Neurology Central

Angelman syndrome and Dup15q syndrome: two rare diseases working together to solve each other’s puzzles – a conversation with Jill Silverman and Nathalie Buscher

At present, over 1000 rare neurological diseases have been recorded. With some of these diseases affecting only a handful of individuals worldwide, the very nature of them means that recognizing clinical features and developing treatments is a significant challenge not only for researchers and clinicians, but so too for patients and their families.
Today marks Rare Disease Day, an international effort to raise awareness about rare diseases and their impact on patients’ lives. In honor of this, we spoke to Jill Silverman and Nathalie Buscher (both from University of California (UC), Davis, CA, USA), whose work centers on the rare neurological genetic disease Dup15q syndrome, which, interestingly, has a number of parallels with another rare neurological disorder, Angelman syndrome. They both involve mutations in the gene UBE3A and are, if you like, two sides of the same coin. In this interview, Drs Silverman and Buscher discuss their work, and how these two rare diseases are shedding light not only on each other, but also a wealth of other neurological disorders.

First, please could you tell us a little about your background?

I (Jill) have been in the Behavioral Neuroscience research field since 1997 – nearly two decades. In 2007, I was recruited by Jacqueline Crawley to join her laboratory of Behavioral Neuroscience at the National Institute of Mental Health (NIMH; MD, USA). My postdoctoral projects employed a multi-tiered comprehensive strategy, which has led to the discovery of clinically relevant phenotypes in mutant mouse models of human disorders including autism spectrum disorder (ASD) and intellectual disabilities. These endpoints may move forward drug discovery efforts for ASD. In 2012, I joined the faculty of the UC Davis MIND Institute to build a laboratory with the overarching goal of applying my experience with rodent model systems to discover translational strategies for medical treatments for neurodevelopmental disorders characterized by autism, intellectual disabilities and pediatric epilepsy.

Natalie Buscher joined my lab in 2016 after completing her PhD with Johnson & Johnson in Machelen, Belgium. She has a wide range of expertise using translational learning and memory-focused behavioral paradigms, optogenetic technology and other microsurgical approaches to manipulate the CNS. She has developed and optimized EEG read-outs for my lab that will help examine transgenic rodent models with respect to changes in neural activity.

Could you give some background on Angelman and Dup15q syndromes?

Dup15q syndrome is caused by the presence of at least one extra maternally derived copy of the chromosome 15q11.2-q13.1. It is characterized by hypotonia, motor delays, intellectual disability, autism, and epilepsy including infantile spasms.

The prevalence of Dup15q syndrome in the general population is unknown – it could be as high as high as 1:5000. While Dup15q syndrome is a rare disease, it is unique as it is also one of the most common genetic variations associated with autism, accounting for approximately 1–3% of autism.

Angelman Syndrome (AS) is a very rare, severe neurodevelopmental disorder with prevalence estimates ranging from 1 in 12,000 to 1 in 15,000. Clinical features of AS include microcephaly, seizure disorder, ataxia, muscular hypotonia with hyperreflexia, lack of speech and motor delay.

How did you come to work on these?

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