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Pediatric Dermatology May 2017Althouygh Menkes disease has well-recognized neurologic, developmental, and cutaneous features, the initial presentation may resemble child abuse. We describe a...
Althouygh Menkes disease has well-recognized neurologic, developmental, and cutaneous features, the initial presentation may resemble child abuse. We describe a 5-month-old boy with multiple fractures indicative of nonaccidental trauma who was ultimately diagnosed with Menkes disease. Copper deficiency leads to connective tissue abnormalities and may result in subdural hematomas, wormian bones, cervical spine defects, rib fractures, and spurring of the long bone metaphyses. Several of these findings, including fractures and subdural hematomas, may be misinterpreted as child abuse.
Topics: Child Abuse; Diagnosis, Differential; Emergency Service, Hospital; Follow-Up Studies; Fractures, Multiple; Humans; Infant; Infant, Premature; Male; Menkes Kinky Hair Syndrome; Radiography; Risk Assessment
PubMed: 28318055
DOI: 10.1111/pde.13106 -
IUBMB Life Apr 2017The essential transition metal copper is important in lipid metabolism, redox balance, iron mobilization, and many other critical processes in eukaryotic organisms.... (Review)
Review
The essential transition metal copper is important in lipid metabolism, redox balance, iron mobilization, and many other critical processes in eukaryotic organisms. Genetic diseases where copper homeostasis is disrupted, including Menkes disease and Wilson disease, indicate the importance of copper balance to human health. The severe consequences of insufficient copper supply are illustrated by Menkes disease, caused by mutation in the X-linked ATP7A gene encoding a protein that transports copper from intestinal epithelia into the bloodstream and across the blood-brain barrier. Inadequate copper supply to the body due to poor diet quality or malabsorption can disrupt several molecular level pathways and processes. Though much of the copper distribution machinery has been described and consequences of disrupted copper handling have been characterized in human disease as well as animal models, physiological consequences of sub-optimal copper due to poor nutrition or malabsorption have not been extensively studied. Recent work indicates that insufficient copper may be important in a number of common diseases including obesity, ischemic heart disease, and metabolic syndrome. Specifically, marginal copper deficiency (CuD) has been reported as a potential etiologic factor in diseases characterized by disrupted lipid metabolism such as non-alcoholic fatty-liver disease (NAFLD). In this review, we discuss the available data suggesting that a significant portion of the North American population may consume insufficient copper, the potential mechanisms by which CuD may promote lipid biosynthesis, and the interaction between CuD and dietary fructose in the etiology of NAFLD. © 2016 IUBMB Life, 69(4):263-270, 2017.
Topics: Adenosine Triphosphatases; Blood-Brain Barrier; Cation Transport Proteins; Copper; Copper-Transporting ATPases; Diet; Humans; Iron; Lipid Metabolism; Lipids; Liver; Menkes Kinky Hair Syndrome; Non-alcoholic Fatty Liver Disease
PubMed: 28271632
DOI: 10.1002/iub.1613 -
The Journal of Biological Chemistry Mar 2017Copper is an essential biometal, and several inherited diseases are directly associated with a disruption to normal copper homeostasis. The best characterized are the...
Copper is an essential biometal, and several inherited diseases are directly associated with a disruption to normal copper homeostasis. The best characterized are the copper deficiency and toxicity disorders Menkes and Wilson diseases caused by mutations in the p-type Cu-ATPase genes and , respectively. Missense mutations in the C-terminal portion of have also been shown to cause distal motor neuropathy, whereas polymorphisms in are associated with increased risk of Alzheimer's disease. We have generated a single, model for studying multiple pathogenic mutations in ATP7 proteins using , which has a single orthologue of ATP7A and ATP7B. Four pathogenic mutations and two mutations were introduced into a genomic rescue construct containing an in-frame C-terminal GFP tag. Analysis of the wild type transgene confirmed that ATP7 is expressed at the basolateral membrane of larval midgut copper cells and that the transgene can rescue a normally early lethal deletion allele to adulthood. Analysis of the transgenes containing pathogenic mutations showed that the function of ATP7 was affected, to varying degrees, by all six of the mutations investigated in this study. Of particular interest, the ATP7B Alzheimer's disease susceptibility allele was found, for the first time, to be a loss of function allele. This system allows us to assess the severity of individual / mutations in an invariant genetic background and has the potential to be used to screen for therapeutic compounds able to restore function to faulty copper transport proteins.
Topics: Alzheimer Disease; Animals; Cation Transport Proteins; Copper-Transporting ATPases; Disease Models, Animal; Drosophila melanogaster; Female; Hepatolenticular Degeneration; Male; Menkes Kinky Hair Syndrome; Motor Neurons; Mutation
PubMed: 28119449
DOI: 10.1074/jbc.M116.756163 -
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 -
Folia Biologica 2017Menkes disease is a severe X-linked recessive disorder caused by a defect in the ATP7A gene, which encodes a membrane copper-transporting ATPase. Deficient activity of...
Menkes disease is a severe X-linked recessive disorder caused by a defect in the ATP7A gene, which encodes a membrane copper-transporting ATPase. Deficient activity of the ATP7A protein results in decreased intestinal absorption of copper, low copper level in serum and defective distribution of copper in tissues. The clinical symptoms are caused by decreased activities of copper-dependent enzymes and include neurodegeneration, connective tissue disorders, arterial changes and hair abnormalities. Without therapy, the disease is fatal in early infancy. Rapid diagnosis of Menkes disease and early start of copper therapy is critical for the effectiveness of treatment. We report a molecular biology-based strategy that allows early diagnosis of copper transport defects and implementation of individual therapies before the full development of pathological symptoms. Low serum copper and decreased activity of copperdependent mitochondrial cytochrome c oxidase in isolated platelets found in three patients indicated a possibility of functional defects in copper-transporting proteins, especially in the ATPA7 protein, a copper- transporting P-type ATPase. Rapid mutational screening of the ATP7A gene using high-resolution melting analysis of DNA indicated presence of mutations in the patients. Molecular investigation for mutations in the ATP7A gene revealed three nonsense mutations: c.2170C>T (p.Gln724Ter); c.3745G>T (p.Glu1249Ter); and c.3862C>T (p.Gln1288Ter). The mutation c.3745G>T (p.Glu1249Ter) has not been identified previously. Molecular analysis of the ATOX1 gene as a possible modulating factor of Menkes disease did not reveal presence of pathogenic mutations. Molecular diagnostics allowed early onset of individual therapies, adequate genetic counselling and prenatal diagnosis in the affected families.
Topics: Carrier Proteins; Child; Copper; Copper Transport Proteins; Copper-Transporting ATPases; Humans; Infant; Male; Menkes Kinky Hair Syndrome; Metallochaperones; Models, Biological; Molecular Chaperones; Mutation
PubMed: 29687769
DOI: No ID Found -
Neurology. Genetics Dec 2016Menkes disease is an X-linked multisystem disorder with epilepsy, kinky hair, and neurodegeneration caused by mutations in the copper transporter . Other mutations have...
Menkes disease is an X-linked multisystem disorder with epilepsy, kinky hair, and neurodegeneration caused by mutations in the copper transporter . Other mutations have been linked to juvenile occipital horn syndrome and adult-onset hereditary motor neuropathy. About 5%-10% of the patients present with "atypical Menkes disease" characterized by longer survival, cerebellar ataxia, and developmental delay. The intracellular copper transport is regulated by 2 P type ATPase copper transporters ATP7A and ATP7B. These proteins are expressed in the trans-Golgi network that guides copper to intracellular compartments, and in copper excess, it relocates copper to the plasma membrane to pump it out from the cells. mutations cause Wilson disease with dystonia, ataxia, tremor, and abnormal copper accumulation in the brain, liver, and other organs..
PubMed: 27878136
DOI: 10.1212/NXG.0000000000000119 -
American Journal of Medical Genetics.... Nov 2016
Topics: Humans; Infant; Male; Menkes Kinky Hair Syndrome; Skin
PubMed: 27748070
DOI: 10.1002/ajmg.a.37696 -
Medicine Sep 2016Menkes disease (MD) is a disorder of copper metabolism due to ATP7A gene mutation that leads to severe copper deficiency. Deformed blood vessels can be found in many...
BACKGROUND
Menkes disease (MD) is a disorder of copper metabolism due to ATP7A gene mutation that leads to severe copper deficiency. Deformed blood vessels can be found in many parts of the body, and intracranial hematoma is generally reported.
METHODS
We report a Taiwanese boy with MD who had recurrent spontaneous subserosal hematoma of ileum presenting as intestinal obstruction, with the 2 episodes 23 months apart. The patient returned to the usual physical status after surgical removal of the hematoma.
RESULTS
The defective copper metabolism causes dysfunction of a plenty of copper-dependent enzymes, giving rise to unique kinky hair appearance, progressive neurodegeneration, and connective tissue abnormalities. To our knowledge, this is the first report on recurrent subserosal hemorrhage of intestine in MD.
CONCLUSION
Owing to the fragile structure of blood vessels, subserosal hematoma should be considered when patients with MD having intestinal obstruction.
Topics: Child, Preschool; Hematoma; Humans; Ileal Diseases; Intestinal Obstruction; Male; Menkes Kinky Hair Syndrome; Recurrence
PubMed: 27631241
DOI: 10.1097/MD.0000000000004842 -
Scientific Reports Sep 2016Copper (Cu) is an indispensable metal for normal development and function of humans, especially in central nervous system (CNS). However, its redox activity requires...
Copper (Cu) is an indispensable metal for normal development and function of humans, especially in central nervous system (CNS). However, its redox activity requires accurate Cu transport system. ATP7A, a main Cu(2+) transporting-ATPase, is necessary to efflux Cu across the plasma membrane and synthesize cuproenzymes. Menkes disease (MD) is caused by mutations in ATP7A gene. Clinically, MD is Cu deficiency syndrome and is treated with Cu-histidine injections soon after definite diagnosis. But outcome of the most remains poor. To estimate the standard therapy, Cu distribution in the treated classic MD patients is analyzed by synchrotron-generated X-ray fluorescence technique (SR-XRF), which identifies and quantifies an individual atom up to at subcellular level of resolution with wide detection area. SR-XRF analysis newly reveals that Cu exists in spinal cord parenchyma and flows out via venous and lymph systems. By systemic analysis, excess Cu is detected in the proximal tubular cells of the kidney, the mucosal epithelial cells of the intestine, and the lymph and venous systems. The current study suggests that the standard therapy supply almost enough Cu for patient tissues. But given Cu passes through the tissues to venous and lymph systems, or accumulate in the cells responsible for Cu absorption.
Topics: Central Nervous System; Copper; Copper-Transporting ATPases; Fluorescence; Histidine; Humans; Kidney; Menkes Kinky Hair Syndrome; Mutation; Radiography; Synchrotrons; X-Rays
PubMed: 27629586
DOI: 10.1038/srep33247 -
Hospital Pediatrics Oct 2016
Topics: Bronchiolitis; Child Abuse; Diagnosis, Differential; Humans; Incidental Findings; Infant; Male; Menkes Kinky Hair Syndrome; Patient Care Management; Predictive Value of Tests; Radiography, Thoracic; Rib Fractures; Sensitivity and Specificity
PubMed: 27609945
DOI: 10.1542/hpeds.2015-0267