Angelman Syndrome

Alternative Names

  • AS
  • Happy Puppet Syndrome
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WHO-ICD-10 version:2010

Congenital malformations, deformations and chromosomal abnormalities

Chromosomal abnormalities, not elsewhere classified

OMIM Number

105830

Mode of Inheritance

Autosomal dominant (loss of maternal allele)

Gene Map Locus

15q11.2,Xp26.3

Description

Angelman syndrome (AS) is a genetic disorder that affects the nervous system. It is characterized by developmental delay, intellectual disability, severe speech impairment, gait ataxia, tremulousness of the limbs, seizures, microcephaly, and a unique behavior with inordinately happy disposition (frequent laughing, smiling, and excitability). Developmental delays are the first feature of AS to be observed at the age of six to 12 months, however, the other clinical features of the disease appear later in early childhood. Patients mostly have a short attention span. Unusually fair skin and light-coloured hair may be noticed in some patients with AS. The incidence rate of AS is unknown, but some researches have estimated it to be 1:20,000. The disease is diagnosed usually by clinical manifestation as well as EEG findings. Management strategies include physical and psychomotor therapy, speech therapy, psychological and educational approaches, and drugs for treating epilepsy, behavior and sleep disorders.

Usually, Angelman syndrome (AS) is not inherited, but occurs due to random events that happen during the formation of the germ cells or in early fetal development. The disease results from de novo maternal deletion in 15q11.2-q13 region that is known as the Angelman syndrome/Prader-Willi syndrome (AS/PWS) region. Five different mechanisms are known to cause the loss of the maternally contributed AS/PWS region; these are - deletion (70% of the cases), paternal uniparental disomy, imprinting defects, mutation of the ubiquitin-protein ligase (UBE3A) gene, and other unidentified mechanisms. The five mechanisms will result in having similar manifestations of the disease. However, the risk to sibs of a patient with AS depends upon the genetic mechanism that causes the loss of the maternally contributed AS/PWS region. For example, those sibs will be at a higher risk if the disease is caused by mutations in the UBE3A gene, whereas a lower risk will exist in cases with deletion or uniparental disomy. In addition, it has been found that the oculocutaneous albinism, type II (OCA2) gene is associated with AS which is often deleted in cases with AS. This gene encodes a protein that is responsible for the pigmentation of skin, hair, and eyes, thereby, some patients are presenting with light-colored hair and fair skin.

Epidemiology in the Arab World

View Map
Subject IDCountrySexFamily HistoryParental ConsanguinityHPO TermsVariantZygosityMode of InheritanceReferenceRemarks
105830.1United Arab EmiratesMaleYesNo Macrocephaly; Plagiocephaly; Delayed spe...NM_000462.3:c.2576_2579delHeterozygousAutosomal, DominantSaleh et al. 2021 Father and siblings ...

Other Reports

Kuwait

Al-Awadi et al. (2000) presented six Kuwaiti subjects with Angelman syndrome (AS). The study included two siblings and three patients from consanguineous families. All patients suffered from mental retardation, microcephaly, brachycephaly, hypotonia, and abnormal EEG. Their mothers were found to have experienced 1-2 miscarriages during early phases of gestation. FISH technique was employed to understand the molecular basis of AS in the patients and revealed deletions in the 15q11-12 region among five patients. Two of these deletions were paternal and three were maternal. One male patient showed no deletion in 15q suggesting the possibility of imprinting error or the role of a recessive gene.

[Al-Awadi S, Abu-Henedi M, Bastaki L, Abulhasan S, Al-Naggar R. The Angelman syndrome: brief clinical & FISH report on Kuwaiti patients. The Egyptian J Med Human Genet. 2000; 1(1):73-82.]

Tunisia

Abaied et al. (2010) reported 14 patients from a highly consanguineous Tunisian family with Angelman syndrome. Genetic analysis identified a heterozygous truncating mutation in the UBE3A gene. All the affected individuals were in the same generation, and inherited the mutation from their carrier mothers, who were sisters. These four sisters were suspected to have inherited the mutation from their unaffected father. Abaied et al. (2010) noted that the detection of mutations in large Angelman syndrome families emphasizes the importance of available genetic counselling and meticulous family history investigation.

United Arab Emirates

Murthy et al. (2007) studied a rare case of a 15q11.2 microdeletion (253 kb) between breakpoint 1 and breakpoint 2 of the PWS/AS region spanning four genes (NIPA1, NIPA2, CYFIP1, and TUBGCP5). The case was a three and a half year old boy who presented with features of Angelman syndrome (AS) including mental retardation, developmental delay, neurological defects, hyperactivity, and speech impairment.  His parents were second cousins. The father was also observed to be subnormal with very slow understanding, a peculiar smiling face, and a childhood history of developmental delay. The  deletion was  detected in both the proband and his  father. Mental retardation and developmental delay were noted in other family members of the extended family.

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