Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene.

Laura Marti-Sanchez, Heidy Baide-Mairena, Anna Marcé-Grau, Roser Pons, Anastasia Skouma, Eduardo López-Laso, Maria Sigatullina, Cristiano Rizzo, Michela Semeraro, Diego Martinelli, Rosalba Carrozzo, Carlo Dionisi-Vici, Luis González-Gutiérrez-Solana, Marta Correa-Vela, Juan Dario Ortigoza-Escobar, Ángel Sánchez-Montañez, Élida Vazquez, Ignacio Delgado, Sergio Aguilera-Albesa, María Eugenia Yoldi, Antonia Ribes, Frederic Tort, Luca Pollini, Serena Galosi, Vincenzo Leuzzi, Manuela Tolve, Laura Pérez-Gay, Luis Aldamiz-Echevarría, Mireia Del Toro, Antonio Arranz, Filip Roelens, Roser Urreizti, Rafael Artuch, Alfons Macaya, Belén Pérez-Dueñas

Journal: Journal of inherited metabolic disease 2021;44(2):401-414

PMID: 32677093

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Abstract

The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11; HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management.

Address: Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.; Universitat de Barcelona, Barcelona, Spain.; Pediatric Neurology Research Group, Hospital Vall d'Hebrón, Barcelona, Spain.; Universitat Autònoma de Barcelona, Barcelona, Spain.; Department of Paediatrics, Hospital General de Granollers, Granollers, Spain.; Pediatric Neurology Research Group, Hospital Vall d'Hebrón, Barcelona, Spain.; Department of Paediatric Neurology, Hospital Agia Sofia, Athens, Greece.; Institute of Child Health, Agia Sofia Children's Hospital, Athens, Greece.; Unit of Paediatric Neurology, Department of Pediatrics, University Hospital Reina Sofía, Córdoba, Spain.; Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain.; CIBERER-ISCIII, Centro de Investigaciones Biomédicas en Red de Enfermedades Raras, Madrid, Spain.; Division of Metabolism, Bambino Gesù Children's Hospital, Rome, Italy.; CIBERER-ISCIII, Centro de Investigaciones Biomédicas en Red de Enfermedades Raras, Madrid, Spain.; Department of Pediatric Neurology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.; Pediatric Neurology Research Group, Hospital Vall d'Hebrón, Barcelona, Spain.; Universitat Autònoma de Barcelona, Barcelona, Spain.; Department of Paediatric Neurology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.; Department of Neuroradiology, Hospital Vall d'Hebron - Institut de Recerca (VHIR), Barcelona, Spain.; Unit of Paediatric Neurology, Department of Pediatrics, Complejo Hospitalario de Navarra, Navarrabiomed, Pamplona, Spain.; CIBERER-ISCIII, Centro de Investigaciones Biomédicas en Red de Enfermedades Raras, Madrid, Spain.; Secció d'Errors Congènits del Metabolisme -IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain.; Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.; Department of Experimental Medicine, Sapienza University, Rome, Italy.; Unit of Paediatric Neurology, Hospital Universitario Lucus Augusti, Lugo, Spain.; Department of Pediatric Metabolism, University Cruces Hospital, Barakaldo, Spain.; Pediatric Neurology, AZ Delta, Roeselare, Belgium.; Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.; CIBERER-ISCIII, Centro de Investigaciones Biomédicas en Red de Enfermedades Raras, Madrid, Spain.; Pediatric Neurology Research Group, Hospital Vall d'Hebrón, Barcelona, Spain.; Universitat Autònoma de Barcelona, Barcelona, Spain.; CIBERER-ISCIII, Centro de Investigaciones Biomédicas en Red de Enfermedades Raras, Madrid, Spain.

DOI: 10.1002/jimd.12288

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MeSH Terms: Abnormalities, Multiple, Amino Acid Metabolism, Inborn Errors, Brain, Child, Preschool, Dystonia, Enoyl-CoA Hydratase, Female, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, Infant, Internationality, Leigh Disease, Magnetic Resonance Imaging, Male, Metabolic Networks and Pathways, Mutation, Phenotype, Survival Rate, Thiolester Hydrolases, Valine