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PubMed1985

Temporal evolution of hypoxic-ischaemic brain lesions in asphyxiated full-term newborns as assessed by computerized tomography.

Hypoxic-ischaemic brain lesions may be detected as low density (LD) areas by means of computerized tomography (CT), but the clinical significance of such LD areas has been controversial. Since timing might be a critical factor, we studied the temporal evolution of LD areas in 9 asphyxiated term babies who had had two or more CT, and compared the changes to the neurodevelopmental outcome. Scans were classified according to the elapsed time after asphyxia as early (day 1-7, n = 6), intermediate (week 2-4, n = 7; week 4-7, n = 3) and late CT (3 months or more, n = 7). In early scans, no, or only ill defined, LD areas were seen in the periventricular region. In intermediate CT's, LD-zones were further diminished in those babies who later were normal. Sharply accentuated LD areas, however, appeared in those who later suffered from neurodevelopmental disorders. These LD areas, probably representing hypoxic-ischaemic lesions, were located periventricularly, extending into the subcortical white matter and the cortex, and usually involved both hemispheres symmetrically. They began to disappear at 4 to 7 weeks in some regions, possibly because of glial proliferation. LD persisting more than 4-7 weeks tended to transform into cyst-like lesions, or marked atrophy. We conclude (1) that hypoxic-ischaemic lesions appear as zones of low density on CT scans performed after the first week and (2) that the extent of such lesions can best be assessed between 9 to 23 days after asphyxia.

Asphyxia Neonatorum↗

PubMedDate not supplied

Detection of antinuclear and antilaminin antibodies in autistic children who received thimerosal-containing vaccines.

Autism, a neurodevelopmental disorder, may involve autoimmune pathogenesis. Since mercury is potentially a risk factor for autoimmunity, we conducted a study of mercury-induced antinuclear and antilaminin antibodies in autistic and normal children who had been pre-administered with thimerosal-containing vaccines. Laboratory analysis by different immunoassays showed that the serum level of these two autoimmune markers did not significantly differ between autistic and normal children. This finding suggests that the mercury as in thimerosal-containing vaccines is likely not related to autoimmune phenomenon in autism.

Antibodies, Antinuclear↗

PubMedDate not supplied

Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism.

Autoimmunity to the central nervous system (CNS), especially to myelin basic protein (MBP), may play a causal role in autism, a neurodevelopmental disorder. Because many autistic children harbor elevated levels of measles antibodies, we conducted a serological study of measles-mumps-rubella (MMR) and MBP autoantibodies. Using serum samples of 125 autistic children and 92 control children, antibodies were assayed by ELISA or immunoblotting methods. ELISA analysis showed a significant increase in the level of MMR antibodies in autistic children. Immunoblotting analysis revealed the presence of an unusual MMR antibody in 75 of 125 (60%) autistic sera but not in control sera. This antibody specifically detected a protein of 73-75 kD of MMR. This protein band, as analyzed with monoclonal antibodies, was immunopositive for measles hemagglutinin (HA) protein but not for measles nucleoprotein and rubella or mumps viral proteins. Thus the MMR antibody in autistic sera detected measles HA protein, which is unique to the measles subunit of the vaccine. Furthermore, over 90% of MMR antibody-positive autistic sera were also positive for MBP autoantibodies, suggesting a strong association between MMR and CNS autoimmunity in autism. Stemming from this evidence, we suggest that an inappropriate antibody response to MMR, specifically the measles component thereof, might be related to pathogenesis of autism.

Adolescent↗

PubMed2004

[Thiomersal and immunisations].

Thiomersal was used in the 1930s for the first time for the preservation of vaccines to prevent bacterial and fungal contamination. Thiomersal is an organic compound containing 49% mercury (Hg) by weight. It is generally well known that mercury and its compounds, including thiomersal, ethylmercury, and methylmercury, act as nephro- and neurotoxicants, however, at much higher doses than used in vaccines. In the 1990s the question of toxicity of thiomersal in vaccines was reassessed since the numbers of vaccines recommended for routine administration to infants and children, and therefore the cumulative thiomersal dose in children, increased in some countries. Various international committees (European Agency for the Evaluation of Medicinal Products, EMEA, US Public Health Service/American Academy of Pediatrics, Institute of Medicine, IOM) concluded after an extensive risk/benefit analysis that scientific evidence is inadequate to reject or explicitly recommend thiomerosal-containing vaccines for children. However (in line with the global goal of reducing exposure to mercury), they recommended promoting the elimination of thiomerosal from paediatric vaccines. This has largely been achieved in Germany. Today a child in Germany can be immunised in accordance with the official recommendations (STIKO) almost without the administration of thiomerosal (residual amounts). Results of new pharmacokinetic and epidemiological studies are discussed. The evidence available to date does not support the hypothesis of a potential relationship between neurodevelopmental disorders and thiomersal-containing vaccines.

Adverse Drug Reaction Reporting Systems↗

PubMed2003

Rett syndrome: the complex nature of a monogenic disease.

Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively girls. It is currently considered a monogenic X-linked dominant disorder due to mutations in MECP2 gene, encoding the methyl-CpG binding protein 2. A few RTT male cases, resulting from mosaicism for MECP2 mutations, have been reported. Male germline MECP2 mutations cause either severe encephalopathy with death at birth (usually in brothers of classical RTT females) or X-linked recessive mental retardation (XLMR). To date the wide phenotypic heterogeneity associated with MECP2 mutations in females (from classical RTT to healthy carriers) has been explained by differences in X chromosome inactivation. However, conflicting results have been obtained in different studies, with both random and highly skewed X-inactivation reported in healthy carrier females. Consequently it is possible that mechanisms other than X-inactivation play a role in the expressivity of MECP2 mutations. To explain the phenotypic heterogeneity associated with MECP2 mutations we propose a digenic model in which the presence of a "mutated" allele in a second gene, leading to a less functional protein, determines the clinical severity of the MECP2 mutation. The model is supported by the identification of the same mutation in XLMR and RTT cases. The carrier mothers of XLMR families are clinically asymptomatic and present balanced X chromosome inactivation. Therefore the same mutation arising in different genetic backgrounds can cause XLMR in males, remain silent in the carrier females and cause classic RTT in females. MECP2 mutations account for approximately 70-80% of classic RTT cases. MECP2 negative cases might result from mutations in noncoding regions of MECP2 gene. Alternatively, these cases might be due to mutations in other genes (locus heterogeneity). This hypothesis is supported by the identification of several chromosomal rearrangements in MECP2 negative patients with RTT and RTT-like phenotypes. MeCP2 is considered a general transcriptional repressor. However, conditional mouse mutants with selective loss of Mecp2 in the brain develop clinical manifestations similar to RTT, indicating that MECP2 is exclusively required for central nervous system function. The involvement of MeCP2 in methylation-specific transcriptional repression suggests that MECP2 related disorders result from dysregulated gene expression. Studies on gene expression have been performed in mouse and human brains. A relatively small number of gene expression changes were identified. It is possible that MeCP2 causes dysregulation of a very small subset of genes that are not detected with this method of analysis, or that very subtle changes in many genes cause the neuronal phenotype.

Animals↗

PubMed2003

Latent inhibition in 35-day-old rats is not an "adult" latent inhibition: implications for neurodevelopmental models of schizophrenia.

RATIONALE: Latent inhibition (LI) refers to retarded conditioning to a stimulus as a consequence of its inconsequential preexposure. Amphetamine-induced disruption of LI and its potentiation by antipsychotic drugs (APDs) in the adult rat are well-established models of schizophrenia and antipsychotic drug action, respectively. It is not clear whether LI can be similarly modulated at prepubertal age. OBJECTIVES: In view of the notion that schizophrenia is a neurodevelopmental disorder whose overt expression depends on postpubertal brain maturational processes, we investigated whether several manipulations known to modulate LI in adult rats, including systemic administration of amphetamine and the atypical APD clozapine, are capable of producing the same effects in prepubertal (35-day-old) rats. METHODS: LI was measured in a thirst motivated conditioned emotional response (CER) procedure in which rats received 10 or 40 tone preexposures followed by 2 or 5 tone-footshock pairings. RESULTS: Like in adults, LI was present with 40 preexposures and 2 conditioning trials. In contrast to findings in adults, LI was resistant to disruption by amphetamine at a dose (1 mg/kg) that significantly increased locomotor activity, as well as by reducing the number of preexposures to ten, increasing the number of conditioning trials to five, or changing the context between preexposure and conditioning. Clozapine (5 mg/kg) and the selective 5HT2A antagonist M100907 (0.3 mg/kg) administered in conditioning were without an effect on "persistent" LI with extended conditioning, but were capable of disrupting LI when administered in the preexposure stage, as found in adults. CONCLUSION: The results point to functionality within brain systems regulating LI acquisition but not those regulating LI expression in periadolescent rats, further suggesting that postpubertal maturation of the latter systems may underlie schizophrenia-mimicking LI disruption reported in adult rats following perinatal manipulations and possibly disrupted LI observed in schizophrenia.

Aging↗

PubMed2005

Moderate sedation for MRI in young children with autism.

UNLABELLED: Autism is a pervasive neurodevelopmental disorder. Because of the deficits associated with the condition, sedation of children with autism has been considered more challenging than sedation of other children. OBJECTIVE: To test this hypothesis, we compared children with autism against clinical controls to determine differences in requirements for moderate sedation for MRI. MATERIALS AND METHODS: Children ages 18-36 months with autism (group 1, n = 41) and children with no autistic behavior (group 2, n = 42) were sedated with a combination of pentobarbital and fentanyl per sedation service protocol. The sedation nurse was consistent for all patients, and all were sedated to achieve a Modified Ramsay Score of 4. Demographics and doses of sedatives were recorded and compared. RESULTS: There were no sedation failures in either group. Children in group 1 (autism) were significantly older than group 2 (32.02+/-3.6 months vs 28.16+/-6.7 months) and weighed significantly more (14.87+/-2.1 kg vs 13.42+/-2.2 kg). When compared on a per-kilogram basis, however, group 1 had a significantly lower fentanyl requirement than group 2 (1.25+/-0.55 mcg/kg vs 1.57+/-0.81 mcg/kg), but no significant difference was found in pentobarbital dosing between groups 1 and 2, respectively (4.92+/-0.92 mg/kg vs 5.21+/-1.6 mg/kg). CONCLUSION: Autistic children in this age range are not more difficult to sedate and do not require higher doses of sedative agents for noninvasive imaging studies.

Anesthetics, Intravenous↗

PubMed2000

Comparative genomic sequence analysis of the Williams syndrome region (LIMK1-RFC2) of human chromosome 7q11.23.

Williams syndrome (WS) is a complex neurodevelopmental disorder arising from a microdeletion at Chr band 7q11.23, which results in a hemizygous condition for a number of genes. Within this region we have completely characterized 200 kb containing the genes LIMK1, WBSCR1, and RFC2. Evidence was also found for WBSCR5 in this region, but not the previously proposed genes WSCR2 and WSCR6. The syntenic region in mouse was also sequenced (115 kb) and characterized, and a comparative sequence analysis with a percent identity plot (PIP) easily allowed us to identify coding exons. This genomic region is GC rich (50.1% human, 49.9% mouse) and contains an unusually high abundance of repetitive elements consisting primarily of Alu (45.4%, one of the highest levels identified to date) in human, and the B family of SINES (30.6% of the total sequence) in mouse. WBSCR1 corresponds to eukaryotic initiation factor 4H, identified in rabbit, and is herein found to be constitutively expressed in both human and mouse, with two RNA and protein products formed (exon 5 is alternatively spliced). The transcription pattern of WBSCR5 was also examined and discussed along with its putative amino acid sequence.

Amino Acid Sequence↗

PubMed2002

MECP2 mutations in Rett syndrome adversely affect lymphocyte growth, but do not affect imprinted gene expression in blood or brain.

Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2, encoding methyl-CpG-binding protein 2 (MeCP2). As female somatic cells are mosaic for expression of mutant MECP2, we performed single cell cloning of T lymphocytes from four RTT patients with MECP2 mutations to isolate cells expressing mutant MECP2. Mutant-expressing clones were present at a significantly lower frequency (P<0.0001) than wild-type clones. These results demonstrate that although MECP2 is not essential for lymphocyte growth, expression of the MECP2 mutation causes a growth disadvantage in cultured clonal T cells by reducing the response to mitogenic stimulation. Mutant MECP2 was expressed at normal transcript and protein levels, and exhibited no significant effect on acetylated histones or methyl-binding protein 3 (MBD3) levels. Since MeCP2 was predicted to silence transcription of methylated genes, we hypothesized that MeCP2 may be required for silencing imprinted or methylated gene expression. The allelic expression of three different imprinted genes (SNRPN, IPW and IGF2) was examined by RT-PCR and RFLP analysis, and demonstrated normal monoallelic expression of all RTT clones. We also examined the expression of five imprinted genes (SNRPN, IPW, NECDIN, H19 and IGF2) in RTT brain samples and observed exclusive monoallelic expression. Expression levels were also normal in MECP2 mutant-expressing T cells for IFNG, a non-imprinted, but methylated gene differentially expressed in T cells, and LINE-1 retrotransposons hypothesized to be silenced by MeCP2. The histone deacetylase inhibitor Trichostatin A did not alter SNRPN expression, but did reverse silencing of IFNG in a MECP2-mutant-expressing clone. In conclusion, our results do not support an essential role for either MeCP2 or HDAC in the silencing of several imprinted genes.

Acetylation↗

PubMed2007

Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels.

Autism is a neurodevelopmental disorder of unclear etiology. The consistent finding of platelet hyperserotonemia in a proportion of patients and its heritability within affected families suggest that genes involved in the serotonin system play a role in this disorder. The role in autism etiology of seven candidate genes in the serotonin metabolic and neurotransmission pathways and mapping to autism linkage regions (SLC6A4, HTR1A, HTR1D, HTR2A, HTR5A, TPH1 and ITGB3) was analyzed in a sample of 186 nuclear families. The impact of interactions among these genes in autism was assessed using the multifactor-dimensionality reduction (MDR) method in 186 patients and 181 controls. We further evaluated whether the effect of specific gene variants or gene interactions associated with autism etiology might be mediated by their influence on serotonin levels, using the quantitative transmission disequilibrium test (QTDT) and the restricted partition method (RPM), in a sample of 109 autistic children. We report a significant main effect of the HTR5A gene in autism (P = 0.0088), and a significant three-locus model comprising a synergistic interaction between the ITGB3 and SLC6A4 genes with an additive effect of HTR5A (P < 0.0010). In addition to the previously reported contribution of SLC6A4, we found significant associations of ITGB3 haplotypes with serotonin level distribution (P = 0.0163). The most significant models contributing to serotonin distribution were found for interactions between TPH1 rs4537731 and SLC6A4 haplotypes (P = 0.002) and between HTR1D rs6300 and SLC6A4 haplotypes (P = 0.013). In addition to the significant independent effects, evidence for interaction between SLC6A4 and ITGB3 markers was also found. The overall results implicate SLC6A4 and ITGB3 gene interactions in autism etiology and in serotonin level determination, providing evidence for a common underlying genetic mechanism and a molecular explanation for the association of platelet hyperserotonemia with autism.

Adolescent↗

PubMed1998

UBE3A "mutations" in two unrelated and phenotypically different Angelman syndrome patients.

Angelman syndrome (AS) is a rare neurodevelopmental disorder. Recently, several mutations have been found in the E6-AP ubiquitin protein ligase gene (UBE3A) in a group of patients who are nondeleted and do not have uniparental disomy or imprinting defects. Most of the reported mutations cluster within exons 9 or 16 of the UBE3A gene, and nearly all are predicted to give rise to truncated E6-AP ligases. Here, we describe two AS patients with dissimilar phenotypes. At the molecular level, they are both nondeleted, do not display uniparental disomy, and have normal imprint patterns. One has the typical AS phenotype and carries the previously reported 1344delAG de novo mutation involving a functionally significant region of UBE3A. The other expresses an atypical phenotype in that she has less severe ataxia, no inappropriate laughing, or epilepsy, and her EEG was normal at an early age. A 14-bp deletion in the 3' untranslated region of exon 16 (3'UTRdel14) adjacent to the poly(A) signal was identified. Further investigation revealed that the DNA change was a neutral polymorphism. Haplotype analysis indicated that both the AS patient and her normal sibling had inherited the same maternal UBE3A gene and its 5' flanking region. Although the 14-bp change has no functional significance, it assists with counseling to determine future risks of recurrence in this family.

Angelman Syndrome↗

PubMed1998

Evaluation of methylation analysis for diagnostic testing in 258 referrals suspected of Prader-Willi or Angelman syndromes.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurodevelopmental disorders with interrelated genetic mechanisms because genomic imprinting within the chromosome 15q11-13 region affects both the PWS and the AS locus. Methylation analysis is one method of distinguishing between the maternally and paternally inherited chromosome 15. Here we present clinical and molecular data on a large series of 258 referred patients, evaluated with methylation analysis: 115 with suspected PWS and 143 with suspected AS. In these patients, the clinical phenotype was graded into three groups: classical (group 1); not classical but possible (group 2); not classical and unlikely (group 3). For PWS, a fourth group consisted of hypotonic babies. DNA methylation analysis confirmed the diagnosis of PWS in 30 patients (26%) and AS in 28 patients (20%). For 21 PWS patients the mechanism was established: 15 had deletions, 4 had uniparental disomy (UPD) and 2 a presumed imprinting defect. Clinically all those with an abnormal methylation pattern had the classical phenotype and none of those with a normal methylation pattern had classical PWS. For 23 AS patients in whom a mechanism was established, 17 had a deletion, 3 had UPD and 3 had a presumed imprinting defect. There was greater clinical overlap in AS, with 26 classical AS patients having a normal methylation pattern while an abnormal methylation pattern was seen in one patient from group 2. In addition, there were a further 40 patients with a normal methylation pattern in whom AS was still a possible diagnosis. Our conclusion is that methylation analysis provides an excellent screening test for both syndromes, providing approximately 99% diagnosis for PWS and for AS, a 75% diagnostic rate, supplemented for the remaining 25% with an essential basic starting point to further investigations.

Adolescent↗

PubMed2004

Review on structural neuroimaging findings in autism.

Autism is now widely viewed as a neurodevelopmental disorder, although the underlying biological causes remain to be established. In this review, we examine the literature in magnetic resonance imaging (MRI) as applied to autism, discuss the findings that have emerged, and give directions for potential future research. To date, structural MRI results are inconsistent, partly due to the heterogeneity of the disorder itself, and partly due to the different composition and the varied degree of matching of the studied groups. However, recent studies have begun to elucidate the underlying neuroanatomical abnormalities and brain-behavior relationships in autism, with the most consistent finding being increased brain volume in autism. Future large-scale longitudinal structural imaging studies, starting at very young ages, investigating homogeneous groups of patients and extensively matched control groups, and making use of (combinations of) newer and more sophisticated techniques, hold a great promise to further elucidate the enigma of autism.

Age Factors↗

PubMed2003

Rett Syndrome -- an update.

Rett syndrome is a progressive, usually sporadic and rarely familial, disabling neurodevelopmental disorder with onset in early childhood presenting clinically with mental retardation, behavioral changes, late movement disturbances, loss of speech and hand skills, ataxia, apraxia, irregular breathing with hyperventilation while awake, and frequent seizures. It occurs almost exclusively in females with an estimated prevalence of 1 in 10-22000 births and is considered a manifestation of defective brain maturation caused by dominant mutation of the MeCP2 gene encoding the transcriptional repressor methyl-CpG-binding protein 2 related to the Xq28 locus. Although many different mutations of this protein are being studied in humans and in mice, the molecular pathogenesis of this disorder remains unclear. Electroencephalography is abnormal in the final stages of the syndrome. Neuroimaging showing brain atrophy may be required for differential diagnosis that includes neurodegenerative and metabolic disorders. Neuropathology shows decreased brain growth and reduced size of individual neurons, with thinned dendrites in some cortical layers and abnormalities in substantia nigra (decreased neuromelanin content), suggestive of deficient synaptogenic development, probably starting before birth. Neurometabolic changes include reduced levels of dopamine, serotonin, noradrenalin, choline acetyltransferase (ChAT), nerve growth factors, endorphines, glutamate, and other amino acids and their receptor levels in brain. Current treatment includes symptomatic, anticonvulsive and physiotherapy.

Brain↗

PubMed2002

Autistic symptoms following herpes encephalitis.

Autism is a childhood onset neurodevelopmental disorder characterized by reciprocal social deficits, communication impairment, and rigid ritualistic interests, with the onset almost always before three years of age. Although the etiology of the disorder is strongly influenced by genes, environmental factors are also important. In this context, several reports have described its association with known medical conditions, including infections affecting the central nervous system. In this report, we describe an 11-year-old Asian youngster who developed the symptoms of autism following an episode of herpes encephalitis. In contrast to previous similar reports, imaging studies suggested a predominant involvement of the frontal lobes. At follow-up after three years, he continued to show the core deficits of autism. This case further supports the role of environmental factors, such as infections, in the etiology of autism, and suggests that in a minority of cases, autistic symptoms can develop in later childhood.

Autistic Disorder↗

PubMed2001

MECP2 mutation screening in Swedish classical Rett syndrome females.

Rett syndrome (RS) is a neurodevelopmental disorder almost exclusively affecting females. We have studied the mutation spectrum of the responsible gene MECP2, encoding methyl-CpG-binding protein 2 (MeCP2), in 16 sporadic classical RS females from Sweden. In 13 of 16 patients (81%) we detected nonsense or missense mutations in the coding parts of MECP2. This mutation rate is in agreement with other reports (65-80%). In all, 12 different mutations and one polymorphism were found; three of the mutations have not been reported previously. The missense mutations were restricted to highly conserved regions of the gene. None of the mutations was detected in parents; thus, they had probably arisen de novo. In contrast, two normal variants, one intron deletion and one silent mutation, were seen singly only in two patients' mothers; neither has been reported previously. One patient showed two different mutations closely located, i.e. 802C > T (R268W) together with 808C > T (R270X). Another patient had a mutation in the stop codon 1459T > C (X487R), leading to a gene product prolonged with 27 amino acids. In conclusion, our results indicate that the majority of Swedish RS patients (81%) have mutations in MECP2 that are sporadic cases with de novo mutations. Moreover, both missense and nonsense mutations occur, but in different parts of the gene, probably reflecting the function of the domains in MeCP2. This study has improved our ability to offer these families an early confirmation of Rett diagnoses.

Child↗

PubMed2006

MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome.

Rett syndrome (RTT) is a progressive neurodevelopmental disorder that is caused by mutations in the X-linked methyl-CpG-binding protein2 (MECP2) gene. In this study, the MECP2 sequences in 121 unrelated Chinese patients with classical or atypical RTT were screened for deletions and mutations. In all, we identified 45 different MECP2 mutations in 102 of these RTT patients. The p. T158M mutation (15.7%) was the most common, followed in order of frequency by p. R168X (11.8%), p. R133C (6.9%), p. R270X (6.9%), p. G269fs (6.9%), p. R255X (4.9%), and p. R306C (3.9%). In addition, we identified five novel MECP2 mutations: three missense (p. K305E, p. V122M, p. A358T), one insertion (c.45-46insGGAGGA), and one 22 bp deletion (c.881-902del22). Large deletions represented 10.5% of all identified MECP2 mutations. Conversely, mutations in exon 1 appeared to be rare (0.9%). The remaining cases without MECP2 mutations were screened for the cyclin-dependent kinase-like 5 (CDKL5) gene using denaturing high-performance liquid chromatography (DHPLC). One synonymous mutation (p. I72I) was found in exon 5, suggesting that CDKL5 is a rare cause of RTT. The overall MECP2 mutation detection rate for this patient series was 84.3:87.9% in 107 classical RTT cases and 57.1% in 14 atypical RTT cases. Moreover, there were two patients with homozygous mutations and normal female karyotypes. However, we did not pinpoint a significant relationship between genotype and phenotype in these cases.

Adolescent↗

PubMed2000

Mutational analysis of the MECP2 gene in Japanese patients with Rett syndrome.

Rett syndrome is a neurodevelopmental disorder observed almost exclusively in girls, and is characterized by autistic tendency, severe mental retardation, stereotyped hand movements, seizures, and acquired microcephaly. Recently, the MECP2 (methyl-CpG-binding protein 2) gene, mapped on chromosome Xq28, was reported to be responsible for Rett syndrome. We performed mutational analysis of the MECP2 gene in 26 Japanese patients with Rett syndrome (who were sporadic cases), and identified disease alleles in 19 patients. The mutations consisted of 12 different types including 3 missense, 3 nonsense, and 6 frameshift mutations. Of these, 8 mutations are novel. Most of these mutations affect the functional domains, methyl-CpG binding domain (MBD), and transcriptional repression domain (TRD), and therefore may critically affect the function of MeCP2. The disease phenotype of patients with mutations in the MBD tended to be more severe than the phenotype of those with mutations in the TRD. We also identified 2 types of silent mutations and 4 types of missense mutations as benign variants, and these are all novel ones. Most of the nucleotide substitutions involve C-->T transitions at CpG hotspots. The novel disease alleles and benign variants of the MECP2 gene found in this study should contribute to the establishment of a reliable diagnosis of Rett syndrome.

Chromosomal Proteins, Non-Histone↗