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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 -
Cellular and Molecular Life Sciences :... Jan 2008Menkes disease is caused by mutations in the copper-transporting P(1B)-type ATPase ATP7A. ATP7A has a dual function: it serves to incorporate copper into... (Review)
Review
Menkes disease is caused by mutations in the copper-transporting P(1B)-type ATPase ATP7A. ATP7A has a dual function: it serves to incorporate copper into copper-dependent enzymes, and it maintains intracellular copper levels by removing excess copper from the cytosol. To accomplish both functions, the protein traffics between different cellular locations depending on copper levels. The mechanism for sensing the concentration of copper, for trafficking, as well as the details of the mechanism of copper translocation across the membrane are unknown.
Topics: Adenosine Triphosphatases; Cation Transport Proteins; Copper; Copper-Transporting ATPases; Humans; Menkes Kinky Hair Syndrome; Mutation
PubMed: 17989919
DOI: 10.1007/s00018-007-7439-6 -
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 -
AJNR. American Journal of Neuroradiology Oct 2017Menkes disease is a rare multisystem X-linked disorder of copper metabolism. Despite an early, severe, and progressive neurologic involvement, our knowledge of brain... (Review)
Review
Menkes disease is a rare multisystem X-linked disorder of copper metabolism. Despite an early, severe, and progressive neurologic involvement, our knowledge of brain involvement remains unsatisfactory. The first part of this retrospective and review MR imaging study aims to define the frequency rate, timing, imaging features, and evolution of intracranial vascular and white matter changes. According to our analysis, striking but also poorly evolutive vascular abnormalities characterize the very early phases of disease. After the first months, myelination delay becomes evident, often in association with protean focal white matter lesions, some of which reveal an age-specific brain vulnerability. In later phases of the disease, concomitant progressive neurodegeneration might hinder the myelination progression. The currently enriched knowledge of neuroradiologic finding evolution provides valuable clues for early diagnosis, identifies possible MR imaging biomarkers of new treatment efficacy, and improves our comprehension of possible mechanisms of brain injury in Menkes disease.
Topics: Brain; Disease Progression; Female; Humans; Magnetic Resonance Imaging; Male; Menkes Kinky Hair Syndrome; Neuroimaging; Retrospective Studies; White Matter
PubMed: 28495946
DOI: 10.3174/ajnr.A5186 -
The Turkish Journal of Pediatrics 2022Hair microscopy is a fast and effortless diagnostic method for many diseases affecting hair in daily practice. Many diseases can present with hair shaft disorders in...
BACKGROUND
Hair microscopy is a fast and effortless diagnostic method for many diseases affecting hair in daily practice. Many diseases can present with hair shaft disorders in pediatric neurology practice.
METHODS
Children with pathological hair findings were included in our study. Microscopic evaluation of the hair was performed under light microscopy. The clinical findings, pathological hair shaft findings, laboratory tests, and final diagnosis of the patients were evaluated.
RESULTS
In our study, 16 patients with rare pathological hair findings were identified. Of these 16 patients, nine were diagnosed with giant axonal neuropathy, three with Griscelli syndrome, two with Menkes disease, and two with autosomal recessive woolly hair disease. In hair inspection, curly and tangled hair in patients with giant axonal neuropathy; silvery blond hair in patients with Griscelli syndrome; sparse, coarse, and light-colored hair in patients with Menkes disease; and hypotrichosis in patients with autosomal recessive woolly hair were remarkable findings. Dystrophic hair was detected in most of the patients on light microscopy. In addition, signs of trichorrhexis nodosa, tricoptylosis, and pili torti were found. In particular, pigment deposition in the hair shaft of two patients diagnosed with Griscelli syndrome and pili torti findings in two patients with Menkes disease were the most important findings suggestingthe diagnosis.
CONCLUSIONS
Detection of hair findings in the physical examination and performing light microscopic evaluation facilitates the diagnosis of rare diseases accompanied by hair findings. A hair examination should be performed as a part of physical and neurological examinationson eachpatient regardless of thecomplaint.
Topics: Humans; Child; Menkes Kinky Hair Syndrome; Giant Axonal Neuropathy; Hair; Hair Diseases; Nervous System Diseases; Primary Immunodeficiency Diseases; Amino Acid Metabolism, Inborn Errors
PubMed: 36583891
DOI: 10.24953/turkjped.2022.221 -
Frontiers in Bioscience (Landmark... Jun 2009The transition metal copper (Cu) is an essential trace element for all biota. Its redox properties bestow Cu with capabilities that are simultaneously essential and... (Review)
Review
The transition metal copper (Cu) is an essential trace element for all biota. Its redox properties bestow Cu with capabilities that are simultaneously essential and potentially damaging to the cell. Free Cu is virtually absent in the cell. The descriptions of the structural and functional organization of the metallothioneins, Cu-chaperones and P-type ATPases as well as of the mechanisms that regulate their distribution and functioning in the cell have enormously advanced our understanding of the Cu homeostasis and metabolism in the last decade. Cu is stored by metallothioneins and distributed by specialized chaperones to specific cell targets that make use of its redox properties. Transfer of Cu to newly synthesized cuproenzymes and Cu disposal is performed by the individual or concerted actions of the P-type ATPases ATP7A and ATP7B expressed in tissues. In mammalians liver is the major captor, distributor and excreter of Cu. Mutations in the P-type ATPases that interfere with their functioning and traffic are cause of the life-threatening Wilson (ATP7B) and Menkes (ATP7A) diseases.
Topics: Adenosine Triphosphatases; Animals; Cation Transport Proteins; Copper; Copper-Transporting ATPases; Diet; Electron Transport Complex IV; Glutathione; Hepatolenticular Degeneration; Homeostasis; Humans; Liver; Menkes Kinky Hair Syndrome; Metallothionein; Models, Biological; Molecular Chaperones; Mutation; Oxidation-Reduction; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 19482593
DOI: 10.2741/3575 -
Neurobiology of Disease Sep 2015ATP7A mutations impair copper metabolism resulting in three distinct genetic disorders in humans. These diseases are characterized by neurological phenotypes ranging... (Review)
Review
ATP7A mutations impair copper metabolism resulting in three distinct genetic disorders in humans. These diseases are characterized by neurological phenotypes ranging from intellectual disability to neurodegeneration. Severe ATP7A loss-of-function alleles trigger Menkes disease, a copper deficiency condition where systemic and neurodegenerative phenotypes dominate clinical outcomes. The pathogenesis of these manifestations has been attributed to the hypoactivity of a limited number of copper-dependent enzymes, a hypothesis that we refer as the oligoenzymatic pathogenic hypothesis. This hypothesis, which has dominated the field for 25 years, only explains some systemic Menkes phenotypes. However, we argue that this hypothesis does not fully account for the Menkes neurodegeneration or neurodevelopmental phenotypes. Here, we propose revisions of the oligoenzymatic hypothesis that could illuminate the pathogenesis of Menkes neurodegeneration and neurodevelopmental defects through unsuspected overlap with other neurological conditions including Parkinson's, intellectual disability, and schizophrenia.
Topics: Adenosine Triphosphatases; Animals; Cation Transport Proteins; Computational Biology; Copper-Transporting ATPases; Humans; Menkes Kinky Hair Syndrome; Mice; Mutation; Neurodegenerative Diseases; Neurodevelopmental Disorders
PubMed: 25583185
DOI: 10.1016/j.nbd.2014.12.024 -
Nihon Hinyokika Gakkai Zasshi. the... Jun 1991Menkes' kinky hair disease is a poor prognostic congenital disease with X-linked recessive inheritance. This disease is clinically characterized by seizures, friable... (Review)
Review
Menkes' kinky hair disease is a poor prognostic congenital disease with X-linked recessive inheritance. This disease is clinically characterized by seizures, friable hair, growth failure, mental retardation and others. Recently it has been known that this disease is also characterized by multiple diverticula of the bladder and other urological abnormalities. A 6-year-old boy was diagnosed as having Menkes' kinky hair disease at another hospital several weeks after birth because of seizures, friable hair and low serum copper level. He voided by Credé's maneuver by the nurse because he could not void for himself. He was referred to our hospital for macrohematuria and micturition pain on October 8, 1989. Right renal staghorn calculus and multiple diverticula of the bladder were found by roentgenographic examination. He has been treated conservatively after discharge because of his poor condition.
Topics: Child; Diverticulum; Humans; Kidney Calculi; Male; Menkes Kinky Hair Syndrome; Urinary Bladder Diseases
PubMed: 1908921
DOI: 10.5980/jpnjurol1989.82.994 -
Advances in Nutrition (Bethesda, Md.) Mar 2011Copper (Cu) is an essential micronutrient. Its ability to exist in 2 oxidation states (Cu(1+) and Cu(2+)) allows it to function as an enzymatic cofactor in hydrolytic,... (Review)
Review
Copper (Cu) is an essential micronutrient. Its ability to exist in 2 oxidation states (Cu(1+) and Cu(2+)) allows it to function as an enzymatic cofactor in hydrolytic, electron transfer, and oxygen utilization reactions. Cu transporters CTR1, ATP7A, and ATP7B play key roles in ensuring that adequate Cu is available for Cu-requiring processes and the prevention of excess Cu accumulation within cells. Two diseases of Cu metabolism, Menkes disease and Wilson disease, which are caused by mutations in ATP7A and ATP7B, respectively, exemplify the critical importance of regulating Cu balance in humans. Herein, we review recent studies of the biochemical and cell biological characteristics of CTR1, ATP7A, and ATP7B, as well as emerging roles for Cu in new areas of physiology.
Topics: Adenosine Triphosphatases; Animals; Biological Transport; Cation Transport Proteins; Copper; Copper Transporter 1; Copper-Transporting ATPases; Epithelial Cells; Hepatolenticular Degeneration; Humans; Mammals; Menkes Kinky Hair Syndrome; SLC31 Proteins; Trace Elements
PubMed: 22332042
DOI: 10.3945/an.110.000273 -
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