Since then over 20 cases have been reportedfew in combination with a sufficiently. The most promising therapy to date, very early subcutaneous copper injections. The population frequency of sporadic cases is compatible with the expected for an x. Other studies of linkage with 2 rflps, mgu22 which is close to the centromere and l1. Enable javascript to view the expandcollapse boxes. Menkes disease is caused by a defect in the atp7a gene. Copperregulated trafficking of the menkes disease copper. Here, we describe a completely workedup case of a 4monthold male infant with very typical history and radiological features confirmed by biochemical and trichoanalysis. Menkes disease is an xlinked disorder caused by impaired intracellular transport of copper. Segregation analysis supports recessive inheritance of disease, with residual heritability for 64 cu uptake in cultured cells. In 1962 menkes et tablished a new syndrome among the numerous neurodegenerative disorders of early childhood.
Both mnk and wnd belong to the family of cationtransporting. Assuming that human milk may contain lmw copper as well as zinc complexes, williams et al 5 have suggested that human milk may also be of therapeutic value in the treatment of menkes kinky hair disease, a sexlinked genetic disorder in humans that is manifested by abnormal intestinal copper absorption and many characteristics similar to those. John hans menkes december 20, 1928 november 22, 2008 was an austrianamerican pediatric neurologist and author of fictional novels and plays. Pdf menkes disease is an xlinked lethal multisystem disorder caused by the disturbances of copper distribution in different tissues due to the. Diagnostic copper imaging of menkes disease by synchrotron. Correction of the copper transport defect of menkes. A 7monthsold, male infant presented to our outpatient department in june 2016 with.
In menkes disease, which is a copper deficiency disorder, many of the biochemical and clinical symptoms are attributable to reduced levels of critical copperrequiring enzymes. Cerebral infarction in menkes disease pediatric neurology. The occurrence of these disorders indicates the fundamental importance of atp7a and atp7b. Menkes disease is a rare neurodegenerative disorder due to an intracellular defect of a copper transport protein. Wilson disease, menkes disease, occipital horn syndrome, and xlinked distal hereditary motor neuropathy are genetic disorders of copper metabolism that span a broad spectrum of neurological dysfunction table 180. The affected individual suffers from malfunction of copper containing enzymes resulting in multi systemic. Menkes disease is an inherited disorder in which the body has a problem absorbing copper. This suggests that mnk protein contains active signals that are involved in the retention of the protein to the transgolgi network and retrieval of the. Phenotypic convergence of menkes and wilson disease. The defect makes it hard for the body to properly distribute transport copper throughout the body. Menkes disease presenting with epilepsia partialis continua. A drosophila model of menkes disease reveals a role for. Dysmorphic face may be seen in patients with propionic and methylmalonic acidemias, multiple coenzyme a dehydrogenase deficiency, peroxisomal disorders, and maple syrup urine disease. Caenorhabditis elegans cdna for a menkeswilson disease.
Currently, no therapy effectively arrests the relentless neurodegeneration of menkes disease. Copper accumulates at abnormally low levels in the liver and brain, but at higher than normal levels in the kidney and intestinal lining. Previous neuroimaging reports of patients with menkes disease describe a range of abnormalities, including intracranial vessel tortuosity and cerebral white matter changes. Characterization of atp7a missense mutants suggests a. Atp7a is a coppertransporting ptype atpase that is defective in the copper deficiency disorder, menkes disease. The clinical features of wilsons disease stem from an accumulation of hepatic copper to toxic levels. Menkes disease is an xlinked lethal multi system disorder caused by disturbances of copper distribution in different tissues due to mutation of p atpase7 gene.
In the present study, we attempted to construct a drosophila model of menkes disease by rna interference rnaiinduced silencing of dmatp7, the drosophila orthologue of mammalian atp7a, in the digestive tract. However, in cells exposed to excessive copper, mnk traffics to the plasma membrane. Mutations in atp7b lead to wilson disease, which is characterized by a predominantly hepatic copper. Copper is an essential transition metal that permits the facile transfer of electrons in a series of critical biochemical pathways. Menkes disease information page national institute of.
Signs and symptoms appear during infancy, typically after a two to threemonth period of. Figure 1 characteristics of scalp hair in menkes disease hair is sparse, short, thin, fragile, and lightcolored, and has a steelwool appearance. The protein encoded by the menkes disease gene mnk is localised to the golgi apparatus and cycles between the transgolgi network and the plasma membrane in cultured cells on addition and removal of copper to the growth medium. Menkes disease is caused by a defective gene named atpta1 that regulates the metabolism of copper in the body. We noticed that in published, later biopsy material, the granules are larger and there are clear halos around them. Individuals with menkes disease have an abnormally low level of copper in the brain and liver and excess copper in the intestines and kidneys.
Genetic study or plasma catecholamine levels were not done because of non availability of facility and high cost. The menkes and wilson disease genes counteract in copper. Pdf menkes disease md is a lethal multisystemic disorder of copper metabolism. Menkes syndrome is an xlinked recessive multisystem disease which is usually fatal prior to 5 years of age. This gene is responsible for production of the atpase enzyme that regulates copper levels in the body. The ct scans varied from showing no abnormalities early in the disease to showing diffuse cortical atrophy, subdural accumulation of fluid. Menkes disease is an xlinked lethal multisystem disorder caused by disturbances of copper distribution in different tissues due to mutation of atpase 7a gene.
In 1852, samuel wilks of guys hospital first described the condition, although the term trichorrhexis nodosa was not proposed until 1876 by m. Two hereditary disorders, menkes disease and the occipital horn syndrome, mimic the effects of copper deficiency. Menkes disease md is caused by mutations in atp7a, encoding a coppertransporting ptype atpase which exhibits copperdependent trafficking. Menkes disease is an xlinked multisystem disorder characterized by early. Progressive neurodegeneration and connective tissue. Menkes disease is an xlinked lethal multisystem disorder caused by the disturbances of copper. Human menkes disease is a lethal neurodegenerative disorder of copper metabolism that is caused by mutations in the atp7a coppertransporting gene.
Atp7arelated copper transport disorders ncbi bookshelf. B t1 and c t2 mri sequences demonstrate generalized neuroatrophy and delayed myelination. Mnk is localized in thetransgolgi network and transports copper to enzymes synthesized within secretory compartments. Menkes disease md is a lethal multisystemic disorder of copper metabolism. Figure 1 typical sparse wooly hair of menkes kinky hair disease menkes disease md is a genetic disease of x linked recessive inheritance first described by menkes et al in 1962.
Menkes disease nord national organization for rare. Although the initial clinical presentations were similar, head growth and serial ct scans showed striking individual differences. Menkes disease is an xlinked genetic disorder caused by mutations in the atp7a gene. Menkes disease mnk, also known as menkes syndrome, is an xlinked recessive disorder. Although the causes of the abnormal copper utilization seen in menkes disease remain unknown, a candidate gene reported by three laboratories has narrowed the search for the defective or missing factor. In the 52 years since the original description of menkes kinky hair disease mkhd, advances in understanding the clinical, biochemical, and molecular aspects of this rare disorder of copper metabolism have outstripped progress in the design of effective therapies. The patient was diagnosed as menkes disease and treated symptomatically. Pdf menkes disease presenting with epilepsia partialis. The patient was diagnosed as menkes disease and treated.
The clinical courses and serial computerized tomography ct scans of four patients with menkes disease are described. The disease affects development, both mental and physical. Menkes disease and wilsons disease are inherited disorders of copper metabolism resulting from the absence or dysfunction of homologous coppertransporting atpases that reside in the transgolgi network of all cells. The estimated incidence of the disease is 1 in 1,00,000 to1 in 2,50,000. Inborn errors of copper metabolism pubmed central pmc. New ocular and electroretinographic findings ophthalmology 1998. Identification of a dileucine motif within the c terminus. Disorders of copper homeostasis are currently recognized across. Letter to the editor is it a pathogenic atp7a variation and is it menkes disease.
Further research to clarify the mechanisms suggested by these clinical and. We aim to describe a female patient with menkes disease who presented with epilepsia partialis continua. Menkes disease md, also known as menkes kinky hair disease, is a fatal neurodegenerative disease caused by a defect in copper metabolism. Menkes disease md is an xlinked recessive disorder, caused by mutation in the cutransporting atpase gene atp7a 1,2. Menkes syndrome the disorder causes severe cerebral degeneration and arterial changes, resulting in death in infancy.
Pdf an eight month old male infant with protein energy malnutrition was admitted in the hospital with the history. Other atp7a mutations have been linked to juvenile occipital horn syndrome and adultonset hereditary motor neuropathy. Menkes disease, also known as kinky hair disease, is an xlinked neurodegenerative disease of impaired copper transport. Wilsons disease and menkes disease american journal. This topic will present an overview of the diagnosis and treatment of md. The saccharomyces cerevisiae mutant with a disrupted ccc2 gene yeast menkeswilson disease gene homologue was rescued by the cdna for the c. The symptoms involve multiple organ systems, such as the brain, lung, gastrointestinal tract, urinary tract, connective tissue, and skin. Letter to the editor is it a pathogenic atp7a variation. Menkes disease md is an xlinked, multisystemic lethal disorder of copper metabolism caused by mutations in the atp7a gene. Menkes disease, or trichopoliodystrophy, is an x chromosomelinked recessive disorder that is characterized by a defect in copper transporting protein in the mitochondria and disturbed absorption of copper from the gastrointestinal tract. The estimated prevalence of the disease is 1 in 00 to 1 in 250000. Menkes kinky hair disease is a rare xlinked recessive disease nearly exclusively affecting males who present at 23 months of age due to abnormal functioning of copperdependent enzymes due to deficiency of copper. Menkes disease is an x linked disorder resulting in profound systemic copper deficiency. Spontaneous retroperitoneal hemorrhage in menkes disease.
Devastating metabolic brain disorders of newborns and. In addition to a career in academic medicine, he pursued a career in writing. Menkes disease is an xlinked multisystem disorder with epilepsy, kinky hair, and neurodegeneration caused by mutations in the copper transporter atp7a. Additional signs and symptoms include weak muscle tone hypotonia, sagging facial features, seizures.
Menkes syndrome is a disorder that affects copper levels in the body. Update on wilson disease annu aggarwal1, mohit bhatt wilson disease clinic, kokilaben dhirubhai ambani hospital and medical research institute, mumbai, india. Menkes disease patients suffer from severe neurological impairment and failure to thrive. The menkes disease gene is atp7a encodes an enzyme p type atpase which is required for systemic absorbtion, distribution and metabolism of copper in tissues. Menkes disease, involving atp7a, is a fatal neurodegenerative disorder of copper deficiency. Though originally felt to be a disorder of copper deficiency, it now appears to be a copper storage disease, with the observed defects resulting from inappropriate systemic copper distribution. These genetic studies also suggest that a copper atpase may be important in normal copper metabolism. A number of other eponyms, such as menkes steely hair disease, menkes kinky hair disease, trichopoliodystrophy, and menkes syndrome, have. The deleterious effects of a disrupted copper metabolism are illustrated by hereditary diseases caused by mutations in the genes coding for the copper transporters atp7a and atp7b. Seventeenmonthsold saudi infant was presented with repetitive seizures and was diagnosed to have epilepsia partialis continua. All of these patients had normal or elevated levels of alpha,antitrypsin.
The disease can often be diagnosed by looking at a victims hair, which appears to be both whitish and kinked when viewed under a microscope. We describe a 7 months male patient who presented with seizures, hypoactivity and absence of visual contact. The essential abnormality of trichorrhexis nodosa is the formation of nodes along the hair shaft through which breakage readily occurs. Menkes disease md is a rare xlinked recessive fatal neurodegenerative disorder caused by mutations in the atp7a gene, and most patients.
Is it a pathogenic atp7a variation and is it menkes disease. Menkes disease, kinky hair, ceruloplasmin, neurodegenerative, copper. The severe classical form of md is characterised by progressive neurodegeneration, connective tissue abnormalities, distinctive kinky hair and ultimately death in. Figure 2 imaging a magnetic resonance angiography reveals highly tortuous arteries of the brain. A laparoscopy showed that the hepatic ate or mild menkes disease and especially of those with artery appeared sinuous. Portal hyperpressure was ex ohs, except for the abdominal pain crises and the spiccluded, and blood clearance of alpha1antitrypsin was ules of the incisors, which to our knowledge have not normal. Menkes disease european journal of human genetics nature. Menkes disease and ohs are characterized by low concentrations of copper in some tissues as a result of impaired intestinal copper absorption, accumulation of copper in other tissues, and reduced activity of copperdependent enzymes such as dopamine beta hydroxylase dbh and lysyl oxidase. Treatment consists of parenteral copper supplementation, however, the disease is usually lethal in early childhood 9.
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