Paula and Bobby
Parents of Lillie
What is Angelman syndrome?
Angelman syndrome is a rare genetic condition occurring in 1 in every 15,000 live births, and it affects around 500,000 people worldwide.
Developmental delays, usually related to crawling and walking, can be a first symptom of the syndrome. Angelman syndrome is rarely inherited, although a case within the family may lead to a higher risk of future children developing the syndrome.
Health conditions associated with Angelman syndrome include seizures, sleep issues, severe speech delay, and intellectual disability. Obesity can be a problem in adolescents with Angelman syndrome due to a large appetite.
This syndrome is also known as:
Happy Puppet Syndrome, Formerly
What gene change causes Angelman syndrome?
Angelman syndrome occurs due to mutations in the UB3A gene.
Microdeletion inheritance occurs when there is a deletion of several genes on a chromosome. The specific chromosome on which the deletions occur will determine the syndrome they cause.
Normally we inherit one copy of each chromosome pair from each biological parent. In the case of disomy, both copies of the chromosome pair are received from one parent and none from the other. This is also often known as uniparental disomy. With most genes this is not an issue, and will not cause any medical or health issues. However when specific genes are concerned, issues with genomic imprinting, can cause specific genetic syndromes.
Genes, locations and inheritance modes:
GABRB3, 15q12 - Microdeletion, Disomy
UBE3A, 15q11.2 - Microdeletion, Disomy
CDKL5, Xp22.13 - Microdeletion, Disomy
OMIM Number - 105830 (please check the OMIM page for updated information)
what are the main symptoms of Angelman syndrome?
The main symptoms of Angelman syndrome include developmental delays and issues with walking and balance. Seizures are a major symptom of the condition. Most individuals with Angelman syndrome will have minimal if any speech. Sleep issues are associated with Angelman syndrome, although these may improve over time and with intervention. Individuals with Angelman syndrome often have happy and excitable personalities, and frequent smiling and laughing are common symptoms.
Possible clinical traits/features:
Abnormality of the dentition, Abnormality of the tongue, Blue irides, Behavioral abnormality, Cerebral cortical atrophy, Absent speech, Brachycephaly, Broad-based gait, Strabismus, Limb tremor, Scoliosis, Protruding tongue, Sporadic, Sleep-wake cycle disturbance, Progressive gait ataxia, Muscular hypotonia, Macroglossia, Mandibular prognathia, Intellectual disability, progressive, Intellectual disability, severe, Neurological speech impairment, Myopia, Incoordination, Hypopigmentation of the skin, Hypoplasia of the maxilla, Global developmental delay, Cognitive impairment, Hyperactivity, Hernia of the abdominal wall, Hyperreflexia, Autosomal dominant inheritance, Paroxysmal bursts of laughter, Wide mouth, Nystagmus, Obesity, Seizure, Widely spaced teeth, Constipation, Clumsiness, Drooling, Deeply set eye, EEG abnormality, Motor delay, Malar flattening, Postnatal microcephaly, Fair hair, Flat occiput, Feeding difficulties in infancy, Exotropia
How does someone get tested for Angelman syndrome?
The initial testing for Angelman syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Angelman syndrome
The cardinal features are mental retardation with a disproportionate emphasis on a profound speech deficit, microcephaly and a jerky movement disorder affecting especially the trunk but also the upper limbs. These jerky movements have been shown to be a unique pattern of fast burning cortical myoclonus (Guerrini et al., 1996). The hair maybe fair and the skin depigmented. This is thought to be due to deletions of the P gene (Saitoh et al., 2000). The onset of walking is significantly delayed because of the ataxia but most children learn to walk and the gait disturbance improves. Outbursts of laughter, often accompanied by hand flapping, are frequent and the children in general have a happy disposition. Seizures may develop but these are relatively easy to control. However, in a follow-up of 23 patients with a deletion, Uemura et al., (2005) state that nearly 50% had had status epilepticus and 25% had been seizure free for three years. Valente et al., (2006) state that patients did best on Valproate and that carbamazepine, carbazepine and vigabatrin aggravated the seizure disorder. Hall, (2002) reported that the response to a standard tuning fork with infectious laughter was a relatively specific test for Angelman syndrome. The EEG is said to be characteristic (see Boyd et al., 1988 and Dan and Boyd, 2003), but note the article by Valente et al., (2003) pointing out the difficulties and possible misinterpretations. Laan et al., (1996), Sandanam et al., (1997) and Buckley et al., (1998) report the features in adulthood. Rufa et al., (2003) reported retinochoroidal atrophy associated with optic disk paleness in two adult patients. The patient reported by Oiglane-Shlik et al., (2005) had severe osteoporosis ( environmental) and brachydactyly type B. She had a microdeletion.
The prevalence has been estimated to between 1 in 10,000-20,000 (Clayton-Smith and Pembrey, 1992; Steffenburg et al., 1996). The diagnostic criteria were reviewed by Williams et al., (2006).
Deletions or re-arrangements of the long arm of chromosome 15 at 15q11-q13 are seen in 60-75% of cases, and the deletion is always on the maternal 15. Gimelli et al., (2003) presented evidence that some mothers of AS patients with deletions of the 15q11-q13 region have a heterozygous inversion involving the region that is deleted in the affected offspring. An inversion was detected in the mothers of four of six AS cases with the breakpoint 2-3 (BP2/3) 15q11-q13 deletion. The patient reported by Ninomiya et al., (2005) had a deletion of the matrnal D15S986 locus, which lies within 15q11-15q13. He had no features of Angelman syndrome (the authors suggested he looked more like Prader-Willi - but quite different).
A small proportion of cases have paternal disomy for chromosome 15 (Malcolm et al., 1991). Robinson et al., (2000) showed that paternal disomy occurs through a somatic segregation at error in about 75% of paternal UPD15 cases. There is a suggestion that cases resulting from paternal uniparental disomy can have a milder phenotype (Bottani et al., 1994). Fridman et al., (2000) reported three cases with maternal UPD15 suggesting that these have a somewhat better verbal development, a weight above the 75th centile, and an OFC in the upper normal range. Similarly cases with imprinting mutations show less microcephaly or hypopigmentation (Saitoh et al., 1997). Conversely, Smith et al., (1996) showed that a series of 27 deletion cases had more severe clinical features than the Angelman group as a whole. Moncla et al., (1999) also found that deletion cases had a more severe phenotype. In general the UPD patients tend to be milder than deletion patients (Varela et al., 2004). Lossie et al., (2001) also showed that patients with UPD, or an imprintor mutation had a milder phenotype. However at least 20% of affected individuals have normal chromosomes and no evidence of disomy (Chan et al., 1993). Laan et al., (1998) presented 12 cases of Angelman syndrome without a 15q11-13 deletion and could not detect a significant clinical difference from those with a deletion. Greger et al., (1997) reported detailed studies on a case with maternal inheritance of a paracentric inversion involving bands 15q1.2 and 15q24.3. Fridman et al., (1998) reported a boy with an apparently balanced 15q15q translocation. He was shown to have paternal uniparental disomy for this chromosome (see below). There were some unusual features in this case including height between the 90th and 97th centiles, OFC above the 98th centile, weight above the 98th centile, and hyperphagia.
Some affected sibs have been noted amongst these cases and recurrence risks may be relatively high (Clayton-Smith et al., 1992). Wagstaff et al., (1992) reported three normal sisters who had all given birth to children with Angelman syndrome. This was shown to be due to a mutation in 15q11-13 that resulted in Angelman syndrome when transmitted by females, but no phenotypic effect when transmitted by a male (ie: the grandfather). This finding also demonstrated that the loci responsible for Angelman and Prader-Willi syndromes must be distinct. Further studies by Wagstaff et al., (1993) suggested that the grandfather in this pedigree may have received a new mutation. Reis et al., (1994) reported normal paternal imprinting of a maternal allele in the 15q11-q13 region in a small proportion of cases.
Robinson et al., (1993) showed that in cases of Angelman syndrome with an additional marker chromosome derived from 15, paternal uniparental disomy can be demonstrated. Hulten et al., (1991) reported a family where a balanced (15;22)(q13;q11) was segregating. Unbalanced paternal transmission of the derived 15 resulted in Prader-Willi syndrome, whereas maternal transmission resulted in Angelman syndrome. Burke et al., (1996) reported a further case resulting from a maternal 14:15 cryptic translocation which suggested that the Angelman locus was distal to the D15S10 marker.
Meijers-Heijboer et al., (1992) reported an extended family with eight affected individuals. The disease locus mapped to 15q11-q13 but there was no cytogenetic or molecular deletion and the pedigree was compatible with paternal imprinting. Nelen et al., (1994) reported two sibs with the condition. In one there was a crossover in the Angelman region which excluded the GABRB3 locus as the candidate gene. Beuten et al., (1996) reported three cases in different branches of an extended consanguineous family. One case had paternal UPD of chromosome 15 and the other two had abnormal methylation patterns. Haplotype analysis suggested independent mutations had occurred in this family. Connerton-Moyer et al., (1997) reported two families with affected cousins, where this just appeared to be due to chance because one linking parent was a male in both families. Kokkonen and Leisti (2000) reported a family where two sibs were affected and both were shown to have a 15q11-q13 deletion, although this was not found in the blood of the mother. Germ-line mosaicism was postulated.
Lossie and Driscoll (1999) reported an affected mother with a 15q11-13 deletion who became pregnant. An affected fetus was diagnosed by prenatal diagnosis.
Driscoll et al., (1992) identified parental differences in DNA methylation at the D15S9 locus, identified by the highly evolutionary conserved cDNA, DN34. Parent-of-origin-specific DNA methylation has also been found at other loci (ZNF127, D15S63 and SNRPN) (Glenn et al., 1993). Buiting et al., (1995) identified a putative imprinting centre proximal to the Angelman syndrome critical region on 15. Deletions of this locus cause paternal-type imprinting of maternal chromosome 15s (Burger et al., 1997). Note that some families with imprinting centre deletions have atypical features such as macrocephaly (Ronan et al., 2008). Ohta et al., (1999) narrowed the critical region to a 1.15kb region by the study of two large families. Buiting et al., (1998) studied patients with Prader-Willi syndrome and Angelman syndrome with abnormalities of imprinting, but no evidence of a microdeletion of the imprinting centre. All cases were sporadic, and the authors suggested that these cases have a low recurrence risk. Buiting et al., (2001) reported studies on two sibs with Angelman syndrome who did not have an imprinting centre deletion but instead had a 1-1.5 Mb inversion separating the two imprinting centre elements. The case reported by Lawson-Yuen et al., (2006), had mosaic methylation and a milder clinical picture (no microcephaly and some speech).
Dittrich et al., (1996) identified novel transcripts of the SNRPN gene, lacking protein coding potential, and showed that five Angelman syndrome families with apparent imprinting mutations had intragenic deletions of the SNRPN gene. The authors suggest that deletions and point mutations of the BD exons of the SNRPN are associated with a block of the paternal to maternal imprint switch. Farber et al., (1999) showed that this region of chromosome 15 has undergone multiple duplication events and showed that an upstream exon of SNRPN is deleted in all Angelman syndrome patients with an imprinting syndrome microdeletion. Glenn et al., (2000) presented data suggesting that methylation studies at the SNRPN locus are most reliable for diagnosing Angelman and Prader-Willi syndromes in CVS and amniotic fluids specimens.
Kishino et al., (1997) and Matsuura et al., (1997) reported missense, nonsense, frameshift, splice-site, and duplication mutations in the UBE3A gene coding for the protein ubiquitination. Vu and Hoffman (1997) and Rougeulle et al., (1997) showed that this gene was imprinted in brain in humans. Albrecht et al., (1997) showed similar findings in the mouse. Imprinted expression seems to be restricted to hippocampal and Purkinje neurons. Further mutations in the UBE3A gene were reported by Malzac et al., (1998). These were detected in 14% of 35 sporadic cases and 80% of 10 familial cases. van den Ouweland et al., (1999) reported UBE3A mutations in eight patients from four families with typical EEG and clinical features of Angelman syndrome. Tsai et al., (1998) reported prenatal diagnosis by detecting a point mutation in the UBE3A gene inherited from the asymptomatic mother. Fang et al., (1999) studied 56 patients with clinical features of Angelman syndrome but normal DNA methylation studies. Mutations in the UBE3A gene were found in 17 (30%). Mutations were found in 75% of familial cases but only 23% of isolated cases. Of the 11 isolated cases, the mutation was de novo in nine. Similar findings were reported Moncla et al., (1999) who found UBE3A mutations in 83% of familial cases and 43% of sporadic cases with biparental inheritance of chromosome 15 and a normal methylation pattern. Somatic mosaicism was found in two out of eight families. Patients with a UBE3A mutation showed myoclonus. There was tendency for less ataxia, generalised epilepsy, and microcephaly. Baumer et al., (1999) found UBE3A mutations in 5% of a series of 101 cases ascertained by non-stringent clinical criteria. Lossie et al., (2001) demonstrated UBE3A mutations in 44% of sporadic cases with normal DNA methylation. Burger et al., (2002) reported a family where a 570kbp deletion of the UBE3A gene was segregating, causing Angelman syndrome when passed on by females. Methylation studies were normal. Molfetta et al., (2004) presented two cousins with a frameshift UBE3A mutation with quite different phenotypes. One was very severely spastic, couldn't walk and had polymicrogyria. Meguro et al., (2001) demonstrated a maternally expressed gene, ATP10C that was consistently deleted in Angelman deletions. ATP10C expression was also virtually absent from Angelman syndrome patients with imprinting mutations. This gene codes for a putative aminophospholipid translocase.
LaSalle and Lalande (1996) demonstrated association between maternal and paternal chromosome 15s during late S phase of mitosis. This was not present in cells from Angelman or Prader-Willi patients.
Clayton-Smith et al., (1993) reported a 6-year-old girl with duplication of 15q11-13 who had developmental delay, ataxia, and some features of Angelman syndrome, but with a normal EEG. Arn et al., (1998) reported a ten year old boy with features of the condition who was in fact found to have methylenetetrahydrofolate reductase deficiency (qv).
Stalker and Williams (1998), Stalker et al., (1998) and Jiang et al., (1999) provide good reviews of the genetic counselling in different categories of Angelman syndrome.
Dupont et al., (1999) reported a five year old girl with clinical features of Prader-Willi syndrome who had paternal isodisomy for chromosome 15. Gillessen-Kaesbach et al., (1999) also reported seven patients presenting with obesity, muscular hypotonia, mental retardation, and absence of speech together with other neurological features of Angelman syndrome. There was evidence of incomplete imprinting or cellular mosaicism of imprinting of the Angelman region. Brockmann et al., (2000) reported a four-year-old girl with exceptionally mild Angelman syndrome who had an incomplete imprinting defect. She walked at 14 months and spoke 20 single words and several two word sentences at the age of three years. Tekin et al., (2000) reported a child with mosaicism for a deletion of the Angelman critical region in approximately 40% of lymphocytes. Somatic mosaicism was again reported by Nazlican et al., (2004). These authors suggest that the role of mosaic imprinting defects in mental retardation is underestimated.
It is now apparent that some children with possible clinical features of Angelman syndrome can have mutations in the MECP2 (Rett) gene. Imessaoudene et al., (2001) studied 78 patients diagnosed as possible Angelman syndrome, looking for mutations of the MECP2 (Rett) gene. Missense, nonsense, and frameshift mutations were identified in six patients including one isolated male case with non-fatal, non-progressive encephalopathy of neonatal onset. Watson et al., (2001) reported five further cases with this phenotype, including a male with possible mosaicism for a MECP2 mutation. Features that are atypical for Angelman syndrome are growth failure, small cold feet, subtle but repetitive hand movements, excess bruxism, tremors and absence of the typical EEG findings. Williams et al., (2001) review conditions that can mimic Angelman syndrome including Rett syndrome, ATR-X, and several microdeletions or microduplications including regions of chromosomes 2, 4, 17, 22 and 15. Cox et al., (2002) reported two children caused by a sporadic imprinting defect who had been conceived by intracytoplasmic sperm injection (ICSI). Orstavik et al., (2003) reported a similar case. See also Gosden et al., (2003) for discussion.
Varela et al., (2006) describe a patient with a 1Mb microdeletion at 17q21.31 with clinical features that resemble classical Angelman syndrome to a great extend. The patient was somewhat less severely retarded, had no ataxia, and a VSD and ASD, but otherwise has all major features. The authors suggest that possibly the Microtubule Associated Protein Tau (MAPT) gene is involved.
Cassidy et al., (2000) provides a good review of the clinical and molecular features up to 2000. Clayton-Smith and Laan (2003) provide an excellent review up to the beginning of 2003.
Le Fevre et al., (2017) described three patients with atypical Angelman syndrome phenotype due to mosaic state for 15q11-q13 imprinting defect on the maternal allele, comprising the UBE3A gene. Clinical characteristics included developmental and speech delay, happy demeanor, obesity, bilateral clinodactyly, deep-set eyes, midface retrusion, wide mouth, and large tongue. When compared to previously reported cases, the most frequent clinical features included speech delay with good comprehension skills, developmental delay, abnormal EEG, hyperphagia, behavioral problems, sleeping difficulties, happy predisposition, and Prader-Willi syndrome as referral diagnosis.
Aguilera et al., (2017) reported two unrelated patients with typical characteristics and novel intragenic deletions.
* This information is courtesy of the L M D.
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