No other abnormalities were present.
Patient 2 did not present with any dysmorphic features. Metaphase and interphase FISH. Typical findings of classic Rett syndrome are a regression of motor skills, communicative abilities and especially a loss of purposeful hand movements, accompanied by secondary microcephaly after a period of near to normal development. Patient 2 was born at 40 weeks of gestation by spontaneous vaginal delivery as the third of four children of non-consanguineous Turkish parents following an uncomplicated pregnancy.
Her psychomotor development was slow, but the parents did not report regression, and no epilepsy or stereotypies were reported. The parents of patient 1 also showed normal karyotypes.
In patient 2, the relative copy of selected genomic regions was determined by quantitative PCR as described ly data not shown. She learned to walk and spoke her first words at the age of 19 months. In this study, we demonstrate two more female patients with an MECP2 duplication, and further delineate the aspect that, as Reardon et al 11 first suggested, the random XCI may be causative for the phenotype. Learn More. All position coordinates given below are based on Human Genome Build She had constipation from birth, for which she had to be treated with a laxative.
Microsatellite analysis was performed with four di-nucleotide sequences within the region of interest. The origin of the duplication was identified by an allele-specific elevation of al intensity in the patient in comparison with the parental genotypes. Semi-quantitative analysis indicates a paternal origin of the MECP2 duplication in patient 2 data not shown.
She never learnt to read or write. Adenoids were removed at the age of 5 years, but overall there was no history of recurrent or severe infectious diseases. She still displayed autistic behavior, spending most of her time engaged in role-playing games with her dolls.
The few affected males with deleterious MECP2 mutations usually present with clinical features consisting of fatal seizures and severe mental retardation including microcephaly that often le to death during the initial years. The highly polymorphic CAG n motif within the human androgen receptor gene HUMARA was used to distinguish and compare the methylation activity of the X chromosomes in both patients as described ly.
After a first year at regular school, she changed to a special school. Speech development was delayed and started at 3 years. XCI. In addition, patient 1 showed a second de novo duplication of 2q Illustration of the genomic aberration of the MECP2 region with the 6. During the years, large cohorts of mentally retarded patients of both sexes were investigated with high-resolution arrays for submicroscopic genomic imbalances through different array technologies.
Informed consent for the investigation was obtained from both families. An investigation bias favoring affected boys to be investigated for MECP2 duplications may have occurred, while girls were simply not investigated for this disorder. Furthermore, duplications of the genes IRAKMECP2 and GDI1 were confirmed in patient 2 according to the gene-specific probes from the multiple ligation-dependent probe amplification kit, whereas a normal al was obtained for the probe against the proximal flanking IRAK gene.
Bilateral simian creases as well as a sacral hemangioma were noted. Female carriers usually show a normal intellectual performance due to skewed X-inactivation XCI. We report on two female patients with a de novo MECP2 duplication associated with moderate mental retardation. She mostly played alone and revealed some autistic features. We report on two unrelated female patients with a de novo MECP2 duplication and a random XCI, revealing a moderate but unspecific mental retardation in childhood and the development of neurological features in the second decade of life.
Try out PMC Labs and tell us what you think. These should have shown MECP2 duplications in females, and yet no further affected girls have been reported. Xq28 duplications including MECP2 are a well-known cause of severe mental retardation in males with seizures, muscular hypotonia, progressive spasticity, poor speech and recurrent infections that often lead to early death.
Her three brothers were healthy. Her course of puberty was described as normal and no endocrinological problems were reported.
Both patients were examined for diagnostic evaluation because of mental retardation. The SNP-microarray data were evaluated considering the genotype and the corresponding probe als within the duplicated region, thus providing a correlation of a specific genotype and the respective al height.
This marker and all other tested markers were not informative for patient 1. The XCI in patient 1 is The lower traces show a female positive control with complete skewing of X-inactivation in c undigested and d digested samples. Her non-verbal IQ was Her constipation improved, but sometimes a drug therapy was necessary. She visited a school for the mentally retarded, and was not able to write or count. Besides genotyping, we measured peak heights for all duplication carriers compared with normal controls in order to identify duplicated and non-duplicated alleles as described ly.
showing random X inactivation in both patients and proof of complete digestion with methylation-sensitive restriction endonuclease Hpa II after PCR amplification of HUMARA male control and female positive control, respectively.
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At the age of 10 years, standardized non-verbal testing SON showed a developmental age of 6 years and a cognitive score of On physical examination at the age of 10 years, her weight was The EEG at that age was irregular, with alpha-rhythm and abnormal beta waves. At the age of 5 years, the parents reported a stagnation of development, but no regression.
In familial cases with X-linked pedigrees, the asymptomatic female carriers show a ificant skewing of X-inactivation XCI. The reported duplications vary from 0. In both patients, the de novo duplication occurred on the paternal allele, and both patients show a random XCI, which can be assumed as the triggering factor for the phenotype. Samples were processed according to the manufacturer's instructions. The lower two traces show the male control c undigested and d after digestion. The multiplex ligation-dependent probe amplification profiles were obtained using normal and pathological DNA samples as controls.
The fact that all females carrying the duplication were described as intellectually normal could have added to that effect. Gene content of the region is shown from the Ensembl genome browser version In patients 1 and 2, the duplication in Xq28 was confirmed by interphase FISH based on the presentation of three hybridization als for the BAC clone RPL14 Figure 2 A localization of the duplicated region on an autosome was excluded for both patients in metaphase spre.
This is confirmed by the identification of only two cases out of our cohort of unselected patients with mental retardation incidence of 0. During her initial years of life, she presented with a high frequency of respiratory infections. The parental origin of the duplication was determined by microsatellite analysis, and the al intensities for specific probes were determined on the 6. For patient 1 performed on ABI, Genotyper v3. The de novo duplication of Xq28 material, including the MECP2 gene, was identified in both patients using array analyses. The parents noted autistic behavioral features in their daughter — for example, that she mostly played alone.
We conclude that MECP2 duplications are a comparatively rare cause of mental retardation in females. The analysis of the SNP-microarray data regarding the correlation of genotype and al height within the duplicated region indicates a paternal origin in both patients.
Genomic DNA was isolated from peripheral blood leukocytes using routine procedures. To investigate the localization of the duplicated segment, FISH analyses were performed on metaphase spre and interphase nuclei of both patients and the parents of patient 2.
She achieved normal motor milestones. We examined patient 1 for diagnostic evaluation at the age of 6 years and again at 7 years. als are only present on both X chromosomes. The brain MRI was normal. At the age of 18 years, a spastic hypertonia of the legs appeared, which led to gait disturbances. There were a considerable of reports on mentally retarded boys with MECP2 duplications during the years following the first publication.
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Furthermore, we describe the phenotype that might be restricted to unspecific mild-to -moderate mental retardation with neurological features in early adulthood. Karyotype analysis was performed for each patient on metaphase chromosomes from cultured blood lymphocytes using Giemsa banding at bands resolution with normal. She had no facial dysmorphism, but facial similarity to her father, who also presented with synophrys.
Her further psychomotor development was delayed.