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SSBP Information Sheet First description: In 1965, Doctor Harry Angelman, a general paediatrician in Warrington, described three children with severe developmental delay, ataxia, prolonged bouts of laughter, seizures and similar craniofacial features. He referred to these patients as 'puppet children'. Relatively few patients were reported until the end of the 1980's, when it became apparent that electroencephalography and cytogenetic testing could greatly contribute to identifying affected patients. Clinical diagnostic criteria rest on physical and behavioural features (Williams et al. 1995). Incidence/prevalence: Prevalence has been estimated to be between 1 in 10 000 and 1 in 40 000 (Clayton-Smith & Laan, 2003). Genetic aspects: The syndrome is caused by genetic abnormalities affecting the maternally inherited copy of chromosome 15q1 1-13. Most cases are sporadic. A deletion in this region is found in over two thirds of cases (deletions in the corresponding region of the paternally inherited chromosome 15 result in Prader-Willi syndrome). In about 2-3% of patients, paternal uniparental disomy of chromosome 15 is responsible for the syndrome. In another 5%, abnormal genomic imprinting of that region is demonstrated. Such imprinting defects may be caused by imprinting centre mutations. A fourth class of genetic defects underlying the syndrome consists of mutations of the UBE3A gene. This gene's product has a role in proteic scavenging processes. Finally, 15-20% of patients do not have any of these described deficits. The syndrome is thought to result from impaired expression of UBE3A and perhaps other genes. This expression is normally determined epigenetically by a methylation pattern which is specific to the maternally inherited chromosome. Abnormal imprinting in various regions of the brain and the cerebellum are probably responsible for most of the phenotype. Angelman syndrome phenotype has been associated with mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) which has been incriminated in Rett syndrome. According to the mechanism of inheritance, the recurrence risk may be close to 0 or to 50%. Physical phenotype: Craniofacial features include microbrachycephaly, short, hooked nose, prognathism, wide smiling mouth and widely space teeth. Hypopigmented hair, skin and eyes relative to other family members can be seen. Axial hypotonia is present from birth. Limb hypertonia predominating at the lower extremities appears in infancy. Developmental milestones are delayed. Movements may be ataxic. Most patients develop walking. Gait is typical, with medially rotated, extended lower limbs, flexed elbows and out-turned wrists. Scoliosis may develop, especially in less mobile patients. Over 80% of patients have a seizure disorder, which may be severe, including convulsive and non-convulsive status epilepticus. The EEG shows highly characteristic features in almost all cases (Boyd et al. 1988). Cognitive aspects: Cognitive functions are severely to profoundly impaired in all cases. Early social interaction is usually not delayed, but vocalisation is poor or absent. Attention span short. Patients exceptionally acquire more than 5 words and one third of the patients have no words. Speech impairment is partly related to oral dyspraxia and probably to impaired semantic processing. Receptive verbal language is usually better than expressive speech. Non-verbal communication can be developed to some extent. Patients have relatively good visuo-spatial skills. Behavioural aspects: The patients are very sociable. They have a distinctive mirthful demeanour. They may laugh in response to minimal stimulation, including supposedly unpleasant event. They enjoy repetitive games and are fascinated by water. Hyperactivity is almost universal in childhood. It gradually disappears and adults tend to be rather placid, though sociable. Sleep disturbances may be a major problem in childhood. Life expectancy: Probably close to normal, as health is generally good, except for seizure disorder, which is not usually severe beyond childhood. Key references: Clayton-Smith J, Laan L. Angelman syndrome: a review of the clinical and genetic aspects. J Med Genet 2003; 40: 87-95. Williams CA, Angelman H, Clayton-Smith J, Driscoll DJ et al. Angelman
syndrome:consensus for diagnostic criteria. Am J Med Genet 1995; 56:
237-238. |