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Pflugers Archiv : European Journal of... Oct 2020Copper is an essential element in cells; it can act as either a recipient or a donor of electrons, participating in various reactions. However, an excess of copper ions... (Review)
Review
Copper is an essential element in cells; it can act as either a recipient or a donor of electrons, participating in various reactions. However, an excess of copper ions in cells is detrimental as these copper ions can generate free radicals and increase oxidative stress. In multicellular organisms, copper metabolism involves uptake, distribution, sequestration, and excretion, at both the cellular and systemic levels. Mammalian enterocytes take in bioavailable copper ions from the diet in a Ctr1-dependent manner. After incorporation, cuprous ions are delivered to ATP7A, which pumps Cu from enterocytes into the blood. Copper ions arrive at the liver through the portal vein and are incorporated into hepatocytes by Ctr1. Then, Cu can be secreted into the bile or the blood via the Atox1/ATP7B/ceruloplasmin route. In the bloodstream, this micronutrient can reach peripheral tissues and is again incorporated by Ctr1. In peripheral tissue cells, cuprous ions are either sequestrated by molecules such as metallothioneins or targeted to utilization pathways by chaperons such as Atox1, Cox17, and CCS. Copper metabolism must be tightly controlled in order to achieve homeostasis and avoid disorders. A hereditary or acquired copper unbalance, including deficiency, overload, or misdistribution, may cause or aggravate certain diseases such as Menkes disease, Wilson disease, neurodegenerative diseases, anemia, metabolic syndrome, cardiovascular diseases, and cancer. A full understanding of copper metabolism and its roles in diseases underlies the identification of novel effective therapies for such diseases.
Topics: Animals; Copper; Copper-Transporting ATPases; Hepatolenticular Degeneration; Humans; Menkes Kinky Hair Syndrome; Molecular Chaperones
PubMed: 32506322
DOI: 10.1007/s00424-020-02412-2 -
Science (New York, N.Y.) May 2020Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is...
Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is characterized by progressive neurological injury culminating in death, typically by 3 years of age. Severe copper deficiency leads to multiple pathologies, including impaired energy generation caused by cytochrome c oxidase dysfunction in the mitochondria. Here we report that the small molecule elesclomol escorted copper to the mitochondria and increased cytochrome c oxidase levels in the brain. Through this mechanism, elesclomol prevented detrimental neurodegenerative changes and improved the survival of the mottled-brindled mouse-a murine model of severe Menkes disease. Thus, elesclomol holds promise for the treatment of Menkes and associated disorders of hereditary copper deficiency.
Topics: Animals; Biological Transport; Brain; Cell Line; Copper; Copper Transporter 1; Disease Models, Animal; Electron Transport Complex IV; Hydrazines; Male; Menkes Kinky Hair Syndrome; Mice; Mice, Knockout; Mitochondria; Neurodegenerative Diseases; Rats
PubMed: 32381719
DOI: 10.1126/science.aaz8899 -
Molecular Genetics and Metabolism Jan 2019Menkes disease is a rare X-linked neurodegenerative disorder caused by defect in copper metabolism. Parenteral copper supplementation has been used as a potential...
Menkes disease is a rare X-linked neurodegenerative disorder caused by defect in copper metabolism. Parenteral copper supplementation has been used as a potential disease-modifying treatment of Menkes disease for decades. However, recent evidence suggests its efficacy only when treatment is started within days after birth, which also has important implications related to the techniques that enable early diagnosis. We aim at proposing a guideline for prenatal and neonatal diagnosis and for disease-modifying treatment of Menkes disease, guided by a systematic review of the literature, and built in conjunction with medical experts, methodologists and patient representatives. Thirteen articles were used for our recommendations that were based on GRADE system. Reviewed evidence suggests that prenatal genetic diagnosis in families with previous diagnosis of Menkes disease is feasible; analysis of plasma catecholamine levels is accurate for neonatal diagnosis of Menkes disease; treatment with copper-histidine is effective to increase survival and reduce neurologic burden of the disease if initiated in the neonatal period; and, treatment indication should not be guided by patient's genotype. In conclusion, our guideline can contribute to standardize some aspects of the clinical care of patients with Menkes disease, especially reducing disease burden and mortality and providers' and families' anxiety.
Topics: Catecholamines; Clinical Trials as Topic; Copper; Early Diagnosis; Female; Humans; Male; Menkes Kinky Hair Syndrome; Mutation; Practice Guidelines as Topic; Pregnancy; Prenatal Diagnosis
PubMed: 30594472
DOI: 10.1016/j.ymgme.2018.12.005 -
Archives of Iranian Medicine Dec 2021
Topics: Copper; Humans; Menkes Kinky Hair Syndrome
PubMed: 35014241
DOI: 10.34172/aim.2021.138 -
Radiology Aug 2020HistoryAn 8-month-old previously healthy boy was referred to our institution by the maternal child health center for progressive truncal hypotonia and developmental...
HistoryAn 8-month-old previously healthy boy was referred to our institution by the maternal child health center for progressive truncal hypotonia and developmental delay. This infant was born after an uncomplicated pregnancy with no perinatal complications. He was delivered at full term via spontaneous vaginal delivery. Two of his older male siblings died around 2-3 years of age due to pneumonia. According to the parents, these siblings also displayed reduced muscle tone, and one of them developed recurrent seizure.On physical examination, the child showed marked head lag and did not reach out to objects. Visual and auditory development were normal. His head circumference was below the third percentile, and his body weight was at the 10th percentile. His hair was sparse and coarse. A mild pectus excavatum deformity was present. Skull and chest radiographs were obtained (Figs 1, 2), and the patient underwent MRI of the brain (Fig 3).
Topics: Brain; Copper; Copper-Transporting ATPases; Humans; Infant; Magnetic Resonance Imaging; Male; Menkes Kinky Hair Syndrome; Radiography; Ribs; Skull
PubMed: 32687459
DOI: 10.1148/radiol.2020182237 -
Giornale Italiano Di Dermatologia E... Feb 2017This article explores three neurocutaneous syndromes (NCSs), i.e. genetic disorders producing developmental abnormalities of the skin and an increased risk of... (Review)
Review
This article explores three neurocutaneous syndromes (NCSs), i.e. genetic disorders producing developmental abnormalities of the skin and an increased risk of neurological complications. In this review, different aspects of ataxia telangiectasia, Menkes kinky hair disease and neurocutaneous melanosis are examined: clinical features, genetic defect, mutation spectrum, pathogenesis, and neurobiological basis; indications for clinical practice are also provided to the readers. The aim of this review is to stress the importance of cooperation among dermatologists, neurologists and psychiatrists, in order to provide patients suffering from these diseases with timely diagnosis and targeted treatments.
Topics: Ataxia Telangiectasia; Cooperative Behavior; Humans; Interdisciplinary Communication; Melanosis; Menkes Kinky Hair Syndrome; Neurocutaneous Syndromes
PubMed: 27002302
DOI: 10.23736/S0392-0488.16.05083-5 -
Metallomics : Integrated Biometal... Sep 2016
Topics: Animals; Brain; Copper; Copper-Transporting ATPases; Humans; Mammals; Menkes Kinky Hair Syndrome; Superoxide Dismutase
PubMed: 27399272
DOI: 10.1039/c6mt90026g -
Journal of Multidisciplinary Healthcare 2016Disorders of copper homeostasis are currently recognized across the life span. Their recognition and links to human disease have spanned several decades, beginning with... (Review)
Review
Disorders of copper homeostasis are currently recognized across the life span. Their recognition and links to human disease have spanned several decades, beginning with the recognition of a degenerative disorder in the offspring of sheep grazing in copper-deficient pastures, through to the description of infants suffering from a progressive neurodegenerative disorder characterized by epileptic seizures, developmental regression, failure to thrive, and an unusual hair quality (giving the condition its distinctive label of "kinky hair disease"). In this review, we trace the historical background and describe the biochemistry and physiology of copper metabolism and transport, inheritance patterns, molecular genetics, and genotype-phenotype correlations based on current understanding of the disorder. It is clear from the clinical presentations and variants that disorders of copper homeostasis include phenotypes ranging from mild occipital horn syndrome to intermediate and severe forms of classical Menkes disease. The symptoms involve multiple organ systems such as brain, lung, gastrointestinal tract, urinary tract, connective tissue, and skin. A multisystem disorder needs a multidisciplinary approach to care, as treatment interventions permit longer survival for some individuals. Animal models have been developed to help screen treatment options and provide a better understanding of these disorders in the laboratory. Finally, we propose a multidisciplinary approach to promote continued research (both basic and clinical) to improve survival, quality of life, and care for these conditions.
PubMed: 27574440
DOI: 10.2147/JMDH.S93454 -
Indian Pediatrics Jan 2016
Topics: Cerebral Veins; Humans; Infant; Male; Menkes Kinky Hair Syndrome
PubMed: 26840692
DOI: No ID Found -
JAMA Dermatology Jan 2017
Topics: Dermatology; History, 20th Century; History, 21st Century; Menkes Kinky Hair Syndrome; Neurology; Pediatrics
PubMed: 28114526
DOI: 10.1001/jamadermatol.2016.0163