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Journal of Inorganic Biochemistry Jan 2019Dysregulation of copper homeostasis in humans is primarily found in two genetic diseases of copper transport, Menkes and Wilson diseases, which show symptoms of copper... (Review)
Review
Dysregulation of copper homeostasis in humans is primarily found in two genetic diseases of copper transport, Menkes and Wilson diseases, which show symptoms of copper deficiency or overload, respectively. However, both diseases are copper storage disorders despite completely opposite clinical pictures. Clinically, Menkes disease is characterized by copper deficiency secondary to poor loading of copper-requiring enzymes although sufficient body copper. Copper accumulates in non-hepatic tissues, but is deficient in blood, liver, and brain. In contrast, Wilson disease is characterized by symptoms of copper toxicity secondary to accumulation of copper in several organs most notably brain and liver, and a saturated blood copper pool. It is a challenge to correct copper dyshomeostasis in either disease though copper depletion in Menkes disease is most challenging. Both diseases are caused by defective copper export from distinct cells, and we seek to give new angles and guidelines to improve treatment of these two complementary diseases. Therapy of Menkes disease with copper-histidine, thiocarbamate, nitrilotriacetate or lipoic acid is discussed. In Wilson disease combination of a hydrophilic chelator e.g. trientine or dimercaptosuccinate with a brain shuttle e.g. thiomolybdate or lipoate, is discussed. New chelating principles for copper removal or delivery are outlined.
Topics: Chelating Agents; Drug Therapy, Combination; Hepatolenticular Degeneration; Humans; Menkes Kinky Hair Syndrome
PubMed: 30384011
DOI: 10.1016/j.jinorgbio.2018.10.009 -
Journal of Inherited Metabolic Disease Nov 2018Menkes disease (MD) is an X-linked recessive disorder caused by dysfunction of a copper-transporting protein, leading to severe neurodegeneration in early childhood. We...
INTRODUCTION
Menkes disease (MD) is an X-linked recessive disorder caused by dysfunction of a copper-transporting protein, leading to severe neurodegeneration in early childhood. We investigated whether a lipophilic copper chelator, disulfiram, could enhance copper absorption from the intestine and transport copper across the blood-brain barrier in MD model mice.
METHODS
Wild type and MD model mice were pretreated with disulfiram for 30 min before oral administration of CuCl. Each organ was sequentially analyzed for radioactivity with γ counting. Copper uptake into the brain parenchyma was assessed by ex vivo autoradiography.
RESULTS
In wild type mice, orally administered copper was initially detected in the intestine within 2 h, reaching a maximum level in the liver (19.6 ± 3.8 percentage injected dose per gram [%ID/g]) at 6 h. In MD model mice, the copper reached the maximum level in the liver (5.3 ± 1.5 %ID/g) at 4 h, which was lower than that of wild type mice (19.0 ± 7.4 %ID/g) (P < 0.05). Pretreatment of disulfiram in MD model mice increased the copper level in the brain (0.59 ± 0.28 %ID/g) at 24 h compared with MD model mice without disulfiram (0.07 ± 0.05 %ID/g) (P < 0.05). Ex vivo autoradiography revealed that high levels of copper uptake was observed in the cerebral cortex upon disulfiram pretreatment.
CONCLUSION
Our data demonstrated that disulfiram enhanced the delivery of orally administered copper into the central nervous system in MD model mice. The administration of disulfiram will enable patients to avoid unpleasant subcutaneous copper injection in the future.
Topics: Animals; Autoradiography; Blood-Brain Barrier; Copper; Disease Models, Animal; Disulfiram; Drug Carriers; Male; Menkes Kinky Hair Syndrome; Mice; Mice, Inbred C3H
PubMed: 30132231
DOI: 10.1007/s10545-018-0239-3 -
Pediatric Research Nov 2018Menkes disease is a copper metabolism disorder caused by mutations in ATP7A, a copper-transporting P-type ATPase. In this study, oral copper supplementation via...
BACKGROUND
Menkes disease is a copper metabolism disorder caused by mutations in ATP7A, a copper-transporting P-type ATPase. In this study, oral copper supplementation via glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) (CuGTSM), a lipophilic copper complex, was investigated in male hemizygous macular (Mo) mice, a mouse model of Menkes disease.
METHODS
CuGTSM was administered by oral gavage on postnatal days 5, 8, 11, 17, 23, and 32. The copper levels in the organs and serum, copper-dependent enzyme activities in the brain, and ceruloplasmin (Cp) activity in the serum were measured at 15 days and 3 and 8 months of age. Histological analysis of the intestines and the rotarod test were also performed.
RESULTS
CuGTSM treatment extended the lifespan of Mo mice and partly restored the copper concentrations and cytochrome oxidase and DBH activities in the brain; however, the rotarod test showed impaired motor performance. The treatment also increased copper concentrations and Cp activity in the serum. In suckling Mo mice, CuGTSM treatment transiently induced diarrhea accompanied by copper accumulation and altered villus morphology in the ileum.
CONCLUSION
Oral administration of CuGTSM extended the lifespan of Mo mice. Oral administration is attractive, but pharmaceutical studies are needed to reduce the adverse enteral effects.
Topics: Administration, Oral; Animals; Coordination Complexes; Copper; Copper-Transporting ATPases; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Menkes Kinky Hair Syndrome; Mice; Mutation; Survival Rate; Thiosemicarbazones; Tissue Distribution; Weight Gain
PubMed: 30127521
DOI: 10.1038/s41390-018-0116-7 -
BMJ Case Reports May 2018Menkes disease is a rare neurodegenerative metabolic disease with a reported incidence of 1 per 300 000 live births. It occurs due to mutations in ATP7A gene located... (Review)
Review
Menkes disease is a rare neurodegenerative metabolic disease with a reported incidence of 1 per 300 000 live births. It occurs due to mutations in ATP7A gene located on X-chromosome leading to deficiency of several copper-containing enzymes. The patient presents with history of neuroregression with characteristic kinky hair. MRI is the imaging modality of choice. Characteristic imaging findings are: bilateral subdural hygromas, cerebral and cerebellar atrophy, white matter changes and tortuous intracranial vessels on angiography. The rarity of this condition prompted us to report this case of Menkes disease along with the characteristic neuroimaging findings and brief review of literature.
Topics: Copper; Fatal Outcome; Humans; Infant; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Male; Menkes Kinky Hair Syndrome; Neuroimaging
PubMed: 29789304
DOI: 10.1136/bcr-2017-223858 -
Turkish Journal of Haematology :... Aug 2019
Topics: Bone Marrow; Child, Preschool; Erythroid Cells; Humans; Male; Menkes Kinky Hair Syndrome; Myeloid Cells; Vacuoles
PubMed: 29716882
DOI: 10.4274/tjh.galenos.2018.2018.0104 -
Neurology Mar 2018
Topics: Blood Vessels; Consanguinity; Copper-Transporting ATPases; Diagnosis, Differential; Hair; Head; Humans; Infant; Male; Menkes Kinky Hair Syndrome
PubMed: 29581334
DOI: 10.1212/WNL.0000000000005208 -
Metallomics : Integrated Biometal... Mar 2018Copper is essential for eukaryotic life, and animals must acquire this nutrient through the diet and distribute it to cells and organelles for proper function of...
Copper is essential for eukaryotic life, and animals must acquire this nutrient through the diet and distribute it to cells and organelles for proper function of biological targets. Indeed, mutations in the central copper exporter ATP7A contribute to a spectrum of diseases, including Menkes disease, with symptoms ranging from neurodegeneration to lax connective tissue. As such, a better understanding of the fundamental impacts of ATP7A mutations on in vivo copper distributions is of relevance to those affected by these diseases. Here we combine metal imaging and optical imaging techniques at a variety of spatial resolutions to identify tissues and structures with altered copper levels in the Calamity zebrafish model of Menkes disease. Rapid profiling of tissue slices with LA-ICP-MS identified reduced copper levels in the brain, neuroretina, and liver of Menkes fish compared to control specimens. High resolution nanoSIMS imaging of the neuroretina, combined with electron and confocal microscopies, identified the megamitochondria of photoreceptors as loci of copper accumulation in wildtype fish, with lower levels of megamitochondrial copper observed in Calamity zebrafish. Interestingly, this localized copper decrease does not result in impaired photoreceptor development or altered megamitochondrial morphology, suggesting the prioritization of copper at sufficient levels for maintaining essential mitochondrial functions. Together, these data establish the Calamity zebrafish as an optically transparent in vivo model for the study of neural copper misregulation, illuminate a role for the ATP7A copper exporter in trafficking copper to the neuroretina, and highlight the utility of combining multiple imaging techniques for studying metals in whole organism settings with spatial resolution.
Topics: Animals; Copper; Copper-Transporting ATPases; Disease Models, Animal; Laser Therapy; Menkes Kinky Hair Syndrome; Mitochondria; Multimodal Imaging; Mutation; Nanotechnology; Phenotype; Photoreceptor Cells, Vertebrate; Spectrometry, Mass, Electrospray Ionization; Spectrometry, Mass, Secondary Ion; Zebrafish
PubMed: 29507920
DOI: 10.1039/c7mt00349h -
Medicine Feb 2018Menkes disease (MD), also known as Menkes kinky hair disease, is a fatal neurodegenerative disease caused by a defect in copper metabolism. The symptoms involve multiple...
RATIONALE
Menkes disease (MD), also known as Menkes kinky hair disease, is a fatal neurodegenerative disease caused by a defect in copper metabolism. The symptoms involve multiple organ systems, such as the brain, lung, gastrointestinal tract, urinary tract, connective tissue, and skin. There is currently no cure for this disease entity, and patients with the classic form of MD usually die from complications between 6 months and 3 years of age. Intracranial hemorrhage secondary to tortuous intracranial arteries is a well-known complication of MD, but spontaneous retroperitoneal hemorrhage, to the best of our knowledge, has never been reported in a patient with MD. Herein, we describe the first case of retroperitoneal hematoma as a complication of MD in a 4-year-old boy.
PATIENT CONCERNS
A 4-year-old Taiwanese male patient with MD was referred to the hospital and presented with a palpable epigastric mass.
DIAGNOSES
On the basis of the findings of ultrasonography and enhanced computed tomography, the diagnosis was retroperitoneal hematoma.
INTERVENTIONS
Interventions included laparotomy with evacuation of the hematoma, manual compression, and suture of the bleeding vessels.
OUTCOMES
There were no postoperative complications.
LESSONS
This case emphasizes that bleeding in patients with MD is possible at any site in the body owing to the unstable structure of the connective tissues. Timely diagnosis with proper imaging studies can lead to prompt and appropriate management and save patients from this life-threatening condition.
Topics: Child, Preschool; Hematoma; Hemostasis, Surgical; Humans; Laparotomy; Male; Menkes Kinky Hair Syndrome; Retroperitoneal Space; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography
PubMed: 29419699
DOI: 10.1097/MD.0000000000009869 -
Cell Systems Mar 2018Rare neurological diseases shed light onto universal neurobiological processes. However, molecular mechanisms connecting genetic defects to their disease phenotypes are...
Rare neurological diseases shed light onto universal neurobiological processes. However, molecular mechanisms connecting genetic defects to their disease phenotypes are elusive. Here, we obtain mechanistic information by comparing proteomes of cells from individuals with rare disorders with proteomes from their disease-free consanguineous relatives. We use triple-SILAC mass spectrometry to quantify proteomes from human pedigrees affected by mutations in ATP7A, which cause Menkes disease, a rare neurodegenerative and neurodevelopmental disorder stemming from systemic copper depletion. We identified 214 proteins whose expression was altered in ATP7A fibroblasts. Bioinformatic analysis of ATP7A-mutant proteomes identified known phenotypes and processes affected in rare genetic diseases causing copper dyshomeostasis, including altered mitochondrial function. We found connections between copper dyshomeostasis and the UCHL1/PARK5 pathway of Parkinson disease, which we validated with mitochondrial respiration and Drosophila genetics assays. We propose that our genealogical "omics" strategy can be broadly applied to identify mechanisms linking a genomic locus to its phenotypes.
Topics: Adenosine Triphosphatases; Animals; Cation Transport Proteins; Computational Biology; Copper; Copper-Transporting ATPases; Disease Models, Animal; Drosophila; Female; Fibroblasts; Homeostasis; Humans; Male; Menkes Kinky Hair Syndrome; Mice; Mice, Inbred C57BL; Mitochondria; Mutation; Pedigree; Phenotype; Proteomics; Rare Diseases; Ubiquitin Thiolesterase
PubMed: 29397366
DOI: 10.1016/j.cels.2018.01.008 -
Nihon Eiseigaku Zasshi. Japanese... 2018The deficiency or excess intake of trace elements, including zinc, copper, selenium and iodine, has often been reported. Zinc deficiency is often observed in infants fed... (Review)
Review
The deficiency or excess intake of trace elements, including zinc, copper, selenium and iodine, has often been reported. Zinc deficiency is often observed in infants fed breast milk with low zinc concentration, individuals administered chelating medicines, athletes and patients with diabetes mellitus, hepatic cirrhosis or nephrosis syndrome. Menkes disease is associated with severe copper deficiency, and there is no effective treatment. Deficiencies of selenium and iodine are observed in patients who receive special formulas of milk and enteral formula with low selenium and iodine concentrations, respectively. In contrast, neonatal transient hypothyroidism due to excess intake of iodine in pregnant women has also reported in Japan. It is expected that collaborative studies by researchers and clinicians will contribute to clarify the detail mechanism, diagnosis and treatment of these abnormalities.
Topics: Clinical Medicine; Copper; Female; Hepatolenticular Degeneration; Humans; Hypothyroidism; Infant, Newborn; Japan; Male; Menkes Kinky Hair Syndrome; Pregnancy; Selenium; Trace Elements; Zinc
PubMed: 29386451
DOI: 10.1265/jjh.73.75