Precision therapy for a new disorder of AMPA receptor recycling due to mutations inATAD1.
OBJECTIVE
ATAD1encodes Thorase, a mediator of α-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptor recycling; in this work, we characterized the phenotype resulting fromATAD1mutations and developed a targeted therapy in both mice and humans.


METHODS
Using exome sequencing, we identified a novelATAD1mutation (p.E276X) as the etiology of a devastating neurologic disorder characterized by hypertonia, seizures, and death in a consanguineous family. We postulated that pathogenesis was a result of excessive AMPA receptor activity and designed a targeted therapeutic approach using perampanel, an AMPA-receptor antagonist.


RESULTS
Perampanel therapy inATAD1knockout mice reversed behavioral defects, normalized brain MRI abnormalities, prevented seizures, and prolonged survival. TheATAD1patients treated with perampanel showed improvement in hypertonicity and resolution of seizures.


CONCLUSIONS
This work demonstrates that identification of novel monogenic neurologic disorders and observation of response to targeted therapeutics can provide important insights into human nervous system functioning.
Section of Biochemical Genetics (R.C.A.-N., N.S.), Division of Human Genetics (R.C.A.-N., M.A.D., A.B.W.), Department of Pathology and Laboratory Medicine (L.K.C., A.B.S., A.N.), Division of Child Neurology (E.D.M.), Children's Hospital of Philadelphia, PA; Department of Pediatrics (R.C.A.-N., N.S., M.A.D., E.D.M.) and Department of Neurology (E.D.M.), Perelman School of Medicine, and Department of Clinical Pathology (L.K.C., A.B.S.), University of Pennsylvania, Philadelphia; GeneDx (J.J.), Gaithersburg, MD; Neuroregeneration and Stem Cell Programs (G.K.E.U., T.M.D., V.L.D.), Institute for Cell Engineering; Departments of Neurology (G.K.E.U., T.M.D.), Solomon H. Snyder Department of Neuroscience (T.M.D., V.L.D.), Pharmacology and Molecular Sciences (T.M.D., V.L.D.), Physiology (V.L.D.), and Public Health (E.M.), Johns Hopkins University, Baltimore, MD.
Rebecca C
RC
Ahrens-Nicklas
Section of Biochemical Genetics (R.C.A.-N., N.S.), Division of Human Genetics (R.C.A.-N., M.A.D., A.B.W.), Department of Pathology and Laboratory Medicine (L.K.C., A.B.S., A.N.), Division of Child Neurology (E.D.M.), Children's Hospital of Philadelphia, PA; Department of Pediatrics (R.C.A.-N., N.S., M.A.D., E.D.M.) and Department of Neurology (E.D.M.), Perelman School of Medicine, and Department of Clinical Pathology (L.K.C., A.B.S.), University of Pennsylvania, Philadelphia; GeneDx (J.J.), Gaithersburg, MD; Neuroregeneration and Stem Cell Programs (G.K.E.U., T.M.D., V.L.D.), Institute for Cell Engineering; Departments of Neurology (G.K.E.U., T.M.D.), Solomon H. Snyder Department of Neuroscience (T.M.D., V.L.D.), Pharmacology and Molecular Sciences (T.M.D., V.L.D.), Physiology (V.L.D.), and Public Health (E.M.), Johns Hopkins University, Baltimore, MD.
George K E
GK
Umanah
Section of Biochemical Genetics (R.C.A.-N., N.S.), Division of Human Genetics (R.C.A.-N., M.A.D., A.B.W.), Department of Pathology and Laboratory Medicine (L.K.C., A.B.S., A.N.), Division of Child Neurology (E.D.M.), Children's Hospital of Philadelphia, PA; Department of Pediatrics (R.C.A.-N., N.S., M.A.D., E.D.M.) and Department of Neurology (E.D.M.), Perelman School of Medicine, and Department of Clinical Pathology (L.K.C., A.B.S.), University of Pennsylvania, Philadelphia; GeneDx (J.J.), Gaithersburg, MD; Neuroregeneration and Stem Cell Programs (G.K.E.U., T.M.D., V.L.D.), Institute for Cell Engineering; Departments of Neurology (G.K.E.U., T.M.D.), Solomon H. Snyder Department of Neuroscience (T.M.D., V.L.D.), Pharmacology and Molecular Sciences (T.M.D., V.L.D.), Physiology (V.L.D.), and Public Health (E.M.), Johns Hopkins University, Baltimore, MD.
Neal
N
Sondheimer
Section of Biochemical Genetics (R.C.A.-N., N.S.), Division of Human Genetics (R.C.A.-N., M.A.D., A.B.W.), Department of Pathology and Laboratory Medicine (L.K.C., A.B.S., A.N.), Division of Child Neurology (E.D.M.), Children's Hospital of Philadelphia, PA; Department of Pediatrics (R.C.A.-N., N.S., M.A.D., E.D.M.) and Department of Neurology (E.D.M.), Perelman School of Medicine, and Department of Clinical Pathology (L.K.C., A.B.S.), University of Pennsylvania, Philadelphia; GeneDx (J.J.), Gaithersburg, MD; Neuroregeneration and Stem Cell Programs (G.K.E.U., T.M.D., V.L.D.), Institute for Cell Engineering; Departments of Neurology (G.K.E.U., T.M.D.), Solomon H. Snyder Department of Neuroscience (T.M.D., V.L.D.), Pharmacology and Molecular Sciences (T.M.D., V.L.D.), Physiology (V.L.D.), and Public Health (E.M.), Johns Hopkins University, Baltimore, MD.
Matthew A
MA
Deardorff
Section of Biochemical Genetics (R.C.A.-N., N.S.), Division of Human Genetics (R.C.A.-N., M.A.D., A.B.W.), Department of Pathology and Laboratory Medicine (L.K.C., A.B.S., A.N.), Division of Child Neurology (E.D.M.), Children's Hospital of Philadelphia, PA; Department of Pediatrics (R.C.A.-N., N.S., M.A.D., E.D.M.) and Department of Neurology (E.D.M.), Perelman School of Medicine, and Department of Clinical Pathology (L.K.C., A.B.S.), University of Pennsylvania, Philadelphia; GeneDx (J.J.), Gaithersburg, MD; Neuroregeneration and Stem Cell Programs (G.K.E.U., T.M.D., V.L.D.), Institute for Cell Engineering; Departments of Neurology (G.K.E.U., T.M.D.), Solomon H. Snyder Department of Neuroscience (T.M.D., V.L.D.), Pharmacology and Molecular Sciences (T.M.D., V.L.D.), Physiology (V.L.D.), and Public Health (E.M.), Johns Hopkins University, Baltimore, MD.
Alisha B
AB
Wilkens
Section of Biochemical Genetics (R.C.A.-N., N.S.), Division of Human Genetics (R.C.A.-N., M.A.D., A.B.W.), Department of Pathology and Laboratory Medicine (L.K.C., A.B.S., A.N.), Division of Child Neurology (E.D.M.), Children's Hospital of Philadelphia, PA; Department of Pediatrics (R.C.A.-N., N.S., M.A.D., E.D.M.) and Department of Neurology (E.D.M.), Perelman School of Medicine, and Department of Clinical Pathology (L.K.C., A.B.S.), University of Pennsylvania, Philadelphia; GeneDx (J.J.), Gaithersburg, MD; Neuroregeneration and Stem Cell Programs (G.K.E.U., T.M.D., V.L.D.), Institute for Cell Engineering; Departments of Neurology (G.K.E.U., T.M.D.), Solomon H. Snyder Department of Neuroscience (T.M.D., V.L.D.), Pharmacology and Molecular Sciences (T.M.D., V.L.D.), Physiology (V.L.D.), and Public Health (E.M.), Johns Hopkins University, Baltimore, MD.
Laura K
LK
Conlin
Section of Biochemical Genetics (R.C.A.-N., N.S.), Division of Human Genetics (R.C.A.-N., M.A.D., A.B.W.), Department of Pathology and Laboratory Medicine (L.K.C., A.B.S., A.N.), Division of Child Neurology (E.D.M.), Children's Hospital of Philadelphia, PA; Department of Pediatrics (R.C.A.-N., N.S., M.A.D., E.D.M.) and Department of Neurology (E.D.M.), Perelman School of Medicine, and Department of Clinical Pathology (L.K.C., A.B.S.), University of Pennsylvania, Philadelphia; GeneDx (J.J.), Gaithersburg, MD; Neuroregeneration and Stem Cell Programs (G.K.E.U., T.M.D., V.L.D.), Institute for Cell Engineering; Departments of Neurology (G.K.E.U., T.M.D.), Solomon H. Snyder Department of Neuroscience (T.M.D., V.L.D.), Pharmacology and Molecular Sciences (T.M.D., V.L.D.), Physiology (V.L.D.), and Public Health (E.M.), Johns Hopkins University, Baltimore, MD.
Avni B
AB
Santani
Section of Biochemical Genetics (R.C.A.-N., N.S.), Division of Human Genetics (R.C.A.-N., M.A.D., A.B.W.), Department of Pathology and Laboratory Medicine (L.K.C., A.B.S., A.N.), Division of Child Neurology (E.D.M.), Children's Hospital of Philadelphia, PA; Department of Pediatrics (R.C.A.-N., N.S., M.A.D., E.D.M.) and Department of Neurology (E.D.M.), Perelman School of Medicine, and Department of Clinical Pathology (L.K.C., A.B.S.), University of Pennsylvania, Philadelphia; GeneDx (J.J.), Gaithersburg, MD; Neuroregeneration and Stem Cell Programs (G.K.E.U., T.M.D., V.L.D.), Institute for Cell Engineering; Departments of Neurology (G.K.E.U., T.M.D.), Solomon H. Snyder Department of Neuroscience (T.M.D., V.L.D.), Pharmacology and Molecular Sciences (T.M.D., V.L.D.), Physiology (V.L.D.), and Public Health (E.M.), Johns Hopkins University, Baltimore, MD.
Addie
A
Nesbitt
Section of Biochemical Genetics (R.C.A.-N., N.S.), Division of Human Genetics (R.C.A.-N., M.A.D., A.B.W.), Department of Pathology and Laboratory Medicine (L.K.C., A.B.S., A.N.), Division of Child Neurology (E.D.M.), Children's Hospital of Philadelphia, PA; Department of Pediatrics (R.C.A.-N., N.S., M.A.D., E.D.M.) and Department of Neurology (E.D.M.), Perelman School of Medicine, and Department of Clinical Pathology (L.K.C., A.B.S.), University of Pennsylvania, Philadelphia; GeneDx (J.J.), Gaithersburg, MD; Neuroregeneration and Stem Cell Programs (G.K.E.U., T.M.D., V.L.D.), Institute for Cell Engineering; Departments of Neurology (G.K.E.U., T.M.D.), Solomon H. Snyder Department of Neuroscience (T.M.D., V.L.D.), Pharmacology and Molecular Sciences (T.M.D., V.L.D.), Physiology (V.L.D.), and Public Health (E.M.), Johns Hopkins University, Baltimore, MD.
Jane
J
Juulsola
Section of Biochemical Genetics (R.C.A.-N., N.S.), Division of Human Genetics (R.C.A.-N., M.A.D., A.B.W.), Department of Pathology and Laboratory Medicine (L.K.C., A.B.S., A.N.), Division of Child Neurology (E.D.M.), Children's Hospital of Philadelphia, PA; Department of Pediatrics (R.C.A.-N., N.S., M.A.D., E.D.M.) and Department of Neurology (E.D.M.), Perelman School of Medicine, and Department of Clinical Pathology (L.K.C., A.B.S.), University of Pennsylvania, Philadelphia; GeneDx (J.J.), Gaithersburg, MD; Neuroregeneration and Stem Cell Programs (G.K.E.U., T.M.D., V.L.D.), Institute for Cell Engineering; Departments of Neurology (G.K.E.U., T.M.D.), Solomon H. Snyder Department of Neuroscience (T.M.D., V.L.D.), Pharmacology and Molecular Sciences (T.M.D., V.L.D.), Physiology (V.L.D.), and Public Health (E.M.), Johns Hopkins University, Baltimore, MD.
Erica
E
Ma
Section of Biochemical Genetics (R.C.A.-N., N.S.), Division of Human Genetics (R.C.A.-N., M.A.D., A.B.W.), Department of Pathology and Laboratory Medicine (L.K.C., A.B.S., A.N.), Division of Child Neurology (E.D.M.), Children's Hospital of Philadelphia, PA; Department of Pediatrics (R.C.A.-N., N.S., M.A.D., E.D.M.) and Department of Neurology (E.D.M.), Perelman School of Medicine, and Department of Clinical Pathology (L.K.C., A.B.S.), University of Pennsylvania, Philadelphia; GeneDx (J.J.), Gaithersburg, MD; Neuroregeneration and Stem Cell Programs (G.K.E.U., T.M.D., V.L.D.), Institute for Cell Engineering; Departments of Neurology (G.K.E.U., T.M.D.), Solomon H. Snyder Department of Neuroscience (T.M.D., V.L.D.), Pharmacology and Molecular Sciences (T.M.D., V.L.D.), Physiology (V.L.D.), and Public Health (E.M.), Johns Hopkins University, Baltimore, MD.
Ted M
TM
Dawson
Section of Biochemical Genetics (R.C.A.-N., N.S.), Division of Human Genetics (R.C.A.-N., M.A.D., A.B.W.), Department of Pathology and Laboratory Medicine (L.K.C., A.B.S., A.N.), Division of Child Neurology (E.D.M.), Children's Hospital of Philadelphia, PA; Department of Pediatrics (R.C.A.-N., N.S., M.A.D., E.D.M.) and Department of Neurology (E.D.M.), Perelman School of Medicine, and Department of Clinical Pathology (L.K.C., A.B.S.), University of Pennsylvania, Philadelphia; GeneDx (J.J.), Gaithersburg, MD; Neuroregeneration and Stem Cell Programs (G.K.E.U., T.M.D., V.L.D.), Institute for Cell Engineering; Departments of Neurology (G.K.E.U., T.M.D.), Solomon H. Snyder Department of Neuroscience (T.M.D., V.L.D.), Pharmacology and Molecular Sciences (T.M.D., V.L.D.), Physiology (V.L.D.), and Public Health (E.M.), Johns Hopkins University, Baltimore, MD.
Valina L
VL
Dawson
Section of Biochemical Genetics (R.C.A.-N., N.S.), Division of Human Genetics (R.C.A.-N., M.A.D., A.B.W.), Department of Pathology and Laboratory Medicine (L.K.C., A.B.S., A.N.), Division of Child Neurology (E.D.M.), Children's Hospital of Philadelphia, PA; Department of Pediatrics (R.C.A.-N., N.S., M.A.D., E.D.M.) and Department of Neurology (E.D.M.), Perelman School of Medicine, and Department of Clinical Pathology (L.K.C., A.B.S.), University of Pennsylvania, Philadelphia; GeneDx (J.J.), Gaithersburg, MD; Neuroregeneration and Stem Cell Programs (G.K.E.U., T.M.D., V.L.D.), Institute for Cell Engineering; Departments of Neurology (G.K.E.U., T.M.D.), Solomon H. Snyder Department of Neuroscience (T.M.D., V.L.D.), Pharmacology and Molecular Sciences (T.M.D., V.L.D.), Physiology (V.L.D.), and Public Health (E.M.), Johns Hopkins University, Baltimore, MD.
Eric D
ED
Marsh