 expression in the central nervous system; neurobiologic abnormalities in MECP2 -mutant mice; and MECP2 target genes in the central nervous system.

Animals↗

PubMed2005

Natural history of Rett syndrome.

Rett syndrome is a unique neurodevelopmental disorder, with onset of hypotonia, autistic tendency, and abnormalities of fine finger movements and gross movements of the arms in early infancy. Clinical features include specific age-dependent symptoms. Studies of early and late signs correlated locomotive dysfunction to language disability and stereotypy to regression of higher cortical functions. Studies of sleep parameters revealed early hypofunction of brainstem aminergic neurons and late occurrence of hypofunction of dopaminergic neurons, followed by receptor supersensitivity. The syndrome's pathophysiology suggests that early hypofunction of aminergic neurons interferes with the development of higher neuronal systems. Particular symptoms surface at different ages throughout the natural course of Rett syndrome, with regressional and static periods.

Age Factors↗

PubMed2005

Does genotype predict phenotype in Rett syndrome?

Mutations in the X-linked gene encoding the methyl-CpG binding protein MeCP2 are the primary cause of classic and atypical Rett syndrome and have recently been shown to contribute to other neurodevelopmental disorders of varying severity. To determine whether there are molecular correlates to the phenotypic heterogeneity, numerous groups have performed genotype-phenotype correlation studies. These studies have yielded conflicting results, in part because they used different criteria for determining severity and classifying mutations. Evolution of the phenotype with age and variable expressivity arising from individual variability in X-chromosome inactivation patterns are among other reasons the findings varied. Nonetheless, evidence of differences in the phenotypic consequences of specific types of mutations is emerging. This review analyzes the available literature and makes recommendations for future studies.

Brain Diseases↗

PubMed2006

Parenting stress and its relationship to the behavior of children with Joubert syndrome.

This study describes the relationship between parenting stress and behavior in children with Joubert syndrome, a rare genetic neurodevelopmental disorder. Parents (N = 43) reported severely impaired child adaptive behaviors. Most children did not show maladaptive behaviors, but a subset of approximately 20% displayed significant problems in areas such as inattention, overactivity, social withdrawal, and atypical behaviors. Mothers (59%) and fathers (40%) reported elevated levels of parenting stress. A hierarchical regression, including demographics, adaptive behavior, and maladaptive behavior, predicted 67% of the variance in mothers' stress and 40% of the variance in fathers' stress. Maladaptive behaviors uniquely contributed to maternal and paternal stress. The child's adaptive behavior level contributed significantly to parenting stress for mothers but not for fathers. Findings provide a better understanding of the impact of child behavior on parents caring for a child with Joubert syndrome.

Activities of Daily Living↗

PubMed2006

Tourette syndrome: the self under siege.

Tourette syndrome is a neurodevelopmental disorder characterized by motor and vocal tics--rapid, repetitive, stereotyped movements or vocalizations. Tourette syndrome typically has a prepubertal onset, and boys are more commonly affected than girls. Symptoms usually begin with transient bouts of simple motor tics. By age 10 years, most children are aware of nearly irresistible somatosensory urges that precede the tics. These urges likely reflect a defect in sensorimotor gating because they intrude into the child's conscious awareness and become a source of distraction and distress. A momentary sense of relief typically follows the completion of a tic. Over the course of hours, tics occur in bouts, with a regular intertic interval. Tics increase during periods of emotional excitement and fatigue. Tics can become "complex" in nature and appear to be purposeful. Tics can be willfully suppressed for brief intervals and can be evoked by the mere mention of them. Tics typically diminish during periods of goal-directed behavior, especially those that involve both heightened attention and fine motor or vocal control, as occur in musical and athletic performances. Over the course of months, tics wax and wane. New tics appear, often in response to new sources of somatosensory irritation, such as the appearance of a persistent vocal tic (a cough) following a cold. Over the course of years, tic severity typically peaks between 8 and 12 years of age. By the end of the second decade of life, many individuals are virtually tic free. Less than 20% of cases continue to experience clinically impairing tics as adults. Tics rarely occur in isolation, and other coexisting conditions--such as behavioral disinhibition, hypersensitivity to a broad range of sensory stimuli, problems with visual motor integration, procedural learning difficulties, attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, depression, anxiety, and emotional instability--are often a greater source of impairment than the tics themselves. Emerging behavioral treatments of Tourette syndrome are based in part on an understanding of the moment-to-moment experience of somatosensory urges and motor response. With identification of specific genes of major effect and advances in our understanding of the neural circuitry of sensorimotor gating, habit formation, and procedural memory--together with insights from postmortem brain studies, in vivo brain imaging, and electrophysiologic recordings--we might be on the threshold of a deeper understanding of the phenomenology and natural history of Tourette syndrome.

Adolescent↗

PubMed2006

Predictors of scoliosis in Rett syndrome.

Scoliosis is a common clinical manifestation of Rett syndrome, a neurodevelopmental disorder that almost exclusively affects girls. Following apparently normal development, these girls typically regress and lose previously attained cognitive, social, and motor skills. Severe intellectual and physical disabilities remain throughout life. Mutations in the methyl-CpG-binding protein 2 gene, MECP2, are detected in approximately 80% of cases and are associated with phenotypic variability. Population-based data on Australian cases were used to study the association between early developmental and genetic factors and the onset of scoliosis. The median age at scoliosis onset was 9.80 years, and three quarters of subjects had developed scoliosis by 13 years of age. Children with compromised early development before 6 months, those who were less mobile at 10 months, and those who never walked were more likely to have an earlier onset of scoliosis. When seven common point mutations and large genomic and C-terminal deletions were compared, the R294X mutation appeared to provide some protective effect against the development of scoliosis.

Adolescent↗

PubMed1998

Rett syndrome: significant clinical overlap with Angelman syndrome but not with methylation status.

Rett syndrome and Angelman syndrome are neurodevelopmental disorders characterized by severe intellectual disability, microcephaly, speech disturbance, movement disorders with gait and/or truncal ataxia, and occasionally a similar facial appearance. Both conditions can be difficult to diagnose in girls early in their clinical course and can be difficult to distinguish from each other. Genomic imprinting is a known association in Angelman syndrome and previously has been suggested in Rett syndrome. Our aim was to evaluate the methylation status in a cohort of classical patients with Rett syndrome, using a methylation system for chromosome 15q11-13. Methylation analysis of chromosome 15 has not been previously reported in Rett syndrome. Furthermore, we document the clinical features of 31 girls with classical Rett syndrome and confirm the phenotypic similarities between Rett syndrome and Angelman syndrome. The methylation studies in these girls with Rett syndrome were normal. This excludes an imprinting error of the Angelman syndrome critical region on chromosome 15 (15q11-13) as an association with Rett syndrome, and indicates that methylation studies may be useful in distinguishing Rett syndrome from Angelman syndrome in young patients with an overlapping clinical phenotype. A normal methylation pattern, however, does not exclude the diagnosis of Angelman syndrome and clear distinction between the two syndromes will evolve over time.

Adolescent↗

PubMed1999

Rett syndrome: randomized controlled trial of L-carnitine.

Rett syndrome is a severe neurodevelopmental disorder of unknown etiology, occurring almost exclusively in female patients. The etiology and functional significance of plasma carnitine deficiency seen in some patients with Rett syndrome is unknown. To investigate whether L-carnitine might be of benefit in Rett syndrome, a randomized, placebo-controlled, double-blind crossover trial of L-carnitine has been completed in 35 subjects. Eight-week treatment phases were completed for both a placebo and L-carnitine. Outcome was measured by parents/caregivers and at medical follow-up using three established tools: the Rett Syndrome Motor Behavioral Assessment, the Hand Apraxia Scale, and the Patient Well-Being Index. Analysis comparing change between baseline and week 8 of treatment for L-carnitine and the placebo showed that both parents/caregivers and medical follow-up detected improvements in the subjects' well-being. In addition, medical review showed an improvement on the Hand Apraxia Scale for a higher proportion of girls on L-carnitine. Identification of predictors of clinical improvement has been limited by the power of the study. These findings suggest that L-carnitine is of benefit in some patients with Rett syndrome. While L-carnitine did not lead to major functional changes in ability, the type of changes reported could still have a substantial impact on the girls and their families. Information is still needed, however, to determine if only subgroups of girls with the disorder are responsive to L-carnitine and the appropriate duration of therapy.

Adolescent↗

PubMed1999

Patterns of pregnancy loss, perinatal mortality, and postneonatal childhood deaths in families of girls with Rett syndrome.

Rett syndrome is a neurodevelopmental disorder that occurs predominantly in girls and results in severe physical and intellectual handicap. A popular genetic mechanism is an X-linked dominant disorder, lethal in males. A case control study design was used to investigate fetal wastage as indicated by reported miscarriage and stillbirth prevalence, and the prevalence and cause of reported neonatal and other childhood deaths. There was no disturbance in the sibling sex ratio when case and control families were compared. In the parental generation and in the proband generation miscarriages were reported in similar proportions in case and control families. The reported stillbirth rates in case families was almost double that in control families and reported perinatal loss was more common on the maternal side in case families than in control families. Stillbirths and neonatal deaths affected slightly more boys in the parental and proband generations of case families (19 of 30) than in control families (10 of 21). Childhood deaths also occurred a little more commonly in Rett syndrome families. Sudden infant death syndrome was reported in three siblings of Rett syndrome probands but in no control siblings. Confirmation of this pattern of perinatal loss and infant mortality could indicate an alternative expression of the Rett syndrome gene.

Abortion, Spontaneous↗

PubMed1999

Rett syndrome: 1H spectroscopic imaging at 4.1 Tesla.

Rett syndrome, a neurodevelopmental disorder predominantly affecting girls, is characterized by regression of psychomotor development, communication dysfunction, and hand stereotypies. Brain morphologic studies demonstrate increased neuronal packing density and reduced dendritic arborizations, suggesting an arrest or interruption of normal maturation. Numerous neurotransmitter systems have been implicated. Among these, cerebrospinal fluid glutamate levels are elevated and glutamate receptors, particularly in putamen, are reduced. Therefore, 1H spectroscopy at 4.1 Tesla was used to evaluate glutamate, creatine, and N-acetylaspartate in six girls with Rett syndrome and four normal sibling controls. The ratio of creatine to N-acetylaspartate was significantly elevated in white matter, primarily reflecting reduced N-acetylaspartate levels, and normal in gray matter. The glutamate to N-acetylaspartate ratio was elevated in gray matter and normal in white matter. These findings are consistent with previous neuropathologic and neurochemical findings and indicate the feasibility of imaging these metabolites in vivo.

Aspartic Acid↗

PubMed1999

Molecular approaches to the Rett syndrome gene.

Rett syndrome is a neurodevelopmental disorder affecting 1 in 10,000 to 15,000 females worldwide. Apparently normal at birth, girls with Rett syndrome undergo developmental regression and acquire a neurologic and behavioral profile that has been used to define diagnostic criteria for the disorder. Neurochemical and anatomic alterations indicate that Rett syndrome appears to result from an arrest of normal neuronal maturation. Although Rett syndrome generally occurs sporadically, rare familial recurrences indicate a genetic basis for the disorder. Data from familial recurrences are consistent with an X-linked dominant locus causing the classic phenotype in female patients and a distinct, more severe phenotype in hemizygous male patients. Exclusion mapping data from rare kindreds with recurrent Rett syndrome localize the gene to the distal long arm of the X chromosome (Xq27.3-Xqter).

Adolescent↗

PubMed2002

Mechanisms of hypoxic neurodegeneration in the developing brain.

Asphyxia and other insults to the developing brain are responsible for several human neurodevelopmental disorders. The pattern of neonatal brain injury differs from that seen in the adult nervous system, and there are wide differences in regional vulnerability. Recent evidence suggests that two events that contribute to this pattern of selective vulnerability are developmental changes in excitatory glutamate-containing neurotransmitter circuits and the propensity for immature neurons to die by apoptosis rather than necrosis. Developmental up-regulation of NMDA receptors with enhanced function and increased expression of caspase-3 at critical periods in development are linked to these mechanisms. Although these molecular changes enhance the developing brain's capacity for plasticity by helping to prune redundant synapses and neurons, they can become "Achilles heels" in the face of a brain energy crisis.

Apoptosis↗

PubMed2004

Frizzled 9 knock-out mice have abnormal B-cell development.

The binding of frizzled (Fzd) receptors by their Wnt ligands results in the inhibition of beta-catenin degradation and subsequent transcription of beta-catenin/LEF-inducible genes. The beta-catenin pathway is known to be involved in development, tumorigenesis, and stem cell self-renewal. In humans, the FZD9 gene lies in the region of chromosome 7q11.23 deleted in the neurodevelopmental disorder, Williams-Beuren syndrome (WBS). Fzd9-/- mice show no obvious features of WBS, but reveal a role for Fzd9 in lymphoid development and maturation. Fzd9-/- mice show pronounced splenomegaly, thymic atrophy, and lymphadenopathy with age, with accumulation of plasma cells in lymph nodes. There is a depletion of developing B cells in the bone marrow (BM), particularly in the pre-B stage where immunoglobulin heavy chains are expressed and the cells are undergoing clonal expansion prior to light chain rearrangement. The pre-B defect is partially intrinsic to the hematopoietic system; as in competitive BM reconstitution studies, Fzd9-/- -derived BM exhibits defective B-cell development when implanted into a wild-type host. Mature B cells are present in normal numbers in lymph node and spleen. These findings suggest a role for Fzd9 signaling in lymphoid development, particularly at points where B cells undergo self-renewal prior to further differentiation.

Animals↗

PubMed2006

Sensory defects in Necdin deficient mice result from a loss of sensory neurons correlated within an increase of developmental programmed cell death.

BACKGROUND: The human NECDIN gene is involved in a neurodevelopmental disorder, Prader-Willi syndrome (PWS). Previously we reported a mouse Necdin knock-out model with similar defects to PWS patients. Despite the putative roles attributed to Necdin, mainly from in vitro studies, its in vivo function remains unclear. In this study, we investigate sensory-motor behaviour in Necdin deficient mice. We reveal cellular defects and analyse their cause. RESULTS: We report sensory differences in Necdin deficient mice compared to wild type animals. These differences led us to investigate sensory neuron development in Necdin deficient mouse embryos. First, we describe the expression pattern of Necdin in developing DRGs and report a reduction of one-third in specified sensory neurons in dorsal roots ganglia and show that this neuronal loss is achieved by E13.5, when DRGs sensory neurons are specified. In parallel, we observed an increase of 41% in neuronal apoptosis during the wave of naturally occurring cell death at E12.5. Since it is assumed that Necdin is a P75NTR interactor, we looked at the P75NTR-expressing cell population in Necdin knock-out embryos. Unexpectedly, Necdin loss of function has no effect on p75NTR expressing neurons suggesting no direct genetic interaction between Necdin and P75NTR in this context. Although we exclude a role of Necdin in axonal outgrowth from spinal sensory neurons in early developmental stages; such a role could occur later in neuronal differentiation. Finally we also exclude an anti-proliferative role of Necdin in developing sensory neurons. CONCLUSION: Overall, our data show clearly that, in early development of the nervous system, Necdin is an anti-apoptotic or survival factor.

Animals↗

PubMed2001

A necdin/MAGE-like gene in the chromosome 15 autism susceptibility region: expression, imprinting, and mapping of the human and mouse orthologues.

BACKGROUND: Proximal chromosome 15q is implicated in neurodevelopmental disorders including Prader-Willi and Angelman syndromes, autistic disorder and developmental abnormalities resulting from chromosomal deletions or duplications. A subset of genes in this region are subject to genomic imprinting, the expression of the gene from only one parental allele. RESULTS: We have now identified the NDNL2 (also known as MAGE-G) gene within the 15q autistic disorder susceptibility region and have mapped its murine homolog to the region of conserved synteny near necdin (Ndn) on mouse Chr 7. NDNL2/MAGE-G is a member of a large gene family that includes the X-linked MAGE cluster, MAGED1 (NRAGE), MAGEL2 and NDN, where the latter two genes are implicated in Prader-Willi syndrome. We have now determined that NDNL2/Ndnl2 is widely expressed in mouse and human fetal and adult tissues, and that it is apparently not subject to genomic imprinting by the PWS/AS Imprinting Center. CONCLUSION: Although NDNL2/MAGE-G in the broadly defined chromosome 15 autistic disorder susceptibility region, it is not likely to be pathogenic based on its wide expression pattern and lack of imprinted expression.

Amino Acid Sequence↗

PubMed2005

Tourette Syndrome and learning disabilities.

BACKGROUND: Tourette Syndrome (TS) is a neurodevelopmental disorder of childhood. Learning disabilities are frequently comorbid with TS. Using the largest sample of TS patients ever reported, we sought to identify differences between subjects with TS only and subjects with TS and a comorbid learning disability. METHODS: We used the Tourette Syndrome International Consortium database (TIC) to compare subjects with comorbid Tourette Syndrome and learning disabilities (TS + LD) to subjects who did not have a comorbid learning disability (TS-LD). The TIC database contained 5,500 subjects. We had usable data on 5,450 subjects. RESULTS: We found 1,235 subjects with TS + LD. Significant differences between the TS + LD group and the TS-LD group were found for gender (.001), age onset (.030), age first seen (.001), age at diagnosis (.001), prenatal problems (.001), sibling or other family member with tics (.024), two or more affected family members (.009), and severe tics (.046). We used logistic modeling to identify the optimal prediction model of group membership. This resulted in a five variable model with the epidemiologic performance characteristics of accuracy 65.2% (model correctly classified 4,406 of 5,450 subjects), sensitivity 66.1%, and specificity 62.2%. CONCLUSION: Subjects with TS have high prevalence rates of comorbid learning disabilities. We identified phenotype differences between the TS-LD group compared to TS + LD group. In the evaluation of subjects with TS, the presence of a learning disability should always be a consideration. ADHD may be an important comorbid condition in the diagnosis of LD or may also be a potential confounder. Further research on etiology, course and response to intervention for subjects with TS only and TS with learning disabilities is needed.

Attention Deficit Disorder with Hyperactivity↗

PubMed2003

Insomnia is a frequent finding in adults with Asperger syndrome.

BACKGROUND: Asperger syndrome (AS) is a neurodevelopmental disorder belonging to autism spectrum disorders with prevalence rate of 0,35% in school-age children. It has been most extensively studied in childhood while there is scarcity of reports concerning adulthood of AS subjects despite the lifelong nature of this syndrome. In children with Asperger syndrome the initiation and continuity of sleep is disturbed because of the neuropsychiatric deficits inherent of AS. It is probable that sleep difficulties are present in adulthood as well. Our hypothesis was that adults with AS suffer from difficulty in initiating and maintaining sleep and nonrestorative sleep (insomnia). METHODS: 20 AS without medication were compared with 10 healthy controls devoid of neuropsychiatric anamnesis. Clinical examination, blood test battery and head MRI excluded confounding somatic illnesses. Structured psychiatric interview for axis-I and axis-II disorders were given to both groups as well as Beck Depression Inventory and Wechsler adult intelligence scale, revised version.Sleep quality was assessed with sleep questionnaire, sleep diary during 6 consecutive days and description of possible sleep problems by the participants own words was requested. RESULTS: compared with controls and with normative values of good sleep, AS adults had frequent insomnia. In sleep questionnaire 90% (18/20), in sleep diary 75% (15/20) and in free description 85% (17/20) displayed insomnia. There was a substantial psychiatric comorbidity with only 4 AS subject devoid of other axis-I or axis-II disorders besides AS. Also these persons displayed insomnia. It can be noted that the distribution of psychiatric diagnoses in AS subjects was virtually similar to that found among patient with chronic insomnia. CONCLUSIONS: the neuropsychiatric deficits inherent of AS predispose both to insomnia and to anxiety and mood disorders. Therefore a careful assessment of sleep quality should be an integral part of the treatment plan in these individuals. Conversely, when assessing adults with chronic insomnia the possibility of autism spectrum disorders as one of the potential causes of this condition should be kept in mind.

Adult↗

PubMed2006

Atypically diffuse functional connectivity between caudate nuclei and cerebral cortex in autism.

BACKGROUND: Autism is a neurodevelopmental disorder affecting sociocommunicative behavior, but also sensorimotor skill learning, oculomotor control, and executive functioning. Some of these impairments may be related to abnormalities of the caudate nuclei, which have been reported for autism. METHODS: Our sample was comprised of 8 high-functioning males with autism and 8 handedness, sex, and age-matched controls. Subjects underwent functional MRI scanning during performance on simple visuomotor coordination tasks. Functional connectivity MRI (fcMRI) effects were identified as interregional blood oxygenation level dependent (BOLD) signal cross-correlation, using the caudate nuclei as seed volumes. RESULTS: In the control group, fcMRI effects were found in circuits with known participation of the caudate nuclei (associative, orbitofrontal, oculomotor, motor circuits). Although in the autism group fcMRI effects within these circuits were less pronounced or absent, autistic subjects showed diffusely increased connectivity mostly in pericentral regions, but also in brain areas outside expected anatomical circuits (such as visual cortex). CONCLUSION: These atypical connectivity patterns may be linked to developmental brain growth disturbances recently reported in autism and suggest inefficiently organized functional connectivity between caudate nuclei and cerebral cortex, potentially accounting for stereotypic behaviors and executive impairments.

Journal Article↗