Clinical trial NCT00296764: Characterization of Angelman Syndrome
Official title: Angelman Syndrome Natural History Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Angelman Syndrome
Keywords: Developmental Disorders
Lead sponsor: Boston Children's Hospital
Sponsor class: OTHER
Collaborators: name: Rady Children's Hospital, San Diego
name: Baylor College of Medicine
name: Greenwood Genetic Center
name: Children's Hospital Medical Center, Cincinnati
name: Vanderbilt University Medical Center
name: National Center for Research Resources (NCRR)
First posted: 2006-02-27
Enrollment: 302
Sex: ALL
Minimum age (years): 1
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with Angelman syndrome (molecular or clinical diagnosis) between the ages of 1 day and 60 years.

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.

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.

Eligibility 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

Primary outcomes:
measure: medical morbidity
timeFrame: annually
measure: developmental progress
timeFrame: annually
Secondary outcomes:
measure: autism
timeFrame: annually
Other outcomes:
Locations:
city: San Diego
country: United States
facility: Rady Children's Hospital San Diego
state: California
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital and Medical Center
state: Ohio
city: Greenwood
country: United States
facility: Greenwood Genetic Center
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
Study officials:
affiliation: Baylor College of Medicine, Department of Molecular and Human Genetics
name: Carlos A. Bacino, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rady Childrens Hospital San Diego, UCSD Dept of Pediatrics
name: Lynne Bird, MD
role: STUDY_CHAIR
affiliation: Greenwood Genetic Center
name: Steven A. Skinner, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Boston Children's Hospital
name: Wen-Hann Tan, BMBS
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Medical Center, Cincinnati
name: Logan K Wink, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt University Medical Center
name: Sarika Peters, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.