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Robert B. Rucker - One of the best experts on this subject based on the ideXlab platform.
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Expression and accumulation of lysyl oxidase, elastin, and type I procollagen in human Menkes and mottled mouse fibroblasts.
Archives of biochemistry and biophysics, 1993Co-Authors: S. Gacheru, Carl L Keen, Carl Mcgee, Janet Y. Uriu-hare, Taru Kosonen, S. Packman, Donald Tinker, Stephen A. Krawetz, Karen M. Reiser, Robert B. RuckerAbstract:Menkes Syndrome in humans is an X-linked disorder characterized in part by abnormal copper transport, cellular copper sequestration, and defective crosslinking of collagen and elastin. A decrease in the functional activity of lysyl oxidase, a cuproenzyme, is thought in part to be responsible for the decreased crosslinking of collagen and elastin. It has also been suggested that low levels of lysyl oxidase activity may occur secondarily to disturbances in intracellular copper translocation and consequently impaired incorporation of copper into lysyl oxidase. Herein, we examine the expression and accumulation of selected extracellular matrix proteins in fibroblasts from a Menkes patient, as well as fibroblasts from the tortoiseshell (MoTo/y) mouse. The MoTo mutation is an allele of the mottled (Mo) locus, which is considered to be a murine analog of the human Menkes locus. In both Menkes and tortoiseshell fibroblasts, levels of lysyl oxidase mRNA transcripts were less than 15% of levels for corresponding controls. The level of elastin mRNA transcripts was also markedly lower in both cell lines in comparison to controls. In contrast, the levels of procollagen Type I mRNA were similar or enhanced in Menkes and MoTo/y fibroblasts compared to their respective controls. Consequently, we conclude that the connective tissue defects associated with Menkes Syndrome and those occurring in mottled mouse mutants involve more than abnormal copper utilization in the formation of lysyl oxidase holoenzyme. Based on the present studies in cell culture, the production of essential enzymes and matrix proteins, such as lysyl oxidase and elastin, appear to be altered at the level of transcription or mRNA turnover.
Nina Horn - One of the best experts on this subject based on the ideXlab platform.
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Molecular diagnosis of Menkes disease: genotype-phenotype correlation.
Biochimie, 2009Co-Authors: Lisbeth Birk Møller, Mie Mogensen, Nina HornAbstract:Menkes Syndrome is an X-linked, fatal neurodegenerative disorder of copper metabolism, caused by mutations in the ATP7A gene, encoding a copper-transporting P1B-type ATPase. To date, a total of approximately 160 different mutations have been reported worldwide. The clinical phenotypes observed in these patients include progressive neuro-degeneration, connective-tissue abnormalities and peculiar hair. There is phenotypic variability. While the majority of the patients do not survive early childhood, milder cases leading to longer survival have been reported. In this review we focus on mutations, identified in patients with milder forms of Menkes disease, and discuss the possibility of establishing a genotype-phenotype correlation. The presence of small amounts of normal protein, or the presence of partly functional protein variants containing a less essential amino acid substitution or a truncation of the N- or C-terminus, might all result in a milder, atypical phenotype. A clear phenotype-genotype correlation is however difficult to establish, clearly illustrated by the presence of inter- and even intra-familial variability.
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Clinical expression of Menkes Syndrome in females
Clinical genetics, 2008Co-Authors: A.-m. Gerdes, T. Tønnesen, Nina Horn, T. Grisar, W. Marg, A. Müller, R. Reinsch, N. W. Barton, P. Guiraud, A. JoannardAbstract:Three female patients with Menkes Syndrome are described. Clinically, they have typical Menkes Syndrome. Biochemically, they have significantly increased 64Cu-uptake in cultured fibroblasts. The chromosomal analysis was normal for two of the patients and abnormal for one patient (45X/46XX mosaicism).
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Life-span and Menkes kinky hair Syndrome: report of a 13-year course of this disease
Clinical genetics, 2008Co-Authors: Conrad Sander, Helmut Niederhoff, Nina HornAbstract:The life-span of Menkes Syndrome patients is discussed in connection with a boy suffering from this disease who lived to the age of 13.5 years. The copper metabolism defect is described. Therapeutic trials, mainly copper substitution, and prospects are summed up.
V. Fanos - One of the best experts on this subject based on the ideXlab platform.
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Urological complications and copper replacement therapy in childhood Menkes Syndrome.
Acta paediatrica (Oslo Norway : 1992), 2006Co-Authors: Marco Zaffanello, V. Fanos, Claudio Maffeis, Massimo Franchini, Giorgio ZamboniAbstract:Background: Urological complications are frequent in Menkes Syndrome, a very rare X-linked recessive disorder of copper (Cu) metabolism. Aim: To evaluate the role of Cu therapy in preventing the progression of urological complications. Subjects and methods: We retrospectively enrolled 57 patients with Menkes Syndrome (55 published case reports and two of our own unpublished cases) and investigated the reported urological complications, distinguishing the patients with or without Cu replacement therapy and evaluating the efficacy of this therapy in the prevention of urological complications. Results: The most frequent urological complication was bladder diverticulum (38.6% of the total patients); obstruction bladder outflow and rupture of the kidney were less frequent (both 1.8% of the total). The number of congenital urological complications increased progressively by age category; in fact, 77.8% of patients did not report urological complications at the age of 0.4±0.2 y, and 28.6% of them displayed ≥ two congenital urological complications at the age of 9.3±2.6 y. The percentage of urological complications found in younger patients not on Cu therapy did not differ from that of older patients treated with Cu therapy. A comparison between patients of the same age interval, who were or were not treated with Cu, showed that treated children had fewer urological complications than untreated children. Conclusion: Our investigation suggests that Cu therapy in patients with Menkes Syndrome does not prevent the progression of urological complications; however, it might delay their worsening.
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Rare Urological Abnormalities in 2 Cases of Menkes’ Syndrome
The Journal of Urology, 2003Co-Authors: Marco Zaffanello, V. FanosAbstract:Menkes’ Syndrome (MS) is a rare inborn disorder of copper metabolism with X-linked recessive inheritance. Defective intestinal copper absorption results in copper accumulation in the intestine, low serum levels of copper and decreased activity of copper enzymes. Usually the prognosis is unfavorable, and the Syndrome is frequently associated with a life span of 3 years or less. We describe 2 patients with MS who survived more than 3 years and had development of rare urinary abnormalities.
Kari I. Kivirikko - One of the best experts on this subject based on the ideXlab platform.
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Expression of mRNAs for lysyl oxidase and type III procollagen in cultured fibroblasts from patients with the Menkes and occipital horn Syndromes as determined by quantitative polymerase chain reaction.
Archives of biochemistry and biophysics, 1996Co-Authors: Ritva Kemppainen, Helena Kuivaniemi, Eija-riitta Hämäläinen, Gerard Tromp, Taina Pihlajaniemi, Kari I. KivirikkoAbstract:Abstract The Menkes Syndrome and the occipital horn Syndrome are two X-linked recessively inherited disorders characterized by abnormalities in copper metabolism. These abnormalities are associated with a reduction in the activity of lysyl oxidase (EC 1.4.3.13), an extracellular copper enzyme that initiates the crosslinking of collagens and elastin. We report here that the amount of lysyl oxidase mRNA, as studied by Northern blotting, and the number of lysyl oxidase mRNA molecules per picogram of RNA, as determined by a quantitative PCR method, were decreased in three cultured skin fibroblast lines from patients with the Menkes Syndrome and two from patients with the occipital horn Syndrome compared with four control cell lines. The decreased lysyl oxidase activity found in these disorders thus appears to be at least in part due to a pretranslational mechanism. No decrease was found in the number of the β-actin mRNA molecules in the Menkes cell lines, but rather a slight increase, whereas a decrease was found in these molecules in the occipital horn cell lines. An additional abnormality found in the Menkes cell lines was a significant increase in the number of mRNA molecules for type III procollagen in two of the three cell lines investigated. The present and previous data indicate that the Menkes Syndrome may involve several abnormalities in the expression of genes for connective tissue proteins.
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molecular cloning of human lysyl oxidase and assignment of the gene to chromosome 5q23 3 31 2
Genomics, 1991Co-Authors: Eija-riitta Hämäläinen, Taina Pihlajaniemi, Tania A Jones, Denise Sheer, Kirsi Taskinen, Kari I. KivirikkoAbstract:Abstract Lysyl oxidase (EC 1.4.3.13) initiates the crosslinking of collagens and elastin by catalyzing oxidative deamination of the ϵ-amino group in certain lysine and hydroxylysine residues. We report here on the isolation and characterization of cDNA clones for the enzyme from human placenta and rat aorta λgt11 cDNA libraries. A cDNA clone for human lysyl oxidase covers all the coding sequences, 230 nucleotides of the 5′ and 299 nucleotides, of the 3′ untranslated sequences, including a poly(A) tail of 23 nucleotides. This cDNA encodes a polypeptide of 417 amino acid residues, including a signal peptide of 21 amino acids. Sequencing of two rat lysyl oxidase cDNA clones indicated six differences between the present and the previously published sequence for the rat enzyme [Trackman et al. (1990) Biochemistry 29: 4863–4870], resulting in frame-shifts in the translated sequence. The human lysyl oxidase sequence was found to be 78% identical to the revised rat sequence at the nucleotide level and 84% identical at the amino acid level, with the degree of identity unevenly distributed between various regions of the coded polypeptide. Northern blot analysis of human skin fibroblast RNA indicated that the human lysyl oxidase cDNA hybridizes to at least four mRNA species; their sizes are about 5.5, 4.3, 2.4, and 2.0 kb. Analysis of a panel of 25 human × hamster cell hybrids by Southern blotting mapped the human lysyl oxidase gene to chromosome 5, and in situ hybridization mapped it to 5q23.3–31.2. This assignment excludes primary defects in this gene as causes of the deficiency in lysyl oxidase activity and enzyme protein which are found in two X-linked recessively inherited disorders, the Menkes Syndrome and the type IX variant of the Ehlers-Danlos Syndrome.
Stephen G. Kaler - One of the best experts on this subject based on the ideXlab platform.
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Menkes' Syndrome: ophthalmic findings.
Ophthalmology, 2002Co-Authors: Alice T Gasch, Rafael C. Caruso, Stephen G. Kaler, Muriel I. Kaiser-kupferAbstract:Abstract Purpose To report the prevalence and clinical significance of ocular findings in 20 patients with Menkes' Syndrome recruited for a clinical trial at the National Institute of Child Health and Human Development (NICHHD). Design Retrospective observational case series. Participants Twenty patients with Menkes' Syndrome enrolled in a clinical trial at the NICHHD, who underwent ophthalmic evaluation at the National Eye Institute from 1990 through 1997. Methods Review of clinical ophthalmic examination records, photographs, and visual evoked potential recordings. Main outcome measures Prevalence of ophthalmic signs of unusual frequency in patients with Menkes' Syndrome. Results There was a high prevalence of very poor visual acuity (8 patients), myopia at 21 months old or younger (5 of 9 patients this age who underwent cycloplegic refraction), strabismus (11 of 18 patients whose motility was evaluated), blue irides (15 of 16 patients whose iris color was documented), iris stromal hypoplasia and bilateral peripheral transillumination (7 and 3 patients, respectively), peripheral retinal hypopigmentation (7 of 18 patients whose retinal periphery was noted at the initial examination), and aberrant eyelashes (5 patients). Conclusions Patients with Menkes' Syndrome exhibit a high prevalence of several ocular findings, including some (very poor visual acuity, myopia, strabismus) that may warrant special care. Early ocular examination is thus indicated for patients with Menkes' Syndrome, particularly those with mild variants of the disease, whose neurologic status is better and lifespan is longer.
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Diagnosis and therapy of Menkes Syndrome, a genetic form of copper deficiency.
The American Journal of Clinical Nutrition, 1998Co-Authors: Stephen G. KalerAbstract:In the 25 y since copper deficiency was first delineated in persons with Menkes Syndrome, advances in our understanding of the clinical, biochemical, and molecular aspects of this rare disorder have surpassed progress in the design of effective therapies. In contrast with purely nutritional copper deficiency, in which copper replacement can be curative, the nature of the basic defect in Menkes Syndrome suggests that corrective efforts are likely to be more complicated, a point supported by the cumulative literature on this topic as well as by emerging molecular data. In this paper, certain clinical, biochemical, and molecular aspects of copper histidine treatment in 25 Menkes Syndrome patients at the National Institutes of Health are reviewed. The delineation of a distinctive neurochemical pattern in plasma and cerebrospinal fluid, reflecting deficiency of the copper enzyme dopamine β-monooxygenase, is arguably the most important finding in the study of Menkes Syndrome. This abnormal pattern has proven extremely reliable as a rapid diagnostic test, enabling early identification of affected infants-a fundamental requirement for improving clinical outcomes. Of 11 patients identified by prenatal or prompt postnatal testing and treated within the first 10 d of age, one walked at 14 mo of age and has normal neurodevelopment at age 3 y and another infant's early progress appears promising. However, five patients died in infancy and neurodevelopmental outcome was suboptimal in four others. Consideration of additional therapeutic strategies seems necessary, therefore, for most patients and families facing this troublesome form of copper deficiency.