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CFERV 2019 GRIN Variant Patient Registry

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The GRIN Variant Patient Registry (GVPR) was created to link functional analyses of GRIN variants obtained through the Center for Functional Evaluation of Rare Variants (CFERV) with
standardized patient/family reported clinical information. The main goal of this registry to create a platform that will facilitate determining better treatments and cures for GRIN disorders. Initially, we are using the registry to create a database of clinical features, medication usage, and assessments (MRI and EEG results) associated with GRIN variants. Features include epilepsy, developmental delay, movement disorders, and vision impairment. The next step is to link clinical information with
functional information from laboratory experiments. By linking clinical and functional information, we hope to inform future clinical trials that incorporate treatments specific to GRIN functional changes. The current registry will inform the selection of data collection instruments to be used to shift the registry from its current retrospective data collection to a prospective natural history study that includes both parent and clinician reported information. Natural history data is crucial to
determining the effectiveness of future interventions; we need to know if particular symptoms worsen or improve on their own over time to understand if interventions were actually helping or not. In order to enroll, families contact the study coordinator (Jenifer.Sargent@childrenscolorado.org). Families then send a copy of their genetic report for review to determine if the variant appears to be pathogenic. After passing review, the families then sign and review a consent form. The study coordinator will then email The GRIN Questionnaire (TGQ) to be completed by the family; clinicians who know the family can help complete TGQ. The family can ask the study coordinator to engage
one of the Study Doctors (Benke, Marsh, or Poduri) to assist the family to complete TGQ. The family then emails TGQ to the study coordinator. TGQ information is entered into a secure RedCAP database. If there are new medications or other health updates, the family can fill in and return an updated TGQ. Every effort is performed to ensure data security and privacy. To date, we have enrolled families whose children have variants in GRIN1 (23), GRIN2A (8), GRIN2B (14), and GRIN2D (1). Our goal is to enroll at least 50 subjects in each group to begin to make generalizations about functional links between symptoms and disorders. Our goal is to provide an opportunity for all interested families to enroll, with an estimated total of 500.

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CFERV 2019 GRIN Variant Patient Registry

  1. 1. GRIN Variant Patient Registry (GVPR) Tim Benke, MD, PhD; Austin Drake BS; Jenifer Sargent, BS Children’s Hospital Colorado University of Colorado/School of Medicine Eric Marsh MD, PhD Children’s Hospital Philadelphia/U Penn Ann Poduri MD MPH Boston Children’s/Harvard Scott Myers PhD; Steve Traynelis PhD Emory © Tim Benke, MD, Ph.D.
  2. 2. Disclosures Unrestricted research funding: NIH-NINDS, NICHD Questcor/Mallinkrodt Ponzio Family Chair in Neurology Research IFCR, RSRT, CURE, LouLou Foundation Clinical Advisory Boards: Avexis, Marinus, Neuren, Takeda, IRSF, LouLou Foundation, IFCR, LGS, GRIN2B, CureGRIN © Tim Benke, MD, Ph.D.
  3. 3. • Definition: • Unique constellation of developmentally regulated symptoms • Not described by “intellectual disability” and/or “autism spectrum disorder”. • A few examples • Rett syndrome & MECP2-related disorders • CDKL5 deficiency disorder • FOXG1 Syndrome • Dravet Syndrome • GRIN disorders Developmental (and Epileptic) Encephalopathy (DE-E) © Tim Benke, MD, Ph.D.
  4. 4. DEEs How do they get diagnosed? Pattern recognition This is a specific disorder (Rett) This is in a category of disorders (epilepsy, intellectual disability, autism) Genetic testing Specific gene (the MeCP2 gene gets sequenced) Gene panel (several genes, including MeCP2 get sequenced) Current: GRIN disorders not routinely recognized as a “pattern” Diagnosis via gene panel testing © Tim Benke, MD, Ph.D.
  5. 5. Sleep Where we are with GRIN disorders Epilepsy Language CVI Motor GI Behavior Respiratory Dysautonomia © Tim Benke, MD, Ph.D.
  6. 6. Hypothesis: if we know effect of mutation on GRIN function, we can make sense of this Epilepsy CVI LanguageMotor GI Behavior Respiratory Dysautonomia Sleep THERAPY© Tim Benke, MD, Ph.D.
  7. 7. GRIN disorders: what we know (1)• GRIN1 – 64 patients described across 25 studies. – Most • intellectual disability and epilepsy, many were non-verbal (50%) – Often • abnormal tone, movement disorders, cortical visual impairment, feeding difficulties, abnormal MRI brain scans. • Functional characterization of GRIN1 variants has generally not been performed and linked to clinical characteristics, nor have GRIN specific treatments been reported. • GRIN2A – 156 patients described and clinical features have been linked to functional characterization. – 90% have epilepsy and speech/language disorders and 60% have intellectual disability. – Often: Movement disorders and abnormal MRI brain scans. – More severe phenotypes were associated with gain-of-function changes; more extensive characterizations would likely be beneficial. – Few GRIN2A patients have been treated with GRIN-specific drugs with no clear benefit despite a previous report. © Tim Benke, MD, Ph.D.
  8. 8. GRIN disorders: what we know (2)• GRIN2B – 86 patients have been described; clinical features have not been fully linked to functional characterizations. – All: some degree of intellectual disability, developmental delays, and/or autism spectrum disorder – 50% have epilepsy. – Often: Abnormal tone, movement disorders, cortical visual impairment, abnormal MRI scans. – Few GRIN2B patients have been treated with GRIN-specific drugs. • GRIN2D – 13 patients have been described – All with epilepsy and developmental delays or intellectual disability; movement disorders were also noted – GRIN-specific drugs were tried for medically refractory epilepsy with benefit, consistent with functional studies where this may be true for some variants References 1.Pierson TM, Yuan H, Marsh ED, Fuentes-Fajardo K, Adams DR, Markello T, et al. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol. 2014;1(3):190-198. 2.Li D, Yuan H, Ortiz-Gonzalez XR, Marsh ED, Tian L, McCormick EM, et al. GRIN2D Recurrent De Novo Dominant Mutation Causes a Severe Epileptic Encephalopathy Treatable with NMDA Receptor Channel Blockers. Am J Hum Genet. 2016;99(4):802-816. 3.Platzer K, Lemke JR. GRIN1-Related Neurodevelopmental Disorder. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. GeneReviews((R)). Seattle (WA)1993. 4.Strehlow V, Heyne HO, Vlaskamp DRM, Marwick KFM, Rudolf G, de Bellescize J, et al. GRIN2A-related disorders: genotype and functional consequence predict phenotype. Brain. 2019;142(1):80-92. 5.Platzer K, Yuan H, Schutz H, Winschel A, Chen W, Hu C, et al. GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. J Med Genet. 2017;54(7):460-470. 6.Yu Y, Lin Y, Takasaki Y, Wang C, Kimura H, Xing J, et al. Rare loss of function mutations in N-methyl-D-aspartate glutamate receptors and their contributions to schizophrenia susceptibility. Transl Psychiatry. 2018;8(1):12. 7.Tsuchida N, Hamada K, Shiina M, Kato M, Kobayashi Y, Tohyama J, et al. GRIN2D variants in three cases of developmental and epileptic encephalopathy. Clin Genet. 2018;94(6):538-547. 8.XiangWei W, Kannan V, Xu Y, Kosobucki GJ, Schulien AJ, Kusumoto H, et al. Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy. Brain. 2019. © Tim Benke, MD, Ph.D.
  9. 9. GRIN “phenotyping”: Why make a patient registry? • As a parent: – What can I expect for the future? – What are best therapies? • As a scientist: – Can I predict the future based on your specific change in GRIN? – Can I predict the future based on the functional change of the GRIN? – Can I predict best therapies? © Tim Benke, MD, Ph.D.
  10. 10. GRIN “phenotyping”: Why make a patient registry? • As the FDA: – Is this a real disease with real symptoms? • ICD10/11 code needed – Is there an interested and organized Patient Advisory Group? – Is there natural history data? – Are there interested companies or scientists willing to pursue clinical trials? – New drugs versus new indications for old drugs © Tim Benke, MD, Ph.D.
  11. 11. GRIN features to categorize: • GRIN change • Developmental milestones • Epilepsy (not just seizure counts) • Vision • Movement disorders • Growth • Puberty • Medications • Therapies • Sleep • GI/Autonomic • Other illnesses and longevity © Tim Benke, MD, Ph.D.
  12. 12. Approach • Funding from CURE (Traynelis, PI) • Questionnaire to capture features: The GRIN Questionnaire (TGQ) • Approval from an Investigational Review Board – COMIRB 16-1520 – Issues: Patient safety, patient and data privacy and protection • Questionnaire into a database format • Find, consent, enroll, collect – Collect: patient/family fill out forms: The GRIN Questionnaire (TGQ) – Collect: provider/physician fill out forms – Collect: hybrid © Tim Benke, MD, Ph.D.
  13. 13. © Tim Benke, MD, Ph.D.
  14. 14. Results • 7SEP2019: – 41 completed questionnaires have been returned (GRIN1: 19, GRIN2A: 7, GRIN2B: 14, GRIN2D: 1) – 3 incomplete (or not returned) – 1 subject was removed from analysis (GRIN variant was not causative) – 10 are in the consenting process. – All patients with either DD, ID, and/or ASD – 42 functional GRIN analyses have been completed or are in process; subjects with deletions (GRIN2A: 1, GRIN2B: 2) or duplications (GRIN2A: 1, GRIN2D: 1) are not functionally analyzed – 8 GRIN-specific drug exposures were noted in 5 subjects (1 with an incomplete questionnaire); only one for medically refractory epilepsy • 3 “worse (1 with MR epilepsy)”, 2 “helpful”. • Further Analyses pending more enrollment • Goals: 200+ subjects – Gain of function vs loss of function – Use of GRIN-related medications © Tim Benke, MD, Ph.D.
  15. 15. DQ = sum: Handedness 0-3; Language 0-5; Motor 0-3. Max 11 © Tim Benke, MD, Ph.D.
  16. 16. © Tim Benke, MD, Ph.D.
  17. 17. Summary • The clinical features noted in prior studies have been captured. – Additional features should be added • Key limitations: reliance on parent completion of forms. • EEG and MRI reports are infrequently returned (~25%). • Our IRB has limited the number of times the coordinator can contact families to return this information. Few subjects have been appropriately exposed to GRIN-drugs; this exposure was not necessarily for medically refractory epilepsy. • Further Analyses pending more enrollment • Goals: 200+ subjects – Gain of function vs loss of function – Use of GRIN-related medications © Tim Benke, MD, Ph.D.
  18. 18. Challenges • How to get complete genetic reports? – Patient and parent reports needed • How to get families to agree to participate? • How to get families to return the forms? – We can only contact 3 times, per IRB – We can pull some data from records for you (EEG, MRI), send us those records © Tim Benke, MD, Ph.D.
  19. 19. Questions? • Special thanks to: – Patients, families – Jenifer Sargent • Jenifer.Sargent@childrenscolorado.org • Sign up! Return the forms! – Dr. Steve Traynelis, CFERV – CURE – GRIN2B – New partner: Dr Kristen Park, MD © Tim Benke, MD, Ph.D.

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