Neonatal Hypertonia and Progressive Respiratory Failure due to Novel Heterozygous Mutation in ATAD1

Abstract

ATAD1-related encephalopathy is a novel monogenic disorder first reported in 2017. 1 Ahrens-Nicklas Rebecca C. Umanah George K.E. Neal Sondheimer Deardorff Matthew A. Wilkens Alisha B. Conlin Laura K. Santani Avni B. et al. “Precision Therapy for a New Disorder of AMPA Receptor Recycling Due to Mutations in ATAD1.”. Neurology Genetics. February 1, 2017; 3https://doi.org/10.1212/NXG.0000000000000130 Crossref Scopus (30) Google Scholar ATAD1 encodes a thorase involved in mitochondrial and peroxisome function that regulates post-synaptic alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate receptors (AMPAR). 2 Piard Juliette Essien Umanah George K Harms Frederike L Abalde-Atristain Leire Daniel Amram Chang Melissa Chen Rong et al. “A Homozygous ATAD1 Mutation Impairs Postsynaptic AMPA Receptor Trafficking and Causes a Lethal Encephalopathy.”. Brain. March 1, 2018; 141 (61): 651https://doi.org/10.1093/brain/awx377 Crossref Scopus (52) Google Scholar There are eight confirmed cases of ATAD1-related encephalopathy in five families due to three loss of function and one gain of function mutations. 2 Piard Juliette Essien Umanah George K Harms Frederike L Abalde-Atristain Leire Daniel Amram Chang Melissa Chen Rong et al. “A Homozygous ATAD1 Mutation Impairs Postsynaptic AMPA Receptor Trafficking and Causes a Lethal Encephalopathy.”. Brain. March 1, 2018; 141 (61): 651https://doi.org/10.1093/brain/awx377 Crossref Scopus (52) Google Scholar ,3 Bunod Roxane Doummar Diane Whalen Sandra Keren Boris Chantot-Bastaraud Sandra Kim Maincent Marie-Charlotte Villy et al. “Congenital Immobility and Stiffness Related to Biallelic ATAD1 Variants.”. Neurology Genetics. December 1, 2020; 6https://doi.org/10.1212/NXG.0000000000000520 Crossref Scopus (1) Google Scholar All but one family were consanguineous and all patients had homozygous mutations. 3 Bunod Roxane Doummar Diane Whalen Sandra Keren Boris Chantot-Bastaraud Sandra Kim Maincent Marie-Charlotte Villy et al. “Congenital Immobility and Stiffness Related to Biallelic ATAD1 Variants.”. Neurology Genetics. December 1, 2020; 6https://doi.org/10.1212/NXG.0000000000000520 Crossref Scopus (1) Google Scholar The syndrome is characterized by progressive peripheral hypertonia with onset at birth, absent or near absent spontaneous movements, respiratory distress and other symptoms including tremor, clinical seizures, feeding difficulties, hernias, abnormal electroencephalogram (EEG), normal initial neuroimaging with varied abnormalities at later age, and abnormal brainstem auditory evoked response test. 1 Ahrens-Nicklas Rebecca C. Umanah George K.E. Neal Sondheimer Deardorff Matthew A. Wilkens Alisha B. Conlin Laura K. Santani Avni B. et al. “Precision Therapy for a New Disorder of AMPA Receptor Recycling Due to Mutations in ATAD1.”. Neurology Genetics. February 1, 2017; 3https://doi.org/10.1212/NXG.0000000000000130 Crossref Scopus (30) Google Scholar , 2 Piard Juliette Essien Umanah George K Harms Frederike L Abalde-Atristain Leire Daniel Amram Chang Melissa Chen Rong et al. “A Homozygous ATAD1 Mutation Impairs Postsynaptic AMPA Receptor Trafficking and Causes a Lethal Encephalopathy.”. Brain. March 1, 2018; 141 (61): 651https://doi.org/10.1093/brain/awx377 Crossref Scopus (52) Google Scholar , 3 Bunod Roxane Doummar Diane Whalen Sandra Keren Boris Chantot-Bastaraud Sandra Kim Maincent Marie-Charlotte Villy et al. “Congenital Immobility and Stiffness Related to Biallelic ATAD1 Variants.”. Neurology Genetics. December 1, 2020; 6https://doi.org/10.1212/NXG.0000000000000520 Crossref Scopus (1) Google Scholar , 4 Wolf Nicole I Zschocke Johannes Jakobs Cornelis Dietz Rating Hoffmann Georg F “ATAD1 Encephalopathy and Stiff Baby Syndrome: A Recognizable Clinical Presentation.”. Brain. June 1, 2018; 141: e49https://doi.org/10.1093/brain/awy095 Crossref Scopus (4) Google Scholar Loss of ATAD1 disrupts internalization of post-synaptic AMPA receptors, which result in excessive glutamatergic signaling in the brain. 2 Piard Juliette Essien Umanah George K Harms Frederike L Abalde-Atristain Leire Daniel Amram Chang Melissa Chen Rong et al. “A Homozygous ATAD1 Mutation Impairs Postsynaptic AMPA Receptor Trafficking and Causes a Lethal Encephalopathy.”. Brain. March 1, 2018; 141 (61): 651https://doi.org/10.1093/brain/awx377 Crossref Scopus (52) Google Scholar In the original report, Perampanel, an AMPAR antagonist, was trialed based on successful mouse data with improvement in patients’ hypertonicity and seizure resolution. 1 Ahrens-Nicklas Rebecca C. Umanah George K.E. Neal Sondheimer Deardorff Matthew A. Wilkens Alisha B. Conlin Laura K. Santani Avni B. et al. “Precision Therapy for a New Disorder of AMPA Receptor Recycling Due to Mutations in ATAD1.”. Neurology Genetics. February 1, 2017; 3https://doi.org/10.1212/NXG.0000000000000130 Crossref Scopus (30) Google Scholar Among prior cases, six of eight patients died of respiratory failure and/or cardiac sequalae of respiratory distress at a mean age of five months. 3 Bunod Roxane Doummar Diane Whalen Sandra Keren Boris Chantot-Bastaraud Sandra Kim Maincent Marie-Charlotte Villy et al. “Congenital Immobility and Stiffness Related to Biallelic ATAD1 Variants.”. Neurology Genetics. December 1, 2020; 6https://doi.org/10.1212/NXG.0000000000000520 Crossref Scopus (1) Google Scholar This case highlights unsuccessful Perampanel use in an infant with ATAD1-related encephalopathy.