Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022716 (Menkes)
 1,057 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thalamic degeneration was present in 5 autopsied cases of X-chromosome-linked copper malabsorption (X-cLCM), Menkes' kinky hair disease. Among the thalamic nuclei, those in the formatio paraventricularis, intralamellaris, and extralamellaris were spared. The nuclei projecting to the granular cortices had severe neuronal depopulation. The thalamic nuclei that send axons to the agranular cortices were less often and less severely involved. The thalamic afferent system was intact except for degeneration of the red nucleus. Cerebral cortical lesions varied from case to case and usually were less marked than thalamic neuronal changes.
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PMID:Thalamic degeneration in X-chromosome--linked copper malabsorption. 44 70

The cerebellar cortices in two patients with X-chromosome-linked copper malabsorption (Menkes kinky-hair disease) were examined with both the light and electron microscope. Somatic sprouts and grotesque dendritic arborization were among the obvious light microscopical changes. At the fine structural level, the Purkinje cells were characterized by the presence of somatic spines although the surviving granule cells had already descended. Most spines were parts of synaptic complexes, but some were unattached to any presynaptic element. Similar spines were also observed on dendritic trunks. Astrocytic gliosis and nonspecific endothelial cell changes were noted.
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PMID:Fine structure of the cerebellar cortex in Menkes Kinky-hair disease. X-chromosome-linked copper malabsorption. 83 87

We have performed 28 first trimester diagnoses for Menkes disease in 27 high risk pregnancies by direct copper measurement on chorionic villi (c.v.) Two male fetuses were found to be affected because of significantly increased copper content. In one male fetus a slightly increased copper content was observed indicating an exogenous copper contamination of the sample. This view was supported by normal results observed after abortion. Three out of 15 diagnostic c.v. samples with a female karyotype showed increased copper levels. In two of these cases, part of the copper content might have been released from the cannulae used for these particular biopsies. Histochemical visualization of copper accumulation in fixed chorionic villi of two affected fetuses and one female fetus was observed. [64Cu]-uptake studies have been performed on 11 diagnostic and 10 control c.v. samples. As the control samples in some cases were found to incorporate more [64Cu] than the corresponding diagnostic sample, this method cannot at present be used for diagnosis. Compiled results on newborn females gave evidence that two carriers expressed the paternal X-chromosome, and two carriers expressed the maternal X-chromosome in in chorionic villi.
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PMID:Experience with first trimester prenatal diagnosis of Menkes disease. 367 35

The clinical and morphological features were studied in female heterozygotes of the sex-linked brindled mutant mice, which are an appropriate animal model for human Menkes' kinky hair disease (MKHD). Clinically, female heterozygotes presented phenotypical variety. In these heterozygotes, we distinguished the unique group of mice, which showed mottled white and dark brown fur and curly whiskers. We designated this unique group "heterozygote, variant type", in contrast to the remaining group--"heterozygote, usual type"--, of which the fur was mottled dark and light brown, and the whiskers were straight. Ultrastructurally, various degrees of mitochondrial changes, from an almost normal appearance of the mitochondria to similar to those of the hemizygotes, were observed. Furthermore we noticed that, in the heterozygotes, there were positive correlations between this morphological spectrum and those phenotypical varieties. These findings were interpreted as a possible subclinical copper deficiency in the heterozygotes, and the morphological alterations in heterozygotes were probably due to X-chromosome inactivation according to Lyon's hypothesis. The presence, however, of clinical and morphological varieties in the heterozygotes leads us to the hypothesis that the inactivation rate is not necessarily the same for all carriers. Moreover, it can be speculated that pathologic changes similar to those in heterozygotes may be present in the female carriers of human MKHD.
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PMID:Neuropathologic study in the heterozygotes of X-linked brindled mutant mouse. 405 Mar 46

Previous studies by others indicated that alterations in brain catecholamines were different for perinatal copper deficiency produced by diet in rats and that resulting from a genetic mutation of the X-chromosome, Menkes' syndrome in humans and brindled mice. Thus, copper deficiency was studied in a model in which dietary and genetic deficiency (brindled mice) were compared in two strains of the same species. C57BL and C3H/HeJ mice. Dietary copper deficiency was also produced in rats for comparison. In brain, both dietary and genetic copper deficiency resulted in impaired growth, low brain copper levels, greatly decreased norepinephrine concentrations but normal dopamine levels. The activity of brain cytochrome oxidase was greatly depressed following both dietary and genetic copper deficiency, suggesting a functional deficit of copper. However, the activity of another cuproenzyme, dopamine-beta-hydroxylase, was significantly elevated in deficient animals. The elevation was observed when either copper or N-ethylmaleimide was added to inactivate an endogenous inhibitor. The cause of low brain norepinephrine remains unknown; however, depressed brain norepinephrine may be partly responsible for functional changes in the deficient animals, such as hypomyelination, since the activity of the myelin protein, 2',3'-cyclic nucleotide 3'-phosphodiesterase, was lower in the most deficient animals.
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PMID:Effect of dietary or genetic copper deficiency on brain catecholamines, trace metals and enzymes in mice and rats. 628 8

Increased 64Cu uptake into cultured cells is a biochemical marker for mutant cells in Menkes' disease (McKusick 30940). Using this marker selective prenatal diagnosis has been carried out in more than 80 at-risk pregnancies. The 64Cu uptake into cultures from affected male fetuses is however, negatively correlated to the fetal age at amniocentesis. After the 18th week of gestation the risk of false negatives is significant. Using copper uptake into uncloned cultures, a number of obligate and possible carriers showed significantly increased values, but the range of values of obligate carriers considerably overlapped those of the normal controls. All values of normal controls were within a limited range and values above the upper limit in females at risk must, therefore, be caused by mutant cells and establish the carrier diagnosis. However, the extreme skewing of the distribution towards normal values in obligate carriers indicates a strong selection against the mutant cell type and this will hamper the detection of all female carriers in risk families. C-banding heteromorphism of the X-chromosome provides a supplementary carrier detection method. Linkage analysis in five Danish families demonstrated a close physical relationship between the gene for Menkes' disease and the centromere region. By comparative gene mapping (mouse/man) the most likely localization of the gene for Menkes' disease can be suggested to be in band q13 on the long arm of the human X-chromosome. This regional assignment facilitates the choice of appropriate X-specific DNA probes in search for linkage at the DNA level.
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PMID:Menkes' X-linked disease: prenatal diagnosis and carrier detection. 641 76

A search with the proposed amino acid translation product from the new 'candidate gene' for human Menkes disease against protein sequence libraries showed a remarkable similarity to that for the cadmium efflux ATPase from Staphylococcus aureus resistance plasmids. The Menkes sequence appears closer to the CadA Cd2+ sequence than to P-type ATPases from animal sources. Menkes syndrome is an X-chromosome invariably fatal disease that results from aberrant copper metabolism. The gene that is defective in Menkes patients, i.e. the Menkes candidate gene, encodes a P-type ATPase, whose properties satisfactorily explain the phenotype of the disease. P-type ATPases are all cation pumps, either for uptake (e.g. the bacterial Kdp K+ ATPase), for efflux (e.g. the muscle sarcoplasmic reticulum Ca2+ ATPase), or for cation exchange (e.g. the animal cell Na+/K+ ATPase). These enzymes have a conserved aspartate residue that is transiently phosphorylated from ATP during the transport cycle, hence the name 'P-type' ATPase. The Menkes sequence shares with the staphylococcal CadA ATPase those regions common to all P-type ATPases and also an N-terminal dithiol region that was proposed to be a 'metal-binding motif'. There are one or two copies of this motif in the available CadA sequences and six copies in the Menkes sequence.
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PMID:Human Menkes X-chromosome disease and the staphylococcal cadmium-resistance ATPase: a remarkable similarity in protein sequences. 796 20

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.
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PMID:Menkes kinky hair syndrome: a case report. 2321 45

Mutations in ATP7A lead to at least three allelic disorders: Menkes disease (MD), Occipital horn syndrome and X-linked distal motor neuropathy. These disorders are mainly seen in male individuals, but a few affected females have been described. More than 400 different mutations have been identified in the ATP7A gene. We have conducted several studies in the hope of uncovering the relationship between genotype and phenotype. We have examined the X-inactivation pattern in affected females, the effect of exon-deletions and--duplications, and splice-site mutations on the composition and amount of ATP7A transcript, and we have examined the structural location of missense mutations. The X-inactivation pattern did not fully explain the manifestation of MD in a small fraction of carriers. Most of the affected females had preferential inactivation of the X-chromosome with the normal ATP7A gene, but a few individuals exhibited preferential inactivation of the X-chromosome with the mutated ATP7A gene. The observed mild phenotype in some patients with mutations that effect the composition of the ATP7A transcript, seems to be explained by the presence of a small amount of normal ATP7A transcript. The location of missense mutations on structural models of the ATP7A protein suggests that affected conserved residues generally lead to a severe phenotype. The ATP7A protein traffics within the cells. At low copper levels, ATP7A locates to the Trans-Golgi Network (TGN) to load cuproenzymes with copper, whereas at higher concentrations, ATP7A shifts to the post-Golgi compartments or to the plasma membrane to export copper out of the cell. Impaired copper-regulation trafficking has been observed for ATP7A mutants, but its impact on the clinical outcome is not clear. The major problem in patients with MD seems to be insufficient amounts of copper in the brain. In fact, prenatal treatment of mottled mice as a model for human MD with a combination of chelator and copper, produces a slight increase in copper levels in the brain which perhaps leads to longer survival and more active behavior. In conclusion, small amounts of copper at the right location seem to relieve the symptoms.
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PMID:Small amounts of functional ATP7A protein permit mild phenotype. 2517 13

We report on the case of a child who presented with recurrent, multiple, and voluminous bladder diverticula. Bladder diverticula are defined as a herniation of the mucosa through the bladder muscle or the detrusor. Causes are numerous and diverticula can be classified into primary congenital diverticula (para-ureteral - or Hutch diverticula - and posterolateral diverticula); secondary diverticula (resulting from chronic mechanical obstruction or from neurological disease; and diverticula secondary to connective tissue or muscle fragility. The latter is seen in disease entities such as prune belly syndrome, Ehlers-Danlos syndrome, cutis laxa syndrome, OHS (occipital horn syndrome), Menkes disease, and Williams-Beuren syndrome. In this patient, the cause of these diverticula was OHS, a genetic, recessive X-chromosome-linked syndrome, responsible for abnormal tissue caused by a disorder in copper metabolism. This case reminds us of the importance of pushing the diagnostic workup when presented with multiple and/or large bladder diverticula, and in particular to search for rare malformation syndromes after exclusion of an obstacle.
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PMID:[Multiple bladder diverticula caused by occipital horn syndrome]. 2638 12


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