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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angelman syndrome (AS) is a human genetic disorder characterized by mental retardation, seizures, inappropriate laughter, abnormal galt, tremor and ataxia. There is strong genetic evidence that the disorder is associated with a maternally expressed, imprinted gene mapping to chromosome 15q11-13. Affected patients demonstrate varied molecular abnormalities, including large maternal deletions, uniparental paternal disomy (UPD). Imprinting mutations and loss of function mutations of E6-associated-protein (E6-AP) ubiquitin-protein ligase (UBE3A). All of these abnormalities are associated with loss of maternal expression of UBE3A. Although mutations in UBE3A cause AS, indicating that maternal-specific expression of UBE3A is essential for a normal phenotype, evidence for maternal-specific expression of UBE3A has been lacking. Using mice with partial paternal UPD encompassing Ube3a to differentiate maternal and paternal expression, we found by in situ hybridization that expression of Ube3a in Purkinje cells, hippocampal neurons and mitral cells of the olfactory bulb in UPD mice was markedly reduced compared to non-UPD littermates. In contrast, expression of Ube3a in other regions of the brain was only moderately or not at all reduced in UPD mice. The major phenotypic features of AS correlate with the loss of maternal-specific expression of Ube3a in hippocampus and cerebellum as revealed in the mouse model.
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PMID:Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. 928 1

Angelman syndrome (AS) is a rare neurodevelopmental disorder. Recently, several mutations have been found in the E6-AP ubiquitin protein ligase gene (UBE3A) in a group of patients who are nondeleted and do not have uniparental disomy or imprinting defects. Most of the reported mutations cluster within exons 9 or 16 of the UBE3A gene, and nearly all are predicted to give rise to truncated E6-AP ligases. Here, we describe two AS patients with dissimilar phenotypes. At the molecular level, they are both nondeleted, do not display uniparental disomy, and have normal imprint patterns. One has the typical AS phenotype and carries the previously reported 1344delAG de novo mutation involving a functionally significant region of UBE3A. The other expresses an atypical phenotype in that she has less severe ataxia, no inappropriate laughing, or epilepsy, and her EEG was normal at an early age. A 14-bp deletion in the 3' untranslated region of exon 16 (3'UTRdel14) adjacent to the poly(A) signal was identified. Further investigation revealed that the DNA change was a neutral polymorphism. Haplotype analysis indicated that both the AS patient and her normal sibling had inherited the same maternal UBE3A gene and its 5' flanking region. Although the 14-bp change has no functional significance, it assists with counseling to determine future risks of recurrence in this family.
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PMID:UBE3A "mutations" in two unrelated and phenotypically different Angelman syndrome patients. 960 Feb 50

Angelman syndrome (AS) is a neurological disorder with a heterogeneous genetic aetiology. It most frequently results from a de novo interstitial deletion in the 15q11-q13 region, but in a few cases it is caused by paternal uniparental disomy (UPD) or an imprinting mutation. The remaining 20 to 30% of AS patients exhibit biparental inheritance and a normal pattern of allelic methylation in the 15q11-q13 region. In this latter group, mutations in the UBE3A gene have recently been shown to be a cause of AS. Here we describe the phenotypic expression in 14 AS cases involving eight UBE3A mutations. These comprise 11 familial cases from five families and three sporadic cases. Subtle differences from the typical phenotype of AS were found. Consistent manifestations were psychomotor delay, a happy disposition, a hyperexcitable personality, EEG abnormalities, and mental retardation with severe speech impairment. The other main manifestations of AS, ataxia, epilepsy, and microcephaly, were either milder or absent in various combinations among the patients. In addition, myoclonus of cortical origin was frequently observed with severe fits inducing myoclonic seizures. The majority of the patients were overweight. This study showed that ataxia, myoclonus, EEG abnormalities, speech impairment, characteristic behavioural phenotype, and abnormal head circumference are attributable to a deficiency in the maternally inherited UBE3A allele. Furthermore, analysis of mutation transmission showed an unexpectedly high rate of somatic mosaicism in normal carriers. These data have important consequences for genetic counselling.
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PMID:Angelman syndrome resulting from UBE3A mutations in 14 patients from eight families: clinical manifestations and genetic counselling. 1042 18

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically distinct complex disorders mapped to chromosome 15q11-q13. They both have characteristic neurologic, developmental, and behavioral phenotypes plus other structural and functional abnormalities. However, the cognitive and neurologic impairment is more severe in AS, including seizures and ataxia. The behavioral and endocrine disorders are more severe in PWS, including obsessive-compulsive symptoms and hypothalamic insufficiency. Both disorders can result from microdeletion, uniparental disomy, or an imprinting center defect in 15q11-q13, although the abnormality is on the paternally derived chromosome 15 for PWS and the maternally derived 15 for AS because of genomic imprinting. Although the same gene may control imprinting for both disorders, the gene(s) causing their phenotypes differ. AS results from underexpression of a single gene, UBE3A, which codes for E6-AP, a protein that functions to transfer small ubiquitin molecules to certain target proteins, to enable their degradation. The genes responsible for PWS are not determined, although several maternally imprinted genes in 15q11-q13 are known. The most likely candidate is SNRPN, which codes for a small nuclear ribonucleoprotein, a ribosome-associated protein that controls gene splicing and thus synthesis of critical proteins in the brain. Animal models exist for both disorders. The genetic relationship between PWS and AS makes them unique and potentially highly instructive disorders that contribute substantially to the population burden of cognitive impairment.
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PMID:Prader-Willi and Angelman syndromes: sister imprinted disorders. 1118 Feb 21

Angelman syndrome (AS) is a neurodevelopmental disorder characterised by severe learning difficulties, ataxia, a seizure disorder with a characteristic EEG, subtle dysmorphic facial features, and a happy, sociable disposition. Most children present with delay in developmental milestones and slowing of head growth during the first year of life. In the majority of cases speech does not develop. Patients with AS have a characteristic behavioural phenotype with jerky movements, frequent and sometimes inappropriate laughter, a love of water, and sleep disorder. The facial features are subtle and include a wide, smiling mouth, prominent chin, and deep set eyes. It is caused by a variety of genetic abnormalities involving the chromosome 15q11-13 region, which is subject to genomic imprinting. These include maternal deletion, paternal uniparental disomy, imprinting defects, and point mutations or small deletions within the UBE3A gene, which lies within this region. UBE3A shows tissue specific imprinting, being expressed exclusively from the maternal allele in brain. The genetic mechanisms identified so far in AS are found in 85-90% of those with the clinical phenotype and all interfere with UBE3A expression.
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PMID:Angelman syndrome: a review of the clinical and genetic aspects. 1256 16

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation, speech impairment, ataxia, and happy disposition with frequent smiling. AS results from the loss of expression of a maternal imprinted gene, UBE3A, mapped within 15q11-q13 region, due to different mechanisms: maternal deletion, paternal UPD, imprinting center mutation, and UBE3A mutation. Deletion AS patients may exhibit hypopigmentation of skin, eye, and hair correlating with deletion of P gene localized in the distal part of Prader-Willi (PWS)/AS region. Our patient presented developmental delay, severe mental retardation, absence of speech, outbursts of laughter, microcephaly, ataxia, hyperactivity, seizures, white skin, no retinal pigmentation, and gold yellow hair. His parents were of African ancestry. The SNURF-SNRPN methylation analysis confirmed AS diagnosis and microsatellite studies disclosed deletion with breakpoints in BP2 and BP3. All of the 25 exons and flanking introns of the P gene of the patient, his father, and mother were investigated. The patient is hemizygous for the deleted exon 7 of the P gene derived from his father who is a carrier of the deleted allele. Our patient manifests OCA2 associated with AS due to the loss of the maternal chromosome 15 with the normal P allele, and the paternal deletion in the P gene. As various degrees of hypopigmentation are associated with PWS and AS patients, the study of the P gene in a hemizygous state could contribute to the understanding of its effect on human pigmentation during development and to disclose the presence of modifier pigmentation gene(s) in the PWS/AS region.
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PMID:Angelman syndrome associated with oculocutaneous albinism due to an intragenic deletion of the P gene. 1274 60

Angelman syndrome (AS) is an imprinted neurobehavioral disorder characterized by mental retardation, absent speech, excessive laughter, seizures, ataxia, and a characteristic EEG pattern. Classical lesions, including deletion, paternal disomy, or epigenetic mutation, are confirmatory of AS diagnoses in 80% of cases. Loss-of-function mutations of the UBE3A gene have been identified in approximately 8% of AS cases, failing to account for the remaining patient population, and there appears to be a higher prevalence of mutations in familial than sporadic cases. We screened UBE3A in 45 index cases of AS without obvious 15q11-13 abnormalities. Pathological mutations were identified in 3/6 (50%) familial and 4/39 (>10%) sporadic cases. By combining our data with those of the literature, we demonstrate statistically that the frequency of UBE3A mutations is significantly higher in the familial than sporadic subsets of AS. This indicates that an independent molecular mechanism or 'phenocopy' exists for the sporadic group. Rett syndrome (RS), caused by mutations of the MECP2 gene, and patients with deletions of 22q13.3 --> qter, have overlapping clinical features with AS. We screened 24 of the sporadic AS cases without detectable UBE3A mutations for mutations of MECP2, but found none. A separate cohort of 43 atypical patients with features common to AS and RS, in whom 15q11-13 lesions and 22q13.3 --> qter deletion had been ruled out, were also screened for MECP2 mutations. One male patient was mosaic for a frameshift mutation of this gene (previously reported). While MECP2 mutations can cause a phenotype reminiscent of AS in rare cases, they fail to account for the excess of sporadic patients with a definitive clinical diagnosis of AS.
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PMID:Investigation of UBE3A and MECP2 in Angelman syndrome (AS) and patients with features of AS. 1498 18

Angelman syndrome (AS) is a neurodevelopmental disorder caused by maternal deficiency of the UBE3A gene that encodes E6-AP ubiquitin-protein ligase. Expression of the UBE3A gene from the maternal chromosome is essential to prevent AS. AS is characterized by severe mental retardation, ataxia, and a defined behavioral pattern characterized mainly by happy/sociable disposition. This study used the Bayley Scales of Infant Development and the Vineland Adaptive Behavior Scales to examine the cognitive abilities and adaptive behavior of children (n = 20) with the four known molecular classes of AS, including patterns of strengths and weaknesses across adaptive behavior domains, and the relationship between adaptive behavior and overall cognitive abilities. Cognitive skills fell within the severe to profound range of mental deficiency. Differences in cognitive skills according to genetic subtype only partially supported previous research and suggest that there is overlap in abilities across genetic subtypes of AS. Adaptive behavior skills were also significantly delayed, with participants demonstrating a significant strength in socialization, and a weakness in motor skills. Strong, positive correlations emerge between cognitive ability scores and adaptive behaviors scores. These results provide further delineation of a cognitive/behavioral phenotype in AS.
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PMID:Cognitive and adaptive behavior profiles of children with Angelman syndrome. 1521 98

Angelman syndrome is a severe neurological disorder characterized by mental retardation, absent speech, ataxia, seizures, and hyperactivity. The gene affected in this disorder is UBE3A, the gene encoding the E6-associated protein (E6AP) ubiquitin-protein ligase. Most patients have chromosomal deletions that remove the entire maternal allele of UBE3A. However, a small subset of patients have E6AP point mutations that result in single amino acid changes or short in-frame deletions that still allow translation of a full-length protein. By studying these point mutations in E6AP, we found a strong correlation between Angelman-associated mutations and a loss of E3 ubiquitin ligase activity. Interestingly the point mutations affect E6AP activity in different ways. Some mutant proteins cannot form thiol ester intermediates with ubiquitin, others retain the thiol ester formation activity but cannot efficiently transfer ubiquitin to a substrate, and still others are unstable in cells. Our results suggest that the loss of E6AP catalytic activity and likely the improper regulation of E6AP substrate(s) are important in the development of Angelman syndrome.
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PMID:Biochemical analysis of Angelman syndrome-associated mutations in the E3 ubiquitin ligase E6-associated protein. 1526 5

Angelman syndrome (AS) can result from either a 15q11-q13 deletion (del), paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. Here, we describe the phenotypic and behavioral variability detected in 49 patients with different classes of deletions and nine patients with UPD. Diagnosis was made by methylation pattern analysis of exon 1 of the SNRPN-SNURF gene and by microsatellite profiling of loci within and outside the 15q11-q13 region. There were no major phenotypic differences between the two main classes (BP1-BP3; BP2-BP3) of AS deletion patients, except for the absence of vocalization, more prevalent in patients with BP1-BP3 deletions, and for the age of sitting without support, which was lower in patients with BP2-BP3 deletions. Our data suggest that gene deletions (NIPA1, NIPA2, CYF1P1, GCP5) mapped to the region between breakpoints BP1 and BP2 may be involved in the severity of speech impairment, since all BP1-BP3 deletion patients showed complete absence of vocalization, while 38.1% of the BP2-BP3 deletion patients were able to pronounce syllabic sounds, with doubtful meaning. Compared to UPD patients, deletion patients presented a higher incidence of swallowing disorders (73.9% del x 22.2% UPD) and hypotonia (73.3% del x 28.57% UPD). In addition, children with UPD showed better physical growth, fewer or no seizures, a lower incidence of microcephaly, less ataxia and higher cognitive skills. As a consequence of their milder or less typical phenotype, AS may remain undiagnosed, leading to an overall underdiagnosis of the disease.
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PMID:Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects. 1547 Mar 70


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