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PLoS Genetics Jan 2023Copper (Cu) has a multifaceted role in brain development, function, and metabolism. Two homologous Cu transporters, Atp7a (Menkes disease protein) and Atp7b (Wilson...
Copper (Cu) has a multifaceted role in brain development, function, and metabolism. Two homologous Cu transporters, Atp7a (Menkes disease protein) and Atp7b (Wilson disease protein), maintain Cu homeostasis in the tissue. Atp7a mediates Cu entry into the brain and activates Cu-dependent enzymes, whereas the role of Atp7b is less clear. We show that during postnatal development Atp7b is necessary for normal morphology and function of choroid plexus (ChPl). Inactivation of Atp7b causes reorganization of ChPl' cytoskeleton and cell-cell contacts, loss of Slc31a1 from the apical membrane, and a decrease in the length and number of microvilli and cilia. In ChPl lacking Atp7b, Atp7a is upregulated but remains intracellular, which limits Cu transport into the brain and results in significant Cu deficit, which is reversed only in older animals. Cu deficiency is associated with down-regulation of Atp7a in locus coeruleus and catecholamine imbalance, despite normal expression of dopamine-β-hydroxylase. In addition, there are notable changes in the brain lipidome, which can be attributed to inhibition of diacylglyceride-to-phosphatidylethanolamine conversion. These results identify the new role for Atp7b in developing brain and identify metabolic changes that could be exacerbated by Cu chelation therapy.
Topics: Mice; Animals; Copper-Transporting ATPases; Copper; Choroid Plexus; Menkes Kinky Hair Syndrome; Brain
PubMed: 36626371
DOI: 10.1371/journal.pgen.1010558 -
Journal of Medical Genetics Mar 1995
Review
Topics: Female; Humans; Menkes Kinky Hair Syndrome; Pregnancy
PubMed: 7783172
DOI: 10.1136/jmg.32.3.213 -
Journal of Korean Medical Science Jan 2019Menkes disease (MD) is a rare X-linked hereditary multisystemic disorder that is caused by dysfunction of copper metabolism. Patients with MD typically present with...
BACKGROUND
Menkes disease (MD) is a rare X-linked hereditary multisystemic disorder that is caused by dysfunction of copper metabolism. Patients with MD typically present with progressive neurodegeneration, some connective tissue abnormalities, and characteristic "kinky" hair. In addition, various types of urological complications are frequent in MD because of underlying connective tissue abnormalities. In this study, we studied the clinical features and outcomes of MD, focusing on urological complications.
METHODS
A total of 14 unrelated Korean pediatric patients (13 boys and 1 girl) with MD were recruited, and their phenotypes and genotypes were analyzed by retrospective review of their medical records.
RESULTS
All the patients had early-onset neurological deficit, including developmental delay, seizures, and hypotonia. The girl patient showed normal serum copper and ceruloplasmin levels as well as milder symptoms. Mutational analysis of the gene revealed 11 different mutations in 12 patients. Bladder diverticula was the most frequent urological complication: 8 (57.1%) in the 14 patients or 8 (72.7%) in the 11 patients who underwent urological evaluation. Urological imaging studies were performed essentially for the evaluation of accompanying urinary tract infections. Four patients had stage II chronic kidney disease at the last follow-up.
CONCLUSION
Urologic problems occurred frequently in MD, with bladder diverticula being the most common. Therefore, urological imaging studies and appropriate management of urological complications, which may prevent or reduce the development of urinary tract infections and renal parenchymal damage, are required in all patients with MD.
Topics: Child, Preschool; Copper-Transporting ATPases; DNA Mutational Analysis; Diverticulum; Female; Genotype; Humans; Male; Menkes Kinky Hair Syndrome; Phenotype; Prognosis; Retrospective Studies; Ultrasonography; Urinary Bladder
PubMed: 30618512
DOI: 10.3346/jkms.2019.34.e4 -
American Journal of Human Genetics Apr 1995
Review
Topics: Animals; Biological Transport; Copper; Disease Models, Animal; Genes; Hepatolenticular Degeneration; Humans; Menkes Kinky Hair Syndrome
PubMed: 7717393
DOI: No ID Found -
Expert Opinion on Investigational Drugs Jan 2021
Topics: Animals; Copper; Drug Repositioning; Drugs, Investigational; Humans; Hydrazines; Menkes Kinky Hair Syndrome
PubMed: 33081534
DOI: 10.1080/13543784.2021.1840550 -
Molecular Genetics & Genomic Medicine Aug 2019Koolen-de Vries (KdV) syndrome is caused by a 17q21.31 deletion leading to clinical symptoms of hypotonia and developmental delay and can present with abnormal hair...
BACKGROUND
Koolen-de Vries (KdV) syndrome is caused by a 17q21.31 deletion leading to clinical symptoms of hypotonia and developmental delay and can present with abnormal hair texture. Menkes disease is an X-linked recessive inherited disease caused by pathogenic variants in ATP7A, which leads to profound copper deficiency.
METHOD
We identified an infant male who presented with prematurity, hypotonia, and dysmorphic features for whom a family history of clinical Menkes disease was revealed after discussion with the clinical genetics team.
RESULTS
Although initial first-tier genetic testing identified Kdv syndrome (17q21.31 syndrome), the family history led the team to consider a second diagnostic possibility, and testing of ATP7A revealed a pathogenic variant (c.601C>T, p.R201X).
CONCLUSION
Menkes disease and KdV syndrome may both present with hypotonia and abnormal hair, in addition to seizures and failure to thrive. While these genetic conditions have overlapping clinical features, they have different natural histories and different therapeutic options. Here, we report on a patient affected with both disorders and review the diagnostic and therapeutic difficulties this presented.
Topics: Abnormalities, Multiple; Chromosome Deletion; Chromosomes, Human, Pair 17; Comparative Genomic Hybridization; Copper-Transporting ATPases; DNA Mutational Analysis; Fatal Outcome; Genetic Testing; Histidine; Humans; Hypertension, Pulmonary; Infant, Newborn; Intellectual Disability; Male; Medical History Taking; Menkes Kinky Hair Syndrome; Mutation; Nitric Oxide; Organometallic Compounds; Pedigree; Respiratory Insufficiency
PubMed: 31250568
DOI: 10.1002/mgg3.829 -
The Journal of Clinical Investigation May 1987Menkes kinky hair syndrome is an X-linked neurodegenerative disorder, causing tissue-specific increases in copper and metallothionein content. A mouse model is provided...
Menkes kinky hair syndrome is an X-linked neurodegenerative disorder, causing tissue-specific increases in copper and metallothionein content. A mouse model is provided by hemizygotes for mutant alleles at the X-linked mottled locus. Herein we test the possibility that the primary defect in both species is in metallothionein gene regulation. We show that metallothionein-I messenger RNA (mRNA) (mouse) and metallothionein-II mRNA (human) are elevated in mutant fibroblasts. However, comparable dose-response curves in mutant and control cells are generated when mouse metallothionein-I mRNA concentrations are measured in cells exposed to varying concentrations of cadmium or copper (metallothionein inducers). Furthermore, when mutant and control cells are grown to achieve overlapping intracellular copper concentrations in the two cell types, metallothionein-I (mouse) and metallothionein-II (human) mRNA levels are proportional to the intracellular copper concentrations. Finally, in paired determinations in blotchy hemizygote and littermate kidneys containing comparable copper levels, metallothionein-I mRNA contents are very similar. The observations suggest that elevated intracellular copper in these mutants induces metallothionein synthesis by normal regulatory mechanisms.
Topics: Alleles; Animals; Brain Diseases, Metabolic; Cadmium; Copper; Female; Male; Menkes Kinky Hair Syndrome; Metallothionein; Mice; Mice, Mutant Strains; RNA, Messenger
PubMed: 3571489
DOI: 10.1172/JCI112959 -
Journal of Neurology, Neurosurgery, and... Jun 1978The evolution of neurophysiological features including the electroencephalogram (EEG), electroretinogram (ERG), and visual evoked potentials (VEP) is reported in eight...
The evolution of neurophysiological features including the electroencephalogram (EEG), electroretinogram (ERG), and visual evoked potentials (VEP) is reported in eight cases of Menkes' "kinky hair" disease. All EEGs were severely abnormal, with some characteristic features seen from 3-5 months of age, after the onset of clinical symptomatology. From the age of 5 months, the EEGs resembled hypsarrhythmic patterns. The ERG was not affected in any patient, but the VEP was either of low amplitude or completely absent in all but one of the six patients tested. All eight patients received copper injections without substantial effect on either the clinical course of the disease or the EEG features.
Topics: Brain Diseases, Metabolic; Cerebral Cortex; Child, Preschool; Copper; Electroencephalography; Electroretinography; Epilepsies, Partial; Evoked Potentials; Humans; Infant; Male; Menkes Kinky Hair Syndrome; Optic Nerve; Sleep
PubMed: 97372
DOI: 10.1136/jnnp.41.6.505 -
Biochimica Et Biophysica Acta Feb 1997
Review
Topics: Adenosine Triphosphatases; Biological Transport; Carrier Proteins; Cation Transport Proteins; Copper; Copper-Transporting ATPases; Hepatolenticular Degeneration; Humans; Intestinal Absorption; Menkes Kinky Hair Syndrome; Metalloproteins; Mutation; Recombinant Fusion Proteins
PubMed: 9061035
DOI: 10.1016/s0925-4439(96)00064-6 -
American Journal of Human Genetics Jul 1985Type IX of the Ehlers-Danlos syndrome (E-D IX) and the Menkes syndrome are X-linked recessively inherited disorders characterized by abnormalities in copper metabolism....
Type IX of the Ehlers-Danlos syndrome (E-D IX) and the Menkes syndrome are X-linked recessively inherited disorders characterized by abnormalities in copper metabolism. These abnormalities are associated with a severe reduction in the activity of lysyl oxidase, the extracellular copper enzyme that initiates crosslinking of collagens and elastin. No increase in this deficient enzyme activity was obtained when culture media from fibroblasts of patients with E-D IX or the Menkes syndrome were incubated with copper under various conditions in vitro. A distinct, although small, increase in lysyl oxidase activity was obtained, however, when copper-supplemented media were used during culturing of the fibroblasts, although even under these conditions, the enzyme activity in the media from the affected cells remained markedly below that of the controls. Immunoprecipitation, dot-blotting, and immunoperoxidase staining experiments with antisera to human lysyl oxidase indicated that fibroblasts from patients with E-D IX or the Menkes syndrome do not secrete into their medium, or contain inside the cell, any significant amounts of a copper-deficient, catalytically inactive lysyl oxidase protein. These findings appear to be consistent with the hypothesis that synthesis of the lysyl oxidase protein itself is impaired. The possibility is not excluded, however, that a copper-deficient enzyme protein may be synthesized in normal amounts but become degraded very rapidly inside the cell. The failure to obtain any large increase in the deficient lysyl oxidase activity upon various forms of copper administration suggests that it may not be possible to obtain any significant improvement in the connective tissue manifestations of these disorders by copper therapy.
Topics: Adolescent; Adult; Cells, Cultured; Copper; Culture Media; Ehlers-Danlos Syndrome; Fibroblasts; Humans; Menkes Kinky Hair Syndrome; Protein-Lysine 6-Oxidase
PubMed: 9556668
DOI: No ID Found