Characterization of Angelman Syndrome

Angelman Syndrome Natural History Study

Angelman Syndrome (AS) is a developmental disorder that is caused by a deficiency of a maternally transmitted gene. It is inherited at birth, and affects movement, speech, and social demeanor. This study will gain a better understanding of the disease progression and clinical features of AS by observing children with AS over an extended period of time.

Study Overview

• Status: Completed
• Conditions: Angelman Syndrome

Detailed Description

AS is a developmental disorder that affects movement, speech, and social demeanor. The disorder is caused by a deficiency of a maternally transmitted gene and is inherited at birth. Children with AS, however, are often not diagnosed until they are between 3 and 7 years old. Symptoms of AS may include, but are not limited to, functionally severe developmental delay; speech impairments; movement or balance problems; and behavioral uniqueness, including any combination of frequent laughter or smiling, apparent happy demeanor, easily excitable personality, hand flapping movements, and short attention span. There are four molecular variations of AS, but past clinical studies have been inconsistent in highlighting the phenotypic differences between them. This study will gain a better understanding of the disease progression and clinical features of AS by observing children with AS over a period of 5 to 10 years. The study will also attempt to establish genotype-phenotype correlations, which might aid in future clinical care of AS patients.

Participation in this observational study will be limited to current or future patients at one of the five study sites. A clinical evaluation will be performed at baseline, including a general patient history, physical and neurological examinations, a nutritional assessment, neuro-imaging, electroencephalography, laboratory testing, and neurodevelopmental testing. A blood sample or mucosal sample will also be taken at baseline to acquire DNA for potential genetic testing. All assessments except the neuro-imaging, electroencephalography, and blood sampling will be repeated at yearly study visits for as long as funding can be secured. In addition, participants will be photographed and perhaps videotaped on a yearly basis in order to document clinical phenotypes and any neurologic abnormalities. Participants may be followed-up for a total of 10 years.

• Study Type: Observational
• Enrollment (Actual): 302

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92123
      • Rady Children's Hospital San Diego
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital and Medical Center
  • South Carolina
    • Greenwood, South Carolina, United States, 29646
      • Greenwood Genetic Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with Angelman syndrome (molecular or clinical diagnosis) between the ages of 1 day and 60 years.

Description

Inclusion Criteria:

1. Molecular diagnosis of Angelman syndrome OR
2. Meets all major diagnostic criteria for Angelman Syndrome and 3 of the 6 minor criteria:

Major Criteria:

• Functionally severe developmental delay
• Speech impairment; none or minimal words used
• Movement or balance disorder
• Behavioral uniqueness, frequent laughs/smiling, excitable personality, hand flapping, short attention span

Minor Criteria:

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

Exclusion Criteria:

• Does not meet diagnostic criteria for Angelman Syndrome
• Other medical or genetic disorders (except autism)
• Born extremely premature

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
medical morbidity	to characterize the medical problems associated with Angelman syndrome, and to determine the relative prevalence of those problems in the different molecular subclasses of Angelman syndrome	annually
developmental progress	Assess with a variety of neuropsychological instruments, including Bayley Scales of Infant Development, Vineland Adaptive Behavior Scales, Preschool Language Scale	annually

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
autism	Evaluate for autism spectrum disorder using Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised	annually

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Collaborators: Baylor College of Medicine; Vanderbilt University Medical Center; Children's Hospital Medical Center, Cincinnati; National Center for Research Resources (NCRR); Rady Children's Hospital, San Diego; Greenwood Genetic Center
• Investigators: Principal Investigator: Logan K Wink, MD, Children's Hospital Medical Center, Cincinnati; Principal Investigator: Carlos A. Bacino, MD, Baylor College of Medicine, Department of Molecular and Human Genetics; Study Chair: Lynne Bird, MD, Rady Childrens Hospital San Diego, UCSD Dept of Pediatrics; Principal Investigator: Sarika Peters, PhD, Vanderbilt University Medical Center

Publications and helpful links

General Publications

• Williams CA, Lossie A, Driscoll D; R.C. Phillips Unit. Angelman syndrome: mimicking conditions and phenotypes. Am J Med Genet. 2001 Jun 1;101(1):59-64. doi: 10.1002/ajmg.1316.
• Varela MC, Kok F, Otto PA, Koiffmann CP. Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects. Eur J Hum Genet. 2004 Dec;12(12):987-92. doi: 10.1038/sj.ejhg.5201264.
• Peters SU, Beaudet AL, Madduri N, Bacino CA. Autism in Angelman syndrome: implications for autism research. Clin Genet. 2004 Dec;66(6):530-6. doi: 10.1111/j.1399-0004.2004.00362.x.
• Locke DP, Segraves R, Nicholls RD, Schwartz S, Pinkel D, Albertson DG, Eichler EE. BAC microarray analysis of 15q11-q13 rearrangements and the impact of segmental duplications. J Med Genet. 2004 Mar;41(3):175-82. doi: 10.1136/jmg.2003.013813.
• Smith JC. Angelman syndrome: evolution of the phenotype in adolescents and adults. Dev Med Child Neurol. 2001 Jul;43(7):476-80. doi: 10.1017/s0012162201000871.
• Keute M, Miller MT, Krishnan ML, Sadhwani A, Chamberlain S, Thibert RL, Tan WH, Bird LM, Hipp JF. Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment. Mol Psychiatry. 2021 Jul;26(7):3625-3633. doi: 10.1038/s41380-020-0858-6. Epub 2020 Aug 13.
• Frohlich J, Miller MT, Bird LM, Garces P, Purtell H, Hoener MC, Philpot BD, Sidorov MS, Tan WH, Hernandez MC, Rotenberg A, Jeste SS, Krishnan M, Khwaja O, Hipp JF. Electrophysiological Phenotype in Angelman Syndrome Differs Between Genotypes. Biol Psychiatry. 2019 May 1;85(9):752-759. doi: 10.1016/j.biopsych.2019.01.008. Epub 2019 Jan 19.
• Killian JT, Lane JB, Cutter GR, Skinner SA, Kaufmann WE, Tarquinio DC, Glaze DG, Motil KJ, Neul JL, Percy AK. Pubertal development in Rett syndrome deviates from typical females. Pediatr Neurol. 2014 Dec;51(6):769-75. doi: 10.1016/j.pediatrneurol.2014.08.013. Epub 2014 Aug 29.
• Neul JL, Lane JB, Lee HS, Geerts S, Barrish JO, Annese F, Baggett LM, Barnes K, Skinner SA, Motil KJ, Glaze DG, Kaufmann WE, Percy AK. Developmental delay in Rett syndrome: data from the natural history study. J Neurodev Disord. 2014;6(1):20. doi: 10.1186/1866-1955-6-20. Epub 2014 Jul 22.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2006
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: February 24, 2006
• First Submitted That Met QC Criteria: February 24, 2006
• First Posted (Estimate): February 27, 2006

Study Record Updates

• Last Update Posted (Actual): March 2, 2021
• Last Update Submitted That Met QC Criteria: February 28, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Developmental Disorders
• Additional Relevant MeSH Terms: Pathologic Processes; Central Nervous System Diseases; Nervous System Diseases; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Movement Disorders; Abnormalities, Multiple; Chromosome Disorders; Syndrome; Angelman Syndrome
• Other Study ID Numbers: RDCRN 5203; U54RR019478 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO