Caregivers Report on the Pathway to a Formal Diagnosis of Angelman Syndrome: A Comparison Across Genetic Etiologies within the Global Angelman Syndrome Registry

Dsc4728 Rv

Abstract

Objectives
Angelman syndrome (AS) and is typically diagnosed in children under the age of three based upon early behavioural concerns identified by parents, or genetic links with other family members. For some families however, the pathway to diagnosis is not so clear, particularly when children demonstrate differential characteristics, commonly seen for those with UBE3A pathogenic variants (ubiquitin protein ligase EA3), imprinting defects or uniparental disomy (patUPD) etiology. The aim of this paper is to explore parent’s experiences of the pathway to diagnosis involving 394 children with formal diagnoses of AS.

Methods
Data from the Global Angelman Syndrome Registry on the age of formal diagnosis, the process involved in formal diagnosis, professionals involved in the diagnosis, the number of tests taken and the prevalence of misdiagnoses were compared across deletion and non-deletion (UBE3A pathogenic variant, imprinting and patUPD) etiologies.

Results
Compared to those with deletion etiology, individuals with non-deletions are more likely to (a) receive a diagnosis later in childhood (i.e., past the age of 3 years old), (b) have a greater number of professionals and tests involved and (c) to be misdiagnosed with global developmental delay.

Conclusions
The methods identified for formal diagnoses mirrored the current advances in technology and accessibility. The benefit of using parental report from registries to understand the diagnostic process and promote early and accurate diagnosis of AS is discussed.

Data Availability

This data is available on request to the data management committee. Please email curator@angelmanregistry.info for requests.

References

Adams, D., Roche, L., & Heussler, H. (2020). Parent perceptions, beliefs, and fears around genetic treatments and cures for children with Angelman syndrome. American Journal of Medical Genetics Part A, 182, 1716–1724.

Bailus, B. J., & Segal, D. J. (2014). The prospect of molecular therapy for Angelman syndrome and other monogenic neurologic disorders. BMC Neuroscience, 15, 76.

Bent, C. A., Barbaro, J., & Dissanayake, C. (2020). Parents’ experiences of the service pathway to an autism diagnosis for their child: What predicts an early diagnosis in Australia? Research in Developmental Disabilities, 103, 103689.

Beygo, J., Buiting, K., Ramsden, S. C., Ellis, R., Clayton-Smith, J., & Kanber, D. (2019). Update of the EMQN/ACGS best practice guidelines for molecular analysis of Prader-Willi and Angelman syndromes. European Journal of Human Genetics, 27, 1326–1340.

Bryson, S. E., Rogers, S. J., & Fombonne, E. (2003). Autism spectrum disorders: early detection, intervention, education, and psychopharmacological management. The Canadian Journal of Psychiatry, 48, 506–516.

Buntinx, I. M., Hennekam, R. C., Brouwer, O. F., Stroink, H., Beuten, J., Mangelschots, K., & Fryns, J. P. (1995). Clinical profile of Angelman syndrome at different ages. American Journal of Medical Genetics, 56, 176–183.

Clayton-Smith, J., & Laan, L. A. E. M. (2003). Angelman syndrome: A review of the clinical and genetic aspects. Journal of Medical Genetics, 40, 87–95.

Glascoe, F. P. (2000). Evidence-based approach to developmental and behavioural surveillance using parents’ concerns. Child: Care, Health and Development, 26, 137–149.

Guralnick, M. J. (2017). Early intervention for children with intellectual disabilities: An update. Journal of Applied Research in Intellectual Disabilities, 30(2), 211–229.

Horsler, K., & Oliver, C. (2006). Environmental influences on the behavioral phenotype of Angelman syndrome. American Journal on Mental Retardation, 111, 311–321.

Keute, M., Miller, M. T., Krishnan, M. L., Sadhwani, A., Chamberlain, S., Thibert, R. L., Tan, W. H., Bird, L. M., & Hipp, J. F. (2020). Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment. Molecular Psychiatry, 1–9.

Knoll, J. H., Nicholls, R. D., & Lalande, M. (1989). On the parental origin of the deletion in Angelman syndrome. Human Genetics, 83, 205–206.

Lossie, A. C., Whitney, M. M., Amidon, D., Dong, H. J., Chen, P., Theriaque, D., Hutson, A., Nicholls, R. D., Zori, R. T., Williams, C. A., & Driscoll, D. J. (2001). Distinct phenotypes distinguish the molecular classes of Angelman syndrome. Journal of Medical Genetics, 38, 834–845.

Maranga, C., Fernandes, T. G., Bekman, E., & da Rocha, S. T. (2020). Angelman syndrome: A journey through the brain. The FEBS Journal, 2154-2175.

Mertz, L. G. B., Christensen, R., Vogel, I., Hertz, J. M., Nielsen, K. B., Grønskov, K., & Østergaard, J. R. (2013). Angelman syndrome in Denmark. Birth incidence, genetic findings, and age at diagnosis. American Journal of Medical Genetics Part A, 161, 2197–2203.

Napier, K. R., Tones, M., Simons, C., Heussler, H., Hunter, A. A., Cross, M., & Bellgard, M. I. (2017). A web-based, patient driven registry for Angelman syndrome: The global Angelman syndrome registry. Orphanet Journal of Rare Diseases, 12(1), 1–5.

National Disability Insurance Agency [NDIA]. (2020). Operational guidelines. https://www.ndis.gov.au/about-us/operational-guidelines

Raspa, M., Levis, D. M., Kish-Doto, J., Wallace, I., Rice, C., Barger, B., Green, K. K., & Wolf, R. B. (2015). Examining parents’ experiences and information needs regarding early identification of developmental delays: Qualitative research to inform a public health campaign. Journal of Developmental and Behavioral Pediatrics, 36, 575.

Roche, L., Sigafoos, J., & Trembath, D. (2020). Augmentative and alternative communication intervention for people with Angelman Syndrome: A systematic review. Current Developmental Disorders Reports, 7, 28–34.

Sadhwani, A., Willen, J. M., LaVallee, N., Stepanians, M., Miller, H., Peters, S. U., Barbieri-Welge, R. L., Horowitz, L. T., Noll, L. M., Hundley, R. J., Bird, L. M., & Tan, W. H. (2019). Maladaptive behaviors in individuals with Angelman syndrome. American Journal of Medical Genetics Part A, 179, 983–992.

Saitoh, S., Wada, T., Okajima, M., Takano, K., Sudo, A., & Niikawa, N. (2005). Uniparental disomy and imprinting defects in Japanese patients with Angelman syndrome. Brain and Development, 27, 389–391.

Sharkley, E. K., Zoellner, N. L., Abadin, S., Gutmann, D. H., & Johnson, K. J. (2015). Validity of participant-reported diagnoses in an online patient registry: A report from the NF1 patient registry initiative. Contemporaty Clinical Trials, 40, 212–217.

Stalker, H. J., & Williams, C. A. (1998). Genetic counseling in Angelman syndrome: The challenges of multiple causes. American Journal of Medical Genetics, 77, 54–59.

Tan, W. H., Bird, L. M., Thibert, R. L., & Williams, C. A. (2014). If not Angelman, what is it? A review of Angelman-like syndromes. American Journal of Medical Genetics Part A, 164, 975–992.

Taylor, S., Wright, A. C., Pothier, H., Hill, C., & Rosenberg, M. (2019). It’s like i have an advantage in all this: experiences of advocacy by parents of children with disabilities from professional backgrounds. Journal of Society & Social Welfare, 46, 159–184.

Tones, M., Cross, M., Simons, C., Napier, K. R., Hunter, A., Bellgard, M. I., & Heussler, H. (2018). Research protocol: The initiation, design and establishment of the Global Angelman Syndrome Registry. Journal of Intellectual Disability Research, 62, 431–443.

Warr, D., Dickinson, H., Olney, S., Hargrave, J., Karanikolas, A., Kasidiset, V., Katsikis, G., Ozge, J., Peters, D., Wheeler, J., & Wilcox, M. (2017). Choice, control and the NDIS. Melbourne: Melbourne Equity Institute.

Watson, S. L. (2008). “Something you have to do”-Why do parents of children with developmental disabilities seek a differential diagnosis? Developmental Disabilities Bulletin, 36, 168–198.

Wheeler, A. C., Okoniewski, K. C., Wylie, A., DeRamus, M., Hiruma, L. S., Toth, D., & Christian, R. B. (2019). Anxiety-associated and separation distress-associated behaviours in Angelman syndrome. Journal of Intellectual Disability Research, 63(10), 1234–1247.

Williams, C. A., Lossie, A., & Driscoll, D. (2001). Angelman syndrome: mimicking conditions and phenotypes. American Journal of Medical Genetics, 101, 59–64.

Williams, C. A., Beaudet, A. L., Clayton-Smith, J., Knoll, J. H., Kyllerman, M., Laan, L. A., Magenis, R. E., Moncla, A., Schinzel, A. A., Summers, J. A., & Wagstaff, J. (2006). Angelman syndrome 2005: Updated consensus for diagnostic criteria. American Journal of Medical Genetics Part A, 140, 413–418.

Williams, C. A., Driscoll, D. J., & Dagli, A. I. (2010). Clinical and genetic aspects of Angelman syndrome. Genetics in Medicine, 12, 385–395.

Zhang, D., Kaufmann, W. E., Sigafoos, J., Bartl-Pokorny, K. D., Krieber, M., Marschik, P. B., & Einspieler, C. (2017). Parents’ initial concerns about the development of their children later diagnosed with fragile X syndrome. Journal of Intellectual & Developmental Disability, 42, 114–122.

Zhang, D., Krieber-Tomantschger, I., Poustka, L., Roeyers, H., Sigafoos, J., Bölte, S., Marschik, P. B., & Einspieler, C. (2019). Identifying atypical development: A role of day-care workers? Journal of Autism and Developmental Disorders, 49, 3685–3694.

Acknowledgements

We would like to thank the parents and children for the time they took to complete the registry.

Author information

Affiliations
Centre for Children’s Health Research, The University of Queensland, Brisbane, Australia
Laura Roche, Megan Tones & Helen Heussler

School of Education, University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia
Laura Roche

Queensland University of Technology, Brisbane, Australia
Megan Tones

Developmental Disorders Group, Mater Research Institute, The University of Queensland, Brisbane, Australia
Mark G. Williams

Foundation for Angelman Syndrome Therapeutics (FAST), Salisbury, Australia
Meagan Cross & Chloe Simons

Children’s Health Queensland, Brisbane, Australia
Helen Heussler

Contributions
LR: developed the concept and design for the study, assisted with the analysis of results, and wrote the manuscript. MT: assisted in the concept and design of the study, analysed the data, collaborated in writing the manuscript, and is the curator of the Global Angelman Syndrome Registry. MGW: provided expert sections on the genetic mechanisms of diagnosing Angelman syndrome and collaborated in the editing of the manuscript. MC and CS: assisted in the design of the original cohort, collaborated in the writing and editing of the manuscript. HS: assisted in the design of the original cohort, collaborated in the concept and design of the study and collaborated in the data analysis and editing of the manuscript.

Corresponding author
Correspondence to Laura Roche.

Ethics declarations

Ethical Approval
Ethics was approved by Mater Misericordiae Ltd Human Research Ethics Committee (approval number EC00332).

Consent statement
All participants provided informed consent via an electronic consent process. Participants were unable to view or complete registry modules without completion of the consent process.

Conflict of interest
The authors declare that they have no conflict of interest.

Keep up to date for the latest research news

Share This

Select your desired option below to share a direct link to this page

Share on facebook
Share on twitter
Share on linkedin
Share on skype
Share on pinterest
Share on email