Charles-Joris Roux1, Giulia Barcia2, Manuel Schiff3, Marie Sissler4, Raphaël Levy5, Volodia Dangouloff-Ros5, Isabelle Desguerre6, Shimon Edvardson7, Orli Elpeleg7, Agnès Rötig8, Arnold Munnich9, Nathalie Boddaert10. 1. Department of Paediatric Radiology, Hôpital Necker-Enfants Malades, Paris, France. Electronic address: charles-joris.roux@aphp.fr. 2. Department of Genetics, Hospital Necker-Enfants Malades, Paris, France. 3. Institut Imagine, INSERM UMR 1163, Paris, France; Necker Hospital, APHP, Reference Center for Inborn Error of Metabolism, Pediatrics Department, University of Paris, Paris, France. 4. Institut Européen de Chimie et Biologie, INSERM U1212, CNRS UMR 5320, University of Bordeaux, Pessac, France. 5. Department of Paediatric Radiology, Hôpital Necker-Enfants Malades, Paris, France. 6. Department of Neurology and Metabolism, Hôpital Necker-Enfants Malades, Paris, France. 7. Department of Genetics, Hadassah University Hospital, Jerusalem, Israel. 8. Institut Imagine, INSERM UMR 1163, Paris, France. 9. Department of Genetics, Hospital Necker-Enfants Malades, Paris, France; Institut Imagine, INSERM UMR 1163, Paris, France. 10. Department of Paediatric Radiology, Hôpital Necker-Enfants Malades, Paris, France; Institut Imagine, INSERM UMR 1163, Paris, France.
Abstract
BACKGROUND AND PURPOSE: Mitochondrial aminoacyl-tRNA synthetases-encoded by ARS2 genes-are evolutionarily conserved enzymes that catalyse the attachment of amino acids to their cognate tRNAs, ensuring the accuracy of the mitochondrial translation process. ARS2 gene mutations are associated with a wide range of clinical presentations affecting the CNS. METHODS: Two senior neuroradiologists analysed brain MRI of 25 patients (age range: 3 d-25 yrs.; 11 males; 14 females) with biallelic pathogenic variants of 11 ARS2 genes in a retrospective study conducted between 2002 and 2019. RESULTS: Though several combinations of brain MRI anomalies were highly suggestive of specific aetiologies (DARS2, EARS2, AARS2 and RARS2 mutations), our study detected no MRI pattern common to all patients. Stroke-like lesions were associated with pathogenic SARS2 and FARS2 variants. We also report early onset cerebellar atrophy and calcifications in AARS2 mutations, early white matter involvement in RARS2 mutations, and absent involvement of thalami in EARS2 mutations. Finally, our findings show that normal brain MRI results do not exclude the presence of ARS2 mutations: 5 patients with normal MRI images were carriers of pathogenic IARS2, YARS2, and FARS2 variants. CONCLUSION: Our study extends the spectrum of brain MRI anomalies associated with pathogenic ARS2 variants and suggests ARS2 mutations are largely underdiagnosed.
BACKGROUND AND PURPOSE: Mitochondrial aminoacyl-tRNA synthetases-encoded by ARS2 genes-are evolutionarily conserved enzymes that catalyse the attachment of amino acids to their cognate tRNAs, ensuring the accuracy of the mitochondrial translation process. ARS2 gene mutations are associated with a wide range of clinical presentations affecting the CNS. METHODS: Two senior neuroradiologists analysed brain MRI of 25 patients (age range: 3 d-25 yrs.; 11 males; 14 females) with biallelic pathogenic variants of 11 ARS2 genes in a retrospective study conducted between 2002 and 2019. RESULTS: Though several combinations of brain MRI anomalies were highly suggestive of specific aetiologies (DARS2, EARS2, AARS2 and RARS2 mutations), our study detected no MRI pattern common to all patients. Stroke-like lesions were associated with pathogenic SARS2 and FARS2 variants. We also report early onset cerebellar atrophy and calcifications in AARS2 mutations, early white matter involvement in RARS2 mutations, and absent involvement of thalami in EARS2 mutations. Finally, our findings show that normal brain MRI results do not exclude the presence of ARS2 mutations: 5 patients with normal MRI images were carriers of pathogenic IARS2, YARS2, and FARS2 variants. CONCLUSION: Our study extends the spectrum of brain MRI anomalies associated with pathogenic ARS2 variants and suggests ARS2 mutations are largely underdiagnosed.
Authors: Guillem de Valles-Ibáñez; Michael S Hildebrand; Melanie Bahlo; Chontelle King; Matthew Coleman; Timothy E Green; John Goldsmith; Suzanne Davis; Deepak Gill; Simone Mandelstam; Ingrid E Scheffer; Lynette G Sadleir Journal: Epilepsia Open Date: 2021-11-18