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Study Description

This study is a longitudinal multidisciplinary investigation on the natural history, morbidity and mortality of Angelman Syndrome (AS). We will collect detailed longitudinal data on a cohort of AS individuals to gain a better understanding of the disease progression, and to follow the natural history of the clinical features of this cohort including assessment of quality of life and longevity.

The participants to be recruited for the study will include 1) patients who have a documented molecular diagnosis of AS and 2) patients with a clear clinical diagnosis of Angelman Syndrome as determined by the Principal Investigator (PI) and the Co-investigators in this study but who do not have a known molecular defect.

One of the goals of the natural history study will be to characterize the phenotypic differences between patients with Class I deletions and those with Class II deletions, particularly with respect to the issue of autism.

A blood sample may be collected on the participants in order to create a DNA repository, and in some cases, to establish cell lines if further material is required for molecular studies. Alternatively, DNA may be obtained by buccal mucosa swabs/brushing. In those AS patients with known deletions involving the 15q11-q13 regions, a blood sample will be collected to perform comparative genome hybridization (CGH) microarray studies to characterize the extent of the deletion. No drugs or treatments will be administered through this protocol. In rare instances, a skin biopsy to establish a fibroblast cell line may be requested (using separate consent).

  • Study Design:
    • Clinical Trial
  • Study Type:
    • Case Set
Authorized Access
Publicly Available Data (Public ftp)
Study Inclusion/Exclusion Criteria

Inclusion Criteria:

Participants in the proposed study will be between the ages of 1 day to 60 years. Both genders and all racial/ethnic groups will be eligible for participation. All patients included in this database will require a confirmed diagnosis of AS by FISH, DNA methylation studies, microsatellite markers, imprinting center mutation studies and/or UBE3A mutation studies. There will some participants that will meet clinical criteria for AS without a molecular abnormality (15% of cases). These participants will be collected in the database but not primarily used for the aims proposed in the study. These participants will allow us to collect important data, which will be more relevant once new genes or conditions that mimic or cause AS are uncovered. In order to achieve a clinical diagnosis of AS, the participant must have all major criteria and 3/6 minor criteria.

Clinical Diagnostic Criteria for AS

Major Criteria:

  1. Developmental delay, functionally severe.
  2. Speech impairment. None or minimal words used.
  3. Movement or balance disorder.
  4. Behavioral uniqueness, including frequent laughter, excitable personality, hand flapping, and short attention span.

Minor Criteria:

  1. Deceleration in head circumference growth (post-natal).
  2. Seizures (myoclonic, absence, drop, tonic-clonic).
  3. Abnormal EEG (with patterns suggestive of AS, or hypsarrhythmia).
  4. Sleep disturbance.
  5. Attraction to or fascination with water.
  6. Drooling.

Exclusion criteria

Individuals with negative diagnostic studies, who do not meet the clinical diagnostic criteria for AS, are excluded from participation. Individuals with Angelman syndrome-like conditions, who meet clinical diagnostic criteria, but who are found to have an alternative genetic error (e.g. MECP2 gene mutation) or diagnosis (e.g. Pitt-Hopkins syndrome) are excluded from participation. Patients with co-morbid medical or genetic disorders, or extreme prematurity will be excluded from the study. As autism is an important part of the AS phenotype, those participants with a co-morbid diagnosis of autism are eligible for inclusion however.

Study History

Angelman syndrome (AS) is a neurological disorder that causes global developmental delay, minimal or absent speech, seizures, uncoordinated gait (ataxia), sleep disturbances, and other medical and behavioral difficulties. AS is caused by deficiency of the maternally-transmitted gene that encodes E6-AP ubiquitin-protein ligase (gene symbol UBE3A) mapping to chromosome 15q11-q13. This gene is subject to genomic imprinting. There are four molecular mechanisms by which AS may occur:

  1. Large (~5 to 6 Mb) deletions of maternal 15q11-q13. This is the most common abnormality found in AS and accounts for 70% of the patients. Various sizes of deletions have been described. The more common Class II deletion (60% of cases) is smaller than the Class I deletion (40% of cases), which includes the Class II region plus 800-900 kb centromeric to it. The exact size of the different deletion classes is not well defined. There are rare deletions that extend beyond the telomeric breakpoints of the Class I and Class II deletions.
  2. Paternal uniparental disomy (UPD), whereby there are two copies of the paternal chromosome 15 and a deficiency of the maternal 15q11-q13 region. This mechanism accounts for approximately 2-3% of the patients.
  3. Imprinting defects, such that the maternal chromosome has the methylation and gene expression pattern of a paternal chromosome. This mechanism accounts for approximately 3-5% of the patients.
  4. Loss-of-function point mutations in the UBE3A gene. This mechanism accounts for approximately 5% of the patients.
  5. Approximately 15% of patients meet clinical criteria of AS but have none of the above molecular abnormalities.

The diagnosis of AS is currently a clinical diagnosis that can be confirmed by laboratory testing in approximately 85% of cases by chromosome studies, fluorescent in situ hybridization (FISH), and molecular analyses by studying polymorphisms, methylation assays, and sequencing of the UBE3A gene. A positive genetic test confirms the diagnosis, but a normal result does not exclude the diagnosis.

Clinical studies have been inconsistent in highlighting the phenotypic differences and natural history among the four molecular types of AS. Theoretically, one would expect differences in clinical phenotype between the deletion cases of AS and the other molecular types of AS. An expanded or more severe phenotype might be expected since deletions would involve genes in addition to UBE3A; an example of this is hypopigmentation due to haploinsufficiency of the OCA2 gene involved in pigment production. On average, more severe intellectual disability is seen in deletion patients compared to those with UPD, UBE3A loss-of-function mutations and imprinting center defects. Even though the paternal copy of UBE3A is transcriptionally silenced, having two copies (as in UPD cases) rather than a single copy (as in deletion cases) may confer a milder phenotype.

Clinical features of AS include infantile hypotonia, early feeding difficulties, dysmorphic features, microcephaly of post-natal onset, cerebellar abnormalities, ataxia, seizures, and intellectual disability. Abnormal behavioral manifestations and autistic features are also quite common. The prevalence of AS is 1/15,000 to1/20,000 live-born individuals. Adults with AS are reported in the literature, but the life expectancy of AS is essentially unknown, as the diagnosis was not made in many patients due to lack of diagnostic tools in the past. Lack of appropriate intervention and follow-up in those with an accurate diagnosis limit our understanding of the natural history of this condition. Although some aspects of AS are well known to the medical community, the natural history of AS has not been systematically described. Since AS is a rare disorder, few physicians follow more than a handful of patients at any given Center. A collaborative effort is needed to better understand the natural history of this rare condition. It is only with this knowledge that we will be able formulate treatment interventions, devise therapies and propose future clinical trials. Developing new advances and strategies in the treatment and management of AS patients requires a thorough understanding of these conditions at both the clinical and molecular level.

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