Menkes disease (MD) is a serious mother-to-child disease transmitted by the X sexual chromosome. Copper is involved in the formation of red blood cells, the absorption and utilization of iron, the metabolism of cholesterol and glucose, and the synthesis and release of life-sustaining proteins and enzymes. These enzymes in turn produce cellular energy and regulate nerve transmission, blood clotting, and oxygen transport. There is no cure for this disease

Ameen, Fawzi Muhammad Fawzi

Fadhil, Shahad Abdullah Ali

Jassam, Asia Jamal Allawi

Khaleel, Abdulrahman Khalid Yaqoub

Mussa, Safa Hussain Ali

English

European Journal of Medical and Health Research

      Menkes Disease   Fawzi Muhammad Fawzi Ameen  Department of Pathological Analyzes, College of Applied Science,  Samarra University, Iraq Abdulrahman Khalid Yaqoub Khaleel Department of Pathological Analysis, College of applied sciences,  University of Fallujah, Iraq Asia Jamal Allawi Jassam Department of Pathological Analysis, College of applied sciences,  University of Fallujah, Iraq Safa Hussain Ali Mussa Department of Pathological Analysis, College of Applied Sciences,  University of Fallujah, Iraq Shahad Abdullah Ali Fadhil Department of Pathological Analysis, College of Applied Sciences,  University of Fallujah, Iraq  Abstract  Menkes disease (MD) is a serious mother-to-child disease transmitted by the X sexual chromosome. Copper is involved in the formation of red blood cells, the absorption and utilization of iron, the metabolism of cholesterol and glucose, and the synthesis and release of life-sustaining proteins and enzymes. These enzymes in turn produce cellular energy and regulate nerve transmission, blood clotting, and oxygen transport. There is no cure for this disease.   Introduction There are 23 pairs of chromosomes in the human body. This includes 22 pairs of autosomal or somatic chromosomes that are common to both men and women and one chromosome that differs according to what gender a person is (sex chromosomes).   Figure 1: Human Karyotypes The sex chromosomes are the X chromosome and the Y chromosome. In a man, both an X and a Y chromosome are present, giving an XY configuration. In a woman, there are two X chromosomes, giving an XX configuration. The X chromosome is therefore one of the two sex chromosomes that determines an individual’s gender [1]. The X chromosome contains over 153 million base pairs, the building blocks of DNA. In women, the X chromosome represents almost 5% of the total DNA and in men, who have only one X chromosome, it represents about 2.5% of the total DNA. Men inherit the X chromosome they have from their mother and the Y chromosome from their father, while women inherit one X chromosome from the mother and the other from the father [11]. There are around 2000 genes located on the X chromosome and genetic research is focused on identifying these genes. This compares with 78 genes on the Y chromosome out of approximately 20,000 to 25,000 presents in the human genome. More Information How to cite this article: Ameen FMF, Khaleel AKY, Jassam AJA, Mussa SHA, Fadhil SAA. Menkes Disease. Eur J Med Health Res, 2024;2(4):268-72. DOI: 10.59324/ejmhr.2024.2(4).34 Keywords: X-linked recessive type chromosome, hereditary disease, copper metabolism disorder, genetic mutation.   This work is licensed under a Creative Commons Attribution 4.0 International License. The license permits unrestricted use, distribution, and reproduction in any medium, on the condition that users give exact credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if they made any changes.   EUR J MED HEALTH RES                                          Volume 2 | Number 4 | July-August 2024   269  Figure 2: Human X and Y Sex Chromosomes  When X chromosomal genes are mutated, they may give rise to genetic conditions and these are termed X-linked disorders [14]. Menkes syndrome is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons [12]. In about one-third of cases, Menkes syndrome is caused by new mutations in the ATP7A gene. People with a new mutation do not have a history of the disorder in their family. There is no specific treatment for Menkes disease (MD) [10]. Aim of the Study 1 Highlighting genetic diseases related to X chromosome, including Menkes disease. 2 Knowing the seriousness of the genetic mutation and the difficulty of treating the diseases that cause it. 3 Knowing how the genetic mutation occurs and what it causes to the injured person. Menkes Disease (MD) Disease is a fatal X-linked recessive in the long (q) arm of the X chromosome at position 21.1(Xq21.1), disorder that is caused by mutations in the gene encoding ATP7A, a copper-transporting P-type ATPase [6]. MD patients are characterized by progressive neurological degeneration and death in early childhood. ATP7A pumps copper from the cytoplasm into the secretory pathway for incorporation into secreted enzymes or for export [7]. In Menkes disease, intracellular copper levels increase due to defective export. Affected infants appear healthy at birth and develop normally for 6–12 week. Subsequently, hypotonia, seizures, and failure to thrive occur, and death by 3 year of age is typical, although neonatal diagnosis of MD by plasma neurochemical assays and early treatment with copper may improve clinical outcomes (Barnes et al., 2005). It is known that 4 types of point mutations (deletions/insertions, missense mutations, nonsense mutations, and splice- site mutations) are represented almost equally among ATP7A mutations, and many gross deletions of ATP7A have also been described. Occurs in about 1 in 100,000 to 1 in 250,000 newborns (Voskoboinik & Camakaris, 2002).   Figure 3: X Chromosome and the Xq21.1 Locus  Copper Copper is an essential trace element that is vital to the health of all living things (humans, plants, animals, and microorganisms). Copper's essentiality was first discovered in 1928. In humans, Copper deficiency and toxicity can be either of genetic or non-genetic origin. Copper is an essential trace element (i.e., micronutrient) that is required for plant, animal, and human health [3]. Copper is incorporated into a variety of proteins and metalloenzymes which perform essential metabolic functions; the micronutrient is necessary for the proper growth, development, and maintenance of bone, connective tissue, brain, heart, and many other body organs. Copper is involved in the formation of red blood cells, the absorption and utilization of iron, the metabolism of cholesterol and glucose, and the synthesis and release of life-sustaining proteins and enzymes. These enzymes in turn produce cellular energy and regulate nerve transmission, blood clotting, and oxygen transport [5]. ATP7A Gene ATP7A, also known as copper-transporting ATPase 1 (Menkes ATPase). These pumps actively transport copper cations across lipid bilayers, using the energy obtained from ATP hydrolysis. ATP7A gene provides instructions for making a protein that is important for regulating copper levels in the body. Copper is necessary for many cellular functions, but it is toxic EUR J MED HEALTH RES                                          Volume 2 | Number 4 | July-August 2024   270 when present in excessive amounts. The ATP7A protein is found throughout the body, except in liver cells [9].   Figure 4: The Percentage of Copper  in the Human Body  In the small intestine, this protein helps control the absorption of copper from food. In other cells, the ATP7A protein has a dual role and shuttles between two cellular locations. The protein normally resides in a cell structure called the Golgi apparatus, which modifies newly produced proteins, including enzymes. In the Golgi apparatus, the ATP7A protein supplies copper to certain enzymes that are critical for the structure and function of bone, skin, hair, blood vessels, and the nervous system. If copper levels in the cell environment are elevated, however, the ATP7A protein moves to the cell membrane and eliminates excess copper from the cell [8].   Figure 5: The Locations of the ATP7A in the Body   Figure 6: Intracellular Trafficking  of ATP7A (Menkes ATPase)  The gene encoding this copper pump, ATP7A, is located on the long arm of chromosome X (Xq21.1) [6]. This gene was identified in 1993, critical and just prior to the identification of ATP7B [4]. Many mutations can occur at this locus, causing ATP7A dysfunction and copper dysregulation, resulting in three distinct X-linked inherited diseases. Among them, Menkes disease is an often lethal disease occurring in infant males who present at 6–12 weeks of age with specific neurological symptoms such as loss of developmental milestones, truncal hypotonia, and seizures, in conjunction with characteristic changes of the hair (short sparse “kinky” hair) and skin (pronounced laxity) [2]. Many mutations in the ATP7A gene that cause Menkes syndrome. All of these mutations prevent the production of functional ATP7A protein. As a result, the absorption of copper from food is impaired, and copper is not supplied to certain enzymes. The abnormal protein may get stuck in the cell membrane and become unable to shuttle back and forth from the Golgi apparatus [10]. EUR J MED HEALTH RES                                          Volume 2 | Number 4 | July-August 2024   271 ATP7A plays a central role in intracellular copper homeostasis. The localization and function of this copper transporter are regulated by levels of the metal. In normal or copper-depleted states, ATP7A, like the Wilson ATPase, is localized in the trans-Golgi network (TGN) where it pumps copper into the trans-Golgi compartment for metallation of cuproenzymes. Copper is required as a cofactor for various enzymes involved in metabolic pathways. Under higher copper concentrations, ATP7A traffics away from the trans-Golgi network to the plasma membrane, where it pumps out excess copper [8]. The disrupted activity of the ATP7A protein causes copper to be poorly distributed to cells in the body. Copper accumulates in some tissues, such as the small intestine and kidneys, while the brain and other tissues have unusually low levels. The decreased supply of copper can reduce the activity of numerous copper-containing enzymes, affecting the structure and function of bone, skin, hair, blood vessels, and the nervous system. The signs and symptoms of Menkes syndrome are caused by the reduced activity of these copper-containing enzymes [9]. Mutations in the ATP7A Gene Mutations in the ATP7A gene cause Menkes syndrome. The gene encoding this copper pump, ATP7A, is located on the long arm of chromosome X (Xq21.1) [6]. This gene was identified in 1993, critical and just prior to the identification of ATP7B ATP7B [4]. Many mutations can occur at this locus, causing ATP7A dysfunction and copper dysregulation, resulting in three distinct X-linked inherited diseases. Among them, Menkes disease [10]. The ATP7A gene provides instructions for making a protein that is important for regulating copper levels in the body. Mutations in the ATP7A gene result in poor distribution of copper to the body's cells. Copper accumulates in some tissues, such as the small intestine and kidneys, while the brain and other tissues have unusually low levels of copper [5]. Researchers have identified more than 150 mutations in the ATP7A gene that cause Menkes syndrome. Many of these mutations delete part of the gene and likely result in a shortened ATP7A protein. Other mutations insert additional DNA building blocks (nucleotides) into the gene or change single nucleotides. All of these mutations prevent the production of functional ATP7A protein. As a result, the absorption of copper from food is impaired, and copper is not supplied to certain enzymes. The abnormal protein may get stuck in the cell membrane and become unable to shuttle back and forth from the Golgi apparatus [10].   Figure 7: ATP7A Mutations in Menkes Disease  1. Wild type ATP7A intron 6 has the sequence guaagu_ag. 2. The MD1 mutation (IVS6+1G->A) in ATP7A causes the Guanine number 1 to be removed and replaced by Adenine 3. The MD2 mutation (IVS6+5G->A) in ATP7A causes the Guanine number 5 to be removed and replaced by Adenine Symptoms Symptoms of Menkes disease (MD) begin shortly after birth and may vary from person to person. Early signs and symptoms m ay include: • Progressive nervous system decline • Seizures • Kinky, light colored, easily breakable hair • Low muscle tone (hypotonia) • Twisted blood vessels (arterial tortuosities) • Characteristic facial features Bladder sacs or pouches (diverticula) [2]. Diagnosis Menkes disease is typically diagnosed based on the clinical features, medical examination, and genetic testing for alterations in the ATP7A gene. Other types of tests that may be helpful include the analysis of catecholamines (chemicals that are sensitive to copper) and copper levels in the blood [5]. Treatment There is no specific treatment for Menkes disease (MD). Some boys with MD respond to early treatment (started in the first weeks of life) with copper complexes (mainly copper-histidine). This treatment may prevent or slow nervous system damage, decrease the number of seizures, and increase lifespan. Copper treatment does not work for all patients with MD. Other treatments are aimed at preventing and/or managing the symptoms and complications associated with this condition. These may include [2,3]: • Gastrostomy (feeding) tube insertion • Bladder surgery • Seizure medication • Neurologist EUR J MED HEALTH RES                                          Volume 2 | Number 4 | July-August 2024   272 Some of the specialists who might be involved in the care of someone with Menkes disease include [2]: • Gastroenterologist • Developmental specialist • Urologist • Genetics professional Conclusion As Menke's disease is hereditary, medical genetic counselling and prenatal diagnosis are essential to prevent the disease [15]. Newborn blood screening can also be an effective tool for early diagnosis and presymptomatic identification [16]. Further research is needed to help develop such testing and implement it both locally and globally. References [1] Adkin CF, Meloni PL, Fletcher S, Adams AM, Muntoni F, Wong B, Wilton SD. Multiple exon skipping strategies to by-pass dystrophin mutations. Neuromuscul Disord. 2012 Apr;22(4):297-305. doi: 10.1016/j.nmd.2011.10.007 [2] Barnes N, Tsivkovskii R, Tsivkovskaia N, Lutsenko S. The copper-transporting ATPases, menkes and wilson disease proteins, have distinct roles in adult and developing cerebellum. J Biol Chem. 2005 Mar 11;280(10):9640-5. doi: 10.1074/jbc.M413840200 [3] Bertini I, Rosato A. Menkes disease. Cell Mol Life Sci. 2008 Jan;65(1):89-91. doi: 10.1007/s00018-007-7439-6 [4] Donsante A, Tang J, Godwin SC, Holmes CS, Goldstein DS, Bassuk A, Kaler SG. Differences in ATP7A gene expression underlie intrafamilial variability in Menkes disease/occipital horn syndrome. J Med Genet. 2007 Aug;44(8):492-7. doi: 10.1136/jmg.2007.050013 [5] de Bie P, Muller P, Wijmenga C, Klomp LW. Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes. J Med Genet. 2007 Nov;44(11):673-88. doi: 10.1136/jmg.2007.052746 [6] Harris ED. Basic and clinical aspects of copper. Crit Rev Clin Lab Sci. 2003 Oct;40(5):547-86. [7] Kaler SG, Holmes CS, Goldstein DS, Tang J, Godwin SC, Donsante A, Liew CJ, Sato S, Patronas N. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med. 2008 Feb 7;358(6):605-14. doi: 10.1056/NEJMoa070613 [8] Lutsenko S, Washington-Hughes C, Ralle M, Schmidt K. Copper and the brain noradrenergic system. J Biol Inorg Chem. 2019 Dec;24(8):1179-1188. doi: 10.1007/s00775-019-01737-3 [9] Madsen E, Gitlin JD. Copper deficiency. Curr Opin Gastroenterol. 2007 Mar;23(2):187-92. doi: 10.1097/MOG.0b013e32801421bb [10] Prohaska JR. Role of copper transporters in copper homeostasis. Am J Clin Nutr. 2008 Sep;88(3):826S-9S. doi: 10.1093/ajcn/88.3.826S [11] Rose KJ, Burns J, Wheeler DM, North KN. Interventions for increasing ankle range of motion in patients with neuromuscular disease. Cochrane Database Syst Rev. 2010 Feb 17;(2):CD006973. doi: 10.1002/14651858.CD006973.pub2 [12] Tang J, Robertson S, Lem KE, Godwin SC, Kaler SG. 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Menkes Disease

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Menkes Disease

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