Copper Toxicity Associated With an ATP7A-Related Complex Phenotype
Por:
Natera-de Benito D, Sola A, Sousa PR, Boronat S, Exposito-Escudero JM, Carrera-García L, Ortez-Gonzalez CI, Jou-Munoz C, Muchart-Lopez J, Rebollo M, Armstrong-Moron J, Colomer J, Garcia-Cazorla A, Hoenicka J, Palau F and Nascimento-Osorio A
Publicada:
1 jun 2021
Ahead of Print:
1 abr 2021
Resumen:
Background: The ATP7A gene encodes a copper transporter whose mutations cause Menkes disease, occipital horn syndrome (OHS), and, less frequently, ATP7A-related distal hereditary motor neuropathy (dHMN). Here we describe a family with OHS caused by a novel mutation in the ATP7A gene, including a patient with a comorbid dHMN that worsened markedly after being treated with copper histidinate.
Methods: We studied in detail the clinical features of the patients and performed a genomic analysis by using TruSight One Expanded Sequencing Panel. Subsequently, we determined the ATP7A and ATP7B expression levels, mitochondrial membrane potential, and redox balance in cultured fibroblasts of Patient 1.
Results: We found a novel ATP7A late truncated mutation p.Lys1412AsnfsX15 in the two affected members of this family. The co-occurrence of OHS and dHMN in Patient 1 reveals the variable phenotypic expressivity of the variant. A severe clinical and neurophysiologic worsening was observed in the dHMN of Patient 1 when he was treated with copper replacement therapy, with a subsequent fast recovery after the copper histidinate was withdrawn. Functional studies revealed that the patient had low levels of both ATP7A and ATP7B, the other copper transporter, and high levels of superoxide ion in the mitochondria.
Conclusions: Our findings broaden the clinical spectrum of ATP7A-related disorders and demonstrate that two clinical phenotypes can occur in the same patient. The copper-induced toxicity and low levels of both ATP7A and ATP7B in our patient suggest that copper accumulation in motor neurons is the path-ogenic mechanism in ATP7A-related dHMN. (c) 2021 Elsevier Inc. All rights reserved.
Filiaciones:
Natera-de Benito D:
Neuromuscular Unit, Department of Pediatric Neurology, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain
:
Laboratory of Neurogenetics and Molecular Medicine - IPER, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Sousa PR:
Neuromuscular Unit, Department of Pediatric Neurology, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Pediatric Neurology Unit, Department of Pediatrics, Hospital Central do Funchal, Funchal, Portugal
Boronat S:
Department of Pediatrics, Hospital Santa Creu i Sant Pau, Barcelona, Spain
Exposito-Escudero JM:
Neuromuscular Unit, Department of Pediatric Neurology, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Carrera-García L:
Neuromuscular Unit, Department of Pediatric Neurology, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Ortez-Gonzalez CI:
Neuromuscular Unit, Department of Pediatric Neurology, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Jou-Munoz C:
Neuromuscular Unit, Department of Pediatric Neurology, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Department of Pathology, Hospital Sant Joan de Déu, Barcelona, Spain
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
Muchart-Lopez J:
Department of Radiology, Hospital Sant Joan de Déu, Barcelona, Spain
Rebollo M:
Department of Radiology, Hospital Sant Joan de Déu, Barcelona, Spain
Armstrong-Moron J:
Neuromuscular Unit, Department of Pediatric Neurology, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
Department of Genetic and Molecular Medicine - IPER, Hospital Sant Joan de Déu, Barcelona, Spain
Colomer J:
Neuromuscular Unit, Department of Pediatric Neurology, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Garcia-Cazorla A:
Center for Biomedical Research Network On Rare Diseases (CIBERER), ISCIII, Madrid, Spain
Department of Pediatric Neurology, Hospital Sant Joan de Deu, Barcelona, Barcelona, Spain
Hoenicka J:
Laboratory of Neurogenetics and Molecular Medicine - IPER, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
Palau F:
Laboratory of Neurogenetics and Molecular Medicine - IPER, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
Department of Genetic and Molecular Medicine - IPER, Hospital Sant Joan de Déu, Barcelona, Spain
Clinic Institute of Medicine & Dermatology, Hospital Clínic, and Division of Pediatrics, University of Barcelona School of Medicine and Health Sciences, Barcelona, Spain. Electronic address:
Nascimento-Osorio A:
Neuromuscular Unit, Department of Pediatric Neurology, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
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