by Katherine (Kate) Still, Ph.D

Do you wonder how a research publication affects your loved one or the field of Phelan-McDermid research?

The Research Roundup is a summary of significant and recent research related to PMS by our PMSF Scientific Director, Katherine (Kate) Still, Ph.D. The Research Roundup is edited and completed by the 15th of each month. Any research studies coming out after this date will be summarized in the PMSF Our Voice newsletter. 

Assessment tool adapted to be more specific to PMS to be used in a clinical trial

Assessment tool adapted to be more specific to PMS to be used in clinical trial Long term PMS experts (Elizabeth Berry-Kravis, Latha Soorya, Alex Kolevzon, Audrey Thurm), recently adapted an assessment tool to measure the impact of clinical treatments more specifically in people with PMS. The work was funded by Neuren Pharmaceuticals and will be used in the upcoming clinical trial testing NNZ-2591 in people with PMS. The assessment which was adapted was the Clinical Global Impression (CGI) Scale. This is a tool which is often used as an outcome measure in clinical trials for neurodevelopmental disorders. Outcome measures are used to quantify the effect of a treatment on health.  The CGI scale consists of two areas which can be summarized as follows:

1. Severity – Considering the total experience of the physician with this patient population, how ill is this patient? (Rated on a scale from 1-7).
2. Improvement – Compared to the patient’s condition at the beginning of this process the patient’s condition has improved to what degree? (Rated on a scale from 1 – 7).

The scale is used in many disorders and is not specific to any disorders. The PMS experts suggested “anchors” for answering the questions based on symptoms which are relevant to PMS. The team chose the following areas: communication, motor skill, social interaction, self-care, and cognition/learning. The hope is the anchors for this assessment will be used in future clinical trials in PMS to compare improvement between different treatments. It may also serve as a tool for physicians to be educated on how to better assess symptom improvement in people with PMS.

A lack of outcome measures specific to PMS have been an obstacle in attracting pharmaceutical interest, and this is a step in developing more specific tools.

It is important to note that the impression scale is still an impression and is subjective. Additional objective outcome measures are needed. The poster associated with this abstract noted another measure is in progress which focuses on other symptom areas such as GI, sleep, seizures, sensory, and behavior.

Read the abstract here: https://n.neurology.org/content/98/18_Supplement/2909

A suggested shared underlying mechanism between ADNP syndrome and Phelan-McDermid syndrome

ADNP syndrome is a genetic neurodevelopmental disorder that shares many similar features with PMS such as low muscle tone, seizures, developmental delay, and autism. Many genetic neurodevelopmental disorders share these features but are believed to have distinct causes. ADNP syndrome is caused by variations in the ADNP gene “Activity-dependent neuroprotective protein”, a gene on chromosome 20. A recent publication by a research group from Tel Aviv University used computational tools to predict there may be a shared piece, or “domain” of the ADNP protein to that of SHANK3, a protein with critical importance in PMS.

Proteins are large molecules that interact uniquely with other proteins to accomplish specific functions in cells. A shared domain could mean that the ADNP and SHANK3 proteins could have some overlapping functions. The concept that mechanisms could be shared between neurodevelopmental syndromes is an important consideration for scientific inquiry and the potential development of shared treatments.

However, this work on a shared domain is in early stages and will need to be validated with other methods. The domain may have many different functions, and more work is needed to understand its role in each protein during brain development. It is also unclear how many people with ADNP syndrome and Phelan-McDermid syndrome are affected by genetic variants which impact this domain, since genetic variations are variable and occur elsewhere in the genome.

It will take time, likely years, to learn if there is a shared mechanism between the disorders, and if a therapy in the clinic could target both. The article mentions a therapeutic that could be promising for ADNP syndrome, that was tested in animals modeling Phelan-McDermid syndrome. The drug is a shortened form of the ADNP protein called Davunetide, which has been developed previously by the lab which authored this publication.

This drug was previously tested as a possible therapeutic in clinical trials for Alzheimer’s Disease, schizophrenia, and Progressive Supranuclear Palsy between 2006-2012. While this therapeutic was deemed well-tolerated for safety and showed some possible benefit in impacting cognitive function, it was ultimately not FDA-approved to treat these disorders.

In 2018, Davunetide received orphan drug designation to be applied to ADNP syndrome. Orphan drug status indicates a drug is being developed/tested for the benefit of a rare disease affecting less than 200,000 people in the U.S.

In this publication, the study team treated mice lacking SHANK3 (as an animal model of Phelan-McDermid syndrome) with this drug to see if it had positive impacts. There are not yet enough data to make a conclusion. One anxiety test showed worsened anxiety overall in animals treated with the drug, including in healthy mice. Other behavioral tests showed some improvement of grooming and social interaction behaviors in mice with treatment. Additional behavioral tests, including assessment of learning and memory, were not reported. Mice tested had both copies of the Shank3 gene altered (homozygous), whereas in humans, typically only one copy is impacted (heterozygous).

Thus, future work is needed to better understand potential similarities in the ADNP and SHANK3 proteins and whether there is a shared mechanism underlying these disorders which could be targeted therapeutically. Read the research article here: https://europepmc.org/article/med/35538192

Pandemic lifestyle impacts on physical/emotional health

A team of scientists including longstanding PMS researcher Dr. Jimmy Holder recently conducted a study to assess the impact of pandemic-related lifestyle factors on quality of life for people with genetic disorders associated with autism. The study included 230 caregivers of people with PMS and related disorders such as SYNGAP1-related intellectual disability and Rett Syndrome.

Caregivers answered a health-related quality of life outcomes survey (HRQoL) during the pandemic between July 2020 and January 2021. Many participants (~60%) were in the PMS group.

In general, the PMS group scored highest compared with SYNGAP1 and Rett on the quality-of-life scale which includes physical, emotional, social, school, and psychosocial functioning.

Two lifestyle factors during the pandemic were strongly associated with worsened quality of health. A decrease in mental health appointments for caregivers and an increase the child’s time spent watching TV were both linked with negative physical and emotional functioning. Alternatively, time spent outdoors was linked with better physical and emotional health, especially in higher income households. This research could be used in the future to argue for better financial and emotional support for caregivers.

The study showed that survey scores improved significantly in later stages of the pandemic, even from July 2020 to September 2020. This data aligns with COVID-19 restrictions beginning to lift, but also demonstrates resilience in participants. For people with autism where routine is typically considered central and beneficial, this adaptiveness was seen to happen quickly and significantly. This study did have limitations in that it did not have a baseline of scores pre-pandemic for comparison, or a group of typically developing individuals. The categories which were most impactful during the pandemic are likely to be impactful typically. The participants were not racially diverse, and an effort will need to be made to increase diversity in these studies. Read the research article here: https://pubmed.ncbi.nlm.nih.gov/35672615/

Large genotype-phenotype study on 210 Spanish and South American individuals with PMS

One of the largest studies to date linking PMS genetics (genotype) with observable symptoms (phenotype) was recently published as a collaboration between several Spanish and South American hospitals, the Spanish PMS Association, and the Argentinean PMS group. The work is a summary of data collected between 2008 and 2020 on 210 individuals, obtained from review of medical records and parent interviews.

Genotype-phenotype studies can help researchers understand how changes to different genes contribute to symptoms. They can help scientists understand which complications people with SHANK3 variants are most susceptible to versus people with large deletions. Over time, this can help to uncover the most important factors which underlie disease and may be able to be targeted.

There have been many genotype-phenotype studies in recent years. Over time, results that are found by different research teams studying different groups of people with PMS can build confidence in association between altered genes and symptoms.

This study broke up people with PMS into two groups – those with deletions (including simple deletions, Ring 22, unbalanced translocations, etc.), and those with SHANK3-only variants. Both groups displayed some core symptoms of PMS – intellectual disability, speech delay, developmental delay, behavioral abnormalities, and high pain threshold.

The group with deletions were more likely than people with variants in SHANK3 alone to have kidney abnormalities, lymphedema, and more severe language impairment (non-verbal or unable to speak in phrases). Larger deletion sizes related to having a more complex medical history. These findings corroborate findings in previous studies. In contrast, people with SHANK3 variants were found more likely to have sleep disorders, GI problems, recurrent infections, sensitivity to touch, and certain behaviors such as manic behavior. A recent large study primarily found this group to be more susceptible to regression in skills and neuropsychiatric illness, categories which were not a central focus of this publication.

Results between genotype-phenotype studies can vary due to many factors, such as the PMS population studied, including factors like age, the number of people in each group, the access of people to genetic sequencing and other methods, and the types of symptoms assessed. Many studies on many people over time is required to identify themes.

People with larger deletions were more likely to be diagnosed earlier, and more likely to see a doctor for developmental delay, as compared with ASD diagnosis in SHANK3 variants. These findings are consistent with other studies that suggest people with larger deletions do not reach developmental milestones as easily, whereas those with SHANK3 variants are more likely to reach them and regress.

This study also listed several “hotspots” for common breakpoints in the genome for deletions and common areas for SHANK3 variants. These findings can be built upon in the future to create associations between common genetics and symptoms.

Finally, this study suggested a paradigm for genetic testing and diagnosis, which aligns well with practices in the U.S. and throughout Europe. The authors suggested first-line testing of chromosomal microarray analysis, which can detect deletions and additions, to be followed up by sequencing if nothing is seen, or visualization of chromosomes to detect Ring 22 if deletions are detected. Parental testing is especially warranted in some cases where unbalanced translocations are suspected.

Read the research article here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044489/