"Building Bridges of Hope to a Cure"

An Overview of SYNGAP1 Basic

Biology and Clinical Description

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Building Bridges of Hope to a Cure"

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

References 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
National Organization of Rare Disease and the US
database to support research.
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 critical 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

The SYNGAP1 gene provides Connected nerve cells compose the SygGAP helps regulate synapse
instructions for making a protein, “wiring” in the circuitry of the adaptations and promotes proper
After presenting your social media Remember to keep it simple and zero in on
called SYNGAP1 that plays an brain. brain wiring.
overview,
importantyou're
role in ready to show
nerve cells your goals
in the your main goals. For context, present data
and key initiatives. Start by identifyingSynapses
brain. the in able
are easy-to-follow
to change andcharts, which present
The protein’s the is particularly
function
objectives that the team has set for theadapt over progress you have
time, rewiring brain done month to month.
important during a critical period of
SygGAP is found at the junctions
reporting period, then relate these to circuits, which is critical for early brain
Doing so gives you the opportunity to development
show that affects
between nerve cells (synapses)
bigger business objectives. If the teamlearning
has and
howmemory. future cognitive
your social media program has beenability.
where cell-to-cell communication
been embarking on key initiatives,. improving over time, as well.
takes place.

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
A S E
remain DEPENDENT on other
DI SE • 8 in 10 rare diseases are
parties for their basic survival,
A R E caused by a faulty gene
and for all their needs
throughout their lives:
R • 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: BEHAVIOR 
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 Wild 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 haploinsufficiency 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: jmedgenet-
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.2014.05.015. 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 Central

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 Phenotypic 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. Review.

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 Administration. 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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