Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085584 (encephalopathy)
 18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although MECP2 was initially identified as the causative gene in classic Rett syndrome (RTT), the gene has now been implicated in several phenotypes that extend well beyond the clinically defined disorder. MECP2 mutations have been found in people with various disorders, including neonatal onset encephalopathy, X-linked recessive mental retardation (MRX), classic and atypical RTT, autism, and Angelman syndrome, as well as mildly affected females and normal carrier females. To make matters more complex, in approximately 20% of classic sporadic RTT cases and more than 50% of affected sister pairs, no mutation in MECP2 has been found. X-chromosome inactivation patterns can clearly affect the phenotypic expression in females, while the effect of the type and position of the mutation is more apparent in the broader phenotype than in RTT. Both males and females are at risk, although an excess of paternally derived mutations are found in most cases of classic RTT. Thus, because of the range of disparate phenotypes, the gene may account for a relatively large portion of mental retardation in the population.
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PMID:The phenotypic consequences of MECP2 mutations extend beyond Rett syndrome. 1211 34

Mutations in the MECP2 (Methyl-CpG-binding protein) gene recently have been reported to cause Rett syndrome (RTT), an X-linked progressive encephalopathy. We have collected the results of MECP2 analysis conducted in four laboratories in France. A total of 301 RTT alleles have been analyzed, demonstrating a total of 69 different mutations so far observed and accounting for 64% of MECP2 genes in RTT patients living in France. R168X (11.5%) is the most common of MECP2 mutations, followed by R255X (10.9%), R270X (10.5%), T158M (7.8%), and R306C (6.8%). Only 10 mutations had a relative frequency > 2%. A total of 59 mutations were found in a small number of RTT alleles (from 1 to 2). These data demonstrate the high allelic heterogeneity of RTT in France and provide information relevant to the development of strategies for molecular diagnosis and genetic counseling in RTT families.
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PMID:Spectrum of MECP2 mutations in Rett syndrome. 1218 70

Rett syndrome (RTT) is classically defined by meeting certain clinical diagnostic criteria. It affects mostly females, and one possible pathogenic mechanism was considered to involve mitochondrial function. This was based on the finding of ultrastructural alterations in the mitochondria and decreased respiratory chain enzyme activity. However, the principal etiology of RTT has since been found to be mutations in the MECP2 gene, which is located on the X chromosome. Molecular analysis has allowed the phenotype of MECP2 mutations to be broadened beyond RTT to include girls who have mild mental retardation, autism, and an Angelman syndrome phenotype, as well as males with severe encephalopathy. We present a girl with a previously described mutation in the MECP2 gene whose phenotype is of atypical RTT. She presented with hypotonia and developmental delay in infancy without a clear period of normal development. As part of her evaluation for hypotonia, a muscle biopsy and respiratory chain enzyme analysis showed a slight decrease in respiratory chain enzyme activity consistent with previous reports. This report supports broadening the phenotype of patients who should be considered for MECP2 mutation analysis to include cases of developmental delay and hypotonia without evidence of an initial period of normal development. Furthermore, it supports the hypothesis of an underlying secondary defect in energy metabolism contributing to the pathogenesis of RTT.
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PMID:Infantile hypotonia as a presentation of Rett syndrome. 1221 Mar 19

Rett syndrome is a progressive neurodevelopmental disorder with a well-defined clinical spectrum and course. Recently, mutations in the gene encoding X-linked methyl-CpG binding protein 2 (MECP2) have been identified as the cause of Rett syndrome. Along with the classic form, variant forms of Rett syndrome and Rett syndrome phenotypes are also recognized. We report on a girl who, at age 2 months, developed an acute encephalopathy with destructive brain damage 12 hours after acellular pertussis vaccination. Peripheral lymphocyte subset analysis revealed the existence of T lymphocytes double positive for CD4 and CD8 markers. This pattern normalized over the following 3 months. Months later, the girl manifested a Rett syndrome phenotype. DNA screening of the MECP2 gene was unrevealing in the child and her parents. This previously unreported association emphasizes the notion that Rett syndrome phenotypes can result from different (either genetic or environmental) causes.
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PMID:Rett syndrome phenotype following infantile acute encephalopathy. 1250 49

Mutations in the MECP2 (methyl-CpG-binding protein 2) gene are known to cause Rett syndrome, a well-known and clinically defined neurodevelopmental disorder. Rett syndrome occurs almost exclusively in females and for a long time was thought to be an X-linked dominant condition lethal in hemizygous males. Since the discovery of the MECP2 gene as the cause of Rett syndrome in 1999, MECP2 mutations have, however, also been reported in males. These males phenotypically have classical Rett syndrome when the mutation arises as somatic mosaicism or when they have an extra X chromosome. In all other cases, males with MECP2 mutations show diverse phenotypes different from classical Rett syndrome. The spectrum ranges from severe congenital encephalopathy, mental retardation with various neurological symptoms, occasionally in association with psychiatric illness, to mild mental retardation only. We present a 21-year-old male with severe mental retardation, spastic tetraplegia, dystonia, apraxia and neurogenic scoliosis. A history of early hypotonia evolving into severe spasticity, slowing of head growth, breathing irregularities and good visual interactive behaviour were highly suggestive of Rett syndrome. He has a de novo missense mutation in exon 3 of the MECP2 gene (P225L). The clinical spectrum and molecular findings in males with MECP2 mutations are reviewed.
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PMID:Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2). 1261 69

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.
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PMID:Rett syndrome: the complex nature of a monogenic disease. 1275 Aug 21

Plasticity includes the brain's capacity to be shaped or moulded by experience, the capacity to learn and remember, and the ability to reorganize and recover after injury. Mechanisms for plasticity include activity-dependent refinement of neuronal connections and synaptic plasticity as a substrate for learning and memory. The molecular mechanisms for these processes utilize signalling cascades that relay messages from synaptic receptors to the nucleus and the cytoskeleton to control the structure of axons and dendrites. Several paediatric neurological disorders such as neurofibromatosis-1, Fragile X syndrome, Rett syndrome, and other syndromic and non-specific forms of mental retardation involve lesions in these signalling pathways. Acquired disorders such as hypoxic-ischaemic encephalopathy, lead poisoning and epilepsy also involve signalling pathways including excitatory glutamate receptors. Information about these 'plasticity pathways' is useful for understanding their pathophysiology and potential therapy.
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PMID:Brain plasticity in paediatric neurology. 1278 36

Rett syndrome (RTT) is one of the most common neurodevelopmental disorders in females. The disease is caused by mutations in the methyl-CpG-binding protein 2 gene (MECP2), and various mutations have been reported. The phenotypic spectrum in both female and male patients is diverse, ranging from very mild to congenital encephalopathy and prenatal lethality. In this study, the question was addressed as to whether implementation of systematic screening of MECP2 in patients with an unexplained mental retardation in DNA diagnostics would be reasonable, and the spectrum of phenotypes resulting from mutations in this gene was further explored. Mutational analysis of MECP2 was performed in mentally retarded female patients who were negative for FMR1 CGG repeat expansion, in male and female patients with clinical features suggestive of either Angelman or Prader-Willi syndrome without methylation defects on chromosome 15q11-q13. In the cohort of females negative for the molecular Fragile-X studies (N=92), one nonsense mutation (p.Q406X) was found. In the cohort of Angelman-negative patients (N=63), two missense mutations (p.R133C in a female patient and a mosaic p.T158M in a male patient) were found, which have been reported many times in patients with classical RTT syndrome. In the Prader-Willi-negative group (N=98), no pathogenic mutations were found. The results support testing of patients with features suggestive of Angelman syndrome, but without methylation defects on chromosome 15q11-q13 for mutations in MECP2. In the remaining patients with unexplained mental retardation, additional clinical features should determine whether analysis of MECP2 is indicated.
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PMID:MECP2 analysis in mentally retarded patients: implications for routine DNA diagnostics. 1456 Mar 7

Rett syndrome (RS) is a neurodevelopmental disorder, preferentially found in females and specifically involving the functions on which intelligence and its expression depend--learning, hand use and speech--leaving many others intact. Mutations have been identified at Xq28 on the MECP2 gene (methyl-CpG 2), which selectively silences the expression of other genes whose location is still unknown. This is a study on clinical, diagnostic and epidemiological aspects of RS in a Brazilian sample. It included 33 female patients with chronic encephalopathy without known etiology. RS was diagnosed in 24 patients (72.7%): 17 (70.8%) had classical RS; 5 (20.8%), atypical RS and 2 (8.4%), potential RS. In 9 girls clinical data and/or laboratory studies excluded diagnosis of RS. Among the atypical RS patients, 4 were form fruste and one, congenital form. Among the girls with other encephalopathies, cerebral malformation was the most frequent finding.
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PMID:Rett syndrome: clinical and epidemiological aspects in a Brazilian institution. 1476 89

Clinical disorders of brain plasticity are common in the practice of child neurology. Children have an enhanced capacity for brain plasticity compared to adults as demonstrated by their superior ability to learn a second language or their capacity to recover from brain injuries or radical surgery such as hemispherectomy for epilepsy. Basic mechanisms that support plasticity during development include persistence of neurogenesis in some parts of the brain, elimination of neurons through apoptosis or programmed cell death, postnatal proliferation and pruning of synapses, and activity-dependent refinement of neuronal connections. Brain plasticity in children can be divided into four types: adaptive plasticity that enhances skill development or recovery from brain injury; impaired plasticity associated with cognitive impairment; excessive plasticity leading to maladaptive brain circuits; and plasticity that becomes the brain's 'Achilles' Heel' because makes it vulnerable to injury. A broad group of pediatric neurologic disorders can be understood in terms of their impact on fundamental mechanisms for brain plasticity. These include neurofibromatosis, tuberous sclerosis, Fragile X syndrome, other inherited forms of mental retardation, cretinism, Coffin-Lowry syndrome, lead poisoning, Rett syndrome, epilepsy, hypoxic-ischemic encephalopathy and cerebral palsy.
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PMID:Clinical disorders of brain plasticity. 1503 25


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