Last Updated: August 3, 2023
Introduction to Angelman Syndrome
Angelman syndrome (AS) is named after the English physician Harry Angelman who first described the disorder in 1965. He observed three children with a similar constellation of symptoms and he referred to these symptoms as the “happy puppet syndrome” because of their smiling and laughing demeanor and jerky gait. The disease is now known to occur with a frequency of 1 in 15,000 to 20,000 persons worldwide.
Angelman syndrome and Prader-Willi syndrome were the first diseases associated with the process of genomic imprinting. Although the symptoms of these two disorders are quite different it was shown in 1989 that both are caused by alterations in the pattern of genomic imprinting in the same region of chromosome 15. However, the distinct clinical spectrum of PWS and AS results as a consequence of the parental origin of the chromosome 15 alteration. Chromosomal region 15q11.2–q13 contains a cluster of imprinted genes with relevance to these two distinct neurogenetic disorders.
Angelman syndrome results from loss of neuron-specific maternal expression of a ubiquitin ligase gene (UBE3A) in the chromosome 15q11.2-q13 region.
Molecular Biology of Angelman Syndrome
Complex Gene Expression from the 15q11.2-q13 Domain
Analysis of the region of chromosome 15q11.2-q13 has identified several imprinted and non-imprinted genes as well as the AS imprinting control (AS-IC) region and the Prader-Willi imprinting control (PW-IC) region. There are 16 characterized genes in this region of chromosome 15 and a complex locus identified as small nucleolar RNA host gene 14 (SNHG14). Of these 16 genes, 10 are expressed from both the paternal and maternal chromosomes.
The 10 genes expressed from both chromosomes are, in centromere to telomere order, NIPA1 (NIPA magnesium transporter 1, where NIPA is NonImprinted in Prader-Willi/Angelman syndrome), NIPA2 (NIPA magnesium transporter 2), CYFIP1 (cytoplasmic FMR1 interacting protein 1, where FMR1 is the fragile X syndrome gene), TUBGCP5 (tubulin gamma complex associated protein 5), ATP10A (aminophosphoplipid-transporting ATPase), GABRB3 (gamma-aminobutyric acid type A receptor subunit beta3), GABRA5 (gamma-aminobutyric acid type A receptor subunit alpha5), GABRG3 (gamma-aminobutyric acid type A receptor subunit gamma3), OCA2 (OCA2 melanosomal transmembrane protein, where OCA2=oculocutaneous albinism 2), and HERC2 (HECT and RLD domain containing E3 ubiquitin protein ligase 2).
The imprinted genes in the 15q11.2-q13 locus are MKRN3 (makorin ring finger protein 3), MAGEL2 (MAGE-like protein 2, where MAGE family are melanoma antigen proteins), NDN (necdin), NPAP1 (nuclear pore associated protein 1), SNRPN (small nuclear ribonucleoprotein N), and UBE3A (ubiquitin ligase E3A). The MKRN3 encoded protein is a member of a protein family that functions as ubiquitin ligases. Expression of the NDN gene predominates in post mitotic neurons.
All but the UBE3A gene are hypermethylated on the maternal chromosome and as a result are only expressed from the paternal chromosome. Neuronal expression of the UBE3A gene is only from the maternal chromosome due to the paternal expression of the SNRPN gene which is transcribed across the SNHG14 locus forming a long non-coding RNA that interferes with paternal expression of the UBE3A gene.
The SNHG14 locus contains 148 exons and undergoes complex alternative splicing. In addition to the transcriptional complexity of the SNHG14 gene, the introns of the SNHG14 locus encode several small nucleolar RNAs (snoRNAs). The promoter region controlling expression of both the SNRPN and the SNHG14 locus is methylated on the maternal chromosome and therefore not expressed.
UBE3A Gene and its Regulated Expression
The UBE3A gene spans 120 kbp and is composed of 21 exons that generate 28 alternatively spliced mRNAs that collectively encode nine distinct protein isoforms.
The finding that point mutations in UBE3A were associated with AS led to the identification that all chromosomal defects found in AS patients encompass this gene. The parent-of-origin specific expression the UBE3A gene is not the result of differential DNA methylation of the gene but through the imprinted expression of the SNHG14 locus. Of particular significance to the clinical manifestation of AS is the fact that imprinted UBE3A expression is restricted to neurons in the brain.
In neuronal cells, the paternal transcription of the SNHG14 locus extends into the UBE3A gene in the antisense direction relative to the direction of transcription of the UBE3A gene. Transcription of the SNHG14 locus results in interference with expression of the paternal UBE3A gene. The paternal UBE3A gene is not turned off in neuronal cells but the result of the extension of the SNHG14 RNA into the 3′ end of the UBE3A gene results in suppression of transcriptional elongation of the UBE3A mRNA. This phenomenon has been referred to as transcriptional collision. In contrast, in non-neuronal cells, the paternal transcription of the SNHG14 locus does not extend to the UBE3A gene and as a result the UBE3A gene remains biallelically expressed.
Molecular Mechanisms Resulting in Angelman Syndrome
At least four known genetic mechanisms can result in AS. The vast majority of cases (~75%) result from de novo maternal deletion of 5-7 Mb of the chromosome 15q11.2–q13 region. The deletions are the result of non-homologous recombination events that are mediated by repetitive sequence elements that define a series of breakpoint cluster regions on either side of the imprinted chromosome 15q11.2-q13 domain. The deletions that result in AS are classified into two categories, class I and class II. Class I deletions, accounting for ~40% of deletion cases of AS, encompass the entire set of genes in the 15q11.2-q13 region. Class II deletions, accounting for ~50% of deletion cases of AS, do not include the NIPA1, NIPA2, CYFIP1, and TUBGCP5 genes on the centromeric side of the 15q11.2-q13 domain.
Approximately 2% of AS cases involve paternal uniparental disomy (UPD).
Genomic imprinting defects lead to an additional 2%–3% of AS cases. The imprinting defect can be caused by genetic or epigenetic factors that lead to gene expression throughout the imprinted 15q11.2–q13 domain. AS patients in this classification exhibit inheritance of chromosome 15 from both parents but in the maternal copy the normal methylation state of the SNRPN promoter region is absent resulting in expression of the complex SNHG14 locus which in turn suppresses the expression of the UBE3A gene.
The remaining, approximately 25% of AS patients, will harbor mutations in the UBE3A gene. The majority of UBE3A mutations found in AS patients are nonsense mutations. To date 73 different pathogenic variants affecting the maternal allele of UBE3A have been characterized. Most of the mutations in the UBE3A gene reside within the HECT ligase domain. The term HECT is derived from Homologous to the papilloma virus E6 protein associated protein (E6AP) Carboxy Terminus.
Clinical Spectrum of Angelman Syndrome
The characteristic clinical spectrum of Angelman syndrome include microcephaly, seizure disorder, ataxia, muscular hypotonia with hyperreflexia, and motor delay. The psychomotor delay in AS patients is evident by 6 months of age and is associated with hypotonia and feeding difficulties. The microcephaly is not apparent at birth but develops within the first 3 years. The seizure disorder associated with AS typically develops between the first and third years of life. When AS patients are examined with an MRI of the brain it will show delayed myelination but with no structural abnormalities or gross pathology.
Limb movement tremors, typical of AS patients, usually begin in infancy and will progress to ataxia in the trunk. The tremors result in AS infants exhibiting difficulty with crawling. Most children with AS will not begin walking until they are 3–4 years of age and they will have a distinctive marionette-like jerky aspect to their walking.
Individuals with AS can development sufficiently enough to be able to establish intentional relationships such as with their parents and siblings although they generally do not develop expressive speech. Angelman syndrome children are active explorers such that a common description is that they are in constant motion and into everything. The constant motion, laughter, and tremulous movements characterize the distinctive behavioral phenotype of AS children.
The clinical problems associated with AS persist into adulthood. The seizure disorder will diminish in frequency and intensity over time but will not disappear altogether. Physical activity will diminish as AS patients age accompanied by increases in muscle rigidity and/or quivering movements.
The lifespan of AS patients can be quite long as there are individuals with this disorder who are in their 60s and 70s. Early mortality associated with AS can be related to the severity of the seizure disorder as well as to accidental injury due to their hyperactivity coupled with diminished cognitive skills.