Copper Toxicity Associated With an ATP7A-Related Complex Phenotype
Por:
Natera-de Benito, D, Sola, A, Sousa, PR, Boronat, S, Exposito-Escudero, J, Carrera-Garcia, L, Ortez, C, Jou, C, Muchart, J, Rebollo, M, Armstrong, J, Colomer, J, Garcia-Cazorla, A, Hoenicka, J, Palau, F, Nascimento, 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1 when he was treated with copper replacement therapy, with a subsequent fast recovery after the copper histidinate was withdrawn.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:
Hosp St Joan de Deu, Neuromuscular Unit, Dept Pediat Neurol, Barcelona, Spain
Inst Recerca St Joan de Deu, Barcelona, Spain
Sola, A:
Inst Recerca St Joan de Deu, Lab Neurogenet & Mol Med IPER, Barcelona, Spain
Sousa, PR:
Hosp St Joan de Deu, Neuromuscular Unit, Dept Pediat Neurol, Barcelona, Spain
Inst Recerca St Joan de Deu, Barcelona, Spain
Hosp Cent Funchal, Dept Pediat, Pediat Neurol Unit, Funchal, Portugal
Boronat, S:
Hosp Santa Creu & Sant Pau, Dept Pediat, Barcelona, Spain
Exposito-Escudero, J:
Hosp St Joan de Deu, Neuromuscular Unit, Dept Pediat Neurol, Barcelona, Spain
Inst Recerca St Joan de Deu, Barcelona, Spain
Carrera-Garcia, L:
Hosp St Joan de Deu, Neuromuscular Unit, Dept Pediat Neurol, Barcelona, Spain
Inst Recerca St Joan de Deu, Barcelona, Spain
Ortez, C:
Hosp St Joan de Deu, Neuromuscular Unit, Dept Pediat Neurol, Barcelona, Spain
Inst Recerca St Joan de Deu, Barcelona, Spain
Jou, C:
Hosp St Joan de Deu, Neuromuscular Unit, Dept Pediat Neurol, Barcelona, Spain
Inst Recerca St Joan de Deu, Barcelona, Spain
Hosp St Joan de Deu, Dept Pathol, Barcelona, Spain
ISCIII, Ctr Biomed Res Network Rare Dis CIBERER, Madrid, Spain
Muchart, J:
Hosp St Joan de Deu, Dept Radiol, Barcelona, Spain
Rebollo, M:
Hosp St Joan de Deu, Dept Radiol, Barcelona, Spain
Armstrong, J:
Hosp St Joan de Deu, Neuromuscular Unit, Dept Pediat Neurol, Barcelona, Spain
Inst Recerca St Joan de Deu, Barcelona, Spain
ISCIII, Ctr Biomed Res Network Rare Dis CIBERER, Madrid, Spain
Hosp St Joan de Deu, Dept Genet & Mol Med IPER, Barcelona, Spain
Colomer, J:
Hosp St Joan de Deu, Neuromuscular Unit, Dept Pediat Neurol, Barcelona, Spain
Inst Recerca St Joan de Deu, Barcelona, Spain
Garcia-Cazorla, A:
ISCIII, Ctr Biomed Res Network Rare Dis CIBERER, Madrid, Spain
Hosp St Joan de Deu, Dept Pediat Neurol, Barcelona, Spain
Hoenicka, J:
Inst Recerca St Joan de Deu, Lab Neurogenet & Mol Med IPER, Barcelona, Spain
ISCIII, Ctr Biomed Res Network Rare Dis CIBERER, Madrid, Spain
Palau, F:
Inst Recerca St Joan de Deu, Lab Neurogenet & Mol Med IPER, Barcelona, Spain
ISCIII, Ctr Biomed Res Network Rare Dis CIBERER, Madrid, Spain
Hosp St Joan de Deu, Dept Genet & Mol Med IPER, Barcelona, Spain
Univ Barcelona, Sch Med & Hlth Sci, Clin Inst Med & Dermatol, Hosp Clin, Barcelona, Spain
Univ Barcelona, Sch Med & Hlth Sci, Div Pediat, Barcelona, Spain
Nascimento, A:
Hosp St Joan de Deu, Neuromuscular Unit, Dept Pediat Neurol, Barcelona, Spain
Inst Recerca St Joan de Deu, Barcelona, Spain
ISCIII, Ctr Biomed Res Network Rare Dis CIBERER, Madrid, Spain
Green Published
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