Clustered mutations in the <i>GRIK2</i> kainate receptor subunit gene underlie diverse neurodevelopmental disorders

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G&gt;A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.</p

Clustered mutations in the <i>GRIK2</i> kainate receptor subunit gene underlie diverse neurodevelopmental disorders

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development

You Shake My Nerves and You Rattle My Brain

Bradykinesia; Dysphagia; Social withdrawal; Retropulsive gaitA 39-year old male with a progressive inability to perform daily activities, worsening falls and dysphagia presumed to be harbingers of early-onset Parkinson. Previous history significant for traumatic brain injury.Abnormal, intrusive eye movementMRIPositive anti-Ma2 antibodyHormonal antineoplastic agents; IV immunoglobulin1. Castle J, Sakonju A, Dalmau J, Newman-Toker DE, Anti-Ma2-associated encephalitis with normal FDG-PET: a case of pseudo-Whipple's disease, Nature Clinical Practice Neurology, 2 (10), 566-572, 2006. 2. Dalmau J, Graus F, Villargo A, Posner JB, Blumenthal D, Thiessen B, Sarz A, Meneses P, Rosenfeld M, Clinical analysis of anti-Ma 2 associated encephalitis, Brain, 127, 1831-1844, 2004. 3. Gerard A, Sarrot-Reynauld F, Liozon E, Cathebras P, Besson G, Robin C, Vignetto A, Monsnier J, Durieu I, Durand D, Rousset H, Neurologic presentation of Whipple disease: Report of 12 cases and review of the literature, Medicine, 81(6), 443-457, 2002. 4. Louis ED, Lynch T, Kaufman P, Fahn S, Odel J, Diagnostic guidelines in central nervous system Whipple's disease, Annals of Neurology, 40(4), 561-568, 1996. 5. Rosenfeld M, Eichen J, Wade D, Posner J, Dalmau J, Molecular and clinical diversity in paraneoplastic immunity to Ma proteins, Annals of Neurology, 50, 339-348, 2001

Pediatric fibrocartilaginous spine embolism induced by trauma

Fibrocartilaginous embolic infarction of the spinal cord is a rare cause of acute back pain and motor weakness. Most symptoms start after minor trauma that is often considered harmless and forgotten, however these minor injuries can result in lethal consequences. It is quite rare to diagnose fibrocartilaginous embolism in a timely manner and start treatment to prevent poor outcomes. We present the case of a previously healthy eight-year-old female with sudden onset neck pain and progressive bilateral upper extremity weakness following an injury while playing with her younger sister. Magnetic resonance imaging of the cervical spinal cord without contrast revealed a posterior disc protrusion suggestive of post-traumatic spinal cord infarction due to fibrocartilaginous embolism. In young, otherwise healthy, patients with acute motor deficits, radiographic imaging can help identify rare presentations like fibrocartilaginous embolism in order to rapidly diagnose and efficiently treat such patients

You Shake My Nerves and You Rattle My Brain; presentation video

Progressive inability to perform daily activities, worsening falls, and dysphagia.A 39-year-old man with a remote history of traumatic brain injury (TBI) and well-controlled seizures.Coordination was intact but bradykinetic.Solumedrol, IVIG, CeftriaxoneCastle J, Sakonju A, Dalmau J, Newman-Toker DE, Anti-Ma2-associated encephalitis with normal FDG-PET: a case of pseudo-Whipple's disease, Nature Clinical Practice Neurology, 2 (10), 566-572, 2006. Dalmau J, Graus F, Villargo A, Posner JB, Blumenthal D, Thiessen B, Sarz A, Meneses P, Rosenfeld M, Clinical analysis of anti-Ma 2 associated encephalitis, Brain, 127, 1831-1844, 2004. Gerard A, Sarrot-Reynauld F, Liozon E, Cathebras P, Besson G, Robin C, Vignetto A, Monsnier J, Durieu I, Durand D, Rousset H, Neurologic presentation of Whipple disease: Report of 12 cases and review of the literature, Medicine, 81(6), 443-457, 2002. Louis ED, Lynch T, Kaufman P, Fahn S, Odel J, Diagnostic guidelines in central nervous system Whipple's disease, Annals of Neurology, 40(4), 561-568, 1996. Rosenfeld M, Eichen J, Wade D, Posner J, Dalmau J, Molecular and clinical diversity in paraneoplastic immunity to Ma proteins, Annals of Neurology, 50, 339-348, 2001

You Shake My Nerves and You Rattle My Brain; powerpoint

Progressive inability to perform daily activities, worsening falls, and dysphagia.A 39-year-old man with a remote history of traumatic brain injury (TBI) and well-controlled seizures.Coordination was intact but bradykinetic.Solumedrol, IVIG, CeftriaxoneCastle J, Sakonju A, Dalmau J, Newman-Toker DE, Anti-Ma2-associated encephalitis with normal FDG-PET: a case of pseudo-Whipple's disease, Nature Clinical Practice Neurology, 2 (10), 566-572, 2006. Dalmau J, Graus F, Villargo A, Posner JB, Blumenthal D, Thiessen B, Sarz A, Meneses P, Rosenfeld M, Clinical analysis of anti-Ma 2 associated encephalitis, Brain, 127, 1831-1844, 2004. Gerard A, Sarrot-Reynauld F, Liozon E, Cathebras P, Besson G, Robin C, Vignetto A, Monsnier J, Durieu I, Durand D, Rousset H, Neurologic presentation of Whipple disease: Report of 12 cases and review of the literature, Medicine, 81(6), 443-457, 2002. Louis ED, Lynch T, Kaufman P, Fahn S, Odel J, Diagnostic guidelines in central nervous system Whipple's disease, Annals of Neurology, 40(4), 561-568, 1996. Rosenfeld M, Eichen J, Wade D, Posner J, Dalmau J, Molecular and clinical diversity in paraneoplastic immunity to Ma proteins, Annals of Neurology, 50, 339-348, 2001

Recruitment &amp; retention program for the NeuroNEXT SMA Biomarker Study: Super Babies for SMA!

BACKGROUND/AIMS: Recruitment and retention of research participants are challenging and critical components of successful clinical trials and natural history studies. Infants with spinal muscular atrophy (SMA) have been a particularly challenging population to study due to their fragile and complex medical issues, poor prognosis and, until 2016, a lack of effective therapies. Recruitment of healthy infants into clinical trials and natural history studies is also challenging and sometimes assumed to not be feasible. METHODS: In 2011, our group initiated a two-year, longitudinal natural history study of infants with SMA and healthy infant controls to provide data to assist in the analysis and interpretation of planned clinical trials in infants with SMA. The recruitment goal was to enroll 27 infants less than 6 months of age with SMA and 27 age-matched healthy infants within the two-year enrollment period. A detailed recruitment and retention plan was developed for this purpose. In addition, a survey was administered to participant families to understand the determinants of participation in the study. RESULTS: All healthy infants were recruited within the studys first year and 26 SMA infants were recruited within the two-year recruitment period. Thirty-eight participant families responded to the recruitment determinants survey. Nearly half of respondents (18/38, 48%) reported that they first heard of the study from their physician or neurologist. The most common reason to decide to enroll their infant (22/38, 58%) and to remain in the study (28/38, 74%) was their understanding of the importance of the study. Thematic recruitment tools such as a study brochure, video on social media, and presentations at advocacy meetings were reported to positively influence the decision to enroll. CONCLUSIONS: A proactive, thematic and inclusive recruitment and retention plan that effectively communicates the rationale of a clinical study and partners with patients, advocacy groups and the local communities can effectively recruit participants in vulnerable populations. Recommendations for the proactive integration of recruitment and retention plans into clinical trial protocol development are provided

CLINICAL TRIAL OF L-CARNITINE AND VALPROIC ACID IN SPINAL MUSCULAR ATROPHY TYPE I

Introduction: The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). Methods: Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/> 16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude. Results: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. Discussion: This trial provides evidence that, in infants with SMA type I, L-carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I