Characterization of Angelman Syndrome

• ClinicalTrials.gov Identifier: NCT00296764
• Recruitment Status: Completed
• First Posted: February 27, 2006
• Last Update Posted: March 2, 2021
• Sponsor: Boston Children's Hospital
• Collaborators: Rady Children's Hospital, San Diego; Baylor College of Medicine; Greenwood Genetic Center; Children's Hospital Medical Center, Cincinnati; Vanderbilt University Medical Center; National Center for Research Resources (NCRR)
• Information provided by (Responsible Party): Wen-Hann Tan, Boston Children's Hospital

Study Description

Brief Summary:

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.

Condition or disease
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 Design

• Study Type: Observational
• Actual Enrollment: 302 participants
• Observational Model: Case-Only
• Time Perspective: Prospective
• Official Title: Angelman Syndrome Natural History Study
• Actual Study Start Date: February 2006
• Actual Primary Completion Date: August 2014
• Actual Study Completion Date: August 2014

Groups and Cohorts

Outcome Measures

Primary Outcome Measures :

1. medical morbidity [ Time Frame: annually ]
   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
2. developmental progress [ Time Frame: annually ]
   Assess with a variety of neuropsychological instruments, including Bayley Scales of Infant Development, Vineland Adaptive Behavior Scales, Preschool Language Scale

Secondary Outcome Measures :

1. autism [ Time Frame: annually ]
   Evaluate for autism spectrum disorder using Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised

Biospecimen Retention:   Samples With DNA

Blood and cheek swab samples

Eligibility Criteria

• Ages Eligible for Study: up to 60 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

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

Criteria

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

Contacts and Locations

Locations

United States, California

Rady Children's Hospital San Diego

San Diego, California, United States, 92123

United States, Massachusetts

Boston Children's Hospital

Boston, Massachusetts, United States, 02115

United States, Ohio

Cincinnati Children's Hospital and Medical Center

Cincinnati, Ohio, United States, 45229

United States, South Carolina

Greenwood Genetic Center

Greenwood, South Carolina, United States, 29646

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

United States, Texas

Baylor College of Medicine

Houston, Texas, United States, 77030

Sponsors and Collaborators

Boston Children's Hospital

Rady Children's Hospital, San Diego

Baylor College of Medicine

Greenwood Genetic Center

Children's Hospital Medical Center, Cincinnati

Vanderbilt University Medical Center

National Center for Research Resources (NCRR)

Investigators

• 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: Steven A. Skinner, MD; Greenwood Genetic Center
• Principal Investigator: Wen-Hann Tan, BMBS; Boston Children's Hospital
• Principal Investigator: Logan K Wink, MD; Children's Hospital Medical Center, Cincinnati
• Principal Investigator: Sarika Peters, PhD; Vanderbilt University Medical Center

More Information

Publications:

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.

Peters SU, Beaudet AL, Madduri N, Bacino CA. Autism in Angelman syndrome: implications for autism research. Clin Genet. 2004 Dec;66(6):530-6.

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.

Smith JC. Angelman syndrome: evolution of the phenotype in adolescents and adults. Dev Med Child Neurol. 2001 Jul;43(7):476-80.

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. Review.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Wen-Hann Tan, Site PI (Lead PI: Lynne M. Bird, MD - Univ. of California, San Diego), Boston Children's Hospital
• ClinicalTrials.gov Identifier: NCT00296764
• Other Study ID Numbers: RDCRN 5203; U54RR019478 ( U.S. NIH Grant/Contract )
• First Posted: February 27, 2006
• Last Update Posted: March 2, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Wen-Hann Tan, Boston Children's Hospital:

Developmental Disorders

Additional relevant MeSH terms:

Angelman Syndrome; Syndrome; Disease; Pathologic Processes; Movement Disorders; Central Nervous System Diseases; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn