Severe Developmental Disorders Research Articles

Asperger Syndrome Associated With Idiopathic Infantile Nystagmus–A Report of 2 Cases

Asperger syndrome is a severe and chronic developmental disorder. It is closely associated with autism and is grouped under autism spectrum disorder (ASD). Various eye movement abnormalities in AS have been reported in literature such as increased errors and latencies on the antisaccadic task implicating dysfunction of the prefrontal cortex, impairment of the pursuit especially for targets presented in the right visual hemisphere, suggesting disturbance in the left extrastraite cortex. There are no reports in the literature of association between idiopathic infantile nystagmus (IIN) and AS. We report 2 cases of Asperger syndrome associated with idiopathic infantile nystagmus.

Expression of H-RASV12 in a zebrafish model of Costello syndrome causes cellular senescence in adult proliferating cells

Constitutively active, 'oncogenic' H-RAS can drive proliferation and transformation in human cancer, or be a potent inducer of cellular senescence. Moreover, aberrant activation of the Ras pathway owing to germline mutations can cause severe developmental disorders. In this study we have generated transgenic zebrafish that constitutively express low levels, or can be induced to express high levels, of oncogenic H-RAS. We observed that fish carrying the integrated transgene in their germline display several hallmarks of Costello syndrome, a rare genetic disease caused by activating mutations in the gene H-RAS, and can be used as a model for the disease. In Costello-like fish, low levels of oncogenic H-RAS expression are associated with both reduced proliferation and an increase in senescence markers in adult progenitor cell compartments in the brain and heart, together with activated DNA damage responses. Overexpression of H-RAS through a heat-shock-inducible promoter in larvae led to hyperproliferation, activation of the DNA damage response and tp53-dependent cell cycle arrest. Thus, oncogene-induced senescence of adult proliferating cells contributes to the development of Costello syndrome and provides an alternative pathway to transformation in the presence of widespread constitutively active H-RAS expression.

Autism in Economics? A Second Opinion

A popular claim among critics is that economic science is suffering from autism, a severe developmental disorder characterised by impairments in social relations and communication, combined with rigid and repetitive behaviour. So far, this allegation has not been substantiated. This essay explores the claim of autism in economics based on modern schemes of diagnostics. A key finding is that the structure of the critique against mainstream economics bears a striking resemblance to the structure of the diagnostic criteria for autism. Based on an examination of three groups of key symptoms, I conclude that the required set of criteria for the autism diagnosis are not met. However, there are parallels which may serve as constructive reminders for the future development and application of economic theories and models.

Lamines A et syndromes progéroïdes

Hutchinson-Gilford Progeria (HGPS), a rare and severe developmental disorder characterized by features recalling premature aging, and Restrictive Dermopathy (RD), a neonatal lethal genodermatosis, have recently been identified as being primary or secondary << Laminopathies >>. These heterogeneous disorders are caused by altered Lamin maturation pathway. In physiological conditions, mature Lamin A is obtained through a series of post-translational processing steps performed on a protein precursor, Prelamin A. The major pathophysiological mechanism involved in Progeria is an aberrant splicing due to a de novo heterozygous point mutation, leading to the accumulation of truncated Lamin A precursor. The same aberrant splicing mechanism was involved in RD, whereas the majority of RD cases are caused by ZMPSTE24/FACE1 inactivation, a key enzyme involved in the Lamin A maturation pathway. In functional terms, all these conditions share the same pathophysiological mechanism, i.e. the intranuclear accumulation of Lamin A precursors, which cannot be fully processed and exert a toxic effect on nuclear homeostasis. In this article, we review the structure and functions of A-type Lamins, focusing namely on HGPS, RD or MAD disorders, in relation to existing animal models and possible future therapeutic approaches.

Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1

Autism is a severe developmental disorder, whose pathogenetic underpinnings are still largely unknown. Temporocortical gray matter from six matched patient-control pairs was used to perform post-mortem biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier (AGC), which participates in the aspartate/malate reduced nicotinamide adenine dinucleotide shuttle and is physiologically activated by calcium (Ca(2+)). AGC transport rates were significantly higher in tissue homogenates from all six patients, including those with no history of seizures and with normal electroencephalograms prior to death. This increase was consistently blunted by the Ca(2+) chelator ethylene glycol tetraacetic acid; neocortical Ca(2+) levels were significantly higher in all six patients; no difference in AGC transport rates was found in isolated mitochondria from patients and controls following removal of the Ca(2+)-containing postmitochondrial supernatant. Expression of AGC1, the predominant AGC isoform in brain, and cytochrome c oxidase activity were both increased in autistic patients, indicating an activation of mitochondrial metabolism. Furthermore, oxidized mitochondrial proteins were markedly increased in four of the six patients. Variants of the AGC1-encoding SLC25A12 gene were neither correlated with AGC activation nor associated with autism-spectrum disorders in 309 simplex and 17 multiplex families, whereas some unaffected siblings may carry a protective gene variant. Therefore, excessive Ca(2+) levels are responsible for boosting AGC activity, mitochondrial metabolism and, to a more variable degree, oxidative stress in autistic brains. AGC and altered Ca(2+) homeostasis play a key interactive role in the cascade of signaling events leading to autism: their modulation could provide new preventive and therapeutic strategies.

A de novo apparently balanced translocation [46,XY,t(2;9)(p13;p24)] interrupting RAB11FIP5 identifies a potential candidate gene for autism spectrum disorder

Autism spectrum disorder (ASD) is a severe developmental disorder of the central nervous system characterized by impairments in social interaction, communication, and range of interests and behaviors. The syndrome's prevalence is estimated to be as high as 1 in 150 American children yet its etiology remains largely unknown. Examination of observed cytogenetic variants in individuals with ASD may identify genes involved in its pathogenesis. As part of a multidisciplinary study, an apparently balanced de novo translocation between chromosomes 2 and 9 [46,XY,t(2;9)(p13;p24)] was identified in a subject with pervasive developmental disorder not otherwise specified (PDD-NOS), and no distinctive dysmorphic features. Molecular characterization of the rearrangement revealed direct interruption of the RAB11 family interacting protein 5 (RAB11FIP5) gene. RAB11FIP5 is a Rab effector involved in protein trafficking from apical recycling endosomes to the apical plasma membrane. It is ubiquitously expressed and reported to contribute to both neurotransmitter release and neurotransmitter uptake at the synaptic junction. Detailed analysis of the rearrangement breakpoints suggests that the reciprocal translocation may have formed secondary to incorrect repair of double strand breaks (DSBs) by nonhomologous end-joining (NHEJ).

The Optimization of Polar Body Diagnosis – A Consequence of the Embryo Protection Law

Couples wishing to have progeny want to rule out an increased health risk for their children. Most of them do everything possible to recognize a potentially elevated risk in good time. This is a natural, but also justified concern, and medicine has an obligation to help these couples. Sociological reasons are to a great extent responsible for the fact that women’s reproductive time window has become steadily smaller and age at childbirth has increased over the last few decades. While in the old Federal Republic of Germany 8.4% of children were born to women over 35 years of age in 1975, in 2002 this rate had increased to 15.4% in Germany and to as high as 17 % in 2006 (1). The probability of conception decreases rapidly in women from the age of 35 years onwards. Many couples wishing to have children then frequently pin their hopes on reproduction medicine and especially on in vitro fertilization (IVF) techniques and intracytoplasmic sperm injection (ICSI). The older age of these women has in turn led to an increased rate of numerical chromosome aberrations in the oocytes. In a 40-year-old woman, 50% to 70% of the mature oocytes are affected by aneuploidy (2, 3). Most numerical aberrations are associated with such severe developmental disorders that early embryonic demise is the result.

Prenatally detected ureteropelvic junction obstruction: clinical features and associated urologic abnormalities

Urologic congenital anomalies associated with ureteropelvic obstruction (UPJO) have been previously characterized; however, less data are available regarding these associations in a prenatally diagnosed population. A retrospective study was conducted to evaluate significant clinical features and urological anomalies associated with prenatally diagnosed UPJO. The records of 143 children with prenatally diagnosed hydronephrosis secondary to UPJO were retrospectively reviewed. The gender, side of obstruction, degree of hydronephrosis, associated clinical features, and urological anomalies were noted. Hundred and forty-three children (M/F = 2.7) with a total of 198 affected renal units (RU) presenting with unilateral (61%) or bilateral (39%) UPJO were enrolled. In cases of unilateral obstruction, the left side was affected in 60 children (68%). The grade of hydronephrosis was Grade 1 in 56 RU (28%), Grade 2 in 51 RU (26%), Grade 3 in 50 RU (25%) and Grade 4 in 41 RU (21%). Associated clinical features included prematurity (n = 7, 4.9%), twinning (n = 5, 3.5%) and presentation with renal failure (RF) (n = 2). Excluding contralateral UPJO, other urologic anomalies were encountered in 29 patients (20.3%). Associated vesicoureteral reflux (VUR) was encountered in 11 patients (7.7%, M/F = 2.7). Pyeloplasty was required more often in children with associated VUR (54.5 vs. 18.2%) (P = 0.01). Contralateral multicystic dysplastic kidney (MCDK) was encountered in six patients (M/F = 2), one of whom presented with RF. One child carried the diagnosis of Schinzel-Giedion syndrome (SGS), demonstrating severe developmental and neurological disorders and bilateral hydronephrosis. The more frequent occurrence of UPJO in males with predominantly left-sided location, association with VUR and MCDK, and increased frequency of bilaterality in our prenatally diagnosed patients were similar to historical reports. In addition, prematurity and twinning were independently associated with UPJO. The higher rate of pyeloplasty in patients with associated reflux warrants further investigation.

Neural Plasticity: For Good and Bad

The brain’s ability to change its organization and function is necessary for normal development of the nervous system and it makes it possible to adapt to changing demands but it can also cause disorders when going awry. This property, known as neural plasticity, is only evident when induced, very much like genes. Plastic changes may be programmed and providing a “midcourse correction” during childhood development. If that is not executed in the normal way severe developmental disorders such as autism may results. Normal development of functions and anatomical organization of the brain and the spinal cord depend on appropriate sensory stimulation and motor activations. So-called enriched sensory environments have been shown to be beneficial for cognitive development and enriched acoustic environment may even slow the progression of age-related hearing loss. It is possible that the beneficial effect of physical exercise is achieved through activation of neural plasticity. The beneficial effect of training after trauma to the brain or spinal cord is mainly achieved through shifting functions from damaged brain area to other parts of the central nervous system and adapting these parts to take over the functions that are lost. This is accomplished through activation of neural plasticity. Plastic changes can also be harmful and cause symptoms and signs of disorders such as some forms of chronic pain (central neuropathic pain) and severe tinnitus. We will call such disorders “plasticity disorders”.

Children with severe developmental disabilities and behavioral disorders have increased special healthcare needs

We studied whether children with severe developmental disabilities (SDDs) who have a comorbid behavioral disorder also have higher rates of special healthcare needs (SHCNs). We used a matched-comparison control group design to establish whether SHCNs were higher in children with SDDs with behavioral disorders versus children with SDDs without behavioral disorders. Thirty-six children were matched for age (mean 12 y 6 mo; range 5 y 2 mo-18 y 8 mo), sex (24 males, 12 females), ethnicity (22 non-white), mental retardation level (22 moderate, eight severe, six profound), and Diagnostic and Statistical Manual of Mental Disorders, 4th edition axis I diagnosis (18 autism spectrum disorder, 10 specified syndrome, eight mental retardation not otherwise specified). Measures included the Achenbach Child Behavior Checklist, behavioral observation, health status examination, and Childhood Health Questionnaire (CHQ). Children with SDDs with behavioral disorders had significantly higher levels of SHCN, as measured by the CHQ and health status examination. Children with SDDs with behavioral disorders had a twofold higher incidence of SHCNs than children with SDDs without behavioral disorders. No difference was observed in the number or types of prescription medication that children received. The findings suggest that SHCNs contribute to the occurrence and/or intensity of behavioral disorders in children with SDD and may require interdisciplinary care coordination.

Ube3a mRNA and protein expression are not decreased in Mecp2R168X mutant mice.

Mutations in the transcriptional repressor methyl CpG binding protein 2 (MeCP2) are responsible for most cases of Rett Syndrome (RS), a severe neurodevelopmental disorder characterized by developmental regression, minimal speech, seizures, postnatal microcephaly and hand stereotypies. Absence of the maternal copy of ubiquitin protein ligase 3A (UBE3A) results in Angelman syndrome, also a severe developmental disorder that shares some clinical features with RS. As MeCP2 regulates gene expression, this has led to the hypothesis that MeCP2 may regulate UBE3A expression; however, there are conflicting reports regarding the expression of Ube3a in MeCP2 null mutant mice. We have generated a novel MeCP2 mutant knock-in mouse with the mutation R168X, one of the most common mutations in patients with RS. These mice show features similar to RS, including hypoactivity, forelimb stereotypies, breathing irregularities, weight changes, hind limb atrophy, and scoliosis. The male mice experience early death. Analysis of Ube3a mRNA and protein levels in the Mecp2(R168X) male mice showed no significant difference in expression compared to their wild type littermates.

The function of the epigenome in cell reprogramming.

During cell differentiation or metabolic switch, cells undergo profound changes in gene expression. These events are accompanied by complex modifications of chromosomal components and nuclear structures, including covalent modifications of DNA and chromatin up to topological reorganization of chromosomes and genes in the nucleus. To various extents, all these levels of organization appear to contribute to the stability and heritability of transcription programmes and define what is meant as the epigenomic level of gene regulation. Indeed, damage or perturbation of epigenome components may lead to deviations from a determined cellular programme, resulting in severe developmental disorders and tumour progression. Most recent data also suggest that tissue regeneration and transdifferentiation are controlled by epigenetic functions. Thus, the epigenome provides the molecular basis for the preservation and also for the plasticity of cell identity.

The neuropathology, medical management and dental implications of autism

A paucity of information exists in the dental literature about autism and its dental implications. The authors conducted a MEDLINE search for the period 2000 through 2006, using the term "autism," with the aim of defining the condition's clinical manifestations, dental and medical treatment and dental implications. Autism is a severe developmental brain disorder that appears in infancy, persists throughout life, and is characterized by impaired social interaction, abnormalities in communication (both verbal and nonverbal) and restricted interests. Often accompanying the disorder are behavioral disturbances - such as self-mutilation, aggression, psychiatric symptoms and seizures - that necessitate the administration of multiple medications to help the affected person participate effectively in the educational and rehabilitative process. Dentists caring for people with autism must be familiar with the manifestations of the disease and its associated features so that they can garner the maximum level of patient cooperation. They also must be familiar with the medications used to treat the associated features of the disorder because many of them cause untoward orofacial and systemic reactions and may precipitate adverse interactions with dental therapeutic agents.

Ultraviolet A sensitivity in Smith–Lemli–Opitz syndrome: Possible involvement of cholesta-5,7,9(11)-trien-3β-ol

Smith–Lemli–Opitz syndrome (SLOS) is a severe developmental disorder caused by mutations in the DHCR7 gene coding for 7-dehydrocholesterol (7-DHC) reductase, the enzyme involved in the last step of cholesterol biosynthesis. SLOS homozygotes exhibit marked deficiency of cholesterol in plasma and tissues with concomitant increase in 7-DHC. Ultraviolet A (UVA) photosensitivity has been recognized as part of SLOS with maximal response occurring at 350 nm. 7-DHC itself has no UVA absorption and so cannot be the direct cause of SLOS photosensitivity. However, cholesta-5,7,9(11)-trien-3β-ol (9-DDHC), a metabolite of 7-DHC, has been detected in plasma from SLOS patients. Because 9-DDHC has strong absorption in the UVA range (ϵ ∼ 15,000 @ 324 nm), we have examined its photobiology to determine whether it could be involved in SLOS photosensitivity. High levels of 7-DHC (0.65 mg/100 g wet weight) and measurable amounts of 9-DDHC (0.042 mg/100 g wet weight) were found in skin lipids extracted from CD-1 mice treated with AY9944 ( trans-1,4-bis(2-chlorobenzylaminomethyl)cyclohexane dihydrochloride), an inhibitor of 7-DHC reductase. Human HaCaT keratinocytes treated with 9-DDHC (10 μM) and then immediately exposed to UVA (15 J/cm 2) exhibited an 88% decrease in viability (compared to dark controls). No damage was observed in cells exposed to 7-DHC/UVA or UVA alone. However, HaCaT keratinocytes treated with 7-DHC (5 μM) for 15 h and then exposed to UVA (30 J/cm 2) were damaged. 9-DDHC was detected in keratinocytes incubated with 7-DHC. Reactive oxygen species were detected in 9-DDHC/UVA-exposed cells using the fluorescent probe 5-(and 6-)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate acetyl ester. Singlet oxygen was generated when 9-DDHC was UVA irradiated in CCl 4. UVA irradiation of 9-DDHC in acetonitrile generated superoxide and carbon-centered and alkoxyl radicals which were trapped by 5,5-dimethyl-1-pyrroline N-oxide. These findings suggest that reactive oxygen species generated by 9-DDHC may play a role in the UVA skin photosensitivity of SLOS patients. Furthermore, several statin drugs inhibit 7-DHC reductase, in addition to hydroxymethylglutaryl-CoenzymeA reductase, so that 9-DDHC may also be responsible for statin-derived photosensitivity, dermatoses, and cataract formation. Finally, we have previously detected 9-DDHC in skin lipids from normal subjects, so this sterol may also be the skin chromophore responsible for skin photoaging and UV-induced skin cancer.

MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome

Meckel syndrome (MKS) is a severe fetal developmental disorder reported in most populations. The clinical hallmarks are occipital meningoencephalocele, cystic kidney dysplasia, fibrotic changes of the liver and polydactyly. Here we report the identification of a gene, MKS1, mutated in MKS families linked to 17q. Mks1 expression in mouse embryos, as determined by in situ hybridization, agrees well with the tissue phenotype of MKS. Comparative genomics and proteomics data implicate MKS1 in ciliary functions.

The Arabidopsis PEX12 Gene Is Required for Peroxisome Biogenesis and Is Essential for Development

Peroxisomes perform diverse and vital functions in eukaryotes, and abnormalities in peroxisomal function lead to severe developmental disorders in humans. Peroxisomes are also involved in a wide array of physiological and metabolic functions unique to plants, yet many aspects of this important organelle are poorly understood. In yeast and mammals, various steps in peroxisome biogenesis require the function of peroxin (PEX) proteins, among which PEX12 is a RING finger peroxisomal membrane protein involved in the import of matrix proteins. To investigate the role of PEX12 in plants, we identified a T-DNA knockout allele of PEX12 and generated partial loss-of-function pex12 mutants using RNA interference. We show that pex12 null mutants are developmentally arrested during early embryogenesis, and that the embryo-lethal phenotype can be rescued by overexpression of the PEX12-cyan fluorescent protein fusion protein, which targets to the peroxisome. Using virus-induced gene-silencing techniques, we demonstrate that peroxisomal number and fluorescence of the yellow fluorescent protein-peroxisome targeting signal type 1 protein are greatly reduced when PEX12 is silenced. RNA interference plants with partial reduction of the PEX12 transcript exhibit impaired peroxisome biogenesis and function, inhibition of plant growth, and reduced fertility. Our work provides evidence that the Arabidopsis (Arabidopsis thaliana) PEX12 protein is required for peroxisome biogenesis and plays an essential role throughout plant development.

Long-term effects of diazepam treatment of epileptic GABA A receptor beta3 subunit knockout mouse in early life

The knockout mouse for the beta3 subunit of the GABA A receptor exhibits spontaneous epilepsy and hyperactivity, and has been proposed as a model for the severe developmental disorder, Angelman's syndrome, which is known to be of genetic origin. We have used this mutant to test an approach of therapeutic intervention prior to seizure onset by daily injection with diazepam during either the first or second postnatal week. Results showed differences between postnatal week 1 and week 2 injections both acutely, with respect to sedative effects, and in long-term outcome, with respect to EEG and behavioral tests measured at 12–14 weeks of age. The EEG of control mice remained unaffected under all conditions, but the EEG of beta3 (−/−) injected with diazepam in week 1 was worsened, showing increased oscillatory activity at 5–6 Hz, and more myoclonic jerks, particularly among males. For beta3 (−/−) injected with diazepam in week 2, the EEG was normalized in half the mice but worsened similarly to week 1 in the other half. Neonatal diazepam injection had a long-term normalizing effect on behavior of beta3 (−/−) mice injected in week 1, but diazepam treatment in week 2 did not affect the hyperactive and circling behavior characteristic of the beta3 knockout mouse. Diazepam treatment in postnatal week 2 significantly decreased anxiety in the adult beta3 group. Diazepam treatment in both postnatal weeks 1 and 2 improved the motor coordination of beta3 (−/−) on the rotarod, although performance of control mice injected with diazepam in postnatal week 2 was significantly impaired. The observed long-term outcome of neonatal diazepam injections may result from interference with developmental processes, and shows that enhancing GABAergic activity with diazepam during the period where GABA can be excitatory can produce narrow stage-related effects on brain development.

Microphthalmia with linear skin defects (MLS) syndrome: Clinical, cytogenetic, and molecular characterization of 11 cases

The microphthalmia with linear skin defects (MLS) syndrome (MIM 309801) is a severe and rare developmental disorder, which is inherited as an X-linked dominant trait with male lethality. In the vast majority of patients, this syndrome is associated with terminal deletion of the Xp22.3 region. Thirty-five cases have been described to date in the literature since the first description of the syndrome in the early 1990s. We now report on the clinical, cytogenetic, and molecular characterization of 11 patients, 7 of whom have not been described previously. Seven of these patients have chromosomal abnormalities of the short arm of the X-chromosome, which were characterized and defined by fluorescence in situ hybridization (FISH) analysis. Intriguingly, one of the patients displays an interstitial Xp22.3 deletion, which to the best of our knowledge is the first reported for this condition. Finally we report on the identification and molecular characterization of four cases with clinical features of MLS but apparently normal karyotypes, verified by FISH analysis using genomic clones spanning the MLS minimal critical region, and with genome-wide analysis using a 1 Mb resolution BAC microarray. These patients made it possible to undertake mutation screening of candidate genes and may prove critical for the identification of the gene responsible for this challenging and intriguing genetic disease.

A Model of Early Detection and Diagnosis of Autism Spectrum Disorder in Young Children

Autism and autism spectrum disorder (ASD) are a group of severe developmental disorders that are characterized by 3 core sets of developmental abnormalities: impairment of social interaction, verbal and nonverbal communication, and restricted, repetitive patterns of behavior. The disorder is far more common than previously thought. There is no cure for autism but it is apparent that early detection followed by early intervention is likely to provide the best chance of long-term beneficial outcome in this condition. Unfortunately, until recently, there had been no validated method of comprehensive early detection of ASD, nor a tool with adequate sensitivity and specificity to be recommended for universal screening of preschool children with ASD. We describe a model of comprehensive early detection and diagnosis of ASD that is achieved by using the resources of primary care workers and a multidisciplinary team with skill and experience in assessing developmental problems in young children and specific expertise in ASD. Both early detection and diagnosis may be carried out by this team in collaboration with parents and primary care professionals and can result in high rates of detection and diagnosis of ASD.

Comorbidity in severe developmental language disorders: Neuropediatric and psychological considerations

To explore possible patterns of comorbidity in children with severe developmental language disorders (DLD). A retrospective investigation of the clinical records of 28 children relating to oral motor and language problems, psychological profiles, medical history and EEG findings. 36% of all the children had pure expressive language problems, 64% had combined expressive-receptive language problems and 57% had additional oral motor problems. Girls predominated in expressive-receptive problems, while boys predominated in oral motor problems. Children with expressive-receptive disorders were over-represented at the lower end of normal full-scale IQ (p = 0.015). Lower verbal than non-verbal IQ levels were almost as common as equal levels, but a lower non-verbal IQ than verbal IQ was also found. Pre/perinatal problems were found in 21%, and heredity for developmental language problems or dyslexia in 39%. There was a higher proportion of attention and motor problems, EEG abnormalities, and epileptic syndromes than in the general population (p < 0.001). In severe DLD, both pure expressive and mixed expressive-receptive problems are found, and oral motor problems are common. Gender differences regarding symptoms are present. Receptive language ability is associated with the full-scale IQ level. A high proportion of EEG abnormalities and epilepsy is found. There is a complex pattern of comorbidity between speech-language symptoms, psychological characteristics, heredity and EEG findings.