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GRIN2B survey 2018

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GRIN2B patient phenotype data - collected by GRIN2B Europe

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GRIN2B survey 2018

  1. 1. Survey Results EU GRIN2B Symposium Barcelona 2018
  2. 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. 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. 4. 1. Participants • 1.1 Countries • 1.2 Ages • 1.3 Gender
  5. 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. 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. 7. 1.3 Gender Male, 55% Female, 45%
  8. 8. 2. Variants • 2.1 GRIN2B Variants • 2.2 Pattern Inheritance • 2.3 Variant Types • 2.4 Loss or Gain of Function
  9. 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. 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. 11. 2.4 Loss or Gain Of Function GOF, 6% LOF, 22% Unknown, 73%
  12. 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. 13. 3. Intellectual Age • 3.1 Intellectual Age v. Actual Age
  14. 14. 3.1 Intellectual Age v. Actual Age 0 5 10 15 20 25 30 Intellectual Age Age
  15. 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. 16. 4.1 MRIs No MRI, 12% Abnormal, 24% Normal, 65% Q: Has your child had an MRI?
  17. 17. 4.2 EEGs No, 22% Normal, 35% Abnormal, 43% Q: Has your child had an EEG?
  18. 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. 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. 20. 4.5 Autism Diagnosis No, 75% Yes, 20% In Progress, 6%
  21. 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. 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. 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. 24. 5.1 Build 73% 20% 16% 8% 0% 10% 20% 30% 40% 50% 60% 70% 80% Slim Small Average Tall
  25. 25. 5.2.1 Walking Independently, 59% Supported, 10% No, 31%
  26. 26. 5.2.2 Independent Walking by Age 0 1 2 3 4 5 6 7
  27. 27. 5.2.3 Orthotics Used None, 53% Splints, 29% Insoles, 10% Special Shoes, 8%
  28. 28. 5.3.1 Floor Sitting Independently, 78% Supported, 12% No, 10%
  29. 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. 30. 5.3.3 Chair Sitting No, 20% Independently, 57% Supported, 24%
  31. 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. 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. 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. 34. 5.6 Body Tone Hypotonic (Low tone), 61% Variable tone, 22% Normal, 12% Hypertonic (High tone), 6%
  35. 35. 6. Communication • 6.1 Talking by Age • 6.2 Alternative Communication
  36. 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. 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. 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. 39. 7. Feeding • 7.1 Feeding • 7.2 Types of Food • 7.3 Feeding Disorders
  40. 40. 7.1 Feeding by Age
  41. 41. 7.2 Types of Food 47% are having regular food Liquid 8% Pureed 18% Regular 47% Soft Solids 4% Textured 23%
  42. 42. 7.3 Feeding Disorders 0 5 10 15 20 25 30 35 40 11 1 15 8 36 11 2 2 11
  43. 43. 8. Toileting • 8.1 Toileting aged over 3
  44. 44. 8.1 Toileting over age 3 Incontinent, 17 Partially toilet trained, 8 Fully toilet trained, 8
  45. 45. 9. Other Symptoms • 9.1 Other Symptoms • 9.2 Sleeping
  46. 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. 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. 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. 49. 10. Likes & Dislikes • 10.1 Likes • 10.2 Dislikes
  50. 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. 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. 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. 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. 54. 11. Summary • 11.1 Common Symptoms • 11.2 Summary
  55. 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. 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. 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. 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. 59. 12. Thank you
  60. 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. 61. Appendices • Appendix 1 – Details of Variants • Appendix 2 – Additional medical & dietary information • Appendix 3 – Medication, Supplements, Therapies & Treatments tried by families
  62. 62. Appendix 1 See the next pages for details of variants
  63. 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. 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. 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. 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. 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. 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. 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. 70. A.2.6 Special Diets 0 5 10 15 20 25 30 35 40 40 1 6 3 1 1 1
  71. 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. 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. 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. 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. 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. 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. 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. 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. 79. A.3.3 Alternative Treatment • Improve brain function – Neurofeedback • Waste of time – Quantron Resonance System • Too early to tell improvement
  80. 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. 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. 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. 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. 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. 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. 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. 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

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