Genetic diagnosis of basal ganglia disease in childhood
Por:
Baide-Mairena H, Marti-Sanchez L, Marcé-Grau A, Cazurro-Gutiérrez A, Sanchez-Montanez A, Delgado I, Moreno-Galdó A, Macaya-Ruiz A, García-Arumí E and Pérez-Dueñas B
Publicada:
1 jun 2022
Ahead of Print:
1 ene 2022
Resumen:
AIM To correlate clinical, radiological, and biochemical features with genetic findings in children with bilateral basal ganglia lesions of unknown aetiology, and propose a diagnostic algorithm for early recognition. METHOD Children with basal ganglia disease were recruited in a 2-year prospective multicentre study for clinical, biomarker, and genetic studies. Radiological pattern recognition was examined by hierarchical clustering analysis. RESULTS We identified 22 genetic conditions in 30 out of 62 paediatric patients (37 males, 25 females; mean age at onset 2y, SD 3; range 0-10y; mean age at assessment 11y, range 1-25y) through gene panels (n=11), whole-exome sequencing (n=13), and mitochondrial DNA (mtDNA) sequencing (n=6). Genetic aetiologies included mitochondrial diseases (57%), Aicardi-Goutieres syndrome (20%), and monogenic causes of dystonia and/or epilepsy (17%) mimicking Leigh syndrome. Radiological abnormalities included T2-hyperintense lesions (n=26) and lesions caused by calcium or manganese mineralization (n=9). Three clusters were identified: the pallidal, neostriatal, and striatal, plus the last including mtDNA defects in the oxidative phosphorylation system with prominent brain atrophy. Mitochondrial biomarkers showed poor sensitivity and specificity in children with mitochondrial disease, whereas interferon signature was observed in all patients with patients with Aicardi-Goutieres syndrome. INTERPRETATION Combined whole-exome and mtDNA sequencing allowed the identification of several genetic conditions affecting basal ganglia metabolism. We propose a diagnostic algorithm which prioritizes early use of next-generation sequencing on the basis of three clusters of basal ganglia lesions.
Filiaciones:
Baide-Mairena H:
Paediatric Neurology Research Group, Vall d´Hebron Research Institut, Universitat Autònoma de Barcelona, Barcelona, Spain
Department of Pediatrics, Granollers General Hospital, Granollers, Spain
Marti-Sanchez L:
Department of Biochemistry, Sant Joan de Déu Research Institut, Universitat de Barcelona, Barcelona, Spain
Marcé-Grau A:
Paediatric Neurology Research Group, Vall d´Hebron Research Institut, Universitat Autònoma de Barcelona, Barcelona, Spain
Cazurro-Gutiérrez A:
Paediatric Neurology Research Group, Vall d´Hebron Research Institut, Universitat Autònoma de Barcelona, Barcelona, Spain
Sanchez-Montanez A:
Department of Neuroradiology, Vall d'Hebron University Hospital, Barcelona, Spain
Delgado I:
Department of Neuroradiology, Vall d'Hebron University Hospital, Barcelona, Spain
Moreno-Galdó A:
Vall d'Hebron Research Institut (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
Department of Pediatrics, Vall d'Hebron Barcelona Hospital Campus Barcelona, Universitat Autònoma de Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
Macaya-Ruiz A:
Paediatric Neurology Research Group, Vall d´Hebron Research Institut, Universitat Autònoma de Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
Department of Paediatric Neurology, Vall d`Hebron University Hospital, Barcelona, Spain
García-Arumí E:
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
Research Group on Neuromuscular and Mitochondrial Disorders, Vall d'Hebron Research Institut (VHIR), Barcelona, Spain
Department of Clinical and Molecular Genetics, Vall d'Hebron University Hospital, Barcelona, Spain
Pérez-Dueñas B:
Paediatric Neurology Research Group, Vall d´Hebron Research Institut, Universitat Autònoma de Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
Department of Paediatric Neurology, Vall d`Hebron University Hospital, Barcelona, Spain
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