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American Journal of Medical Genetics.... Feb 2015Menkes disease (MD; OMIM 309400) is an X-linked, neurodegenerative disorder resulting from deficient activity of copper-dependent enzymes and caused by alterations in... (Review)
Review
Menkes disease (MD; OMIM 309400) is an X-linked, neurodegenerative disorder resulting from deficient activity of copper-dependent enzymes and caused by alterations in the APT7A gene. In its classic form, it manifests in boys with hypotonia, seizures, skin and joint laxity, hair twisting (pili torti), cerebrovascular tortuosity, and bladder diverticulae. Menkes disease phenotypes have been reported in females with X; autosome translocations-disrupting ATP7A gene function- or ATP7A gene alterations. Those females manifest variable clinical findings, some of which, such as pili torti, seizure presence and/or age of onset, cerebrovascular tortuosity, degree of intellectual disability, and bladder divericulae are largely under-reported and under-studied. Here, we report on three females with Menkes disease and variant phenotypes, sharing characteristic features, one with classic Menkes disease and two with Menkes disease variants. We conclude that Menkes disease in females manifests with a variable spectrum of clinical findings but a few are uniformly present such as neurodevelopmental disability, hypotonia, and connective tissue findings. Others, such as seizures, cerebral atrophy, and cerebrovascular tortuosity may be present but are under-reported and under- studied. We propose that the diagnosis of Menkes disease or variants in females with suspicious clinical findings is an important one to consider as early treatment with parenteral copper may be considered. The effect of this treatment on the disease course in females with MD is unknown and remains to be seen.
Topics: Adenosine Triphosphatases; Cation Transport Proteins; Cerebral Angiography; Child; Child, Preschool; Copper-Transporting ATPases; Exons; Female; Heterozygote; Humans; Infant; Magnetic Resonance Angiography; Menkes Kinky Hair Syndrome; Mutation; Phenotype
PubMed: 25428120
DOI: 10.1002/ajmg.a.36853 -
IUBMB Life 2000Copper is an essential trace element, but its redox reactivity leads to risks of damage to cell and tissues. These are well exemplified by several forms of... (Review)
Review
Copper is an essential trace element, but its redox reactivity leads to risks of damage to cell and tissues. These are well exemplified by several forms of neurodegenerative diseases, either arising as inherited disorders of copper metabolism, such as Menkes' and Wilson's disease, or as conformational diseases such as Alzheimer's disease and prion diseases. This review will cover some aspects of the involvement of copper-mediated oxidative stress in degenerative processes in the central nervous system, with special focus on the familial form of amyotrophic lateral sclerosis (FALS). Furthermore, a possible role of copper reactivity in inducing critical steps in the apoptotic pathways leading to neurodegeneration is envisaged.
Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Apoptosis; Copper; Hepatolenticular Degeneration; Humans; Menkes Kinky Hair Syndrome; Models, Neurological; Nerve Degeneration; Neurodegenerative Diseases; Oxidative Stress; Prion Diseases; Superoxide Dismutase
PubMed: 11327325
DOI: 10.1080/713803724 -
Nature Reviews. Neurology Jan 2011This Review summarizes recent advances in understanding copper-transporting ATPase 1 (ATP7A), and examines the neurological phenotypes associated with dysfunction of... (Review)
Review
This Review summarizes recent advances in understanding copper-transporting ATPase 1 (ATP7A), and examines the neurological phenotypes associated with dysfunction of this protein. Involvement of ATP7A in axonal outgrowth, synapse integrity and neuronal activation underscores the fundamental importance of copper metabolism to neurological function. Defects in ATP7A cause Menkes disease, an infantile-onset, lethal condition. Neonatal diagnosis and early treatment with copper injections enhance survival in patients with this disease, and can normalize clinical outcomes if mutant ATP7A molecules retain small amounts of residual activity. Gene replacement rescues a mouse model of Menkes disease, suggesting a potential therapeutic approach for patients with complete loss-of-function ATP7A mutations. Remarkably, a newly discovered ATP7A disorder-isolated distal motor neuropathy-has none of the characteristic clinical or biochemical abnormalities of Menkes disease or its milder allelic variant occipital horn syndrome (OHS), instead resembling Charcot-Marie-Tooth disease type 2. These findings indicate that ATP7A has a crucial but previously unappreciated role in motor neuron maintenance, and that the mechanism underlying ATP7A-related distal motor neuropathy is distinct from Menkes disease and OHS pathophysiology. Collectively, these insights refine our knowledge of the neurology of ATP7A-related copper transport diseases and pave the way for further progress in understanding ATP7A function.
Topics: Adenosine Triphosphatases; Animals; Cation Transport Proteins; Copper-Transporting ATPases; Cutis Laxa; Ehlers-Danlos Syndrome; Humans; Menkes Kinky Hair Syndrome; Mice
PubMed: 21221114
DOI: 10.1038/nrneurol.2010.180 -
Biometals : An International Journal on... Aug 2014Copper (Cu) is an essential microelement found in all living organisms with the unique ability to adopt two different redox states-in the oxidized (Cu(2+)) and reduced... (Review)
Review
Copper (Cu) is an essential microelement found in all living organisms with the unique ability to adopt two different redox states-in the oxidized (Cu(2+)) and reduced (Cu(+)). It is required for survival and serves as an important catalytic cofactor in redox chemistry for proteins that carry out fundamental biological functions, important in growth and development. The deficit of copper can result in impaired energy production, abnormal glucose and cholesterol metabolism, increased oxidative damage, increased tissue iron (Fe) accrual, altered structure and function of circulating blood and immune cells, abnormal neuropeptides synthesis and processing, aberrant cardiac electrophysiology, impaired myocardial contractility, and persistent effects on the neurobehavioral and the immune system. Increased copper level has been found in several disorders like e.g.: Wilson's disease or Menke's disease. New findings with the great potential for impact in medicine include the use of copper-lowering therapy for antiangiogenesis, antifibrotic and anti-inflammatory purposes. The role of copper in formation of amyloid plaques in Alzheimer's disease, and successful treatment of this disorder in rodent model by copper chelating are also of interest. In this work we will try to describe essential aspects of copper in chosen diseases. We will represent the evidence available on adverse effect derived from copper deficiency and copper excess. We will try to review also the copper biomarkers (chosen enzymes) that help reflect the level of copper in the body.
Topics: Alzheimer Disease; Animals; Copper; Environmental Pollutants; Hepatolenticular Degeneration; Humans; Menkes Kinky Hair Syndrome; Metalloproteins; Oxidation-Reduction; Oxidative Stress
PubMed: 24748564
DOI: 10.1007/s10534-014-9736-5 -
Journal of Medical Genetics Apr 1986Several mutations affecting the transport of copper and zinc in humans and in mice have been discovered over the last 15 years, joining the long known disturbance of... (Review)
Review
Several mutations affecting the transport of copper and zinc in humans and in mice have been discovered over the last 15 years, joining the long known disturbance of copper transport in Wilson's disease. Menkes' disease (classical and mild variant forms) and X linked Ehlers-Danlos syndrome (type IX, X linked cutis laxa) have features in common with one another and with the brindled (Mobr) and blotchy (Moblo) mouse mutants, respectively. There may be one allelic series of mutants in each species or two loci may be involved in each. The toxic milk mutant (tx) in the mouse may be homologous to Wilson's disease in man. The defect of intestinal absorption of zinc in acrodermatitis enteropathica has no homologue yet in the mouse. However, the lethal milk (lm) mutant in the mouse may be homologous to a condition of zinc deficiency described in a few breastfed, low birth weight infants. Many more genetic defects of transport of copper and of zinc may await discovery. Conversely, these mutants are valuable in elucidating the normal processes of copper and zinc transport.
Topics: Acrodermatitis; Alleles; Animals; Biological Transport, Active; Copper; Genetic Linkage; Hepatolenticular Degeneration; Humans; Menkes Kinky Hair Syndrome; Mice; Mice, Mutant Strains; Mutation; Tissue Distribution; Trace Elements; X Chromosome; Zinc
PubMed: 3519972
DOI: 10.1136/jmg.23.2.99 -
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 -
The Journal of Investigative Dermatology Jul 1982Previous morphologic observations have suggested abnormalities in the elastic fibers in a number of both inherited and acquired diseases. Recent progress made in...
Previous morphologic observations have suggested abnormalities in the elastic fibers in a number of both inherited and acquired diseases. Recent progress made in understanding of the normal biology of elastin has allowed us to examine these diseases by biochemical means. In this review we are discussing the current status of the research on the elastin diseases with particular emphasis on clinical conditions affecting skin, as for example, cutis laxa, pseudoxanthoma elasticum, and the Buschke-Ollendorff syndrome. In addition, we present new data which appears to be the first demonstration of an elastin abnormality in the Marfan syndrome.
Topics: Connective Tissue Diseases; Cutis Laxa; Elastin; Humans; Marfan Syndrome; Menkes Kinky Hair Syndrome; Pseudoxanthoma Elasticum; Skin; Skin Diseases
PubMed: 7086187
DOI: 10.1111/1523-1747.ep12546063 -
European Journal of Human Genetics :... Apr 2014Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene. Whereas most of the patients exhibit a severe classical form, about 9%...
Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene. Whereas most of the patients exhibit a severe classical form, about 9% of the patients exhibit a milder form of Menkes disease. The mildest form is called occipital horn syndrome (OHS). Mutations in the ATP7A gene can be identified in 95-98% of the Menkes disease patients by standard screening techniques. Investigation of RNA isolated from the fibroblasts of eleven patients with no identified mutations was performed, and revealed inclusion of new pseudo-exons into the ATP7A mRNA from three unrelated patients: two patients with OHS and one patient with classical Menkes disease. The pseudo-exons were inserted between exons 10 and 11, between exons 16 and 17 and between exons 14 and 15 in the three patients, as a result of deep intronic mutations. This is the first time the activation of pseudo-exons is demonstrated in the ATP7A gene, and it demonstrates the usefulness of RNA analysis, in terms of revealing disease-causing mutations in noncoding regions. The fact that three different mutations cause disease by the activation of pseudo-exon inclusion also indicates that in Menkes disease this is an important mechanism, which has hitherto been overlooked.
Topics: Adenosine Triphosphatases; Adolescent; Alleles; Base Sequence; Cation Transport Proteins; Child; Copper; Copper-Transporting ATPases; Cutis Laxa; Ehlers-Danlos Syndrome; Exons; Humans; Introns; Male; Menkes Kinky Hair Syndrome; Molecular Sequence Data; Mutation; Phenotype; RNA, Messenger; Sequence Analysis, DNA
PubMed: 24002164
DOI: 10.1038/ejhg.2013.191 -
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 -
Current Drug Metabolism Mar 2012Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellular damage. Disruptions to normal copper... (Review)
Review
Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellular damage. Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, occipital horn syndrome, and Wilson's disease. Menkes disease and occipital horn syndrome are characterized by copper deficiency. Typical features of Menkes disease result from low copper-dependent enzyme activity. Standard treatment involves parenteral administration of copper-histidine. If treatment is initiated before 2 months of age, neurodegeneration can be prevented, while delayed treatment is utterly ineffective. Thus, neonatal mass screening should be implemented. Meanwhile, connective tissue disorders cannot be improved by copper-histidine treatment. Combination therapy with copper-histidine injections and oral administration of disulfiram is being investigated. Occipital horn syndrome characterized by connective tissue abnormalities is the mildest form of Menkes disease. Treatment has not been conducted for this syndrome. Wilson's disease is characterized by copper toxicity that typically affects the hepatic and nervous systems severely. Various other symptoms are observed as well, yet its early diagnosis is sometimes difficult. Chelating agents and zinc are effective treatments, but are inefficient in most patients with fulminant hepatic failure. In addition, some patients with neurological Wilson's disease worsen or show poor response to chelating agents. Since early treatment is critical, a screening system for Wilson's disease should be implemented in infants. Patients with Wilson's disease may be at risk of developing hepatocellular carcinoma. Understanding the link between Wilson's disease and hepatocellular carcinoma will be beneficial for disease treatment and prevention.
Topics: Age Factors; Animals; Carcinoma, Hepatocellular; Copper; Cutis Laxa; Ehlers-Danlos Syndrome; Hepatolenticular Degeneration; Humans; Infant; Infant, Newborn; Liver Neoplasms; Mass Screening; Menkes Kinky Hair Syndrome
PubMed: 21838703
DOI: 10.2174/138920012799320455