Copper Toxicity Associated With an ATP7A-Related Complex Phenotype
| العنوان: | Copper Toxicity Associated With an ATP7A-Related Complex Phenotype |
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| المؤلفون: | Andrés Nascimento, Angels García-Cazorla, Abel Sola, Jaume Colomer, Daniel Natera-de Benito, Carlos Ortez, Jordi Muchart, Susana Boronat, Judith Armstrong, Paulo Rego Sousa, Francesc Palau, Cristina Jou, Janet Hoenicka, Mónica Rebollo, Jessica Expósito-Escudero, Laura Carrera-García |
| المصدر: | PEDIATRIC NEUROLOGY r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu instname r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu Fundació Sant Joan de Déu Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Adult, Male, medicine.medical_specialty, ATP7A, Occipital horn syndrome, medicine.disease_cause, Cutis Laxa, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Developmental Neuroscience, 030225 pediatrics, Internal medicine, Distal hereditary motor neuropathy, ATP7B, Medicine, Humans, Expressivity (genetics), Child, Mutation, Portugal, Região Autónoma da Madeira, business.industry, Copper toxicity, Copper replacement therapy, medicine.disease, Phenotype, Pedigree, ATP7A Gene, Endocrinology, Neurology, Copper-Transporting ATPases, Pediatrics, Perinatology and Child Health, Menkes disease, Ehlers-Danlos Syndrome, Neurology (clinical), business, 030217 neurology & neurosurgery, Copper |
| الوصف: | 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. |
| تدمد: | 1873-5150 0887-8994 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6ab1612c7f928bafcaf901dd15005785Test https://pubmed.ncbi.nlm.nih.gov/33894639Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6ab1612c7f928bafcaf901dd15005785 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 18735150 08878994 |
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