Congenital Immobility and Stiffness Due to ATAD1 Biallelic Mutations: Report of Two Novel Unrelated Patients

Objectives: To describe the congenital encephalopathy related to the ATAD1 gene.

Background: The ATAD1 gene encodes for thorase, a protein that regulates the expression of postsynaptic excitatory glutamatergic AMPA receptors. Six patients from three families with biallelic mutations in ATAD1 have been reported to date. All had a congenital encephalopathy characterized by global hypertonia, poor or absent motility, feeding and breathing difficulties, poor eye contact, and limited responsiveness to stimuli. Four of them died in the 1st month of life.

Methods: We report on two novel patients with this congenital immobility and stiffness ATAD1-related (CISAR) syndrome. Patient no. 1 needed intensive cares from birth because of severe stiffness with axial hypotonia, immobility with inexpressive facies, limited responsiveness to stimuli, inability to feed up, and tenuous breathing. He had epileptic seizures at 5 months and died at 6 months. Whole-exome sequencing (WES) revealed the novel homozygous p. (Gly128Val) variant in ATAD1. Patient no. 2 had a similar disease course, except that he had no epilepsy. He died at 4 months of cardiorespiratory failure. We found by WES the previously reported p. (His357Argfs*15) ATAD1 homozygous variant in this patient’s DNA. Both patients had null auditory evoked potentials.

Conclusion: The phenotype of both patients was close to that of published patients, extremely severe from birth (see videos) to their early demise. We confirm absent auditory evoked responses in CISAR which is likely related to the role of AMPA receptor in auditory signals processing. The diagnosis of CISAR should be taken into consideration in newborns with extreme stiffness, along with BRAT1-related encephalopathy.

No conflict of interest has been declared by the author(s).