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Angelman syndrome (AS) is a complex neurological disorder with different genetic aetiologies. It is not known whether the clinical features vary depending on the genetic mechanism. We report four patients with AS owing to uniparental disomy (UPD). There were two males and two females, with a mean age of 8 years (range 7 to 11 years). All patients h...
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A patient with Angelman syndrome and a 46,XY/47,XY,+inv dup(15)(pter-->q11: q11-->pter) karyotype and a patient with Prader-Willi syndrome and a 46,XY/47,XY,+inv dup(15)(pter-->q12: q12-->pter) karyotype were investigated with molecular markers along chromosome 15. Paternal uniparental isodisomy was found for all informative markers in the first ca...
Previously, 158 nuclear families with probands suspected of having either Prader Willi (PWS) or Angelman syndrome (AS) were analyzed with polymorphic DNA markers from the 15q11-13 region. These cases have been re-evaluated with the probe PW71 (D15S63), which detects parent-of-origin-specific alleles after digestion with a methylation-sensitive rest...
Prader-Willi syndrome (PWS) is primarily caused by deletions involving the paternally derived imprinted region at chromosome 15q11.2-q13 and maternal uniparental disomy 15 (upd(15)mat). The underlying mechanisms for upd(15)mat include trisomy rescue (TR), gamete complementation (GC), monosomy rescue and post-fertilization mitotic error, and TR/GC i...
Angelman syndrome (AS) is a neurodevelopmental disorder caused by a deletion on chromosome 15, uniparental disomy, imprinting defect, or UBE3A mutation. It is characterized by intellectual disability with minimal speech and certain behavioral characteristics. We used standardized measures to characterize the developmental profile and to analyze gen...
Angelman syndrome (AS) and Prader–Willi syndrome (PWS) are distinct clinical phenotypes resulting from maternal and paternal deficiencies, respectively, in human chromosome 15q11–q13. Although several imprinted, paternally expressed transcripts have been identified within the PWS candidate region, no maternally expressed gene has yet been identifie...
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... In their recent research, Manoubi et al showed that AS individuals with maternal deletion demonstrated a severe phenotype when compared with UPD patient. 21 Comparison of behavioral and clinical findings between AS deletion and nondeletion patients revealed a younger age at diagnosis among the first group (5.12 vs. 7.33 years), mainly due to the severity of the phenotype, which was also reported by Varela et al and Smith et al. 14,22 In addition, deletion patients presented a higher incidence of epileptic seizures (p ¼ 0.04), ataxia (p ¼ 0.0008), and abnormal EEG profile (p ¼ 0.003). Other clinical features were also predominantly present among deletion group, such as microcephaly, speech impairment, history of hypotonia, and happy demeanor, which support the evidence that these individuals develop a severe phenotype compared with AS patients with other molecular mechanisms, although it must be noted that these observations did not reach the statistical significance. ...
Angelman syndrome (AS) is a rare neurodevelopmental disorder due to genetic defects involving chromosome 15, known by intellectual disability, cognitive and behavioral disorders, ataxia, delayed motor development, and seizures. This study highlights the clinical spectrum and molecular research to establish the genotype–phenotype correlation in the pediatric Moroccan population. Methylation-specific-polymerase chain reaction (MS-PCR) is a primordial technique not only to identify the genetic mechanism of AS but also to characterize the different molecular classes induced in the appearance of the clinical symptoms. Patients with positive methylation profile were additionally studied by fluorescent in situ hybridization. Sequencing analysis of the UBE3A gene was performed for patients with negative MS-PCR. We used Fisher's test to assess differences in the distribution of features frequencies among the deletional and the nondeletional group. Statistical analysis was performed using R project. We identified from 97 patients diagnosed with AS, 14 (2.06%) had a classical AS phenotype, while 70 (84.5%) patients displayed a subset of consistent and frequent criteria. Development delay was shown severe in 63% and moderate in 37%. Nineteen out of 97 of them had MS-PCR positive in which 17 (89.47%) had 15q11-q13 deletion. Deletion patients presented a higher incidence of epileptic seizures (p = 0.04), ataxia (p = 0.0008), and abnormal electroencephalogram (EEG) profile (p = 0.003). We further found out a frameshift deletion located at exon 9 of the UBE3A gene discovered in a 5 years old patient. We report in this study the genotype–phenotype correlation using different molecular testing. Correlation analysis did not reveal any statistical differences in phenotypic dissimilarity between deletion and nondeletion groups for most clinical features, except the correlation was highly significant in the abnormal EEG. According to our findings, we recommend offering MS-PCR analysis to all patients with severe intellectual disability, developmental delay, speech impairment, happy demeanor, and hypopigmentation.
... The EEG was abnormal every time. Our results confirm those found by smith et al. [18]. ...
Background: Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe mental retardation, absent speech, dysmorphic facial features, microcephaly, epileptic seizures, Electroencephalography (EEG) abnormalities and neurological problem. Four known molecular mechanisms lead to a deficiency in maternal UBE3A expression and consequently to AS: (1) Deletion of the AS critical region on the maternal chromosome 15q11.2–q13 (70%), (2) paternal uniparental disomy (pUPD) (2-7%), (3) imprinting defects (3–5%), and (4) mutations in the maternal copy of UBE3A (10%). Materials and methods: Here, we report 11 Tunisian AS patients suspected on the basis of clinical features, behavior, EEG findings and confirmed by molecular analysis using FISH technique, microsatellites study and Methylation Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA). Results: The diagnosis was confirmed in these patients (7 males, 4 females) by detecting the presence of deletion of the critical AS region on chromosome 15 through the use of fluorescence in situ hybridization (FISH) technique in 10 patients, and confirmed by Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA). A microsatellite analysis detected only one patient with uniparental disomy. Conclusion: Deletion and methylation aberration screening by MS-MLPA assay is considered as a rapid and cost-effective method to confirm Angelman syndrome diagnosis contributing to an early interventional therapy and genetic counseling should be provided.*Correspondence to: Wiem Manoubi, Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Sousse, Tunisia, Tel: +216 73 102 500; E-mail: wiem.manoubi@yahoo.frKey words: Angelman syndrome, methylation disorders, 15q11-q13 locus, paternal uniparentalReceived: June 25, 2019; Accepted: July 16, 2019; Published: July 19, 2019Abbreviations: AS: Angelman Syndrome; FISH: Fluorescence In-Situ Hybridization; UPD: Uniparental Disomy; MS-MLPA: Methyla-tion-Specific Multiplex Ligation-dependent Probe Amplification; EEG: Electroencephalography; PWS: Prader-Willi syndrome; MRI: Magnetic Resonance Imaging; IC: Imprinting CenterIntroductionAngelman syndrome (AS) (MIM #105830) is a neurogenetic disease affecting children, first identified in 1965 by a British doctor, Harry Angelman, from whom it also gained its name [1]. It is one of the most common genetic syndromes caused by non-mendelian inheritance in the form of genomic imprinting. The incidence of AS is estimated to be between 1/10,000 and 1/20,000, with equally affected males and females [2,3]. Cases have been reported from all over the world without racial predilection.AS is attributable to the loss of gene expression within the chromosomal region 15q11-q13 [4]. The phenotype is well known in infancy and adulthood, but the clinical features may change with age. The main clinical characteristics include severe mental retardation, epileptic seizures and EEG abnormalities, neurological problems and distinct facial dysmorphic features. Behavioral problems such as hyperactivity and sleeping problems are reported, although these patients present mostly a happy personality with periods of inappropriate laughter [5]. The natural history is typified by normal growth parameters at the early age months. Developmental microcephaly appears by 2 years of age, delayed skill attainment by 6-12 months, speech impairment and seizures in 80% of cases by 3 years, and ataxic gait abnormalities [5]. Dysmorphic phenotypes are seen in about 80% of cases with occipital groove, flat occiput, protruding tongue, wide mouth, wide-spaced teeth, strabismus and prognathia [5]. Neuromuscular manifestations can include tongue thrusting, chewing/mouthing behaviors, swallow/suck disorders, truncal hypotonia during infancy, hyperactive lower extremity deep tendon reflexes, uplifted, flexed arm positioning during ambulation, and wide based gait with pronated or valgus-positioned
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Manoubi W (2019) Screening of Angelman Syndrome deletion and methylation aberration using MS-MLPA assay in a Tunisian populationBiomed Res Clin Prac, 2019 doi: 10.15761/BRCP.1000188 Volume 4: 2-6ankles [5]. Abnormal sleep-wake cycles, heat intolerance, abnormal food related behaviors can also be seen [5]. The EEG is usually more abnormal than clinically expected, but it can also be normal in individuals with genetically proven AS [1].Angelman syndrome is primarily due to maternal copy gene expression, lack of ubiquitin-protein ligase E3A (UBE3A) in fetal brain and adult frontal cortex. This can occur by maternal deletion of 15q11-13locus (68%), mutation in UBE3Agene (11%), paternal uniparental disomy (UPD) (7%), and imprinting center (IC) abnormalities (3%) [6]. However, 10% of AS patients have non diagnostic molecular findings [5].There are a number of techniques that can confirm a diagnosis of AS. The detection of abnormal parent-specific methylation within the AS critical region has been reported in approximately 80% of individuals with AS [5]. The more commonly used methylation assessment techniques include Methylation Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA) and Southern blot analysis. The latter has greatly decreased out of favor due to the need for large amounts of high molecular weight DNA and the time and technical commitments required.MS-MLPA has the ability to determine aberrant methylation status and/or a deletion of the SNRPN locus. In the event of aberrant methylation but a normal diploid complement of the SNRPN locus, the haplotype studies are undertaken to discriminate between UPD and an imprinting defect especially of the imprinting center.The purpose of this study was to evaluate the performance of MS-MLPA assay in a cohort of 11 Tunisian patients with definite diagnosis of AS, confirmed by Fluorescent in situ hybridization (FISH) or haplotype study; in order to assess concordance as well as the advantages and disadvantages of these laboratory techniques.Materials and methodsPatientsEleven suspected patients by AS (7 males and 4 females) with average of 3.68), were referred to the Laboratory of Human Cytogenetic, Molecular Genetics and Reproductive Biology of Farhat Hached University Hospital, over a period of 11 years (2006 and 2017). Patients were characterized with severe mental retardation, speech impairment, epileptic seizures or abnormal EEG findings and dysmorphic facial features (Table 1).Consanguinity was documented in 4 families. patients belonging to 7 unrelated families were investigated as well and are originated from different regions of Tunisia. Consanguineous families were unrelated and originated from different regions of the country. This study was approved by local ethics committees and performed with the patients and their families informed consent.Conventional cytogenetic analysisChromosomal analysis was performed according to standard procedures for the patients and their parents. Briefly, peripheral blood lymphocytes were cultured in RPMI 1640 medium (Gibco®, Grand Island, NY, USA) enriched with 20% fetal calf serum, L-glutamine, antibiotics (penicillin and streptomycin) and phytohemagglutinin. The cells were cultured for 72 hours in a 37°C incubator with 5% CO2. Culture was stopped using colcemid solution (0.05 μg/mL) for 45 minutes. After harvesting, the cells were exposed to hypotonic solution (0.075 mol/L KCl) and fixed with methanol/acetic acid (3:1). The slides were prepared and stained using R-banding. A minimum of 20 metaphases were analyzed from each sample using the Applied imaging CytoVision Karyotyping System®. Karyotypes were assigned according to the recommendation of the International System of Human Cytogenetic Nomenclature (ISCN) 2005 [6,7].Fluorescent in situ hybridization (FISH)Analysis by fluorescence in situ hybridization (FISH) with probes D15Z1/SNRPN/PML [Vysis®, Downers Grove, IL] was performed according to supplier protocol. In all cases, we studied at least 10 metaphases and 50 interphases nuclei where we clearly identified hybridization to a control probes; D15Z1 at the centromeric region (spectrum green), and PML at 15q22-24 (spectrum orange) which can detect all possible translocations.Ten microliters of probe were applied to metaphase slides and co-denaturized for 7 min at 75°C. After overnight hybridization at 37°C and washing, chromosomes were counterstained with 4,6 diamino-2-phenylindole (DAPI) and observed using an Axioskop Zeiss® fluorescentmicroscope and the images were captured with a CCD camera (Cytovision, AppliedImaging®).M S - M L PAWe performed SALSA MLPA probemix kit P245-A2 (MRC-Holland, Amsterdam, Netherlands) that included probes targeting SNRPN and UBE3A genes, according to the method described and manufacturer’s recommendations [8]. This kit contains four probes located in the critical region of the PWS/AS and two control probes located at 15q24.1. Normalization was performed and the peak heights were compared to a synthetic control. Only when the peak was below 0.75 deletion was considered. For the analysis of fragments, we used ABI PRISM®310 Genetic Analyzer (Applied Biosystem), with ROX-500 as the internal size standard. Data interpretations were performed using Coffalyser (MRC-Holland) software.Genotyping of polymorphic markersPCR was carried out using the standard method with polymorphic markers located in the 15q11q13 region to verify paternal uniparental disomy. Eleven microsatellites markers were used (from centromere to telomere): D15S11, D15S646, D15S128, D15S1506, D15S122, D15S210, D15S986, D15S97, GABRB3, D15S966, D15S642 [9-10-11]. Eight of them (D15S11, D15S646, D15S128, D15S1506, D15S122, D15S210, D15S986 and GABRB3) were located within the critical region. PCR products were separated by capillary electrophoresis for 30 min on an ABI PRISM®310 Genetic Analyzer (Applied Biosystem) at 15 kV using a 36 cm capillary and POP4 polymer.ResultsClinical characteristicsGender, age at diagnosis, main clinical features, cytogenetics and molecular analysis results of our patients are shown in table 1.All patients showed severe speech deficit or absent speech, severe developmental delay, movement and behavioral abnormalities. Nine of them (81.81%) could sit without support, 2 (18.1%) could walk with support, and 9 could not walk. Eight of them (72.7%) had absence of speech, and 3 (27.2%) were able to speak a few meaningful words. Dysmorphic facial features like occipital groove, protruding tongue, wide spaced teeth, prognathism were the most associated to
... The number of participants included in the studies ranged from 4 to 92, due in part to the underlying genetic mechanism, with the smallest sample being made up exclusively of individuals with uniparental disomy (UPD), a less common mechanism in Angelman syndrome than maternal deletion (see Williams et al. 2010). The 12 papers covered a broad range of ages, with five studies focused exclusively on children (Bai et al. 2014;Buoni et al. 1999;Smith et al. 1997;Tan et al. 2011;Zori et al. 1992), two exclusively on adults (Clayton-Smith 2001; Sandanam et al. 1997), and three focused on children and adults (Guerrini et al. 1996;Moncla et al. 1999;Smith et al. 1996). For the remaining two studies (Beckung et al. 2004;Saitoh et al. 1994) it was not possible to determine the age of the subgroup of individuals with genetically confirmed Angelman syndrome. ...
... One paper (Sandanam et al. 1997) did report using at least two clinicians for each assessment, which might be expected to increase the reliability of the clinical judgements made, but it was not possible to determine whether this was the case, and inter-rater reliability information was not provided. Whilst the use of a questionnaire or data sheet might ensure consistency in the information asked of each informant, the likely accuracy of this information was unclear, as none of the studies using questionnaire methods (Bai et al. 2014;Saitoh et al. 1994;Smith et al. 1996Smith et al. , 1997Zori et al. 1992) reported on the psychometric properties of their purpose-made measures. ...
... The reported prevalence of ataxic/jerky movements in Angelman syndrome ranged from 72.7% (Beckung et al. 2004;Tan et al. 2011) to 100% (Bai et al. 2014;Buoni et al. 1999;Clayton-Smith 2001;Moncla et al. 1999;Sandanam Smith et al. 1996Smith et al. , 1997, across the 11 studies that provided prevalence estimates. In those with a non-deletion mechanism, ataxic/jerky movement was often reported to be milder or less prevalent (e.g., Moncla et al. 1999;Tan et al. 2011;Smith et al. 1997). ...
Movement disorders are reported in idiopathic autism but the extent to which comparable movement disorders are found in syndromic/co-morbid autism is unknown. A systematic search of Medline, Embase, PsychINFO and CINAHL on the prevalence of specific movement disorder in syndromic autism associated with specific genetic syndromes identified 16 papers, all relating to Angelman syndrome or Rett syndrome. Prevalence rates of 72.7-100% and 25.0-27.3% were reported for ataxia and tremor, respectively, in Angelman syndrome. In Rett syndrome, prevalence rates of 43.6-50% were reported for ataxia and 27.3-48.3% for tremor with additional reports of dystonia, rigidity and pyramidal signs. However, reliable assessment measures were rarely used and recruitment was often not described in sufficient detail.
... Likewise, a mouse model with increased gene dosage of Ube3a demonstrates autism-like behaviors [39]. In addition, AS patients with uniparental disomy, in which two paternally inherited genes are present, generally have a less severe phenotype than deletion patients [42,43], suggesting the incomplete imprinting of Ube3a in the brain could be protecting neuronal function to some degree. Moreover, a recent report indicates that at least one behavioral model can differentiate WT, maternal deletion and Ube3a null mice in multiple motoric assays and licking behavior. ...
Angelman Syndrome (AS) is a devastating neurodevelopmental disorder characterized by developmental delay, speech impairment, movement disorder, sleep disorders and refractory epilepsy. AS is caused by loss of the Ube3a protein encoded for by the imprinted Ube3a gene. Ube3a is expressed nearly exclusively from the maternal chromosome in mature neurons. While imprinting in neurons of the brain has been well described, the imprinting and expression of Ube3a in other neural tissues remains relatively unexplored. Moreover, given the overwhelming deficits in brain function in AS patients, the possibility of disrupted Ube3a expression in the infratentorial nervous system and its consequent disability have been largely ignored. We evaluated the imprinting status of Ube3a in the spinal cord and sciatic nerve and show that it is also imprinted in these neural tissues. Furthermore, a growing body of clinical and radiological evidence has suggested that myelin dysfunction may contribute to morbidity in many neurodevelopmental syndromes. However, findings regarding Ube3a expression in non-neuronal cells of the brain have varied. Utilizing enriched primary cultures of oligodendrocytes and astrocytes, we show that Ube3a is expressed, but not imprinted in these cell types. Unlike many other neurodevelopmental disorders, AS symptoms do not become apparent until roughly 6 to 12 months of age. To determine the temporal expression pattern and silencing, we analyzed Ube3a expression in AS mice at several time points. We confirm relaxed imprinting of Ube3a in neurons of the postnatal developing cortex, but not in structures in which neurogenesis and migration are more complete. This furthers the hypothesis that the apparently normal window of development in AS patients is supported by an incompletely silenced paternal allele in developing neurons, resulting in a relative preservation of Ube3a expression during this crucial epoch of early development.
... The clinical features of our patient are similar to previously published results [4,7,9,12]. The patient's AS symptoms are relatively mild, which correlates well with the previous observations that AS patients with UPD usually have less severe clinical symptoms [8,10,11,13]. The BMI of our patients was > 85%, which correlated well with the previous results of Tan et al. (2011) [4] and further confirmed that AS patients with UPD have significantly higher BMI than AS patients with other underlying genetic abnormalities. ...
Angelman syndrome is a rare neurogenetic disorder that results in intellectual and developmental disturbances, seizures, jerky movements and frequent smiling. Angelman syndrome is caused by two genetic disturbances: either genes on the maternally inherited chromosome 15 are deleted or inactivated or two paternal copies of the corresponding genes are inherited (paternal uniparental disomy). A 16-month-old child was referred with minor facial anomalies, neurodevelopmental delay and speech impairment. The clinical symptoms suggested angelman syndrome. The aim of our study was to elucidate the genetic background of this case.
This study reports the earliest diagnosed angelman syndrome in a 16-month-old Hungarian child. Cytogenetic results suggested a de novo Robertsonian-like translocation involving both q arms of chromosome 15: 45,XY,der(15;15)(q10;q10). Molecular genetic studies with polymorphic short tandem repeat markers of the fibrillin-1 gene, located in the 15q21.1, revealed that both arms of the translocated chromosome were derived from a single paternal chromosome 15 (isodisomy) and led to the diagnosis of angelman syndrome caused by paternal uniparental disomy.
AS resulting from paternal uniparental disomy caused by de novo balanced translocation t(15q;15q) of a single paternal chromosome has been reported by other groups. This paper reviews 19 previously published comparable cases of the literature. Our paper contributes to the deeper understanding of the phenotype-genotype correlation in angelman syndrome for non-deletion subclasses and suggests that patients with uniparental disomy have milder symptoms and higher BMI than the ones with other underlying genetic abnormalities.
... Soon after this discovery , those with the deletion were compared to those without the microdeletion. As additional AS-causing mechanisms were identified, the clinical correlations became more complicated because of overlapping symptoms among all mechanisms [Saitoh et al., 1994; Smith et al., 1997; Fridman et al., 2000; Lossie et al., 2001; Nazlican et al., 2004; Saitoh et al., 2005]. It soon became evident that the core features of the syndrome can be attributed solely to disruption of the UBE3A gene, regardless of the mechanism , but some differences did exist among the genetic types. ...
The Angelman syndrome is caused by disruption of the UBE3A gene and is clinically delineated by the combination of severe mental disability, seizures, absent speech, hypermotoric and ataxic movements, and certain remarkable behaviors. Those with the syndrome have a predisposition toward apparent happiness and paroxysms of laughter, and this finding helps distinguish Angelman syndrome from other conditions involving severe developmental handicap. Accurate diagnosis rests on a combination of clinical criteria and molecular and/or cytogenetic testing. Analysis of parent-specific DNA methylation imprints in the critical 15q11.2-q13 genomic region identifies 75-80% of all individuals with the syndrome, including those with cytogenetic deletions, imprinting center defects and paternal uniparental disomy. In the remaining group, UBE3A sequence analysis identifies an additional percentage of patients, but 5-10% will remain who appear to have the major clinical phenotypic features but do not have any identifiable genetic abnormalities. Genetic counseling for recurrence risk is complicated because multiple genetic mechanisms can disrupt the UBE3A gene, and there is also a unique inheritance pattern associated with UBE3A imprinting. Angelman syndrome is a prototypical developmental syndrome due to its remarkable behavioral phenotype and because UBE3A is so crucial to normal synaptic function and neural plasticity.
... Children with a milder form of attention deficit may have a moderate ID (); a small percentage may obtain better results in some areas, particularly in social abilities. Several reports have suggested that individuals with AS resulting from UPD, imprinting mutations and UBE3A gene mutations show a milder or atypical phenotype than that observed in those with deletion, with a lower incidence and later onset of seizures, less severe ataxia, earlier age of walking, a greater ability to use some symbolic communication, or a lower frequency of anomalies in the facial morphology (Bottani, Robinson, DeLozier-Blanchet, Engel, Morris, Schmitt et al., 1994; Smith, Marks, Haan, Dixon, & Trent, 1997; Smith, Robson, & Buchholz, 1998; Moncla, Malzac, Livet, Voelckel, Mancini, Delaroziere et al., 1999; Fridman, Varela, Kok, Diament, & Koiffman, 2000). Others, however, have argued that the supposed milder phenotype described in cases without deletion is within the range observed in all molecular classes of AS (Smith, Wiles, Haan, McGill, Wallace, Dixon et al., 1996; Prasad & Wagstaff, 1997; Thompson & Bolton, 2003; Pelc et al., 2008). ...
... Repetitive or stereotyped behaviors did not occur during the ADOS evaluation. Data collected by us seem to confirm a less severe phenotype in patients with UBE3A mutations (Bottani et al., 1994; Smith et al., 1997 Smith et al., , 1998 Moncla et al., 1999b; Fridman et al., 2000). The age of acquisition of autonomous walking in our patient (20 months) seems to confirm the report from Lossie et al., (2001) averaging at 2.8 years the age of spontaneous walking in children with UBE3A mutations, earlier than the children with AS due to deletions. ...
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by a severe intellectual disability, severe expressive language deficits, ata-xia and a specific behavior with easy excitability excitable personality and an inappropriately happy predisposition. Phenotypical variations have been described on the basis of the underlying genetic mechanism. Several reports have suggested that individuals with AS resulting from UPD, UBE3A mutations and imprinting mutations show a milder or atypical phenotype than that observed in patients with a deletion of 15q11-q13 re-gion. The purpose of this study is to describe cognitive and adaptive fun-ctioning in a child with AS resulting from UBE3A gene mutation, and especially the linguistic development, verbal and mimic-gestual, whose in-ventory and use are greater than those reported in literature.
... However, some clinical differences correlate with genotype. [43][44][45][46] The 5-7 Mb deletion class results in the most severe phenotype with microcephaly, seizures, motor difficulties (e.g., ataxia, muscular hypotonia, feeding difficulties), and language impairment. Those with the large deletion are more likely to exhibit clinical hypopigmentation (discussed above). ...
Angelman syndrome is characterized by severe developmental delay, speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavioral phenotype that includes happy demeanor and excessive laughter. Microcephaly and seizures are common. Developmental delays are first noted at 3 to 6 months age, but the unique clinical features of the syndrome do not become manifest until after age 1 year. Management includes treatment of gastrointestinal symptoms, use of antiepileptic drugs for seizures, and provision of physical, occupational, and speech therapy with an emphasis on nonverbal methods of communication. The diagnosis rests on a combination of clinical criteria and molecular and/or cytogenetic testing. Analysis of parent-specific DNA methylation imprints in the 15q11.2-q13 chromosome region detects approximately 78% of individuals with lack of maternal contribution. Less than 1% of individuals have a visible chromosome rearrangement. UBE3A sequence analysis detects mutations in an additional 11% of individuals. The remaining 10% of individuals with classic phenotypic features of Angelman syndrome have a presently unidentified genetic mechanism and thus are not amenable to diagnostic testing. The risk to sibs of a proband depends on the genetic mechanism of the loss of the maternally contributed Angelman syndrome/Prader-Willi syndrome region: typically <1% for probands with a deletion or uniparental disomy; as high as 50% for probands with an imprinting defect or a mutation of UBE3A. Members of the mother's extended family are also at increased risk when an imprinting defect or a UBE3A mutation is present. Chromosome rearrangements may be inherited or de novo. Prenatal testing is possible for certain genetic mechanisms.
... This research has added to the growing body of work which recognises differing phenotypes according to genetic mechanism of AS. Previously it has been recognised that children with paternal uniparental disomy walk earlier and have less severe and frequent seizures than children with a deletion (Bottani et al 1994, Smith et al 1997, Moncla et al 1998). It has now been shown that these children also have significantly better understanding of language, they have greater communicative intent, and use a wider range of communication methods. ...
Angelman syndrome (AS) is a neurogenetic disorder caused by maternal deletions of 15q11-13 (classic deletion), paternal uniparental disomy (UPD), imprinting defects, and point mutations or small deletions in the UBE3A gene. It has been suggested that there is a correlation between the genetic mechanism and the behavioural and developmental phenotype, though there is as yet limited evidence concerning communication phenotypes in Angelman syndrome. The aim of the study was to establish whether there is a difference in communication phenotypes to parallel the different genetic mechanisms causing AS. The hypothesis tested was that children and young people with the classic deletion would have lower levels of developmental skills than those with non-deletion AS. Seven children/young people with a classic deletion were matched for age and gender with participants with imprinting defect or UPD. Assessments covered a number of domains of communication: comprehension, production and pragmatic use of language, communication modes and oro-motor skills. A significant group difference was found for five of the nine variables measured. Higher levels of ability were demonstrated by children with imprinting defect or UPD in terms of greater comprehension of phrases and words, more spoken and gestural communication, a greater range of communicative functions and apparently better oral-motor skills. The findings of this study have implications for therapeutic intervention and prognosis for communication development in Angelman syndrome.
... On the whole, UPD patients tend to present with a milder phenotype than those with deletions. UPD patients have a lower incidence and later onset of seizures, less severe ataxia, are able to walk at an earlier age, are more able to use symbolic communication, and may have fewer/less defined facial characteristics (Bottani et al., 1994; Smith et al., 1997 Smith et al., , 1998 Moncla et al., 1999b; Fridman et al., 2000). Patients with imprinting and UBe3A mutations have also been found to exhibit a milder phenotype (Moncla et al., 1999a; Otha et al., 1999). ...
Autism spectrum disorders (ASDs) have been linked with maternally derived duplications/triplications of chromosome 15q11-13 and therefore might occur more frequently in people with Prader-Willi syndrome (PWS) when due to uniparental disomy (UPD), than in other forms of chromosomal abnormality involving this region [i.e. deletion (DEL) forms of PWS and DEL+UPD forms of Angelman's syndrome -(AS)]. Twelve studies regarding ASD in PWS and AS were reviewed. It was noteworthy that among the genetically confirmed UPD and DEL cases of PWS and AS, the rate of ASD was 25.3% (38/150; range 0-36.5%) in PWS and 1.9% in AS (2/104; range 0-100%) (Fisher's exact P<0.0001). Among the subset of cases with confirmed UPD or DEL, the rate of ASD in the UPD cases of PWS was significantly higher (20/53) than in the remaining combined samples (i.e. DEL PWS+UPD AS+DEL AS cases; 20/201) (Fisher's exact P<0.0001). ASD in UPD PWS cases (20/53) compared with DEL PWS cases (18/97) was also statistically significant (Fisher's exact P=0.0176). Thus, the limited available evidence supported the prediction that overexpression of maternally imprinted genes in 15q11-13 confers a risk for ASD. Further research will be required to confirm these findings.
