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

ATAD1-related encephalopathy is a novel monogenic disorder first reported in 2017. 1 Ahrens-Nicklas R.C. Umanah G.K. Sondheimer N. et al. Precision therapy for a new disorder of AMPA receptor recycling due to mutations in ATAD1. Neurol Genet. 2017; 3e130 Crossref Scopus (34) Google Scholar ATAD1 encodes a thorase involved in mitochondrial and peroxisome function that regulates postsynaptic alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate receptors (AMPAR). 2 Piard J. Umanah G.K.E. Harms F.L. et al. A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy. Brain. 2018; 141: 651-661 Crossref PubMed Scopus (54) 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 mutation. 2 Piard J. Umanah G.K.E. Harms F.L. et al. A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy. Brain. 2018; 141: 651-661 Crossref PubMed Scopus (54) Google Scholar ,3 Bunod R. Doummar D. Whalen S. et al. Congenital immobility and stiffness related to biallelic ATAD1 variants. Neurol Genet. 2020; 6: e520 Crossref Scopus (4) Google Scholar All but one family were consanguineous, and all patients had homozygous mutations. 3 Bunod R. Doummar D. Whalen S. et al. Congenital immobility and stiffness related to biallelic ATAD1 variants. Neurol Genet. 2020; 6: e520 Crossref Scopus (4) 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 R.C. Umanah G.K. Sondheimer N. et al. Precision therapy for a new disorder of AMPA receptor recycling due to mutations in ATAD1. Neurol Genet. 2017; 3e130 Crossref Scopus (34) Google Scholar , 2 Piard J. Umanah G.K.E. Harms F.L. et al. A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy. Brain. 2018; 141: 651-661 Crossref PubMed Scopus (54) Google Scholar , 3 Bunod R. Doummar D. Whalen S. et al. Congenital immobility and stiffness related to biallelic ATAD1 variants. Neurol Genet. 2020; 6: e520 Crossref Scopus (4) Google Scholar , 4 Wolf N.I. Zschocke J. Jakobs C. Rating D. Hoffmann G.F. ATAD1 encephalopathy and Stiff Baby syndrome: a recognizable clinical presentation. Brain. 2018; 141: e49 Crossref Scopus (7) Google Scholar Loss of ATAD1 disrupts internalization of postsynaptic AMPA receptors, which results in excessive glutamatergic signaling in the brain. 2 Piard J. Umanah G.K.E. Harms F.L. et al. A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy. Brain. 2018; 141: 651-661 Crossref PubMed Scopus (54) 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 R.C. Umanah G.K. Sondheimer N. et al. Precision therapy for a new disorder of AMPA receptor recycling due to mutations in ATAD1. Neurol Genet. 2017; 3e130 Crossref Scopus (34) Google Scholar Among prior cases, six of eight patients died of respiratory failure and/or cardiac sequelae of respiratory distress at a mean age of five months. 3 Bunod R. Doummar D. Whalen S. et al. Congenital immobility and stiffness related to biallelic ATAD1 variants. Neurol Genet. 2020; 6: e520 Crossref Scopus (4) Google Scholar This case highlights unsuccessful perampanel use in an infant with ATAD1-related encephalopathy.