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AJNR. American Journal of Neuroradiology Oct 2017This is the second part of a retrospective and review MR imaging study aiming to define the frequency rate, timing, imaging features, and evolution of gray matter... (Review)
Review
This is the second part of a retrospective and review MR imaging study aiming to define the frequency rate, timing, imaging features, and evolution of gray matter changes in Menkes disease, a rare multisystem X-linked disorder of copper metabolism characterized by early, severe, and progressive neurologic involvement. According to our analysis, neurodegenerative changes and focal basal ganglia lesions already appear in the early phases of the disease. Subdural collections are less common than generally thought; however, their presence remains important because they might challenge the differential diagnosis with child abuse and might precipitate the clinical deterioration. Anecdotal findings in our large sample seem to provide interesting clues about the protean mechanisms of brain injury in this rare disease and further highlight the broad spectrum of MR imaging findings that might be expected while imaging a child with the suspicion of or a known diagnosis of Menkes disease.
Topics: Brain; Child; Gray Matter; Humans; Magnetic Resonance Imaging; Male; Menkes Kinky Hair Syndrome; Neuroimaging; Retrospective Studies
PubMed: 28495940
DOI: 10.3174/ajnr.A5192 -
Scientific Reports Apr 2017Menkes disease (MD) is caused by mutations in ATP7A, encoding a copper-transporting P-type ATPase which exhibits copper-dependent trafficking. ATP7A is found in the...
Menkes disease (MD) is caused by mutations in ATP7A, encoding a copper-transporting P-type ATPase which exhibits copper-dependent trafficking. ATP7A is found in the Trans-Golgi Network (TGN) at low copper concentrations, and in the post-Golgi compartments and the plasma membrane at higher concentrations. Here we have analyzed the effect of 36 ATP7A missense mutations identified in phenotypically different MD patients. Nine mutations identified in patients with severe MD, virtually eliminated ATP7A synthesis, in most cases due to aberrant RNA splicing. A group of 21 predominantly severe mutations led to trapping of the protein in TGN and displayed essentially no activity in a yeast-based functional assay. These were predicted to inhibit the catalytic phosphorylation of the protein. Four mutants showed diffuse post-TGN localization, while two displayed copper dependent trafficking. These six variants were identified in patients with mild MD and typically displayed activity in the yeast assay. The four post-TGN located mutants were presumably affected in the catalytic dephosphorylation of the protein. Together these results indicate that the severity of MD correlate with cellular localization of ATP7A and support previous studies indicating that phosphorylation is crucial for the exit of ATP7A from TGN, while dephosphorylation is crucial for recycling back to TGN.
Topics: Alleles; Alternative Splicing; Amino Acid Substitution; Biomarkers; Copper; Copper-Transporting ATPases; Fibroblasts; Fluorescent Antibody Technique; Humans; Intracellular Space; Menkes Kinky Hair Syndrome; Models, Biological; Mutation, Missense; Phenotype; Phosphorylation; Proteasome Endopeptidase Complex; Protein Transport; Proteolysis; Severity of Illness Index
PubMed: 28389643
DOI: 10.1038/s41598-017-00618-6 -
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 -
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 -
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 -
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 -
The Journal of Biological Chemistry Aug 2016Copper-transporting ATPase ATP7A is essential for mammalian copper homeostasis. Loss of ATP7A activity is associated with fatal Menkes disease and various other...
Copper-transporting ATPase ATP7A is essential for mammalian copper homeostasis. Loss of ATP7A activity is associated with fatal Menkes disease and various other pathologies. In cells, ATP7A inactivation disrupts copper transport from the cytosol into the secretory pathway. Using fibroblasts from Menkes disease patients and mouse 3T3-L1 cells with a CRISPR/Cas9-inactivated ATP7A, we demonstrate that ATP7A dysfunction is also damaging to mitochondrial redox balance. In these cells, copper accumulates in nuclei, cytosol, and mitochondria, causing distinct changes in their redox environment. Quantitative imaging of live cells using GRX1-roGFP2 and HyPer sensors reveals highest glutathione oxidation and elevation of H2O2 in mitochondria, whereas the redox environment of nuclei and the cytosol is much less affected. Decreasing the H2O2 levels in mitochondria with MitoQ does not prevent glutathione oxidation; i.e. elevated copper and not H2O2 is a primary cause of glutathione oxidation. Redox misbalance does not significantly affect mitochondrion morphology or the activity of respiratory complex IV but markedly increases cell sensitivity to even mild glutathione depletion, resulting in loss of cell viability. Thus, ATP7A activity protects mitochondria from excessive copper entry, which is deleterious to redox buffers. Mitochondrial redox misbalance could significantly contribute to pathologies associated with ATP7A inactivation in tissues with paradoxical accumulation of copper (i.e. renal epithelia).
Topics: 3T3-L1 Cells; Adenosine Triphosphatases; Animals; Biological Transport, Active; Cation Transport Proteins; Cell Line, Transformed; Copper; Copper-Transporting ATPases; Fibroblasts; Humans; Hydrogen Peroxide; Menkes Kinky Hair Syndrome; Mice; Mitochondria; Oxidation-Reduction
PubMed: 27226607
DOI: 10.1074/jbc.M116.727248