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Annals of the New York Academy of... May 2014In more than 40 years since copper deficiency was delineated in pediatric subjects with Menkes disease, remarkable advances in our understanding of the clinical,... (Review)
Review
In more than 40 years since copper deficiency was delineated in pediatric subjects with Menkes disease, remarkable advances in our understanding of the clinical, biochemical, and molecular aspects of the human copper transporter ATP7A have emerged. Mutations in the gene encoding this multitasking molecule are now implicated in at least two other distinctive phenotypes: occipital horn syndrome and ATP7A-related isolated distal motor neuropathy. Several other novel inherited disorders of copper metabolism have been identified in the past several years, aided by advances in human gene mapping and automated DNA sequencing. In this paper, I review the history and evolution of our understanding of disorders caused by impaired ATP7A function, and outline future challenges.
Topics: Adenosine Triphosphatases; Cation Transport Proteins; Copper; Copper-Transporting ATPases; Cutis Laxa; Ehlers-Danlos Syndrome; Gene Transfer Techniques; Humans; Menkes Kinky Hair Syndrome; Metal Metabolism, Inborn Errors
PubMed: 24735419
DOI: 10.1111/nyas.12422 -
Pediatric Neurology Apr 2014Determining the relationship between clinical phenotype and genotype in genetic diseases is important in clinical practice. In general, frameshift mutations are expected...
BACKGROUND
Determining the relationship between clinical phenotype and genotype in genetic diseases is important in clinical practice. In general, frameshift mutations are expected to produce premature termination codons, leading to production of mutant transcripts destined for degradation by nonsense-mediated decay. In X-linked recessive diseases, male patients with frameshift mutations typically have a severe or even lethal phenotype.
PATIENT
We report a case of a 17-month-old boy with Menkes disease (NIM #309400), an X-linked recessive copper metabolism disorder caused by mutations in the ATP7A copper transporter gene. He exhibited an unexpectedly late onset and experienced milder symptoms.
STUDY AND RESULT
His genomic DNA showed a de novo two-nucleotide deletion in exon 4 of ATP7A, predicting a translational frameshift and premature stop codon, and a classic severe phenotype. Characterization of his ATP7A mRNA showed no abnormal splicing.
CONCLUSION
We speculate that translation reinitiation could occur downstream to the premature termination codon and produce a partially functional ATP7A protein. Study of the child's fibroblasts found no evidence of translation reinitiation; however, the possibility remains that this phenomenon occurred in neural tissues and influenced the clinical phenotype.
Topics: Adenosine Triphosphatases; Age of Onset; Base Sequence; Cation Transport Proteins; Copper-Transporting ATPases; DNA Mutational Analysis; Frameshift Mutation; Humans; Infant; Male; Menkes Kinky Hair Syndrome; Phenotype; RNA, Messenger; Sequence Deletion
PubMed: 24630286
DOI: 10.1016/j.pediatrneurol.2014.01.005 -
Annals of the New York Academy of... May 2014Copper is an essential nutrient for the physiology of live organisms, but excessive copper can be harmful. Copper radioisotopes are used for measurement of copper fluxes...
Copper is an essential nutrient for the physiology of live organisms, but excessive copper can be harmful. Copper radioisotopes are used for measurement of copper fluxes in live organisms using a radioactivity assay of body fluids or whole-body positron emission tomography (PET). Hybrid positron emission tomography-computed tomography (PET/CT) is a versatile tool for real-time measurement of copper fluxes combining the high sensitivity and quantification capability of PET and the superior spatial resolution of CT for anatomic localization of radioactive tracer activity. Kinetic analysis of copper metabolism in the liver and extrahepatic tissues of Atp7b(-/-) knockout mice, a mouse model of Wilson's disease, demonstrated the feasibility of measuring copper fluxes in live organisms with PET/CT using copper-64 chloride ((64) CuCl2 ) as a radioactive tracer ((64) CuCl2 -PET/CT). (64) CuCl2 -PET/CT holds potential as a useful tool for the diagnosis of inherited and acquired human copper metabolism disorders and for monitoring the effects of copper-modulating therapy.
Topics: Adenosine Triphosphatases; Animals; Cation Transport Proteins; Copper; Copper Radioisotopes; Copper-Transporting ATPases; Gastrointestinal Tract; Hepatolenticular Degeneration; Liver; Lung; Menkes Kinky Hair Syndrome; Mice; Mice, Inbred C57BL; Myocardium; Positron-Emission Tomography; Radioactive Tracers
PubMed: 24628290
DOI: 10.1111/nyas.12383 -
Journal of Nuclear Medicine : Official... May 2014Menkes disease (MD), an X-linked recessive disorder of copper metabolism caused by mutations in the copper-transporting ATP7A gene, results in growth failure and severe...
UNLABELLED
Menkes disease (MD), an X-linked recessive disorder of copper metabolism caused by mutations in the copper-transporting ATP7A gene, results in growth failure and severe neurodegeneration in early childhood. Subcutaneous copper-histidine injection is the standard treatment for MD, but it has limited clinical efficacy. Furthermore, long-term copper injection causes excess copper accumulation in the kidneys, resulting in renal dysfunction. To attempt to resolve this issue, we used PET imaging with (64)Cu to investigate the effects of disulfiram on copper biodistribution in living mice serving as an animal model for MD (MD model mice).
METHODS
Macular mice were used as MD model mice, and C3H/He mice were used as wild-type mice. Mice were pretreated with 2 types of chelators (disulfiram, a lipophilic chelator, and d-penicillamine, a hydrophilic chelator) 30 min before (64)CuCl2 injection. After (64)CuCl2 injection, emission scans covering the whole body were performed for 4 h. After the PET scans, the brain and kidneys were analyzed for radioactivity with γ counting and autoradiography.
RESULTS
After copper injection alone, marked accumulation of radioactivity ((64)Cu) in the liver was demonstrated in wild-type mice, whereas in MD model mice, copper was preferentially accumulated in the kidneys (25.56 ± 3.01 percentage injected dose per gram [%ID/g]) and was detected to a lesser extent in the liver (13.83 ± 0.26 %ID/g) and brain (0.96 ± 0.08 %ID/g). Copper injection with disulfiram reduced excess copper accumulation in the kidneys (14.54 ± 2.68 %ID/g) and increased copper transport into the liver (29.42 ± 0.98 %ID/g) and brain (5.12 ± 0.95 %ID/g) of MD model mice. Copper injection with d-penicillamine enhanced urinary copper excretion and reduced copper accumulation in most organs in both mouse groups. Autoradiography demonstrated that disulfiram pretreatment induced copper transport into the brain parenchyma and reduced copper accumulation in the renal medulla.
CONCLUSION
PET studies with (64)Cu revealed that disulfiram had significant effects on the copper biodistribution of MD. Disulfiram increased copper transport into the brain and reduced copper uptake in the kidneys of MD model mice. The application of (64)Cu PET for the treatment of MD and other copper-related disorders may be useful in clinical settings.
Topics: Animals; Autoradiography; Brain; Chelating Agents; Copper; Copper Radioisotopes; Disease Models, Animal; Disulfiram; Gamma Rays; Kidney; Liver; Menkes Kinky Hair Syndrome; Mice; Mice, Inbred C3H; Mutation; Penicillamine; Positron-Emission Tomography; Radiopharmaceuticals; Time Factors; Tissue Distribution; Whole Body Imaging
PubMed: 24627433
DOI: 10.2967/jnumed.113.131797 -
Molecules (Basel, Switzerland) Jan 2014Redox active transition metal ions (e.g., iron and copper) have been implicated in the etiology of many oxidative stress-related diseases including also...
EPR spectroscopy of a clinically active (1:2) copper(II)-histidine complex used in the treatment of Menkes disease: a Fourier transform analysis of a fluid CW-EPR spectrum.
Redox active transition metal ions (e.g., iron and copper) have been implicated in the etiology of many oxidative stress-related diseases including also neurodegenerative disorders. Unbound copper can catalyze formation of reactive oxygen species (hydroxyl radicals) via Fenton reaction/Haber-Weiss chemistry and therefore, under physiological conditions, free copper is potentially toxic and very rarely exists inside cells. Copper(II) bound to the aminoacid L-histidine represents a species discovered in blood in the mid 60s and since then extensive research on this complex was carried out. Copper bound to L-histidine represents an exchangeable pool of copper(II) in equilibrium with the most abundant blood plasma protein, human serum albumin. The structure of this complex, in aqueous solution, has been a subject of many studies and reviews, however without convincing success. The significance of the (1:2) copper(II)-L-histidine complex at physiological pH documents its therapeutic applications in the treatment of Menkes disease and more recently in the treatment of infantile hypertrophic cardioencephalomyopathy. While recently the (1:2) Cu(II)-L-His complex has been successfully crystallized and the crystal structure was solved by X-ray diffraction, the structure of the complex in fluid solution at physiological pH is not satisfactorily known. The aim of this paper is to study the (1:2) Cu(II)-L-histidine complex at low temperatures by X-band and S-band EPR spectroscopy and at physiological pH at room temperature by Fourier transform CW-EPR spectroscopy.
Topics: Coordination Complexes; Electron Spin Resonance Spectroscopy; Fourier Analysis; Histidine; Humans; Hydrogen-Ion Concentration; Menkes Kinky Hair Syndrome; Molecular Conformation; Organometallic Compounds; Solutions
PubMed: 24434671
DOI: 10.3390/molecules19010980 -
Advances in Pharmacology (San Diego,... 2013Menkes disease is a lethal X-linked recessive disorder of copper metabolism caused by mutations in ATP7A, a copper-transporting ATPase with diverse and important... (Review)
Review
Catecholamine metabolites affected by the copper-dependent enzyme dopamine-beta-hydroxylase provide sensitive biomarkers for early diagnosis of menkes disease and viral-mediated ATP7A gene therapy.
Menkes disease is a lethal X-linked recessive disorder of copper metabolism caused by mutations in ATP7A, a copper-transporting ATPase with diverse and important biological functions. Partial deficiency of dopamine-beta-hydroxylase is a biochemical hallmark of this illness due to the normal role of ATP7A in delivery of copper as an enzymatic cofactor. We exploited this fact to develop a diagnostic test for Menkes disease, which proved highly sensitive and specific. The assay has enabled early identification of affected patients, leading to enhanced survival and improved neurodevelopment after early copper treatment, including some completely normal outcomes. In preclinical efforts to develop improved therapies for patients with non-copper-responsive ATP7A mutations, we used brain-directed adeno-associated viral gene therapy to rescue a murine model of the disease. Statistically significant improvement in brain catechol ratios correlated with enhanced survival, and cerebrospinal fluid catechols represent candidate surrogate markers of treatment effect in a future gene therapy clinical trial.
Topics: Adenosine Triphosphatases; Animals; Biomarkers; Catecholamines; Catechols; Cation Transport Proteins; Copper; Copper-Transporting ATPases; Dopamine beta-Hydroxylase; Early Diagnosis; Genetic Therapy; Humans; Menkes Kinky Hair Syndrome
PubMed: 24054147
DOI: 10.1016/B978-0-12-411512-5.00011-7 -
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 -
Handbook of Clinical Neurology 2013Two copper-transporting ATPases are essential for mammalian copper homeostasis: ATP7A, which mediates copper uptake in the gastrointestinal tract and copper delivery to... (Review)
Review
Two copper-transporting ATPases are essential for mammalian copper homeostasis: ATP7A, which mediates copper uptake in the gastrointestinal tract and copper delivery to the brain, and ATP7B, which mediates copper excretion by the liver into bile. Mutations in ATP7A may cause three distinct X-linked conditions in infants, children, or adolescents: Menkes disease, occipital horn syndrome (OHS), and a newly identified allelic variant restricted to motor neurons called X-linked distal hereditary motor neuropathy. These three disorders show variable neurological findings and ages of onset. Menkes disease presents in the first several months of life with failure to thrive, developmental delay, and seizures. OHS features more subtle developmental delays, dysautonomia, and connective tissue abnormalities beginning in early childhood. ATP7A-related distal motor neuropathy presents even later, often not until adolescence or early adulthood, and involves a neurological phenotype that resembles Charcot-Marie-Tooth disease, type 2. These disorders may be treatable through copper replacement or ATP7A gene therapy. In contrast, mutations in ATP7B cause a single known phenotype, Wilson disease, an autosomal recessive trait that results from copper overload rather than deficiency. Dysarthria, dystonia, tremor, gait abnormalities, and psychiatric problems may be presenting symptoms, at ages from 10 to 40 years. Excellent treatment options exist for Wilson disease, based on copper chelation. In the past 2 years (2012-2013), three new autosomal recessive copper metabolism conditions have been recognized: 1) Huppke-Brendel syndrome caused by mutations in an acetyl CoA transporter needed for acetylation of one or more copper proteins, 2) CCS deficiency caused by mutations in the copper chaperone to SODI, and 3) MEDNIK syndrome, which revealed that mutations in the σ1A subunit of adaptor protein complex 1 (AP-1) have detrimental effects on trafficking of ATP7A and ATP7B.
Topics: Chelating Agents; Child; Copper; Cutis Laxa; Ehlers-Danlos Syndrome; Hepatolenticular Degeneration; Humans; Infant; Menkes Kinky Hair Syndrome; Penicillamine; Prognosis
PubMed: 23622398
DOI: 10.1016/B978-0-444-59565-2.00045-9 -
Annals of Neurology Feb 2013Menkes disease is a lethal neurodegenerative disorder of infancy caused by mutations in a copper-transporting adenosine triphosphatase gene, ATP7A. Among its multiple...
OBJECTIVE
Menkes disease is a lethal neurodegenerative disorder of infancy caused by mutations in a copper-transporting adenosine triphosphatase gene, ATP7A. Among its multiple cellular tasks, ATP7A transfers copper to dopamine beta hydroxylase (DBH) within the lumen of the Golgi network or secretory granules, catalyzing the conversion of dopamine to norepinephrine. In a well-established mouse model of Menkes disease, mottled-brindled (mo-br), we tested whether systemic administration of L-threo-dihydroxyphenylserine (L-DOPS), a drug used successfully to treat autosomal recessive norepinephrine deficiency, would improve brain neurochemical abnormalities and neuropathology.
METHODS
At 8, 10, and 12 days of age, wild-type and mo-br mice received intraperitoneal injections of 200μg/g body weight of L-DOPS, or mock solution. Five hours after the final injection, the mice were euthanized, and brains were removed. We measured catecholamine metabolites affected by DBH via high-performance liquid chromatography with electrochemical detection, and assessed brain histopathology.
RESULTS
Compared to mock-treated controls, mo-br mice that received intraperitoneal L-DOPS showed significant increases in brain norepinephrine (p < 0.001) and its deaminated metabolite, dihydroxyphenylglycol (p < 0.05). The ratio of a non-beta-hydroxylated metabolite in the catecholamine biosynthetic pathway, dihydroxyphenylacetic acid, to the beta-hydroxylated metabolite, dihydroxyphenylglycol, improved equivalently to results obtained previously with brain-directed ATP7A gene therapy (p < 0.01). However, L-DOPS treatment did not arrest global brain pathology or improve somatic growth, as gene therapy had.
INTERPRETATION
We conclude that (1) L-DOPS crosses the blood-brain barrier in mo-br mice and corrects brain neurochemical abnormalities, (2) norepinephrine deficiency is not the cause of neurodegeneration in mo-br mice, and (3) L-DOPS treatment may ameliorate noradrenergic hypofunction in Menkes disease.
Topics: 3,4-Dihydroxyphenylacetic Acid; Adenosine Triphosphatases; Animals; Antiparkinson Agents; Blood-Brain Barrier; Brain; Brain Chemistry; Cation Transport Proteins; Copper; Copper-Transporting ATPases; Disease Models, Animal; Dopamine; Dopamine beta-Hydroxylase; Droxidopa; Female; Male; Menkes Kinky Hair Syndrome; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Nerve Degeneration; Norepinephrine
PubMed: 23224983
DOI: 10.1002/ana.23787 -
Dermatology Online Journal Nov 2012Menkes kinky hair syndrome, also known as trichopoliodystrophy, is a rare X-linked recessive, progressive neurodegenerative disorder characterized clinically by...
Menkes kinky hair syndrome, also known as trichopoliodystrophy, is a rare X-linked recessive, progressive neurodegenerative disorder characterized clinically by progressive psychomotor impairment, treatment-refractory seizures, and hair shaft abnormalities, most commonly pilli torti. The condition is related to a mutation in a copper transporting gene, located in the X-chromosome, resulting in deficiency of copper dependent enzymes. The diagnosis can be confirmed by a low plasma level of copper and ceruloplasmin. The prognosis of classical Menkes disease is poor. We report a case of Menkes kinky hair disease with characteristic clinical, laboratory, and radiological findings with significant macrocephaly (above 95th percentile for age). Reporting of this case is of significance because of its rarity and association with significant macrocephaly.
Topics: Humans; Infant; Male; Menkes Kinky Hair Syndrome
PubMed: 23217945
DOI: No ID Found