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We'd like to understand how you use our websites in order to improve them. Register your interest. Patients with Angelman syndrome AS are affected by severe intellectual disability with absence of speech, distinctive dysmorphic craniofacial features, ataxia and a characteristic behavioral phenotype.
Functional loss of UBE3A is due to 15q We report here two patients with clinical features of AS referred to our hospital for clinical follow-up and genetic diagnosis. A review of the clinical features of previously reported patients with whole UBE3A gene or partial intragenic deletions is presented here together with these two new patients. Peer Review reports. The behavioural phenotype is characterized by happy disposition, hyperactivity, attention deficit and frequent disruption of sleep cycles.
Other clinical problems are gastrointestinal difficulties with feeding problems, gastroesophageal reflux, constipation, scoliosis, and an increased sensitivity to heat. This region includes a cluster of genes under imprinting control which show differential expression depending on the parental origin, in a tissue-specific manner. The functional loss of UBE3A in the maternal allele is due to different genetic mechanisms: i deletion of the region 15q There are also some reports that describe a proportion of AS patients who harbor microdeletions of the UBE3A gene [ 6 , 7 , 8 , 9 , 10 ].
This domain is encoded by exons 3—10 [ 11 ]. Exons 1 to 5 encode a steroid co-activation region which has several LXXLL motifs that are known to be receptor interacting motifs [ 12 ]. Mutations in the UBE3A gene are widely distributed and have been detected throughout all regions of the gene [ 13 , 14 ].
Rare intragenic deletions and duplications may represent a higher percentage of mutations than expected, because these alterations escape the routine screening [ 15 ]. Neither perinatal problems nor hypotonia was reported. Psychomotor development was delayed. She came to the clinical geneticist when she was 2-yearmonth old.
Neurological examination detected severe intellectual disability, ataxia of gait, receptive and non-verbal communication skills higher than verbal ones, hyperreflexia of the lower extremities, tremulous movement of limbs and frequent drooling. EEG showed generalized slow wave activity with paroxysmal activity. The behavioural phenotype included frequent laugher, happy demeanour, easily excitable personality, hyperactive behaviour, attention deficit and exploration of objects throughout the mouth.
Methylation pattern of the 15q A normal methylation pattern and a heterozygous deletion of exon 9 were observed in patient 2. Red asterisks indicate the deleted exons. In both cases the deletions were de novo.
Exons are depicted as grey boxes. Exons 1 to 5 constitute the steriod co-activation region and exons 3 to 10 constitute the HECT ligase domain, according to Ramamoorthy and Nawaz et al. UBE3A deletions reported here and in the literature are shown as black bars. Parents testing showed that deletion was de novo Fig. In order to investigate in which parental allele the deletion was originated, we used six SNP located in intron 2: rs, rs, rs, rs, rs and rs All of them were not informative so the maternal origin of the deletion could not be confirmed.
No perinatal problems were reported but she was noted to be hypotonic. She presented developmental delay. Oral language was limited to around 10 words. Physical features of the patient included prognathia, wide mouth and wide-spaced teeth. The neurological manifestations included severe intellectual disability, ataxia of gait, uplifted and flexed arm position during deambulation, speech impairment, frequent drooling and seizures.
The EEG showed generalized slow wave activity with paroxysmal activity. At the age of the diagnosis, 5. Subsequently, a DNA sample of the patient was sent to our laboratory for further studies. MLPA analysis confirmed the deletion only involving exon 9 and 10 Fig. The genetic analysis in the parents showed that the deletion encompassing exons 9 and 10 was de novo Fig. In patient 2, two SNPs in intron 9: rs, rs and 1 SNP in exon rs were analyzed to investigate the parental origin of the deletion.
As in patient 1, we could not confirm the maternal origin of the deletion. Angelman syndrome is caused by the lack of expression of the maternal copy in neurons of the UBE3A gene due to four different molecular etiologies: Deletion of the 15q Genotype-phenotype correlations among molecular subclasses have shown that deletion patients show a more severe phenotype in all aspects of neurodevelopmental delay except for expressive language skills that are extremely poor regardless of their molecular subclass [ 17 , 18 , 19 , 20 , 21 ].
However, Mertz et al. In addition, the deletion class is the most severely affected regarding microcephaly, seizures, relative hypopigmentation, motor difficulties while paternal uniparental disomy and imprinting defect individuals have better physical growth, have less movement and ataxia abnormalities, and have a lower prevalence but not absence of seizures [ 18 ].
It has been suggested that AS patients carrying UBE3A mutations show a phenotype somewhere in the middle between deletion and paternal uniparental disomy carriers. They present higher incidences of seizures and microcephaly, similar to deletion patients, while their neurodevelopment delay is similar to paternal uniparental disomy and imprinting defect patient carriers [ 18 , 19 ].
A revision of genotype-phenotype differences has been published recently by La Salle et al. Exon 2 deletion in patient 1 is predicted to eliminate the start codon and consequently no protein will be produced p. Deletion of exons 9 and 10 in patient 2 is predicted to eliminate the last 88 aminoacids p. Only patient 2 and the patient reported by Cali et al. All patients show the consistent clinical features of AS except for patient 1 who does not present stereotypes.
This is surprising because stereotypes have been described as a clinical feature often present in all patients with AS since early in development. Microcephaly is present in almost all patients 7 of nine patients while seizures are present in all except one 7 of eight patients available.
The high incidence of seizures and microcephaly is in accordance to what has been reported before by Lossie et al. Associated clinical features show variability between patients. A comparison of AS patients with mutations and intragenic deletions has not been reported before and from our observations there are no differences between the two groups. In our laboratory, array Comparative Genomic Hybridization aCGH is the first diagnostic tool in neurodevelopmental disorders.
MS-MLPA analysis simultaneously assesses the methylation status and genomic dosage changes at the 15q To date, few reports have evaluated the contribution of exonic deletions to the spectrum of UBE3A mutations. Here, we report two patients with AS who present two novel intragenic deletions within the UBE3A gene that together with those reported in the literature show that UBE3A intragenic deletions may represent a small fraction of AS patients.
Angelman Syndrome. Curr Probl Pediatr. Consensus for diagnostic criteria. Am J Med Genet. Angelman syndrome updated consensus for diagnostic criteria. Am J Med Genet A. Buiting K. Prader-Willi syndrome and Angelman syndrome. Practice guidelines for the molecular analysis of Prader-Willi and Angelman syndromes. BMC Medical Genetics. European Journal of Medical Genetics. Novel deletion of the E3A ubiquitin protein ligase gene detected by multiplex ligation-dependent probe amplification in a patient with Angelman syndrome.
Experimental and Mol Med. Molecular and clinical aspects of Angelman syndrome. Molecular Syndromology. Ramamoorthy S, Nawaz Z. E6-associated protein E6-AP is a dual function coactivator of steroid hormone receptors.
Nucl Recept Signal. Bird L. Angelman syndrome: review of clinical and molecular aspects. Appl Clin Genet. Hum Mutat. Eur J Paediatr Neurol. Clinical and genetic aspects of Angelman syndrome.
Genetics in Medicine. A neurodevelopmental survey of Angelman syndrome with genotype-phenotype correlations. Google Scholar. Distinct phenotypes distinguish the molecular classes of AS. J Med Genet. Phenotype—genotype correlation in 20 deletion and 20 non-deletion Angelman syndrome patients.
Eur J Hum Genet. Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects. Identification of novel deletions of 15q11q13 in Angelman syndrome by array-CGH: molecular characterization and genotype—phenotype correlations.
Neurodevelopmental outcome in Angelman syndrome: genotype—phenotype correlations. Res Dev Disabil.
Adrian Mol - godine lutanja
The most frequent ones were p. RW EG 5. IV 5. Homozygosity value indicated high heterogeneity of Serbian population. The two phenotypes did not match only for patients with p.
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