MECP2 gene nucleotide changes and their pathogenicity in males: proceed with caution.
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Amino Acid Substitution↗
Biomedical subjects
F Hanefeld
Publications and source records attributed to F Hanefeld.
MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin.
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that apparently is lethal in male embryos. RTT almost exclusively affects female offspring and, in 99.5% of all cases, is sporadic and due to de novo mutations in the MECP2 gene. Familial cases of RTT are rare and are due to X-chromosomal inheritance from a carrier mother. We analyzed the parental origin of MECP2 mutations in sporadic cases of RTT, by analysis of linkage between the mutation in the MECP2 gene and intronic polymorphisms in 27 families with 15 different mutations, and we found a high predominance of mutations of paternal origin in 26 of 27 cases (P<.001). The paternal origin was independent of type of mutation and was found for single-base exchanges as well as for deletions. Parents were not of especially advanced age. We conclude that de novo mutations in RTT occur almost exclusively on the paternally derived X chromosome and that this is most probably the cause for the high female:male ratio observed in patients with RTT. Affected males recently have been described in a few cases of familial inheritance. Identification of the parental origin may be useful to distinguish between the sporadic form of RTT and a potentially familial form. This distinction will allow geneticists to offer more-specific counseling and discriminate between higher (maternal origin) and lower (paternal origin) recurrence risk.
Adult↗
Autosomal dominant glut-1 deficiency syndrome and familial epilepsy.
Glut-1 deficiency syndrome was first described in 1991 as a sporadic clinical condition, later shown to be the result of haploinsufficiency. We now report a family with Glut-1 deficiency syndrome affecting 5 members over 3 generations. The syndrome behaves as an autosomal dominant condition. Affected family members manifested mild to severe seizures, developmental delay, ataxia, hypoglycorrhachia, and decreased erythrocyte 3-O-methyl-D-glucose uptake. Seizure frequency and severity were aggravated by fasting, and responded to a carbohydrate load. Glut-1 immunoreactivity in erythrocyte membranes was normal. A heterozygous R126H missense mutation was identified in the 3 patients available for testing, 2 brothers (Generation 3) and their mother (Generation 2). The sister and her father were clinically and genotypically normal. In vitro mutagenesis studies in Xenopus laevis oocytes demonstrated significant decreases in the transport of 3-O-methyl-D-glucose and dehydroascorbic acid. Xenopus oocyte membranes expressed high amounts of the R126H mutant Glut-1. Kinetic analysis indicated that replacement of arginine-126 by histidine in the mutant Glut-1 resulted in a lower Vmax. These studies demonstrate the pathogenicity of the R126H missense mutation and transmission of Glut-1 deficiency syndrome as an autosomal dominant trait.
3-O-Methylglucose↗
Myelinopathia centralis diffusa (vanishing white matter disease): evidence of apoptotic oligodendrocyte degeneration in early lesion development.
We describe histopathological changes in a 2-year-old boy who died from myelinopathia centralis diffusa. Despite extensive white matter destruction, surprisingly high numbers of oligodendrocytes expressing proteolipid protein mRNA were detected. In an active demyelinating lesion in the brainstem, oligodendrocytes showed typical signs of apoptosis. We suggest that death of mature oligodendrocytes is the critical event in the disease.
Apoptosis↗
Mutation spectrum in patients with Rett syndrome in the German population: Evidence of hot spot regions.
Mutations in the MECP2 (Methyl-CpG-binding protein) gene recently have been reported to cause Rett syndrome (RTT), an X-linked dominant neurodevelopmental disease. We investigated 125 sporadic cases of Rett syndrome by direct sequencing. Thirty different mutations were found in 97 patients with Rett syndrome. Seventeen mutations have not been described previously. We provide evidence for the existence of several hot spot regions and of a deletion-prone region located at the 3' most region of the gene. This latter region most probably forms secondary structures in vitro. Similar structures in vivo could explain the high frequency of deletions in this region. Nine of 10 recurrent mutations were located in either the methyl CpG binding domain (MBD) or in the transcriptional repression domain (TRD), and all missense mutations were located in one of these functionally important domains. There was a high frequency of more than 60% of truncating mutations (nonsense mutations along with frameshift mutations). One patient with a mild form of the disease and a normal head growth carries a novel c.27-6C>A mutation that causes a cryptic splice site in intron I resulting in a frameshift transcript. The detection rate in our collective was 77.6%. Our findings show that the majority of German Rett patients carry mutations in the MECP2 gene confirming the suggested locus homogeneity for the disease.
Base Sequence↗
Progressive elevation of liver enzymes in a child treated with sulthiame.
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Alanine Transaminase↗
Endocrinological study on growth retardation in Rett syndrome.
AIM: To determine whether primary or secondary growth hormone (GH) deficiency has a causative role in linear growth retardation, a key feature in Rett syndrome (RTT). METHODS: In 38 patients with Rett syndrome a variable set of investigations was performed including assays of growth and thyroid hormones, gonadotropins, gonadal and adrenal steroids and determination of bone age. Not all measurements were attainable from all patients. In three patients the 24-h growth hormone secretion profile was evaluated using the pulsar method. RESULTS: The bone age determined in 24 patients was found to be normal in 8, retarded in 9 and accelerated in 7 patients. Insulin-like growth factor (IGF)-1 was low in 8 out of 23 patients. IGF-binding protein (IGFBP)-3 and insulin and arginine-stimulated growth hormone secretion were both normal, indicating normal GH secretion in the majority of patients. The 24-h GH secretion profile in the first patient showed a normal day/night rhythm and a normal increase in nocturnal GH secretion. The second patient's overall GH secretion was normal but there was no day/night rhythm. The third patient showed borderline low GH secretion. Normal age-appropriate plasma values were found for the thyroid hormones (T4, TSH), TSH-night rhythm, oestradiol, prolactin and cortisol (08.00, 18.00). CONCLUSION: Our study provides no evidence that growth retardation in RTT is caused by growth hormone deficiency. A disturbed hypothalamic control cannot be excluded but it is unlikely that this is the major cause of growth retardation in RTT.
Adolescent↗
Cytochrome c oxidase partial deficiency-associated Leigh disease presenting as an extrapyramidal syndrome.
Leigh disease is a subacute neurodegenerative disorder characterized by symmetric necrotic lesions in the basal ganglia, cerebellum, thalamus, brain stem, and optical nerves and caused by altered oxidative phosphorylation. We describe the clinical, biochemical, neuroimaging, and molecular studies of a 19-year-old boy with early-onset Leigh disease manifesting as severe extrapyramidal disorder with generalized dystonia and choreoathetosis. He was born of healthy parents after an uneventful pregnancy and delivery. At the age of 2 1/2 years, after a minor respiratory infection, he developed unstable, broad-based gait and tremor of the hands. These symptoms persisted for the next several years, when ataxia became more prominent. Difficulty in swallowing, dysarthria, trunk dystonia, and marked dyskinesia of the arms and hands gradually developed. Nystagmus, transient ptosis, and strabismus also appeared. Abnormal laboratory findings included elevated plasma and cerebrospinal fluid lactate and pyruvate, with an abnormal lactate/pyruvate ratio. Cranial computed tomography and magnetic resonance imaging demonstrated signs of cerebellar atrophy, bilateral and symmetric hypodensities in the lentiform nucleus and thalamus, and transient hyperintensities of cerebral peduncles in T2-weighted sequences suggestive of Leigh disease. Muscle biopsy revealed isolated fiber atrophy, necrotic fibers undergoing phagocytosis, and no ragged-red fibers. The measured catalytic activity of cytochrome c oxidase in skeletal muscle homogenates demonstrated a partial cytochrome c oxidase deficiency No abnormalities in the mitochondrial genome and in the SURF-1 gene were found. The boy is currently receiving levodopa therapy, creatine monohydrate, and a high dosage of thiamine and lipoic acid, his condition is stabilized, and extrapyramidal symptoms are less pronounced.
Adolescent↗
Presence of Chlamydia pneumoniae DNA in the cerebral spinal fluid is a common phenomenon in a variety of neurological diseases and not restricted to multiple sclerosis.
Chlamydial DNA and viable organisms have been reported in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. We investigated whether this phenomenon is specific for MS and not occurring in patients with other neurological diseases (OND) or in healthy controls and whether it is caused by infected blood monocytes having crossed the blood-brain barrier. Twelve (21%) of fifty-eight MS patients and 20 (43%) of 47 OND patients had Chlamydia pneumoniae DNA in the CSF as determined by nested polymerase chain reaction. Viable organisms were cultured from one OND patient. We failed to detect C. pneumoniae in the CSF of 67 neurologically healthy persons. C. pneumoniae was detected in parallel in the blood monocytes of 2 of 6 CSF-positive MS patients and in 8 of 10 CSF-positive OND patients. Thus, chlamydial presence cannot exclusively be explained as being caused by contaminating infected monocytes that have crossed the blood-brain barrier. In peripheral blood mononuclear cell-negative patients, chlamydia have been cleared from the circulation but persist in the central nervous system (CNS), indicating the establishment of a chronic process. In summary, the presence of C. pneumoniae in patients with neurological diseases is a common phenomenon and is not restricted to MS patients. The pathogenetic relevance of a chronic chlamydial CNS infection for neurological diseases remains unclear, but the hypothesis that susceptible patients may be impaired in their ability to clear chlamydiae from the CNS requires further examination.
Adolescent↗
C-MYC expression in medulloblastoma and its prognostic value.
To identify prognostic factors in medulloblastoma, a common malignant brain tumor of childhood, expression of the oncogene c-myc was examined at the mRNA level by in situ hybridization. c-myc mRNA expression was observed in 30 of 72 tumors (42%). The c-myc gene copy number was determined by quantitative PCR from genomic DNA of paraffin-embedded tumors. c-myc gene amplification was present in 5 of 62 cases (8.3%). Therefore, c-myc amplification was obviously not the cause of c-myc mRNA expression in most samples. Kaplan-Meier estimation revealed a significant correlation between c-myc mRNA expression and survival (total mean follow-up 4.6 +/- 3.6 years, log-rank p = 0.02). Multivariate logistic regression analysis including sex, age, histological type, degree of surgical resection and expression of synaptophysin, GFAP and c-myc, was carried out on 54 patients who received both radiotherapy and chemotherapy. The analysis identified expression of c-myc as an independent predictive factor of death from disease.
Adolescent↗
Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients.
UNLABELLED: Only recently have mutations in MECP2 been found to be a cause of Rett Syndrome (RTT), a neuro-developmental disorder characterized by mental retardation, loss of expressive speech, deceleration of head growth and loss of acquired skills that almost exclusively affects females. We analysed the MECP2 gene in 31 patients diagnosed with RTT. Sequencing of the coding region and the splice sites revealed mutations in 24 females (77.40%). However, no abnormalities were detected in any of the parents that were available for investigation. Eleven mutations have not been described previously. Confirming two earlier studies, we found that most mutations are truncating and only a few of them are missense mutations. Several females carrying the same mutation display different phenotypes indicating that factors other than the type or position of mutations influence the severity of RTT. Four females with RTT variants were included in the study. Three of these presented with preserved speech while the fourth patient with congenital RTT lacked the initial period of normal development. Detection of mutations in these cases reveals that they are indeed variants of RTT. They represent the mild and the severe extremes of RTT. CONCLUSIONS: mutations in MECP2 seem to be the main cause for RTT and can be expected to be found in approximately 77% of patients that fulfil the criteria for RTT. Therefore analysis of MECP2 should be performed if RTT is suspected. Three mutation hotspots (T158M, R168X and R255X) were confirmed and a further one (R270X) newly identified. We recommend screening for these mutations before analysing the coding region.
Alleles↗
Quantitative proton magnetic resonance spectroscopy of focal brain lesions.
The diagnostic value of single-voxel proton magnetic resonance spectroscopy (2 T, stimulated echo acquisition mode, TR = 6,000 ms, TE = 20 ms, 4-5 mL volumes-of-interest) was assessed for a differentiation of focal brain lesions of unknown etiology in 17 patients 1-14 years of age. Absolute metabolite concentrations were compared with age-matched control subjects and an individual control region. Most of the brain tumors were characterized by strongly reduced total N-acetylaspartyl compounds and marked increases of myo-inositol and choline-containing compounds, consistent with a lack of neuroaxonal tissue and a proliferation of glial cells. Lactate was elevated in only four patients. When using this pattern for a metabolic discrimination of brain tumors from other focal lesions, proton spectroscopy correctly identified 14 of 17 abnormalities, as confirmed by histologic examination after neurosurgical intervention. One false-positive tumor diagnosis was a severe reactive gliosis mimicking a typical tumor spectrum. Two inconclusive cases comprised an astrocytoma with moderately elevated myo-inositol but reduced choline-containing compounds and a patient with an abscess leading to a marked reduction of all metabolites but strong contributions from mobile lipids. In summary, quantitative proton spectroscopy has considerable clinical value for preoperative characterization of focal brain lesions.
Adolescent↗
Foix-Chavany-Marie (anterior operculum) syndrome in childhood: a reappraisal of Worster-Drought syndrome.
Foix-Chavany-Marie syndrome (FCMS) is a distinct clinical picture of suprabulbar (pseudobulbar) palsy due to bilateral anterior opercular lesions. Symptoms include anarthria/severe dysarthria and loss of voluntary muscular functions of the face and tongue, and problems with mastication and swallowing with preservation of reflex and autonomic functions. FCMS may be congenital or acquired as well as persistent or intermittent. The aetiology is heterogeneous; vascular events in adulthood, nearly exclusively affecting adults who experience multiple subsequent strokes; CNS infections; bilateral dysgenesis of the perisylvian region; and epileptic disorders. Of the six cases reported here, three children had FCMS as the result of meningoencephalitis, two children had FCMS due to a congenital bilateral perisylvian syndrome, and one child had intermittent FCMS due to an atypical benign partial epilepsy with partial status epilepticus. The congenital dysgenetic type of FCMS and its functional epileptogenic variant share clinical and EEG features suggesting a common pathogenesis. Consequently, an increased vulnerability of the perisylvian region to adverse events in utero is discussed. In honour of Worster-Drought, who described the clinical entity in children 40 years ago, the term Worster-Drought syndrome is proposed for this unique disorder in children.
Adolescent↗
Enhanced lymphocyte proliferation in patients with adrenoleukodystrophy treated with erucic acid (22:1)-rich triglycerides.
Lymphocytopenia and depression of natural killer cells have been observed in patients with adrenoleukodystrophy (ALD) treated with glycerol trioleate and glycerol trierucate ('Lorenzo's oil'). To investigate possible alterations of cellular immunoreactivity, we measured lymphocyte proliferation in response to mitogens (PHA, Con A, PWM, OKT3) in 27 patients on treatment and in 14 patients without treatment. In patients on treatment, lymphocyte proliferation in response to the mitogens PHA and Con A was significantly higher than in patients without treatment. Lymphocyte proliferation in patients without treatment was comparable to that of normal control lymphocytes. Additionally, we found increased concentrations of erucic acid, C22:1, in lymphocytes from patients with treatment. The enhanced proliferation of lymphocytes in response to mitogens is an indication of increased reactivity of cellular immunity to unspecific immunological stimuli. Long-term side-effects on cellular immunoreactivity have to be considered in ALD patients treated with Lorenzo's oil.
Adolescent↗
Depigmented hypertrichosis following Blaschko's lines associated with cerebral and ocular malformations: a new neurocutaneous, autosomal lethal gene syndrome from the group of epidermal naevus syndromes?
The lines of Blaschko represent one of the cutaneous patterns of mosaicism followed by various skin disorders. Developmental abnormalities affecting other tissues derived from the embryonic ectoderm and mesoderm are occasionally associated. We describe a 30-year-old man with depigmented, bilateral hypertrichosis and dilated follicular orifices following Blaschko's lines associated with cerebral and ocular malformations. The findings suggest a previously unreported neurocutaneous, autosomal lethal gene syndrome from the group of epidermal naevus syndromes.
Adult↗
Award of the Peter Emil Becker Prize 2000 to Prof. Bengt Hagberg, Gothenburg.
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Awards and Prizes↗
Congenital disorder of glycosylation-Ic: case report and genetic defect.
The clinical phenotype and the molecular defect of a patient with a new subtype of congenital disorders of glycosylation (CDG-Ic, formerly designated as CDGS type V) characterized by a deficiency of Dol-P-Glc: Man9GlcNAc2-PP-Dol glucosyltransferase is described. The clinical picture presents with several features similar to CDG-Ia (phosphomannomutase 2 deficiency) such as hypotonia and atactic-dystonic movements. In contrast to CDG-Ia, the course of the disease appears milder. The head growth, the functioning of the peripheral nerves and the initial cerebellar development were normal. Sequencing of the patient's Dol-P-Glc: Man9GlcNAc2-PP-Dol glucosyltransferase cDNA revealed an in-frame deletion of three nucleotides leading to the loss of isoleucine 299.
Brain↗