SYNGAP1 Resource Guide

"Building Bridges of Hope to a Cure"

An Overview of SYNGAP1 Basic Biology and Clinical Description

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About Us 3

Our History 4

SYNGAP1-Normal Function 5

Uniqueness in SYNGAP1 6

Common Symptoms of SYNGAP1 7

Facts about SYNGAP1 Syndrome 8 Common Indications of SYNGAP1 Cognition, development and behavior 9

Characteristics of SYNGAP1 Epilepsy 10

What About CBD? 11

SYNGAP1 Centers of Excellence 12

R e f e r e n c e s 13

References Continued 14

CBD Cited References 15

Connect with Us 16 "Building Bridges of Hope to a Cure"

Bridge the Gap – SYNGAP Education and Research Foundation is the leading organization advocating and raising funds for research and treatments for SYNGAP1. The Foundation has its origins in the USA, and now with international outreach, gathers critical information from SYNGAP1 patients worldwide. Bridge the Gap-SYNGAP Education and Research Foundation's mission is to improve the quality of life for people affected by SYNGAP1, provide family support, accelerating research and raising awareness

Our Mission To raise awareness and educate the public about SYNGAP1 (MRD5), unite patient families while building a robust data registry and providing meaningful information to researchers.

Our Vision To increase the diagnosis rate of SYNGAP1 patients worldwide and provide the expert care, improving the quality of life for our SYNGAP1 community while searching for treatments. Our Goals Increase Diagnosis Rate will improve patient experience and quality of life a standard of care and SYNGAP1 disease profile. To Create a robust SYNGAP1 (MRD5) Natural History Study using observable recorded data to find and validate bio- markers, outcome measures, to create customized treatment plans for SYNGAP1 Patients. Educate researchers and medical professionals in hopes of improving the time it takes for an early diagnosis. To Shape programs that will benefit scientific research and treatments for SYNGAP1, including increased translational science to find mechanism and function of SYNGAP1 protein. Building Bridges of Hope to a Cure"

In 2014, Monica Weldon became the Founder, This five year project will produce shared specific President and Chief Executive Officer of Bridge the data about SYNGAP1 mutations with researchers Gap – SYNGAP Education and Research Foundation. who study SYNGAP1 to find better treatments. The foundation was established soon after Monica’s son Beckett was diagnosed with a SYNGAP1 mutation In 2018, BTG had our Second International SYNGAP1 in 2012. He was the first child identified at Texas Conference, our scientists called attention to the Children’s Hospital Genetics Clinic and was one of 6 importance of the full range of research in the individuals in the world identified at the time. scientific discovery process and emphasized that innovation often comes from early-career scientists, Since its inception in September of 2014, the while building solid relationships with the patient organization has grown rapidly because of the community. tireless efforts of the volunteer board of trustees and parents. In May of 2015 the foundation and scientific In 2018 a collaboration began between scientists advisory board published the first combined and our patient families that helped to further the descriptive summary of SYNGAP1 mutations understanding of the underlying causes of Sensory published by the National Organization of Rare Processing Disorder in SYNGAP1 patients. Disease. In 2019, BTG released new data that includes BTG is partnering with several on-going research Pediatric Quality of Life, Burden Data and current studies across the globe that are aimed at demographic data from our SYNGAP1 Registry. We understanding epilepsy and autism spectrum currently have four SYNGAP1 Centers of disorders. We are supporting studies focused Excellence, and one International SYNGAP1 Clinic. specifically on epilepsy, autism and are currently in the stages of drug discovery and translational BTG's future focus it to continue to engage the science. patient community, support ongoing education initiatives and continue to build a robust SYNGAP1 In April 2016, the foundation was awarded by the database to support research. National Organization of Rare Disease and the US Food and Drug Administration, the first and largest Natural History Study and Registry for SYNGAP1 (MRD5). "Building Bridges of Hope to a Cure"

The SYNGAP1 gene provides instructions for making a protein, called SynGAP, that plays an important role in nerve cells in the brain. SynGAP is found at the junctions between nerve cells (synapses) where cell-to-cell communication takes place. Connected nerve cells act as the "wiring" in the circuitry of the brain. Synapses are able to change and adapt over time, rewiring brain circuits, which is crit ical for learning and memory. SynGAP helps regulate synapse adaptations and promotes proper brain wiring. The protein's function is particularly important during a critical period of early brain development that affects future cognitive ability.

THE BASICS

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Resource: https://ghr.nlm.nih.gov/gene/SYNGAP1 "Building Bridges of Hope to a Cure"

What Makes SYNGAP1 Different?

GENETIC BASIS It has a genetic basis meaning that the gene that causes the disorder has been identified; a mutation on the SYNGAP1 gene will present with symptoms.

SEVERITIES The severity and onset of the symptoms can vary from patient to patient; it is considered a spectrum disorder. There is a long journey of research and analysis ahead to further inform on SYNGAP1, and the points made here are reflective of that journey.

SYMPTOMS Some of the symptoms are shared with other disorders but the underlying cause of the symptoms differ. It has an emerging collection of symptoms, but there may be insufficient unique clinical characteristics to enable an early clinical diagnosis. What SYNGAP1 has in common with Other Rare Diseases?

There is presently no • 1 in 10 people have a rare cure or approved disease treatments. • 1 in 2 patients diagnosed is a The SYNGAP1 patient has placed child their life in our hands, they will remain DEPENDENT on other • 8 in 10 rare diseases are parties for their basic survival, caused by a faulty gene and for all their needs throughout their lives: RARE DISEASE • 95% of rare diseases lack an FDA approved treatment Social Cognitive • 4.8 years is the average time Physical it takes to receive a diagnosis Emotional "Building Bridges of Hope to a Cure"

"Not all of these symptoms will be present in every affected person. However, to date the most commonly described symptoms are:

Intellectual Disability – can vary across the range, mild to severe

Global Developmental Delay – onset infancy

Hypotonia (low muscle tone)

Spectrum of Epilepsies – usually difficult to achieve seizure control and not always present at birth.

Speech Delay – both receptive and expressive, can remain nonverbal

Delayed development of motor skills

Language Disorder – Apraxia

Autism Spectrum Disorders

Sensory Processing Disorders

Sleep Disturbances

Strabismus - Lazy Eye

Constipation

Joint and Spine issues – likely linked to low EEG SYNGAP1 Mouse Biomarker muscle tone Axial and Facial Hypotonia

Atxtia or Gait instability

High Pain Threshold

Facial Dysmorphia - frontal bossing, long narrow face, almond shaped palpebral fissures, open mouth (features may or may not be related to SYNGAP1) EEG SYNGAP1 Human Biomarker Brain Imaging (MRI) Typically normal

Our Goal is to improve the Quality of Life, While Searching for Effective Treatments "Building Bridges of Hope to a Cure"

Current up to 2020

INTELLECTUAL DISABILITY IMPORTANT TERMS

EPILEPSY

DIAGNOSIS

AUTISM

PREVALANCE 1%-2% OF SYNGAP1 MUTATIONS THAT CAUSE INTELLECTUAL DISABILITY CASES WORLDWIDE ARE SPORADIC (DE NOVO) 5 OUT OF 500 DIAGNOSED WITH EPILEPTIC ENCEPHALOPATHY HAVE SYNGAP1 MUTATION THE FREQUENCY OF SYNGAP1 MUTATIONS IS SIMILAR TO THAT OF FRAGILE X SYNDROME, WHICH IS THE MOST COMMON INHERITED CAUSE OF ID WORLDWIDE "Building Bridges of Hope to a Cure"

Clinical Features in SYNGAP1 Patients

COGNITION AUTISM All Patients have intellectual Over half (>50%) the patients disability, ranging from mild, are diagnosed with Autism moderate to severe Spectrum Disorder (ASD) No association has been found GLOBAL DEVELOPMENTAL between ASD and the severity DELAY of ID, or with the location of Manifest in the first and second the mutation on the gene year of life Motor Delays: B E H A V I O R Sitting unaided average 12 3/4 of SYNGAP1 patients months suffer from severe Walking unaided average 2-3 behavioral problems years Types of Behaviors: Hyper-excitability LANGUAGE Aggression Severely Impaired with delays in Oppositional Behavior expressive & receptive speech Tantrums development Self Injury 1/3 of individuals >5 years old remain non-verbal SLEEP DIFFICULTIES Verbal Patients range from 60% of patients reported single words to brief sentences sleep difficulties, both with Milder phenotypes have been initiation and observed in patients with maintaining sleep mutations in Exons 1-4 as Sleep is managed with compared to more severe melatonin, clonidine or phenotypes in exons 8-15 Trazodone

EATING DIFFICULTIES Oral aversion and oral hypersensitivity are common A small percentage of patients have feeding tubes "Building Bridges of Hope to a Cure"

More than 80% of individuals with SYNGAP1 mutations have generalized epilepsy, with focal seizures occurring only in a minority of cases Absence seizures are the most common The age of seizure onset ranges from 3 type of seizure months to 7 years (most often at 2-3 years) Focal seizures occur only in a minority of cases Developmental delays typically precede seizure onset Patients can manifest multiple seizure types; including eyelid myoclonia with Developmental plateau or regression absences, typical absences, atypical accompanies seizure onset in many absences, and myoclonic absences patients, consistent with a diagnosis of DEE. As many as 35% of patients - eyelid myoclonia (EM) evolving to myoclonic Seizures are quite frequent, as many as seizures followed by drop attacks, or 100 seizures per day, but brief, each EM evolving directly to atonic seizures lasting a few seconds. Other seizure types such as myoclonic, atonic, myoclonic-atonic, and tonic- Evoked by a specific afferent stimulus clonic are also observed flash of light startle reading eating photo-sensitivity

Chewing-induced reflex seizures triggered by chewing biting oral sensory stimuli such as touching the mouth or face

The most commonly observed reflex seizures are eyelid myoclonia

Seizures precipitated by photic stimulation during EEG or sunlight, and eye closure sensitivity (ECS) - eye closure-induced epileptiform discharges, appearing within 2- 4 seconds of eye closure and lasting for 1-4 seconds

Fixation off sensitivity (FOS) has also been observed "Building Bridges of Hope to a Cure"

Cannabidiol (CBD) is one of the major cannabinoids derived from cannabis or synthesized. (1)

CBD has very low affinity for the cannabinoid receptor CB1 and so is lacking euphoric side effects. (1)

Tetrahydrocannabinol (THC) is a major cannabinoid that may be derived from A study of 84 non-FDA approved CBD cannabis or synthesized. (1) products showed nearly 70% were Primarily responsible for marijuana’s mislabeled for CBD content and 20% psychotropic properties. (1) contained undisclosed THC. (3)

Only certain cannabinoid products have undergone or are undergoing a federal testing and approval process.

The rigorous FDA-approval process is undertaken in an effort to establish the efficacy, safety, and quality of a medicine before use by the general public. FDA- approved medicines are available by prescription in both specialty and/or retail pharmacies, not dispensaries. (2) · Cannabinoid products that have not undergone the FDA approval process are sold in dispensaries and online. These should not be considered substitutes or generics for FDA-approved medicines. (3,4) · The importance of growing conditions: Cannabis plants absorb chemicals from the soil. Ground soil can contain toxins such as pesticides, heavy metals, or fertilizers. (5) · Testing standards and labeling vary greatly from state to state and among manufacturers. (6) · Look for manufacturers who meet the World Health Organization’s Good Agricultural Practices and are certified by an accepted certification body. (5) · Product should be labeled with a batch number, expiration date, and serial number to ensure identification and the ability to track each bottle. "Building Bridges of Hope to a Cure"

TEXAS CHILDREN’S HOSPITAL BAYLOR COLLEGE OF MEDICINE Jimmy Holder; MD, PhD Blue Bird Clinic of Neurology Texas Children's Hospital - Clinical Care Center Address: 6701 Fannin St, Houston, TX 77030 Phone: +1 (832) 822-0996 Option #2 For More information Contact Truzella Benton

KENNEDY KRIEGER INSTITUTE SYNGAP1 CLINIC

Constance Smith-Hicks, MD, PhD 707 N Broadway Baltimore, MD 21205 Local: +1 (443) 923-9400 For More Information Contact Barbra Bradford [email protected] THE UNIVERSITY OF MIAMI JOE DIMAGGIO CHILDREN'S HOSPITAL STANFORD CHILDREN'S HEALTH CAROLINAS MEDICAL CENTER SYNGAP1 CLINIC Andres Jimenez Gomez, MD, FAAP Maura Ruzhnikov, MD Pediactric Neurology, Neurodevelopmental Disabilities Clinical Assistant Professor Joe DiMaggio Children's Hospital 730 Welch Rd 2nd Floor 1150 North 35 Avenue, Suite 520 Palo Alto, CA 94304 Hollywood FL 33021 Phone: 605-723-0993 Phone: 954-265-2423 Fax: 650-721-6350 Fax: 954-961-4860

Baharak Moshiree, MD THE PATRICK WILD CENTRE Carolinas Medical Center Atrium Health Gastroenterology and Hepatology Andrew Stanfield, PhD Morehead Medical Plaza Senior Clinical Research Fellow 1025 Morehead Medical Drive, Suite 300 The Patrick Wil d Centre,The University of Charlotte, NC 28204 Edinburgh, Kennedy Tower Phone: 704-355-4593 Royal Edinburgh Hospital Edinburgh EH10 5HF Julia Dallman, PhD Tel: 0131 650 2240 University of Miami - SYNGAP1 Brain-Gut Study Fax: 0131 650 2239 ASSOC. PROFESSOR Email: http://andrew.stanfield.ed.ac.uk/ [email protected] PHONE:(305) 284-3954 "Building Bridges of Hope to a Cure"

Journal Articles

Berryer, MH, Hamdan FF, Klitten LL, et al. Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Hum Mutat 2013;34(2): 385-394.

Clement, JP, Aceti M, Creson TK, et al. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell 2012;151(4): 709-723.

Hamdan, FF, Gauthier J, Spiegelman D, et al. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N Engl J Med. 2009;360(6): 599-605.

Kim, JH, Liao D, Lau LF and Huganir RL. SynGAP: a synaptic RasGAP that associates with the PSD- 95/SAP90 protein family. Neuron 1998;20(4): 683-691.

Aceti M, Creson TK, Vaissiere T, Rojas C, Huang WC, Wang YX, Petralia RS, Page DT, Miller CA, Rumbaugh G. Syngap1 h aploinsufficiency damages a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly. Biol Psychiatry. 2015 May 1;77(9):805-15. doi: 10.1016/j.biopsych.2014.08.001. Epub 2014 Aug 13. Citation on PubMed or Free article on PubMed Central

Clement JP, Aceti M, Creson TK, Ozkan ED, Shi Y, Reish NJ, Almonte AG, Miller BH, Wiltgen BJ, Miller CA, Xu X, Rumbaugh G. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell. 2012 Nov 9;151(4):709-23. doi: 10.1016/j.cell.2012.08.045. Citation on PubMed or Free article on PubMed Central

Clement JP, Ozkan ED, Aceti M, Miller CA, Rumbaugh G. SYNGAP1 links the maturation rate of excitatory synapses to the duration of critical-period synaptic plasticity. J Neurosci . 2013 Jun 19;33(25):10447-52. doi: 10.1523/JNEUROSCI.0765-13.2013. Citation on PubMed or Free article on PubMed Central

Mignot C, von Stülpnagel C, Nava C, Ville D, Sanlaville D, Lesca G, Rastetter A, Gachet B, Marie Y, Korenke GC, Borggraefe I, Hoffmann-Zacharska D, Szczepanik E, Rudzka-Dybała M, Yiş U, Çağlayan H, Isapof A, Marey I, Panagiotakaki E, Korff C, Rossier E, Riess A, Beck-Woedl S, Rauch A, Zweier C, Hoyer J, Reis A, Mironov M, Bobylova M, Mukhin K, Hernandez-Hernandez L, Maher B, Sisodiya S, Kuhn M, Glaeser D, Wechuysen S, Myers CT, Mefford HC, Hörtnagel K, Biskup S; EuroEPINOMICS-RES MAE working group, Lemke JR, Héron D, Kluger G, Depienne C. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. J Med Genet. 2016 Mar 17. pii: jmedg-enet 2015-103451. doi: 10.1136/jmedgenet-2015-103451. [Epub ahead of print] Citation on PubMed

Ozkan ED, Creson TK, Kramár EA, Rojas C, Seese RR, Babyan AH, Shi Y, Lucero R, Xu X, Noebels JL, Miller CA, Lynch G, Rumbaugh G. Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons. Neuron. 2014 Jun 18;82(6):1317-33. doi: 10.1016/j.neuron.2014.05.01 5. Citation on PubMed or Free article on PubMed Central

"Building Bridges of Hope to a Cure"

Parker MJ, Fryer AE, Shears DJ, Lachlan KL, McKee SA, Magee AC, Mohammed S, Vasudevan PC, Park SM, Benoit V, Lederer D, Maystadt I, Study D, FitzPatrick DR. De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability. Am J Med Genet A. 2015 Oct;167A(10):2231-7. doi: 10.1002/ajmg.a.37189. Epub 2015 Jun 15. Citation on PubMed or Free article on PubMed Cent ral

Wang CC, Held RG, Hall BJ. SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks. PLoS One. 2013 Dec 31;8(12):e83941. doi: 10.1371/journal.pone.0083941. eCollection 2013. Citation on PubMed or Free article on PubMed Central

Jimenez-Gomez A, Niu S, Andujar-Perez F, McQuade EA, Balasa A, Huss D, Coorg R, Quach M, Vinson S, Risen S, Holder JL Jr.J Phenot ypic characterization of individuals with SYNGAP1 pathogenic variants reveals a potential correlation between posterior dominant rhythm and developmental progression. Disord. 2019 Aug 8;11(1):18. doi: 10.1186/s11689-019-9276-y.

Gamache TR, Araki Y, Huganir RL.J Twenty Years of SynGAP Research: From Synapses to Cognition.Neurosci. 2020 Feb 19;40(8):1596-1605. doi: 10.1523/JNEUROSCI.0420-19.2020. Re view.

Gou G, Roca-Fernandez A, Kilinc M, Serrano E, Reig-Viader R, Araki Y, Huganir RL, de Quintana- Schmidt C, Rumbaugh G, Bayés À.J SynGAP Splice Variants Display Heterogeneous Spatio-Temporal Expression And Subcellular Distribution In The Developing Mammalian Brain.. 2020 Feb 18:e14988. doi: 10.1111/jnc.14988

Vlaskamp DRM, Scheffer IE. Author response: SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy.Neurology. 2020 Feb 25;94(8):370. doi: 10.1212/WNL.0000000000009010

Internet Sources

Holder JL Jr, Hamdan FF, Michaud JL. SYNGAP1-Related Intellectual Disability. 2019 Feb 21. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537721/ Accessed May 30, 2019.

NIH - U.S. National Library of Medicine, Genetics Home Reference: SYNGAP1 NIH Genetics Home Page

National Organization for Rare Disorders (NORD), Rare Disease Information, SYNGAP1-Related NISD: NORD - SYNGAP1 NSID

Bridge the Gap – SYNGAP Education and Research Foundation, Website: Bridge SYNGAP , SYNGAP1 (MRD5) Natural History Study Cover Neuron Picture Courtesy of Creative Commons Attribution 4.0 International

"Building Bridges of Hope to a Cure"

1. Pertwee RG. Cannabinoid pharmacology: the first 66 years. Brit J Pharmacol. 2006;147(suppl 1):S163- S171.

2. U.S. Food and Drug Administration. What we do. https://www.fda.gov/about-fda/what-we-do. Updated March 28, 2018. Accessed August 20, 2019.

3. Bonn-Miller M, Loflin M, Thomas B, et al. Labeling accuracy of cannabidiol extracts sold online. JAMA. 2017;318(17):1708-1709.

4. U.S. Food and Drug Adm inistration. Warning letters and test results for cannabidiol-related products. https://www.fda.gov/news-events/public-health-focus/warning-letters-and-test-results- cannabidiol-related-products. July 24, 2019. Accessed August 20, 2019.

5. WHO Guidelines on Good Agricultural Practices (GACP) for Medicinal Plants. World Health Organization Geneva. 2003.

6. Guidance for State Medical Cannabis Testing Programs. Association of Public Health Laboratories. Silver Springs, MD. May 2016

More Resources Available Here www.cannabinoidclinical.com

"Building Bridges of Hope to a Cure"

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