GRIN2B patient phenotype data - collected by GRIN2B Europe

1. Survey Results
EU GRIN2B Symposium
Barcelona 2018

2. Content
• Thank you
• 1. Participants
• 2. Variants
• 3. Intellectual Age
• 4. Medical
• 5. Physical Attributes
• 6. Communication
• 7. Feeding
• 8. Toileting
• 9. Other Symptoms
• 10. Likes & Dislikes
• 11. Summary
• Appendix 1 – Details of variants
• Appendix 2 – Other medical information, i.e. Surgeries, MRI results etc.
• Appendix 3 – Medication, Supplements, Therapies & Treatments

3. Thank You!
• We have had 51 people complete our survey from 15 different
countries between July & August 2018
• This is not a professional survey or analysis, or indeed a full
population survey. All data is purely based on the population who
submitted the survey
• Our aim is to
– provide the professionals with information that may make them
look into certain areas they hadn’t considered before
– provide parents with information so they can raise questions
with their own healthcare providers
• We are in no way suggesting you can draw conclusions on prognosis
for your child. Each variant is different and each child is different

4. 1. Participants
• 1.1 Countries
• 1.2 Ages
• 1.3 Gender

5. 1.1 Countries
20
9
5
4
2
2
111111111
USA
UK
Netherlands
Australia
Belgium
Germany
Canada
Denmark
France
Greece
Hong Kong
Italy
New Zealand
Norway
Spain

6. 1.2 Ages
• The ages range from 1-26
– 22 under five
– 18 between five and ten
– 7 between ten and 18
– 4 are adults

7. 1.3 Gender
Male, 55%
Female, 45%

8. 2. Variants
• 2.1 GRIN2B Variants
• 2.2 Pattern Inheritance
• 2.3 Variant Types
• 2.4 Loss or Gain of Function

9. 2.1 GRIN2B Variants
• 12 out of 51 do not know their variant
• Most of the variants are different but we do have 3
variants in this population with more than one child
– c.1555C >T p.Arg519X
– c.2459G>A p.Gly820Glu
– c.2539C>T p.R847X
• Most of the variants are Missense mutations
(26 out of 39 known variants)
• There are 7 Nonsense mutations
• Full details of the individual variants can be found in
the Appendix, at the end of this presentation

10. 2.2 Pattern Inheritance
• All variants discussed are present in the child
only (de novo genetic variants), with the
exception of one that is inherited from the
mother.
• Comments on the GRIN2B parent facebook
group show that there are some where the
variant is also present in another family
member.

11. 2.4 Loss or Gain Of Function
GOF, 6%
LOF, 22%
Unknown, 73%

12. 2.4 Loss or Gain Of Function
• Finding out whether your child has Gain of
Function or Loss of Function is important as it
could help to determine which course of
treatment would be suitable for your child.
• To find out whether your child’s variant is LOF or
GOF you can talk to your neurologist, contact
Barcelona GRIN cluster (xaltafaj@idibell.cat), or
visit CFERV (Centre for Functional Evaluation of
Rare Variants) http://functionalvariants.emory.edu/
for details of how to submit a report for analysis

13. 3. Intellectual Age
• 3.1 Intellectual Age v. Actual Age

14. 3.1 Intellectual Age v. Actual Age
0 5 10 15 20 25 30
Intellectual Age
Age

15. 4. Medical
• 4.1 MRIs
• 4.2 EEGs
• 4.3 Epilepsy
• 4.4 Abnormal EEG & Epilepsy
• 4.5 Autism Diagnosis
• 4.6 Visual Problems
• 4.7 Other Medical Conditions

16. 4.1 MRIs
No MRI, 12%
Abnormal, 24%
Normal, 65%
Q: Has your child had an MRI?

17. 4.2 EEGs
No, 22%
Normal, 35%
Abnormal, 43%
Q: Has your child had an EEG?

18. 4.3 Epilepsy
Focal
Underlying epilepsy during sleep time. No seizures.
Complex partial seizures
Tonic clonic, drop, absent, gelastics seizures
Atonic
Multifocal secondary generalized epilepsy
Mild, 12%
Moderate, 4%
Severe, 6%
No epilepsy, 78%
Types
Q: Does your child have epilepsy?

19. 4.4 Abnormal EEG & Epilepsy
22 children had an abnormal EEG. 12 of those do not have epilepsy
1 child has moderate epilepsy, even though both the EEG and MRI
were normal
No, 12
Mild, 6
Moderate, 1
Severe, 3

20. 4.5 Autism Diagnosis
No, 75%
Yes, 20%
In Progress, 6%

21. 4.6 Visual Problems
39%
51%
14%
14%
14%
8%
6%
4%
2%
2%
2%
0% 10% 20% 30% 40% 50% 60%
No
Strabismus (squint)
Long sighted
Short sighted
Wears glasses
Nystagmus
Visual Cortex Defect
Registered visually impaired
Binocular vision disorder
Marcus gun sydrome
Pseudostrabismus

22. 4.7 Other Medical Conditions
4%
4%
4%
10%
10%
31%
61%
27%
0% 10% 20% 30% 40% 50% 60% 70%
Breathing problems
Cleft
Hearing difficulties
Heart defect
Reflux
Digestive problems
Constipation
None

23. 5. Physical Attributes
• 5.1 Build
• 5.2 Walking
– 5.2.1 Independent Walking
– 5.2.2 Independent Walking by Age
– 5.2.3 Orthotics
• 5.3 Sitting
– 5.3.1 Independent Floor Sitting
– 5.3.2 Independent Floor Sitting by Age
– 5.3.3 Independent Chair Sitting
• 5.4 Physical Abilities
– Physical Abilities by Stage
– Physical Abilities by Age
• 5.5 Movement Disorders
• 5.6 Body Tone

24. 5.1 Build
73%
20%
16%
8%
0% 10% 20% 30% 40% 50% 60% 70% 80%
Slim
Small
Average
Tall

25. 5.2.1 Walking
Independently,
59%
Supported, 10%
No, 31%

26. 5.2.2 Independent Walking by Age
0
1
2
3
4
5
6
7

27. 5.2.3 Orthotics Used
None, 53% Splints, 29%
Insoles, 10%
Special Shoes,
8%

28. 5.3.1 Floor Sitting
Independently,
78%
Supported,
12%
No, 10%

29. 5.3.2 Independent Floor Sitting by Age
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5

30. 5.3.3 Chair Sitting
No, 20%
Independently,
57%
Supported,
24%

31. 5.4.1 Physical Abilities by Stage
0
5
10
15
20
25
30
35
40
45
Not obtained yet
Emerging
Developing
Secure

32. 5.4.2 Physical Ability by Age
0
5
10
15
20
25
30
<1
1-2
3-4
5-7
8-10
11+

33. 5.5 Movement Disorders
0 5 10 15 20 25
Hyperactivity
Stereotypic Movement Disorder
Ataxia
Dyspraxia
Dystonia
Hypermobility
None
1
1
3
8
8
17
22

34. 5.6 Body Tone
Hypotonic (Low
tone), 61%
Variable tone,
22%
Normal, 12%
Hypertonic (High
tone), 6%

35. 6. Communication
• 6.1 Talking by Age
• 6.2 Alternative Communication

36. 6.1 Talking by Age
0
2
4
6
8
10
12
14
16
18
Non Verbal Babbling A few words Lots of words Short
sentences
Full speech
<1
1-2
3-4
5-7
8-10
11+

37. 6.1 Talking by Age
Non Verbal
8
Babbling
4
A few words
6Lots of words
2
Short sentences
5
Full speech
8
Taking the population of 4 and over (33 in total) and their achieved verbal stage

38. 6.2 Alternative Communication
0 5 10 15 20 25 30
Crying
Looking at the object they want
Reaching
Signing
Gestures
Taking your hand to the object they want
Challenging behaviour
Eye Gaze
Symbols
Using pictures
AAC device
Echolalia (the repetition of other people's words).
PECS (Picture Exchange Communication System)
Body Language
Coloured buttons

39. 7. Feeding
• 7.1 Feeding
• 7.2 Types of Food
• 7.3 Feeding Disorders

40. 7.1 Feeding by Age

41. 7.2 Types of Food
47% are having regular food
Liquid
8%
Pureed
18%
Regular
47%
Soft Solids
4%
Textured
23%

42. 7.3 Feeding Disorders
0
5
10
15
20
25
30
35
40
11
1
15
8
36
11
2 2
11

43. 8. Toileting
• 8.1 Toileting aged over 3

44. 8.1 Toileting over age 3
Incontinent, 17
Partially toilet
trained, 8
Fully toilet
trained, 8

45. 9. Other Symptoms
• 9.1 Other Symptoms
• 9.2 Sleeping

46. 9.1 Other Symptoms
0 5 10 15 20 25 30
Sensory Processing Disorder
Hand flapping
Hand biting
Self harm
Hyper active
Stimming
Hair pulling
Hand wringing
Rocking
Toe walking
28
26
22
19
16
16
10
8
8
8

47. 9.1 Other Symptoms
• Finger posturing
• High pain threshold
• Bites clothes
• Ripping paper
• Anxiety
• Dribbling
• Hair eating
• No danger awareness
• Sensory seeking behaviours

48. 9.2 Sleeping
• This was one issue we missed off our survey.
However we know from discussions on the
facebook group that a lot of our children have
sleep issues, either getting to sleep, or staying
asleep.

49. 10. Likes & Dislikes
• 10.1 Likes
• 10.2 Dislikes

50. 10.1 Likes
0 5 10 15 20 25 30 35 40
Music
Water
Specific TV shows
One on one interaction
Movement
Spinning
Mirrors
Bouncing
38
33
25
24
18
17
15
12

51. 10.1 Likes
• Unusual sounds
• Animals
• Faces
• Going out
• Hair
• Making verbal noises
• Other people
• Tickles
• Books
• Colours
• Vibrations
• Food
• Horse Riding
• Lights
• Opening/closing doors
• Running
• Singing
• Strangers
• Swimming
• Trampoline

52. 10.2 Dislikes
0 5 10 15 20 25 30 35 40 45
Loud noises
Crowds
Particular textures
Particular music
Big spaces
Echoes
41
24
14
5
4
3

53. 10.2 Dislikes
• Animals
• Babies
• Insects
• Being touched
• Being held certain ways
• Others crying
• Sirens
• Brushing teeth
• Brushing hair
• Washing hands
• Being too hot
• Grass
• People looking
• Bright lights
• Traffic Lights
• Dry foods
• Sweet Food
• Cold water/food
• Warm water/food

54. 11. Summary
• 11.1 Common Symptoms
• 11.2 Summary

55. 11.1 Common Symptoms
Intellectual
Disability
Communication
Delayed
Physical
Ability
Sleep
Problems
Not
Chewing
Hypotonic
Slim Build Constipation
Strabismus
Sensory
Processing
Disorder
Hand
Flapping
Hand Biting
Self Harm Hypermobility Hyperactive
Epilepsy Abnormal
MRI

56. 11.2 Summary
• Based on a survey population of 51 children aged between 1 to 26 from all
over the world
• Participants
– Slightly more males than females
• Variants
– Most variants are unique and the majority are missense mutations
– More people need to have their results tested to confirm Loss of Function or
Gain of Function
• Intellectual Age
– The majority of children have an intellectual age of under 5
• Medical
– 65% have normal MRI results
– 22 had an abnormal EEG, but only 12 of those have diagnosed epilepsy
– 20% have an Autism diagnosis
– Over half have strabismus (eye squint)
– Constipation and Digestive problems are very common

57. 11.2 Summary
• Physical Attributes
– 73% are described as slim
– 59% walk independently and tend to do so by age 3.
– 78% are floor sitting independently and tend to do so by 18 months
– 39% of our children reach basic physical milestones such as rolling
over, hand transfer, high kneel, crawling by age 2
– 32% have reached jumping and running by age 4.
– 57% of our population has some kind of movement disorder such as
hypermobility, dyspraxia etc.
– 61% have hypotonia (low muscle tone)

58. 11.2 Summary
• Communication
– Speech seems to be a common problem for our bees. Out of our age 4 and
over (33 in total) 13 have achieved full speech or short sentences, whilst 12
are non verbal or babbling only, leaving 20 with minimal speech.
• Feeding
– 35% of the children are self feeding and nearly half are on regular food
– 71% have problems chewing and 30% with gagging
• Toileting
– Just over half of our population aged 4 and over are incontinent with around a
quarter being fully toilet trained
• Other Symptoms
– Other symptoms are Sensory Processing Disorder, Hand flapping, Hand biting
and Self harm

59. 12. Thank you

60. Thank You
A copy of this presentation will be sent by email
to all the attendees and also will be posted on
the facebook groups:
• GRIN2B Parent Support Group
• GRIN Research Discussion Group

61. Appendices
• Appendix 1
– Details of Variants
• Appendix 2
– Additional medical & dietary information
• Appendix 3
– Medication, Supplements, Therapies &
Treatments tried by families

62. Appendix 1
See the next pages for details of variants

63. Genetic variant Protein variant Type Genetic variant Protein variant Type
12p13.1(14,042,568-14,133,113)x1 not given c.2116A>G p.Met706Val Missense
12p13.1p12.3 not given c.2252T>C p.Ile751Thr Missense
12p13.1p13.31 not given c.2341C>G p.Leu781Val Missense
c.2355delA p.Asp786Metfs*24 Deletion c.2459G>A p.Gly820Glu Missense
c.4244delC p.Ser1415X Deletion c.2459G>A p.Gly820Glu Missense
e.6a85_695del p.Leu229Tyrfs Deletion c.2459G>C p.Gly820Ala Missense
c.1451G>A p.Gly484Asp Missense c.2461G>T p.val821Phe Missense
c.1456C>T p.H486Y Missense c.2470A>G p.Met824Val Missense
c.1547A>G p.Asn516Ser Missense c.2515G>A p.Glu839Lys Missense
c.1576T>C p.Ser526Pro Missense c.448A>G p.lle150Val Missense
c.1594A>G p.Thr532Ala Missense c.841T>A p.Ser281Thr Missense
c.1597G>A p.Gly533Ser Missense c2237G>A p.Cys746Tyr Missense
c.1627G>C p.Gly543Arg Missense c.1368C>A p.Cys456X Nonsense
c.1672G>A p.Val558lle Missense c.1555C >T p.Arg519X Nonsense
c.1675T>A p.Trp559Arg Missense c.1555C>T p.Arg519X Nonsense
c.2002G>T p.Asp668Tyr Missense c.2539C>T p.R847X Nonsense
c.2065G>A p.Gly689Ser Missense c.2539C>T p.R847X Nonsense
c.2084T>C p.lle695Thr Missense c.2539C>T p.R847x Nonsense
c.2087G>A p.Arg696His Missense c.706G>T p.Glu236X Nonsense
c.2087G>A p.Arg696His Missense

64. Appendix 2
• A.2.1 MRI Results
• A.2.2 EEG Results
• A.2.3 Additional tests
• A.2.4 Surgeries
• A.2.5 Other medical conditions
• A.2.6 Special diets and comments

65. Missing white matter
Missing frontal part
Reduced white matter
Smaller frontal lobe
A.2.1 MRI Results
Thinner Corpus
Callosum
Left
temporal
lobe hotspot
Cyst in
brain
Sloping
Splenium
Subtle
white
matter
patchiness
More white
matter
Arnold Chiari
1 borderline.
7mm spot on
cerebellum

66. A.2.2 EEG Results
Left centrotemporal
variable frequency
epileptiform discharges
(report describes as
near continual) also
occurring on the right
with far less frequency.
West
Syndrom
Moderated persistence during day
time and moderated-high when
sleeping: Epileptical activity
focused in both temporal regions
(T3 and T4, independently). Peaks
and poli-peaks followed by slow,
medium voltage, isolated waves
grouped in trains of up to 3
seconds. Difussion to anterior
region of each hemisphere and
homologue counter-lateral region.
During the day
prevalence of theta
waves. During the night,
a poorly modulated
pattern, almost
completely devoid of
modulated figures
Encephalopathy,
with some
epileptic features
Bursts of irregular
diffuse sharp
waves up to 2.5
seconds with
parasagital
predominance
without
concominant
clinical seizures
Abnormal
brain waves a
spiking from
the left side
of the brain
No seizure activity,
but abnormal EEG
during sleep and
photic stimulation

67. A.2.3 Additional Tests performed
Muscle biopsy
Lumbar
puncture
Ecographyc
Swallow
study
Ent
scope
Colonoscopy
Reflux
researchDietician
Eyedoctor
(aot CVI)
Orthoptist
Clinical
genetics
Muscle
biopsy
MRS BEB
SEP
VEP
CT
scan

68. A.2.4 Surgeries
Porticath placement
Shunt placement
Evd placement
CraniotomyKidney Stone
Removal
Hip surgery
Pegsonde placement
(Mickey button)
Adenoidectomy
Tonsillectomy
Groinrupture
G-tube placement
Gastrostomy
Fundoplication
Eye Operation
(Strabismus)
Bilateral inguinal hernia repair
Ablation heart
arrhythmias
Open heart surgery
Hypospadias repair

69. A.2.5 Other Medical Conditions
ADHD
Calcium
Deficiency
Digeorge
Syndrome
Dystonia
Eosinophilic
Esophagitis
Failure
to
Thrive
Fragile
Immune
System
Hayfever
History
of
Strokes
Hydrocephalus
Iron
Deficiency
Layrnx
Problems
Underactive
Thyroid
Osiopenic
Bones
Plagiocephaly
Psychomotore
Scoliosis
Sleep
Apnoea
Spasticity
Type 1
Diabetes

70. A.2.6 Special Diets
0
5
10
15
20
25
30
35
40
40
1
6 3 1 1 1

71. A.2.6 Special Diets & Feeding
Comments
• Why a special diet?
– Cows Milk Protein Intolerance
– Related to oral motor functioning and lack of ability to chew properly and lateralize
tongue
– On recommendation of bio medical GP
– Parents' decision
– Trying Ketogenic diet
– Weight problems
• High calorie with supplementation with pediasure, Duocal, MCT oil, microlipids in addition to
high fat/calorie natural foods
• Calogen for nutrients and to gain some weight
• Other Feeding Comments
– Doesn’t eat a lot, picky eater
– Eats a wide variety of foods, and does really enjoy eating
– Very little sense of thirst

72. Appendix 3
Additional information from the survey about
medication, supplements, treatments and
therapies that are used by the GRIN2B
community
A.3.1 Medication
A.3.2 Supplements
A.3.3 Alternative Treatments
A.3.4 Therapies

73. A.3.1 Medication
• For Insomnia and/or epileptiform activity at night
– Melatonin
• This has had good results with better sleep behaviours.
• A negative was excessive sweating if high dose given
– Chloralhydraat
• Wakes less at night
• For Constipation and Trapped Wind
– Mirilax and Movicol
• These have had good results , if a little inconsistent
• For silent reflux / Gastroesophageal reflux disease (GERD)
– Omeprazole
• This helped a little with keeping milk down and feeding more at a time

74. A.3.1 Medication
• For epilepsy
– Keppra
• For excessive drooling
– Glycopyronium Bromide
• helps a little with drooling but not that effective
• can interfere with eyes i.e causes changes in size of pupil
• For processing of stimuli
– Butamine (Clinical Trial)
• Obvious increase in concentration level

75. A.3.2 Supplements
• For General Use
– Vitamin D
– Novaferrum (iron)
• Increased constipation
• Improve Brain Activity
– Fish oil with EPA & DHA
• Effect on cognitive skills, but may be subjective appreciation
• Low incidence of common sickness, but may be subjective
appreciation.
• Immunity
– VD3 vtamin
• Low incidence of common sickness, but may be subjetive
appreciation.
• Reached top blood concentration in 3 months.

76. A.3.2 Supplements
• Vomiting/Diarrhoea
– Blended diet (food made at home, not packet) for
tube fed
• no more diarrhoea, less vomiting, weight gain
• Milk Protein Allergy
– Nutramigen
• protein broken down meaning could take more milk, helped
a little with reflux and weight gain
• Failure to Thrive
– Paediasure (double the calories on whole milk and
fortified with vitamins)
• No side effects

77. A.3.2 Supplements
• Digestion
– Stomach Enzymes & Pancreatic Enzymes
• Helped with digestive problem of leaky gut (food is
absorbed into the bloodstream without being fully
digested)

78. A.3.3 Alternative Treatment
• All Symptoms
– Osteopathy
• loosens tension
• hard to say definitively, but has no spine curvature, or head
malformations
• Stiffness
– Chiropractic
• was too tight to even sit up. Started sitting up again and started
crawling.
• Oxidative Stress
– Hyperbaric Chamber
• Reduced oxidative cell damage
• Helped with motor skills

79. A.3.3 Alternative Treatment
• Improve brain function
– Neurofeedback
• Waste of time
– Quantron Resonance System
• Too early to tell improvement

80. A.3.4 Therapy
• Speech & Language
– Communication, Speech
• Uses drawings in books to invent stories
• expressive en responsive speech has improved
• She is learning to communicate more effectively,
finding her way of doing it. She loves intensive
interaction and has started copying.
• Confidence in language skills

81. A.3.4 Therapy
• Physiotherapy
– Gross Motor Skills, Balance, Strength
• A lot more active and mobile
• slow improvement in development
• Walking independently, holding things, holding on. All physical
gains
• Confidence – strength
• Occupational Therapy
– Planning, Fine Motor Skills
• Development of planning capacity. Develop manual and fingers
dexterity.
• Getting better in pincer grasp and fine motor skill games
• Finger usage skills. Manipulation of objects

82. A.3.4 Therapy
• Music Therapy
– Coordination, social, sleep, cognitive, self control,
behaviour
• coordination, interaction, turn taking, creativity
• Cognitive, recognize and enjoy music a lot. When she
started she did not react at all
• Music therapy works more at psychological level (the
therapist follows a holistic path)
• GREAT advance in self-control of crying.
• Advance in behaviour and self-control
• Increase of maturity to achieve more tasks

83. A.3.4 Therapy
• Hippotherapy (Horse Riding)
– Balance, Posture, Strength
• During this time she learnt to bottom shuffle, sit on chairs, stand
and walk independently
• helped with muscles that aid sitting
• We didn't appreciate any gain.
• Enjoyed. Good relation with animals. Follow instructions.
• Trampolining
– Balance, Posture, Strength
• physical and coordination gains as well as understanding of body
and self
• In two months she passed from falling at home every 4 steps to
being able of running with self confidence
• Great to enforce legs. Also abdominal muscles.

84. A.3.4 Therapy
• Climbing
– Executive Functions, Coordination, Self Asteem
• Climbing is helping him to coordinate movements and self-
esteem.
• Movement planning capacities evolve quickly since first
weeks. Has ability to plan where to move her feet/hands and
find a path to go up.
• Self-confidence. Achieving.
• Kinesitherapy
– Movement
• motor skills improved a lot, it took a long time though

85. A.3.4 Therapy
• Hydrotherapy (swimming)
– Motor skills, strength, coordination
• During this time she learnt to bottom shuffle, sit on chairs, stand
and walk independently. Her first independent standing and
walking was in the pool. She can also get from floor sitting to
standing independently with the support of the water
• allows him to have more freedom with the aid of floats, helps with
core strength
• Psychomotricity autonomy
• Great interest in all water games. Gain force in legs muscles.
• Balneotherapy
– Muscle Tone, coordination
• Confidence - strength

86. A.3.4 Therapy
• Doman resources
– Reading and numbers
• It was not really and objective for us, but we discovered that
she had learned all the letters 2 years earlier than usual at
school. Similar with the numbers.
• When learning to read at school, we realized that he does
global lectural (she tends to read the whole word, rather
than sound to sound).
• Feurestein (the process behind thinking and learning skills
in an organized, structured way)
– Cognitive
• Good results, used at home

87. A.3.4 Therapy
• Sensory Integration
– Motor Skills
• Helped overcome lots of problems with motorskills
• Astronaut Training
– Increased arousal and vestibular / balance
• Started walking during this training
• Wilbarger Brushing
– Sensory Challenges
• Therapeutic Listening Program
– Sensory Challenges
• Compression Garments
– Sensory Challenges