-
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 -
Metallomics : Integrated Biometal... Sep 2016The nineties witnessed the discovery of the copper ATPases, enzymes which transport copper across the cytoplasmic membranes of bacteria and eukaryotes. In the same...
The nineties witnessed the discovery of the copper ATPases, enzymes which transport copper across the cytoplasmic membranes of bacteria and eukaryotes. In the same decade, several other key components of copper homeostasis have also been discovered, like copper chaperones and plasma membrane copper transporters. This has finally led to a molecular understanding of two inherited human diseases related to copper: Menkes disease, manifested by systemic copper deficiency, and Wilson disease, caused by defective secretion of excess copper. A historic perspective and untold stories of the events leading up to these discoveries are presented here.
Topics: Cation Transport Proteins; Copper; Hepatolenticular Degeneration; History, 20th Century; Homeostasis; Humans; Menkes Kinky Hair Syndrome; Mutation
PubMed: 27476637
DOI: 10.1039/c6mt00111d -
Journal of the Medical Association of... Aug 2016Menkes disease is a disorder of copper transportation that results in multi-systems involvement including neurological deterioration, seizure, dysmorphic facies and...
BACKGROUND
Menkes disease is a disorder of copper transportation that results in multi-systems involvement including neurological deterioration, seizure, dysmorphic facies and kinky hair. The authors report a case of Menkes disease that was complicated with bilateral iliac artery aneurysms.
CASE REPORT
A 6-month-old Thai male infant presented with seizure, global delayed development, hypotonia and sparse, short, lightly pigmented and kinky hair. Light microscopic hair analysis showed pili torti. His serum copper and ceruloplasmin levels were low and were compatible with Menkes disease. Radiological finding from magnetic resonance angiography (MRA) revealed irregular tortuosity of abdominal aorta, a large right internal iliac artery aneurysm and a small left common iliac artery aneurysm. Genetic counseling and supportive treatment were provided for this patient.
CONCLUSION
Iliac aneurysms are a serious complication of patients with Menkes disease. Careful investigation with computed tomographic angiography (CTA) or MRA is helpful in those patients.
Topics: Aneurysm; Genetic Counseling; Humans; Iliac Artery; Infant; Magnetic Resonance Angiography; Male; Menkes Kinky Hair Syndrome; Thailand
PubMed: 29906074
DOI: No ID Found -
Nihon Rinsho. Japanese Journal of... Jul 2016Copper is one of essential trace elements. Copper deficiency lead to growth and developmental failure and/or neurological dysfunction. However, excess copper is also...
Copper is one of essential trace elements. Copper deficiency lead to growth and developmental failure and/or neurological dysfunction. However, excess copper is also problems for human life. There are two disorders of inborn error of copper metabolism, Menkes disease and Wilson disease. Menkes disease is an X linked recessive disorder with copper deficiency and Wilson disease is an autosomal recessive disorder with copper accumulation. These both disorders result from the defective functioning of copper transport P-type ATPase, ATP7A of Menkes disease and ATP7B of Wilson disease. In this paper, the author describes about copper metabolism of human, and clinical feature, diagnosis and treatment of Menkes disease and Wilson disease.
Topics: Copper; Genetic Predisposition to Disease; Hepatolenticular Degeneration; Humans; Menkes Kinky Hair Syndrome; Prognosis
PubMed: 27455805
DOI: No ID Found -
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 -
Metallomics : Integrated Biometal... Sep 2016When we were asked to produce articles for this volume, it seemed appropriate to us to co-author an article on the history and impact of copper research in Melbourne. It...
When we were asked to produce articles for this volume, it seemed appropriate to us to co-author an article on the history and impact of copper research in Melbourne. It is appropriate because over many years, decades in fact, we worked closely together and with Professor David Danks to identify the molecular defect in Menkes disease. This work was always carried out with the intention of understanding the nature of the copper homeostatic mechanisms and a "copper pathway" in the cell, that David had the prescience to predict must exist despite scepticism from granting agencies! He indeed inspired us to pursue research careers in this field. This article outlines some of this history.
Topics: Animals; Cation Transport Proteins; Copper; Homeostasis; Humans; Menkes Kinky Hair Syndrome; Mutation
PubMed: 27399171
DOI: 10.1039/c6mt90022d -
Metallomics : Integrated Biometal... Sep 2016Copper is an essential metal ion that provides catalytic function to numerous enzymes and also regulates neurotransmission and intracellular signaling. Conversely, a... (Review)
Review
Copper is an essential metal ion that provides catalytic function to numerous enzymes and also regulates neurotransmission and intracellular signaling. Conversely, a deficiency or excess of copper can cause chronic disease in humans. Menkes and Wilson disease are two rare heritable disorders of copper transport that are characterized by copper deficiency and copper overload, respectively. Changes to copper status are also a common feature of several neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). In the case of AD, which is characterized by brain copper depletion, changes in the distribution of copper has been linked with various aspects of the disease process; protein aggregation, defective protein degradation, oxidative stress, inflammation and mitochondrial dysfunction. Although AD is a multifactorial disease that is likely caused by a breakdown in multiple cellular pathways, copper and other metal ions such as iron and zinc play a central role in many of these cellular processes. Pioneering work by researchers who have studied relatively rare copper transport diseases has shed light on potential metal ion related disease mechanisms in other forms of neurodegeneration such as AD.
Topics: Alzheimer Disease; Copper; Genetic Predisposition to Disease; Humans; Menkes Kinky Hair Syndrome; Mitochondria; Oxidative Stress; Signal Transduction
PubMed: 27397642
DOI: 10.1039/c6mt00095a -
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 -
Brain & Development Sep 2016
Topics: Homovanillic Acid; Humans; Infant; Infant, Newborn; Menkes Kinky Hair Syndrome; Neonatal Screening; Neuroblastoma; Vanilmandelic Acid
PubMed: 27189264
DOI: 10.1016/j.braindev.2016.03.012 -
Brain & Development Sep 2016
Topics: Homovanillic Acid; Humans; Infant; Infant, Newborn; Menkes Kinky Hair Syndrome; Neonatal Screening; Neuroblastoma; Vanilmandelic Acid
PubMed: 27093925
DOI: 10.1016/j.braindev.2016.03.005