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recovery after the copper histidinate was withdrawn.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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