Chimera (genetics)

A chimera (also spelled chimaera) is a single organism composed of genetically distinct cells. This can result in male and female organs, two different blood types, or subtle variations in form.[1] Animal chimeras are produced by the merger of multiple fertilized eggs. In plant chimeras, however, the distinct types of tissue may originate from the same zygote, and the difference is often due to mutation during ordinary cell division. Normally, chimerism is not visible on casual inspection; however, it has been detected in the course of proving parentage.[citation needed]

Another way that chimerism can occur in animals is by organ transplantation, giving one individual tissues that developed from two different genomes. For example, a bone marrow transplant can change someone's blood type.

Animals 

An animal chimera is a single organism that is composed of two or more different populations of genetically distinct cells that originated from different zygotes involved in sexual reproduction. If the different cells have emerged from the same zygote, the organism is called a mosaic. Chimeras are formed from at least four parent cells (two fertilized eggs or early embryos fused together). Each population of cells keeps its own character and the resulting organism is a mixture of tissues. There are some reports of human chimerism.[1]

This condition is either inherited or it is acquired through the infusion of allogeneic hematopoietic cells during transplantation or transfusion. In nonidentical twins, chimerism occurs by means of blood-vessel anastomoses. The likelihood of offspring being a chimera is increased if it is created via in vitro fertilization[citation needed]. Chimeras can often breed, but the fertility and type of offspring depends on which cell line gave rise to the ovaries or testes; varying degrees of intersexuality may result if one set of cells is genetically female and another genetically male.

Tetragametic chimerism 

Tetragametic chimerism is a form of congenital chimerism. This condition occurs through the fertilization of two separate ova by two sperm, followed by the fusion of the two at the blastocyst or zygote stages. This results in the development of an organism with intermingled cell lines. Put another way, the chimera is formed from the merging of two nonidentical twins (although a similar merging presumably occurs with identical twins, but as their DNA is almost identical, the presence would not be immediately detectable in a very early (zygote or blastocyst) phase). As such, they can be male, female, or hermaphroditic.

As the organism develops, it can come to possess organs that have different sets of chromosomes. For example, the chimera may have a liver composed of cells with one set of chromosomes and have a kidney composed of cells with a second set of chromosomes. This has occurred in humans, and at one time was thought to be extremely rare, though more recent evidence suggests that it is not as rare as previously believed.[1][2]

This is particularly true for the marmoset. Recent research shows most marmosets are chimeras, sharing DNA with their fraternal twins.[3] 95% of Marmoset fraternal twins trade blood through chorionic fusions, making them hematopoietic chimeras.[4][5]

Most chimeras will go through life without realizing they are chimeras. The difference in phenotypes may be subtle (e.g., having a hitchhiker's thumb and a straight thumb, eyes of slightly different colors, differential hair growth on opposite sides of the body, etc.) or completely undetectable. Chimeras may also show, under a certain spectrum of UV light, distinctive marks on the back resembling that of arrow points pointing downwards from the shoulders down to the lower back; this is one expression of pigment unevenness called Blaschko's lines.[6]

Affected persons may be identified by the finding of two populations of red cells or, if the zygotes are of opposite sex, ambiguous genitalia and hermaphroditism alone or in combination; such persons sometimes also have patchy skin, hair, or eye pigmentation (heterochromia). If the blastocysts are of opposite sex, genitals of both sexes may be formed, either ovary and testis, or combined ovotestes, in one rare form of intersexuality, a condition previously known as true hermaphroditism.

Note that the frequency of this condition does not indicate the true prevalence of chimerism. Most chimeras composed of both male and female cells probably do not have an intersex condition, as might be expected if the two cell populations were evenly blended throughout the body. Often, most or all of the cells of a single cell type will be composed of a single cell line, i.e. the blood may be composed prominently of one cell line, and the internal organs of the other cell line. Genitalia produce the hormones responsible for other sex characteristics. If the sex organs are homogeneous, the individual will not be expected to exhibit any intersex traits.

Natural chimeras are almost never detected unless they exhibit abnormalities such as male/female or hermaphrodite characteristics or uneven skin pigmentation. The most noticeable are some male tortoiseshell cats or animals with ambiguous sex organs.

The existence of chimerism is problematic for DNA testing, a fact with implications for family and criminal law. The Lydia Fairchild case, for example, was brought to court after DNA testing apparently showed that her children could not be hers. Fraud charges were filed against her and her custody of her children was challenged. The charge against her was dismissed when it became clear that Lydia was a chimera, with the matching DNA being found in her cervical tissue. Another case was that of Karen Keegan, who was also suspected (initially) of not being her children's biological mother, after DNA tests on her adult sons for a kidney transplant she needed seemed to show she wasn't their mother.[1][7]

The tetragametic state has important implications for organ or stem-cell transplantation. Chimeras typically have immunologic tolerance to both cell lines.

Microchimerism 

Main article: Microchimerism

Microchimerism is the presence of a small number of cells that are genetically distinct from those of the host individual. Most people are born with a few cells genetically identical to their mothers' and the proportion of these cells goes down in healthy individuals as they get older. People who retain higher numbers of cells genetically identical to their mothers' have been observed to have higher rates of some autoimmune diseases, presumably because the immune system is responsible for destroying these cells and a common immune defect prevents it from doing so and also causes autoimmune problems. Women often also have a few cells genetically identical to that of their children, and some people also have some cells genetically identical to that of their siblings (maternal siblings only, since these cells are passed to them because their mother retained them).

Parasitic chimerism in anglerfish 

Chimerism occurs naturally in adult Ceratioid anglerfish and is in fact a natural and essential part of their life cycle. Once the male achieves adulthood, it begins its search for a female. Using strong olfactory receptors (i.e. smell receptors), the male searches until it locates a female anglerfish. The male, less than an inch in length, bites into her skin and releases an enzyme that digests the skin of his mouth and her body, fusing the pair down to the blood-vessel level. While this attachment has become necessary for the male's survival, it will eventually consume him, as both anglerfish fuse into a single hermaphroditic individual. Sometimes in this odd ritual, more than one male will attach to a single female as a 'parasite'. They will all be consumed into the body of the larger female angler. Once fused to a female, the males will reach sexual maturity, developing large testicles as their other organs atrophy. This process allows for sperm to be in constant supply when the female produces an egg, so that the chimeric fish is able to have a greater number of offspring.[8]

Germline chimerism 

Germline chimerism occurs when the germ cells (for example, sperm and egg cells) of an organism are not genetically identical to its own. It has recently been discovered that marmosets can carry the reproductive cells of their (fraternal) twin siblings, because of placental fusion during development. (Marmosets almost always give birth to fraternal twins.)[3][9][10]

Humans 

The Dutch sprinter Foekje Dillema was expelled from the 1950 national team after she refused a mandatory sex test in July 1950; later investigations revealed a Y-chromosome in her body cells, and the analysis showed that she probably was a 46,XX/46,XY mosaic female.[11]

In 1953 a human chimera was reported in the British Medical Journal. A woman was found to have blood containing two different blood types. Apparently this resulted from her twin brother's cells living in her body.[12] More recently, a study found that such blood group chimerism is not rare.[13]

Another report of a human chimera was published in 1998, where a male human had some partially developed female organs due to chimerism. He had been conceived by in-vitro fertilization.[14]

In 2002, Lydia Fairchild was denied public assistance when DNA evidence showed that she was not related to her children. A lawyer for the prosecution heard of a human chimera in New England, Karen Keegan, and suggested the possibility to the defence, who were able to show that Fairchild, too, was a chimera with two sets of DNA.[15]

Research 

In biological research, chimeras are artificially produced by selectively transplanting embryonic cells from one organism onto the embryo of another, and allowing the resultant blastocyst to develop. Chimeras are not hybrids, which form from the fusion of gametes from two species that form a single zygote with a combined genetic makeup, or Hybridomas which, as with hybrids, result from fusion of two species' cells into a single cell and artificial propagation of this cell in the laboratory. Essentially, in a chimera, each cell is from either of the parent species, whereas in a hybrid and hybridoma, each cell is derived from both parent species. "Chimera" is a broad term and is often applied to many different mechanisms of the mixing of cells from two different species.

As with cloning, the process of creating and implanting a chimera is imprecise, with the majority of embryos spontaneously terminating. Successes, however, have led to major advancements in the field of embryology, as creating chimeras of one species with different physical traits, such as colour, has allowed researchers to trace the differentiation of embryonic cells through the formation of organ systems in the adult individual.

The first known primate chimeras are the twins Roku and Hex; each having 6 genomes. They were created by mixing cells from toripotent 4 cell blastocysts; although the cells never fused they worked together to form organs. It was discovered that one of these primates, Roku, was a sexual chimera; as four percent of Roku's blood cells contained two x chromosomes.[4]

A major milestone in chimera experimentation occurred in 1984, when a chimeric geep was produced by combining embryos from a goat and a sheep, and survived to adulthood.[16] The creation of the "geep" revealed several complexities to chimera development. In implanting a goat embryo for gestation in a sheep, the sheep's immune system would reject the developing goat embryo, whereas a "geep" embryo, sharing markers of immunity with both sheep and goats, was able to survive implantation in either of its parent species.

In August 2003, researchers at the Shanghai Second Medical University in China reported that they had successfully fused human skin cells and dead rabbit eggs to create the first human chimeric embryos. The embryos were allowed to develop for several days in a laboratory setting, then destroyed to harvest the resulting stem cells.[17] In 2007, scientists at the University of Nevada School of Medicine created a sheep whose blood contained 15% human cells and 85% sheep cells.[18] The implications of increasingly realizable projects using human-animal hybrids for biopharmaceutical production, and potentially for producing cells or organs, have raised a host of ethical and safety issues.

Mice 

Chimeric mice are important tools in biological research, as they allow the investigation of a variety of biological questions in an animal that has two distinct genetic pools within it. These include insights into such problems as the tissue specific requirements of a gene, cell lineage, and cell potential. The general methods for creating chimeric mice can be summarized either by injection or aggregation of embryonic cells from different origins. The first chimeric mouse was made by Beatrice Mintz in the 1960s through the aggregation of eight cell stage embryos.[19] Injection on the other hand was pioneered by Richard Gardner and Ralph Brinster who injected cells into blastocysts to create chimeric mice with germ lines fully derived from injected ES Cells.[20] Chimeras can be derived from mouse embryos that have not yet implanted in the uterus as well as from implanted embryos. ES cells from the inner cell mass of an implanted blastocyst can contribute to all cell lineages of a mouse including the germ line. ES cells are also a useful tool in chimeras because genes can be mutated in them through the use of homologous recombination, thus allowing gene targeting. Since this discovery occurred in 1999, ES cells have become a key tool in the generation of specific chimeric mice.[21]

Underlying biology 

The ability to make mouse chimeras comes from an understanding of early mouse development. Between the stages of fertilization of the egg and the implantation of a blastocyst into the uterus, different parts of the mouse embryo retain the ability to give rise to a variety of cell lineages. Once the embryo has reached the blastocyst stage, it is composed of several parts, mainly the trophectoderm, the inner cell mass, and the primitive endoderm. Each of these parts of the blastocyst gives rise to different parts of the embryo; the inner cell mass gives rise to the embryo proper, while the trophectoderm and primitive endoderm give rise to extra embryonic structures that support growth of the embryo.[22] Two- to eight-cell-stage embryos are competent for making chimeras, since at these stages of development, the cells in the embryos are not yet committed to give rise to any particular cell lineage, and could give rise to the inner cell mass or the trophectoderm. In the case where two diploid eight-cell-stage embryos are used to make a chimera, chimerism can be later found in the epiblast, primitive, endoderm and trophectoderm of the mouse blastocyst.[23][24] It is possible to dissect the embryo at other stages so as to accordingly give rise to one lineage of cells from an embryo selectively and not the other. For example, subsets of blastomeres can be used to give rise to chimera with specified cell lineage from one embryo. The Inner Cell Mass of a diploid blastocyst for example can be used to make a chimera with another blastocyst of eight-cell diploid embryo; the cells taken from the inner cell mass will give rise to the primitive endoderm and to the epiblast in the chimera mouse.[25] From this knowledge, ES cell contributions to chimeras have been developed. ES cells can be used in combination with eight-cell-and two-cell-stage embryos to make chimeras and exclusively give rise to the embryo proper. Embryos that are to be used in chimeras can further be genetically altered in order to specifically contribute to only one part of chimera. An example is the chimera built off of ES cells and tetraploid embryos, tetraploid embryos which are artificially made by electrofusion of two two-cell diploid embryos. The tetraploid embryo will exclusively give rise to the trophectoderm and primitive endoderm in the chimera[26][27]

Methods of production 

There are a variety of combinations that can give rise to a successful chimera mouse and — according to the goal of the experiment — an appropriate cell and embryo combination can be picked; they are generally but not limited to diploid embryo and ES cells, diploid embryo and diploid embryo, ES cell and tetraploid embryo, diploid embryo and tetraploid embryo, ES cells and ES cells. The combination of embryonic stem cell and diploid embryo is a common technique used for the making of chimeric mice, since gene targeting can be done in the embryonic stem cell. These kinds of chimeras can be made through either aggregation of stem cells and the diploid embryo or injection of the stem cells into the diploid embryo. If embryonic stem cells are to be used for gene targeting to make a chimera, the following procedure is common: a construct for homologous recombination for the gene targeted will be introduced into cultured mouse embryonic stem cells from the donor mouse, by way of electroporation; cells positive for the recombination event will have antibiotic resistance, provided by the insertion cassette used in the gene targeting; and be able to be positively selected for.[28][29] ES cells with the correct targeted gene are then injected into a diploid host mouse blastocyst. These injected blastocysts are then implanted into a pseudo pregnant female surrogate mouse which will bring the embryos to term and give birth to a mouse whose germline is derived from the donor mouse's ES cells.[30] This same procedure can be achieved through aggregation of ES cells and diploid embryos, diploid embryos are cultured in aggregation plates in wells where single embryos can fit, to these wells ES cells are added the aggregates are cultured until a single embryo is formed and has progressed to the blastocyst stage, and can then be transferred to the surrogate mouse.[31]

Plants 

Structure 

The distinction between sectorial, mericlinal and periclinal chimeras are widely used.[32][33]

Graft chimeras 

Main article: Graft-chimaera

These are produced by grafting tetically different parents, different cultivars or different species (which may belong to different genera). The tissues may be partially fused together following grafting to form a single growing organism that preserves both types of tissue in a single shoot.[34] Just as the constituent species are likely to differ in a wide range of features, so the behavior of their periclinal chimeras is like to be highly variable.[35] The first such known chimera was probably the Bizzaria which is a confusion of the Florentine citron and the sour orange. Perhaps the best-known example of a graft-chimera is Laburnocytisus 'Adamii', caused by a fusion of a Laburnum and a broom.

Chromosomal chimeras 

These are chimeras in which the layers differ in their chromosome constitution. Occasionally chimeras arise from loss or gain of individual chromosomes or chromosome fragments owing to misdivision.[36] More commonly cytochimeras have simple multiple of the normal chromosome complement in the changed layer. There are various effects on cell size and growth characteristics.

Nuclear gene-differential chimeras 

These chimeras arise by spontaneous or induced mutation of a nuclear gene to a dominant or recessive allele. As a rule one character is affected at a time in the leaf, flower, fruit, or other parts.

Plastid gene-differential chimeras 

These chimeras arise by spontaneous or induced mutation of a plastid gene, followed by the sorting-out of two kinds of plastid during vegetative growth. Alternatively, after selfing or nucleic acid thermodynamics, plastids may sort-out from a mixed egg or mixed zygote respectively. This type of chimera is recognized at the time of origin by the sorting-out pattern in the leaves. After sorting-out is complete, periclinal chimeras are distinguished from similar looking nuclear gene-differential chimeras by their non-mendelian inheritance. The majority of variegated-leaf chimeras are of this kind.

All plastid gene- and some nuclear gene-differential chimeras affect the color of the plasmids within the leaves, and these are grouped together as chlorophyll chimeras, or preferably as variegated leaf chimeras. For most variegation, the mutation involved is the loss of the chloroplasts in the mutated tissue, so that part of the plant tissue has no green pigment and no photosynthetic ability. This mutated tissue is unable to survive on its own but is kept alive by its partnership with normal photosynthetic tissue. Sometimes chimeras are also found with layers differing in respect of both their nuclear and their plastid genes.

Origins 

There are multiple reasons to explain the occurrence of plant chimera during plant recovery stage. (1)The process of shoot organogenesis starts form the multicellular origin.[37] (2)The endogenous tolerance leads to the ineffectiveness of the weak selective agents. (3)A self-protection mechanism (cross protection). Transformed cells serve as guards to protect the untransformed ones.[38] (4)The observable characteristic of transgenic cells may be a transient expression of the marker gene. Or it may due to the presence of agrobacterium cells.

Detection 

Untransformed cells should be easy to detect and remove to avoid chimeras. Because it’s extremely important to maintain the stable ability of the transgenic plants across different generations. Reporter genes such as GUS and Green Fluorescent Protein[39](GFP) are utilized in combination with plant selective markers (herbicide, antibody etc.) However, GUS expression depends on the plant development stage and GFP may be influenced by the green tissue autofluorescence. Quantitative PCR could be an alternative method for chimera detection.[40]

Legislation 

The US and Western Europe have strict codes of ethics and regulations in place that expressly forbid certain subsets of experimentation using human cells, though there is a vast difference in the regulatory framework.[41] In May 2008, a robust debate in the House of Commons of the United Kingdom on the ethics of creating chimeras with human stem cells led to the decision that embryos would be allowed to be made in laboratories, given that they would be destroyed within the first 14 days. No such foundation has been set for chimera research regulation in the US.

Popular culture 

The House episode "Cane and Able" and the CSI: Crime Scene Investigation episode "Bloodlines" both feature human chimerism.

References 

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La vacuna de la COVID-19

  RESUMEN

Este documento sirve para advertir al colegio o instituto que en caso de realizar cualquiera de las acciones que se enumeran en él acudirás ante los órganos judiciales.

Lo que trataremos de hacer con él es advertir que no consentimos que se hagan pruebas a nuestros hijos o se vacune sin nuestro previo consentimiento.

 En caso de que las autoridades sanitarias decidan vacunar a todos los menores del centro educativo, deberán tener en cuenta las necesidades especiales de cada uno, incluyendo las posibles alergias. Es importante saber que si tu hijo sufre cualquier tipo de alergia debes solicitar un certificado de alergias.

La vacuna de la COVID-19 de Pfizer tiene, en principio, las mismas contraindicaciones en los alérgicos que cualquier otra. Así lo afirma la SEAIC, enfatizando que esta no se recomienda en personas que han sufrido reacciones alérgicas previas a sus componentes concretos. No obstante, no contiene trazas de huevo ni antibióticos (como las de triple vírica o gripe), por lo que no podrá alegarse alergia a éstos para evitar la vacuna. Algunas vacunas, como la de Pfizer, se componen de ARN del virus vehiculada en nanopartículas lipídicas de polietilenglicol. El polisorbato es un ingrediente que no está incluido en ninguna de las vacunas ARNm contra el COVID-19 pero que está estrechamente relacionado con el PEG, que sí está incluido en las vacunas. Según la OMS, las personas que son alérgicas al PEG o al polisorbato no deberían recibir la vacuna ARNm contra el COVID-19. (Si necesitas más información sobre esto consulta en el grupo).

Si tienes el certificado de alergias, adjúntalo a este documento para entregarlo ante el colegio o instituto.

Este documento es totalmente válido y legal, basado en las prescripciones legales que en la parte de Fundamentos de Derecho se enumeran. Asimismo, fue creado para compartirse libremente y llegar a todas las personas que lo necesiten, asique puedes compartirlo con quien quieras.

En la siguiente página se recogen las instrucciones para rellenarlo y presentarlo en el centro educativo.

INSTRUCCIONES

1º. Copia el contenido del escrito desde la página 3 a la 7 en un documento Word o cualquier otro procesador de textos para poder trabajar con él mientras observas estas instrucciones

2º. Las partes en color rojo o con puntos suspensivos serán las que debas rellenar con tus datos personales.

3º. IMPORTANTE:

 En el título debes escribir el nombre del colegio o instituto al que va dirigido al completo.

Al final debe constar siempre la fecha en que se presenta y tu firma como persona interesada.

No dejes mucho espacio en blanco entre el final del texto y tu firma. Si el documento tiene un lugar establecido para la firma y está alejado del final del texto, traza una línea en diagonal en dicho espacio para evitar posibles manipulaciones.

La fecha debe ser la del día en que se presenta el escrito ante la institución.

4º. Puedes adaptar el escrito a tus necesidades, quitando y poniendo lo que mejor te convenga. Eso sí, no elimines nada del apartado de Fundamentos de Derecho.

5º. Deben imprimirse 2 copias del documento: una para ti y una para la institución. Esto es muy muy importante porque deberás presentar ambas copias en el colegio. Una será para ti y una será para ellos, pero ambas deben ser selladas para su validez.

Conserva una de las copias firmadas de forma manuscrita. No te conformes con una fotocopia, pues en caso de litigio, la fotocopia tendrá poca validez sin su correspondencia con el original.

El documento deberá ser sellado al final de TODAS Y CADA UNA DE LAS PAGINAS.

Cuando entregue el documento, dígale a la persona encargada de recibirlo que su abogado le ha dicho que le deben sellar todas las páginas. Así evitamos que aleguen el extravío de alguna de sus hojas para eximirse de responsabilidad.

6º. Revisa el documento.

No puede haber palabras en color rojo ni más de dos puntos entre las palabras. Revisa la fecha, debe ser la del día en que presentas el documento.

Si tienes dudas, puedes consultarnos en cualquier momento.

AL INSTITUTO DE EDUCACIÓN SECUNDARIA ……………..

Don o Dña…………….……………..…, con DNI , domicilio a efectos de

notificaciones en Calle ………………, del municipio de ………… con C.P y

número de teléfono , ante el órgano al que me dirijo comparezco y

 EXPONGO

Primero.- Que como madre o padre y actual representante legal del alumno

…………………… de la clase …... del curso , me OPONGO frontalmente

a que se practique sobre el mismo cualquier clase de prueba considerada invasiva, incluyendo cualquier prueba de PCR (Reacción en Cadena de la Polimerasa), serológica, de antígenos, test rápido u otra técnica de diagnóstico molecular, siendo necesaria la previa revisión por parte de su médico de cabecera al conocer de primera mano las necesidades especiales de mi hijo o hija. De modo que, de ser necesaria la práctica de dichas pruebas, se realizarán y aportarán exclusivamente por su médico.

Segundo.- Que por ser el o la representante legal de ……...nombre de tu hijo…., me opongo igualmente a que se le administre VACUNA alguna sin la previa revisión de los componentes y efectos por parte de su médico de cabecera, al suponer un grave riesgo para su vida en virtud de los motivos descritos en el certificado médico que se adjunta. A estos efectos, la administración de una vacuna que provoque cualquier efecto adverso en mi hijo o hija, realizada sin mi consentimiento y previa revisión de su médico, supondrá la comisión de un delito de lesiones o incluso de homicidio o asesinato en grado de tentativa, al conocer de antemano los riesgos a los que se expone el menor y continuar aun así con la decisión de vacunarlo –suponiendo, claro está, que no se provoque su muerte, en cuyo caso sería constitutivo de un delito de homicidio o, en su caso, de asesinato si fuera menor de 16 años de edad -.

Tercero.- Que por ser el o la representante legal de ……...nombre de tu hijo…., me opongo a que se le tome la temperatura o se le realice cualquier otra prueba diagnóstica sin mi previo consentimiento.

Cuarto.- Que por ser el o la representante legal de …….nombre de tu hijo…., me opongo a que realice cualquier salida del centro por motivos sanitarios o por orden de las autoridades sanitarias sin mi previa autorización y puesta en conocimiento de todos los pormenores de dicha salida lo antes posible.

Quinto.- Que por ser el o la representante legal de …….nombre de tu hijo…., me opongo a que mi hijo o hija use mascarilla durante las clases de educación física, al tratarse de una situación de grave riesgo para su salud conforme al Real Decreto-ley 21/2020, de 9 de junio, de medidas urgentes de prevención, contención y coordinación para hacer frente a la crisis sanitaria ocasionada por el COVID-19.

Sexto.- Que todo lo expuesto se basa en los siguientes

FUNDAMENTOS DE DERECHO

Primero.- Sobre los derechos de los pacientes

El apartado segundo del artículo 8 de la Ley básica 41/2002, de 14 de noviembre, reguladora de la Autonomía del Paciente y de Derechos y Obligaciones en materia de información y documentación clínica que dispone que: “2. El consentimiento será verbal por regla general. Sin embargo, se prestará por escrito en los casos siguientes: intervención quirúrgica, procedimientos diagnósticos y terapéuticos invasores y, en general, aplicación de procedimientos que suponen riesgos o inconvenientes de notoria y previsible repercusión negativa sobre la salud del paciente.”

 Es por ello que el presente escrito sirve de prueba fehaciente para negar mi consentimiento ante todo tipo de pruebas y diagnósticos.

Segundo.- Sobre los derechos durante la situación de crisis sanitaria

En relación con el Real Decreto-ley 21/2020, de 9 de junio, de medidas urgentes de prevención, contención y coordinación para hacer frente a la crisis sanitaria ocasionada por el COVID-19 y como fundamento de mis peticiones, cabe recordar los siguientes preceptos:

Artículo 6. Uso obligatorio de mascarillas

Las personas de seis años en adelante quedan obligadas al uso de mascarillas en los siguientes supuestos:

En la vía pública, en espacios al aire libre y en cualquier espacio cerrado de uso público o que se encuentre abierto al público, siempre que no resulte posible garantizar el mantenimiento de una distancia de seguridad interpersonal de, al menos, 1,5 metros.

La obligación contenida en el apartado anterior no será exigible para las personas que presenten algún tipo de enfermedad o dificultad respiratoria que pueda verse agravada por el uso de la mascarilla o que, por su situación de discapacidad o dependencia, no dispongan de autonomía para quitarse la mascarilla, o bien presenten alteraciones de conducta que hagan inviable su utilización.

Tampoco será exigible en el caso de ejercicio de deporte individual al aire libre, ni en los supuestos de fuerza mayor o situación de necesidad o cuando, por la propia naturaleza de las actividades, el uso de la mascarilla resulte incompatible, con arreglo a las indicaciones de las autoridades sanitarias.

Artículo 9. Centros docentes

Las administraciones educativas deberán asegurar el cumplimiento por los titulares de los centros docentes, públicos o privados, que impartan las enseñanzas contempladas en el artículo 3 de la Ley Orgánica 2/2006, de 3 de mayo, de Educación, de las normas de desinfección, prevención y acondicionamiento de los citados centros que aquellas establezcan.

En cualquier caso, deberá asegurarse la adopción de las medidas organizativas que resulten necesarias para evitar aglomeraciones y garantizar que se mantenga una distancia de seguridad de, al menos, 1,5 metros. Cuando no sea posible mantener dicha distancia de seguridad, se observarán las medidas de higiene adecuadas para prevenir los riesgos de contagio.

Artículo 31. Infracciones y sanciones

1. El incumplimiento de las medidas de prevención y de las obligaciones establecidas en este real decreto-ley, cuando constituyan infracciones administrativas en salud pública, será sancionado en los términos previstos en el título VI de la Ley 33/2011, de 4 de octubre, General de Salud Pública.

La vigilancia, inspección y control del cumplimiento de dichas medidas, así como la instrucción y resolución de los procedimientos sancionadores que procedan, corresponderán a los órganos competentes del Estado, de las comunidades autónomas y de las entidades locales en el ámbito de sus respectivas competencias.

 Tercero.- Sobre la responsabilidad civil de los centros educativos

Sin ánimo de extendernos demasiado, conviene citar las siguientes disposiciones:

1º. El artículo 106.2 de la Constitución Española dispone que “los particulares, en los términos establecidos en la ley, tendrán derecho a ser indemnizados por toda lesión que sufran en cualquiera de sus bienes y derechos, salvo en los casos de fuerza mayor, siempre que la lesión sea consecuencia del funcionamiento de los servicios públicos.”

2º.- El artículo 139.1 de la Ley de Régimen Jurídico de las Administraciones Públicas dispone que “los particulares tendrán derecho a ser indemnizados por las Administraciones Públicas correspondientes, de toda lesión que sufran en cualquiera de sus bienes y derechos, salvo en los casos de fuerza mayor, siempre que la lesión sea consecuencia del funcionamiento normal o anormal de los servicios públicos.”

3º.- El artículo 145.1 de la Ley de Régimen Jurídico de las Administraciones Públicas dispone que “para hacer efectiva la responsabilidad patrimonial (…) los particulares exigirán directamente a la Administración pública correspondiente las indemnizaciones por los daños y perjuicios causados por las autoridades y personal a su servicio”

4º- El artículo 1.902 del Código Civil dispone que “el que por acción u omisión causa daño a otro, interviniendo culpa o negligencia, está obligado a reparar el daño causado”.

5º.- El artículo 1.903 del Código Civil dispone en su párrafo cuarto que “las personas o entidades que sean titulares de un Centro docente de enseñanza no superior responderán por los daños y perjuicios que causen sus alumnos menores de edad durante los periodos de tiempo en que los mismos se hallen bajo el control o vigilancia del profesorado del Centro, desarrollando actividades escolares o extraescolares y complementarias”.

6º.- El artículo 1.104 del Código Civil dispone que “la culpa o negligencia del deudor consiste en la omisión de aquella diligencia que exija la naturaleza de la obligación y corresponda a las circunstancias de las personas, del tiempo y del lugar”.

7º.- El artículo 105.1 de la LO 2/2006, de 3 de mayo, de Educación dispone que “Corresponde a las Administraciones educativas respecto del profesorado de los centros públicos, adoptar las medidas oportunas para garantizar la debida protección y asistencia jurídica, así como la cobertura de la responsabilidad civil, en relación con los hechos que se deriven de su ejercicio profesional”

Finalmente, respecto a la responsabilidad de los educadores, la doctrina del Tribunal Supremo ha reiterado que en la culpa o negligencia de los profesores y educadores se da una inversión de la carga de la prueba de forma que el padre o tutor del menor que denuncie, no ha de probar que hubo negligencia en el caso de que se trate, sino que es el demandado, centro o profesor quien tendrá que probar que actuó con la diligencia debida, estableciendo así una presunción de culpa.

Cuarto.- Sobre la responsabilidad penal de los centros educativos

Limitándonos a citar brevemente los posibles delitos en que se puede incurrir:

1º. Respecto al homicidio

 El artículo 138 del Código Penal dispone que “1. El que matare a otro será castigado, como reo de homicidio, con la pena de prisión de diez a quince años. 2. Los hechos serán castigados con la pena superior en grado en los siguientes casos: a) cuando concurra en su comisión alguna de las circunstancias del apartado 1 del artículo 140, o

cuando los hechos sean además constitutivos de un delito de atentado del artículo 550.

El artículo 140 del Código Penal dispone que “1. El asesinato será castigado con pena de prisión permanente revisable cuando concurra alguna de las siguientes circunstancias: 1.ª Que la víctima sea menor de dieciséis años de edad, o se trate de una persona especialmente vulnerable por razón de su edad, enfermedad o discapacidad.

El artículo 142 del Código Penal dispone que “1. El que por imprudencia grave causare la muerte de otro, será castigado, como reo de homicidio imprudente, con la pena de prisión de uno a cuatro años. 2. El que por imprudencia menos grave causare la muerte de otro, será castigado con la pena de multa de tres meses a dieciocho meses.”

2º. Respecto a las lesiones

El artículo 147 del Código Penal dispone que “1. El que, por cualquier medio o procedimiento, causare a otro una lesión que menoscabe su integridad corporal o su salud física o mental, será castigado, como reo del delito de lesiones con la pena de prisión de tres meses a tres años o multa de seis a doce meses, siempre que la lesión requiera objetivamente para su sanidad, además de una primera asistencia facultativa, tratamiento médico o quirúrgico. La simple vigilancia o seguimiento facultativo del curso de la lesión no se considerará tratamiento médico. 2. El que, por cualquier medio o procedimiento, causare a otro una lesión no incluida en el apartado anterior, será castigado con la pena de multa de uno a tres meses.

El artículo 149 del Código Penal dispone que “1. El que causara a otro, por cualquier medio o procedimiento, la pérdida o la inutilidad de un órgano o miembro principal, o de un sentido, la impotencia, la esterilidad, una grave deformidad, o una grave enfermedad somática o psíquica, será castigado con la pena de prisión de seis a 12 años.

El artículo 150 del Código Penal dispone que “El que causare a otro la pérdida o la inutilidad de un órgano o miembro no principal, o la deformidad, será castigado con la pena de prisión de tres a seis años.”

El artículo 152 del Código Penal dispone que “1. El que por imprudencia grave causare alguna de las lesiones previstas en los artículos anteriores será castigado, en atención al riesgo creado y el resultado producido: 1. ° Con la pena de prisión de tres a seis meses o multa de seis a dieciocho meses, si se tratare de las lesiones del apartado 1 del artículo 147. 2. ° Con la pena de prisión de uno a tres años, si se tratare de las lesiones del artículo 149. 3. ° Con la pena de prisión de seis meses a dos años, si se tratare de las lesiones del artículo 150.; 2. El que por imprudencia menos grave causare alguna de las lesiones a que se refieren los artículos 147.1, 149 y 150, será castigado con la pena de multa de tres meses a doce meses.

 El artículo 155 del Código Penal dispone que “En los delitos de lesiones, si ha mediado el consentimiento válida, libre, espontánea y expresamente emitido del ofendido, se impondrá la pena inferior en uno o dos grados. No será válido el consentimiento otorgado por un menor de edad o una persona con discapacidad necesitada de especial protección.”

Quinto.- Sobre la responsabilidad administrativa de los centros educativos en España

El artículo 94 del Estatuto Básico del Empleado Público establece que “las Administraciones Públicas corregirán disciplinariamente las infracciones del personal a su servicio señalado en el artículo anterior cometidas en el ejercicio de sus funciones y cargos, sin perjuicio de la responsabilidad patrimonial o penal que pudieran derivarse de tales infracciones”.

Por todo lo expuesto,

SOLICITO

Que en el ejercicio de la patria potestad que me atribuye el artículo 154 del Código Civil y como representante legal del alumno …………………………., sirva el presente documento como requerimiento fehaciente y a la vez apercibimiento para el caso de dar cumplimiento a cualesquiera de las medidas NO CONSENTIDAS EXPRESAMENTE a las que se hace referencia en este escrito o llegar a mi conocimiento cualquier consecuencia negativa para los menores, con la advertencia de emprender las oportunas acciones legales, tanto civiles como criminales, contra los personalmente responsables como tutores o profesores, así como contra el propio centro educativo en el caso de infringir alguno de los aspectos indicados.

En , a 13 de octubre de 2020

Firma Don/Dña…………………………….

Classification of Epileptic seizures

Epileptic seizures and epilepsies are classified separately.

Classifi cation systems are evolving under the auspices of the

International League against Epilepsy.

Epileptic seizures

The fi rst division is into generalized or focal.

Generalized epileptic seizures

A generalized epileptic seizure is one in which abnormal activity

occurs in both cerebral hemispheres from the onset of the seizure.

Different subtypes include:

Tonic-clonic seizures (GTCS): involuntary muscle contractions

occur which may be sustained (tonic) or interrupted (clonic).

Synonyms include ‘convulsion’ and ‘grand-mal seizure’ (a term

best avoided). Tonic or clonic seizures may occur, as well as

tonic-clonic.

Absence seizures: a brief, 10–30 s loss of consciousness with

staring and unresponsiveness but no loss of posture.

Myoclonic seizures: brief, muscular contractions that occur

singly or are repeated a few times. Consciousness is not

altered.

Astatic (atonic) seizures,‘drop attacks’: a sudden brief reduction

in muscle tone causing loss of posture.

Focal epileptic seizures

A focal seizure is one in which abnormal activity is initially confi

ned to one part of the brain. ‘Partial’, ‘local’, or ‘localized’ are

synonyms. Classifi cation is into simple, in which consciousness is

preserved, and complex, in which consciousness is impaired:

Simple focal seizures:

with motor activity: ‘Jacksonian’ seizures

with sensory symptoms: somatosensory, numbness

with autonomic features: pupillary or skin colour changes

with psychic symptoms: feelings of fear, rage, déjà vu. There

may be visual, auditory or olfactory hallucinations.

Complex focal seizures:

impaired consciousness: may occur alone and may be

present from onset or supervene in an initially simple focal

seizure

automatisms: semi-purposeful activities during which the

patient is vague and unresponsive, may occur.

Seizures occur which do not fi t neatly into the above categories.

It may be diffi cult to determine whether a seizure type is truly

focal or generalized. Examples include:

Focal seizures with rapid secondary generalization

Infantile spasms: widespread muscular contractions.

Epilepsies and epilepsy syndromes

Epilepsies are classifi ed by the type of epileptic seizure occurring

into generalized epilepsies and focal epilepsies. A further

subdivision is made according to aetiology into:

Idiopathic (primary): no identifi able cause apart from genetic

Symptomatic: in which the cause is identifi able or presumed.

Epilepsy syndromes are also defi ned by age of onset, EEG

fi ndings, and additional clinical or pathological features.

The classification continues to evolve in the light of new

research, but a simplifi ed version is as follows:

Generalized epilepsies and syndromes

Idiopathic generalized epilepsy (IGE):

juvenile myoclonic epilepsy (JME)

childhood absence epilepsy (CAE)

juvenile absence epilepsy (JAE)

generalized epilepsy with febrile seizures+ (GEFS+)

benign familial neonatal seizures (BFNS)

benign familial infantile seizures (BFIS)

benign myoclonic epilepsy of infancy

epilepsy with GTCS on awakening

Symptomatic generalized epilepsy:

cerebral malformations

inborn errors of metabolism.

Focal epilepsies and syndromes

Idiopathic focal epilepsy:

benign childhood epilepsy with centrotemporal spikes

autosomal dominant nocturnal frontal lobe epilepsy

Symptomatic focal epilepsy:

temporal lobe epilepsy with hippocampal sclerosis

Rasmussen’s encephalitis

hemiconvulsion–hemiplegia syndrome.

In addition to the above, there are three further categories

which do not fi t easily into the above classifi cation:

Refl ex epilepsies:

idiopathic photosensitive occipital lobe epilepsy

Epileptic encephalopathies:

myoclonic-astatic epilepsy

West syndrome

Dravet syndrome: severe myoclonic epilepsy of infancy

Lennox–Gastaut syndrome

Progressive myoclonic epilepsies:

Unverricht–Lundborg disease or Baltic myoclonus

neuronal ceroid lipofuscinosis

myoclonic epilepsy with ragged red fi bres (MERRF).

Febrile seizures occurring alone are not classifi ed as epilepsy

but also occur, together with afebrile seizures in several epilepsy

syndromes such as childhood absence epilepsy and generalized

epilepsy with febrile seizures plus (GEFS+).

Color Blindness

Color blindness is the inability or decreased ability to see color, or perceive color differences, under normal lighting conditions. Color blindness affects a significant percentage of the population. There is no actual blindness but there is a deficiency of color vision. The most usual cause is a fault in the development of one or more sets of retinal cones that perceive color in light and transmit that information to the optic nerve. This type of color blindness is usually a sex-linked condition. The genes that produce photopigments are carried on the X chromosome; if some of these genes are missing or damaged, color blindness will be expressed in males with a higher probability than in females because males only have one X chromosome (in females, a functional gene on only one of the two X chromosomes is sufficient to yield the needed photopigments).

Color blindness can also be produced by physical or chemical damage to the eye, the optic nerve, or parts of the brain. For example, people with achromatopsia suffer from a completely different disorder, but are nevertheless unable to see colors.

The English chemist John Dalton published the first scientific paper on this subject in 1798, “Extraordinary facts relating to the vision of colours”, after the realization of his own color blindness. Because of Dalton’s work, the general condition has been called daltonism, although in English this term is now used more narrowly for deuteranopia alone.

Color blindness is usually classified as a mild disability, however there are occasional circumstances where it can give an advantage. Some studies conclude that color blind people are better at penetrating certain color camouflages. Such findings may give an evolutionary reason for the high prevalence of red–green color blindness. And there is also a study suggesting that people with some types of color blindness can distinguish colors that people with normal color vision are not able to distinguish.

Color blindness affects a large number of individuals, with protanopia and deuteranopia being the most common types. In individuals with Northern European ancestry, as many as 8 percent of men and 0.5 percent of women experience the common form of red-green color blindness. The typical human retina contains two kinds of light cells: the rod cells(active in low light) and the cone cells (active in normal daylight). Normally, there are three kinds of cone cells, each containing a different pigment, which are activated when the pigments absorb light. The spectral sensitivities of the cones differ; one is most sensitive to short wavelengths, one to medium wavelengths, and the third to medium-to-long wavelengths within the visible spectrum, with their peak sensitivities in the blue, green, and yellow-green regions of the spectrum, respectively. The absorption spectra of the three systems overlap, and combine to cover the visible spectrum. These receptors are often called S cones, M cones, and L cones, for short, medium, and long wavelength; but they are also often referred to as blue cones, green cones, and red cones, respectively.

nmeth.1618-F1Causes

Genetics

Color blindness can be inherited. It is most commonly inherited from mutations on the X chromosome but the mapping of the human genome has shown there are many causative mutations—mutations capable of causing color blindness originate from at least 19 different chromosomes and 56 different genes (as shown online at the Online Mendelian Inheritance in Man (OMIM) database at Johns Hopkins University). Two of the most common inherited forms of color blindness are protanopia, and deuteranopia. One of the common color vision defects is the red-green deficiency which is present in about 8 percent of males and 0.5 percent of females of Northern European ancestry.

Some of the inherited diseases known to cause color blindness are:

cone dystrophy

cone-rod dystrophy

achromatopsia (aka rod monochromatism, aka stationary cone dystrophy, aka cone dysfunction syndrome)

blue cone monochromatism,

Leber’s congenital amaurosis.

retinitis pigmentosa.

Inherited color blindness can be congenital (from birth), or it can commence in childhood or adulthood. Depending on the mutation, it can be stationary, that is, remain the same throughout a person’s lifetime, or progressive. As progressive phenotypes involve deterioration of the retina and other parts of the eye, certain forms of color blindness can progress to legal blindness, i.e., an acuity of 6/60 or worse, and often leave a person with complete blindness.

Color blindness always pertains to the cone photoreceptors in retinas, as the cones are capable of detecting the color frequencies of light.

Other causes

Other causes of color blindness include brain or retinal damage caused by shaken baby syndrome, accidents and other trauma which produce swelling of the brain in the occipital lobe, and damage to the retina caused by exposure to ultraviolet light (10–300 nm). Damage often presents itself later on in life.

Color blindness may also present itself in the spectrum of degenerative diseases of the eye, such as age-related macular degeneration, and as part of the retinal damage caused bydiabetes. Another factor that may affect color blindness includes a deficiency in Vitamin A.

_65756566_colour_blindness2Total color blindness

Achromatopsia is strictly defined as the inability to see color. Although the term may refer to acquired disorders such as cerebral achromatopsia also known as color agnosia, it typically refers to congenital color vision disorders.

Red–green color blindness

Protanopia, deuteranopia, protanomaly, and deuteranomaly are widely common inherited color blindness that affects a substantial portion of the human population, in which those affected have difficulty with discriminating red and green hues due to the absence of the red or green retinal photoreceptors. It is sex-linked: genetic red–green color blindness affects males much more often than females, because the genes for the red and green color receptors are located on the X chromosome, of which males have only one and females have two. Females (46, XX) are red–green color blind only if both their X chromosomes are defective with a similar deficiency, whereas males (46, XY) are color blind if their single X chromosome is defective.

Blue–yellow color blindness

Those with tritanopia and tritanomaly have difficulty discriminating between bluish and greenish hues, as well as yellowish and reddish hues.

Color blindness involving the inactivation of the short-wavelength sensitive cone system is called tritanopia or, loosely, blue–yellow color blindness. The tritanopes neutral point occurs near a yellowish 570 nm; green is perceived at shorter wavelengths and red at longer wavelengths. Mutation of the short-wavelength sensitive cones is called tritanomaly.

Diagnosis

The Ishihara color test, which consists of a series of pictures of colored spots, is the test most often used to diagnose red–green color deficiencies. A figure is embedded in the picture as a number of spots in a slightly different color, and can be seen with normal color vision, but not with a particular color defect. The full set of tests has a variety of figure/background color combinations, and enable diagnosis of which particular visual defect is present. The anomaloscope, described above, is also used in diagnosing anomalous trichromacy.

Congenital Rubella Syndrome

The classic triad presentation of congenital rubella syndrome consists of the following:

Sensorineural hearing loss is the most common manifestation of congenital rubella syndrome. It occurs in approximately 58% of patients. Studies have demonstrated that approximately 40% of patients with congenital rubella syndrome may present with deafness as the only abnormality without other manifestations. Hearing impairment may be bilateral or unilateral and may not be apparent until the second year of life.

Ocular abnormalities including cataract, infantile glaucoma, and pigmentary retinopathy occur in approximately 43% of children with congenital rubella syndrome. Both eyes are affected in 80% of patients, and the most frequent findings are cataract and rubella retinopathy. Rubella retinopathy consists of a salt-and-pepper pigmentary change or a mottled, blotchy, irregular pigmentation, usually with the greatest density in the macula. The retinopathy is benign and nonprogressive and does not interfere with vision (in contrast to the cataract) unless choroid neovascularization develops in the macula.

Congenital heart disease including patent ductus arteriosus (PDA) and pulmonary artery stenosis is present in 50% of infants infected in the first 2 months' gestation. Cardiac defects and deafness occur in all infants infected during the first 10 weeks of pregnancy and deafness alone is noted in one third of those infected at 13-16 weeks of gestation.

Other findings in congenital rubella syndrome include the following:

Intrauterine growth retardation, prematurity, stillbirth, and abortion

CNS abnormalities, including mental retardation, behavioral disorders, encephalographic abnormalities, hypotonia, meningoencephalitis, and microcephaly

Hepatosplenomegaly

Jaundice

Hepatitis

Skin manifestations, including blueberry muffin spots that represent dermal erythropoiesis and dermatoglyphic abnormalities

Bone lesions, such as radiographic lucencies

Endocrine disorders, including late manifestations in congenital rubella syndrome usually occurring in the second or third decade of life (eg, thyroid abnormalities, diabetes mellitus)

Hematologic disorders, such as anemia and thrombocytopenic purpura

Copper deficiency

Copper deficiency is a very rare hematological and neurological disorder.[1] The neurodegenerative syndrome of copper deficiency has been recognized for some time in ruminant animals, in which it is commonly known as "swayback"[2] Copper is ubiquitous and daily requirement is low making acquired copper deficiency very rare. Copper deficiency can manifest in parallel with vitamin B12 and other nutritional deficiencies .[3] The most common cause of copper deficiency is a remote gastrointestinal surgery, such as gastric bypass surgery, due to malabsorption of copper, or zinc toxicity. On the other hand, Menkes disease is a genetic disorder of copper deficiency involving a wide variety of symptoms that is often fatal.[4] Copper is involved in normalized function of many enzymes, such as cytochrome c oxidase, which is complex IV in mitochondrial electron transport chain, ceruloplasmin, Cu/Zn superoxide dismutase, and in amine oxidases.[2] These enzyme catalyze reactions for oxidative phosphorylation, iron transportation, antioxidant and free radical scavenging and neutralization, and neurotransmitter synthesis, respectively.[2] A regular diet contains a variable amount of copper, but may provide 5 mg/day, of which only 20-50% is absorbed.[3] The diet of the elderly may contain a lower copper content than the recommended daily intake.[3] Dietary copper can be found in whole grain cereals, legumes, oysters, organ meats (particularly liver), cherries, dark chocolate, fruits, leafy green vegetables, nuts, poultry, prunes, and soybeans products like tofu.[5] The deficiency in copper can cause many hematological manifestations, such as myelodysplasia, anemia, leukopenia (low white blood cell count) and neutropenia (low count of neutrophils, a type of white blood cell that is often called "the first line of defense" for the immune system).[3] Copper deficiency has long been known for as a cause of myelodysplasia (when a blood profile has indicators of possible future leukemia development), but it was not until recently in 2001 that copper deficiency was associated with neurological manifestations. Some neurological manifestations can be sensory ataxia (irregular coordination due to proprioceptive loss), spasticity, muscle weakness, and more rarely visual loss due to peripheral neuropathy (damage in the peripheral nerves), myelopathy (disease of the spinal cord), and rarely optic neuropathy.

Symptoms   

Hematological Presentation   

The characteristic hematological (blood) effects of copper deficiency are anemia (which may be microcytic, normocytic or macrocytic) and neutropenia.[6] Thrombocytopenia (low blood platelets) is unusual.[3][7]

The peripheral blood and bone marrow aspirate findings in copper deficiency can mimic myelodysplastic syndrome.[8] Bone marrow aspirate in both conditions may show dysplasia of blood cell precursors and the presence of ring sideroblasts (erythoblasts containing multiple iron granules around the nucleus). Unlike most cases of myelodysplastic syndrome, the bone marrow aspirate in copper deficiency characteristically shows cytoplasmic vacuoles within red and white cell precursors, and karyotyping in cases of copper deficiency does not reveal cytogenetic features characteristic of myelodysplastic syndrome.[6][7]

Anemia and neutropenia typically resolve within six weeks of copper replacement.[8]

Neurological Presentation   

Copper deficiency can cause a wide variety of neurological problems including, myelopathy, peripheral neuropathy, and optic neuropathy.[2][7]

Myelopathy   

Copper deficiency myelopathy in humans was discovered and first described by Schleper and Stuerenburg in 2001. (Schleper B, Stuerenburg HJ. Copper deficiency-associated myelopathy in a 46-year-old woman. J Neurol. 2001 Aug; 248 (8): 705 - 6). They described a patient with a history of gastrectomy and partial colonic resection who presented with severe tetraparesis and painful paraesthesias and who was found on imaging to have dorsomedial cervical cord T2 hyperintensity. Upon further analysis, it was found that the patient had decreased levels of serum coeruloplasmin, serum copper, and CSF copper. The patient was treated with parenteral copper and the patient`s paraesthesias did resolve. Since this discovery, there has been heightened and increasing awareness of copper-deficiency myelopathy and its treatment, and this disorder has been reviewed by Kumar. Sufferers typically present difficulty walking (gait difficulty) caused by sensory ataxia (irregular muscle coordination) due to dorsal column dysfunction[7] or degeneration of the spinal cord (myelopathy).[2][9] Patients with ataxic gait have problems balancing and display an unstable wide walk. They often feel tremors in their torso, causing side way jerks and lunges.[10]

In brain MRI, there is often an increased T2[disambiguation needed] signalling at the posterior columns of the spinal cord in patients with myelopathy caused by copper deficiency.[2][7][11] T2 signalling is often an indicator of some kind of neurodegeneration. There are some changes in the spinal cord MRI involving the thoracic cord, the cervical cord or sometimes both.[2][7] Copper deficiency myelopathy is often compared to subacute combined degeneration (SCD).[9] Subacute combined degeneration is also a degeneration of the spinal cord, but instead vitamin B12 deficiency is the cause of the spinal degeneration.[2] SCD also has the same high T2 signalling intensities in the posterior column as copper deficient patient in MRI imaging.[11]

Peripheral Neuropathy   

Another common symptom of copper deficiency is peripheral neuropathy, which is numbness or tingling that can start in the extremities and can sometimes progress radially inward towards the torso.[7][12] In an Advances in Clinical Neuroscience & Rehabilitation (ACNR) published case report, a 69 year old patient had progressively worsened neurological symptoms.[13] These symptoms included diminished upper limb reflexes with abnormal lower limb reflexes, sensation to light touch and pin prick was diminished above the waist, vibration sensation was lost in the sternum, and markedly reduced proprioception or sensation about the self’s orientation.[13] Many people suffering from the neurological effects of copper deficiency complain about very similar or identical symptoms as the patient.[2][12] This numbness and tingling poses danger for the elderly because it increases their risk of falling and injuring themselves. Peripheral neuropathy can become very disabling leaving some patients dependent on wheel chairs or walking canes for mobility if there is lack of correct diagnosis. Rarely can copper deficiency cause major disabling symptoms. The deficiency will have to be present for an extensive amount of time until such disabling conditions manifest.

Optic Neuropathy   

Some patients suffering from copper deficiency have shown signs of vision and color loss.[12] The vision is usually lost in the peripheral views of the eye.[12] The bilateral vision loss is usually very gradual.[14][12] An optical coherence tomography (OCT) shows some nerve fiber layer loss in most patients, suggesting the vision loss and color vision loss was secondary to optic neuropathy or neurodegeneration.[12]

Causes   

Surgery   

Bariatric surgery is a common cause of copper deficiency.[6][2] Bariatric surgery, such as gastric bypass surgery, is often used for weight control of the morbidly obese. The disruption of the intestines and stomach from the surgery can cause absorption difficulties not only as regards copper, but also for iron and vitamin B12 and many other nutrients.[2] The symptoms of copper deficiency myelopathy may take a long time to develop, sometimes decades before the myelopathy symptoms manifest.

Zinc Toxicity   

Increased consumption of zinc is another cause of copper deficiency.[7] Zinc is often used for the prevention or treatment of common colds and sinusitis (inflammation of sinuses due to an infection), ulcers, sickle cell disease, celiac disease, memory impairment and acne.[7] Zinc is found in many common vitamin supplements and is also found in denture creams.[7][14][15] Recently, several cases of copper deficiency myeloneuropathy were found to be caused by prolonged use of denture creams containing high quantities of zinc.[14][15]

Metallic zinc is the core of all United States currency coins, including copper coated pennies. People who ingest massive amount of coins will have elevated zinc levels, leading to zinc toxicity induced copper deficiency and thus displaying neurological symptoms. This was the case for a 57 year old woman diagnosed with schizophrenia. This woman consumed over 600 coins, and started to show neurological symptoms such as unsteady gait and mild ataxia.[16]

Hereditary Disorders   

Menkes disease showing symptoms of the sparse, steel colored "kinky hair" and paleness

Menkes disease is a congenital disease that is a cause of copper deficiency.[4][7][17] Menkes disease is a hereditary condition caused by a defective gene involved with the metabolism of copper in the body.[7] Menkes disease involves a wide variety of symptoms including floppy muscle tone, seizures, abnormally low temperatures, and a peculiar steel color hair that feels very rough.[4][17] Menkes disease is usually a fatal disease with most children dying within the first ten years of life.[4][17]

Other   

It is rarely suggested that excess iron supplementation causes copper deficiency myelopathy.[2] Another rarer cause of copper deficiency is Coeliac disease, probably due to malabsorption in the intestines.[2] Still, a large percentage, around 20%, of cases have unknown causes.[2]

Biochemical Etiology   

Copper functions as a prosthetic group, which permits electron transfers in key enzymatic pathways like the electron transport chain.[18][3][2] Copper is integrated in the enzymes cytochrome c oxidase, which is involved in cellular respiration and oxidative phosphorylation, Cu/Zn dismutase, which is involved in antioxidant defense, and many more listed in the table below.[3]

Neurological Etiology   

Cytochrome c Oxidase     

There have been several hypotheses about the role of copper and some of its neurological manifestations. Some suggest that disruptions in cytochrome c oxidase, also known as Complex IV, of the electron transport chain is responsible for the spinal cord degeneration.[2][9]

Myelinated neuron

Another hypothesis is that copper deficiency myelopathy is caused by disruptions in the methylation cycle.[9] The methylation cycle causes a transfer of a methyl group (-CH3) from methyltetrahydrofolate to a range of macromolecules by the suspected copper dependent enzyme methionine synthase.[9] This cycle is able to produce purines, which are a component of DNA nucleotide bases, and also myelin proteins.[9] The spinal cord is surrounded by a layer of protective protein coating called myelin (see figure). When this methionine synthase enzyme is disrupted, the methylation decreases and myelination of the spinal cord is impaired. This cycle ultimately causes myelopathy.[9]

Hematological Etiology   

Iron Transportation   

The anemia caused by copper deficiency is thought to be caused by impaired iron transport. Hephaestin is a copper containing ferroxidase enzyme located in the duodenal muscosa that oxidizes iron and facilitate its transfer across the basolateral membrane into circulation.[6] Another iron transporting enzyme is ceruloplasmin.[6] This enzyme is required to mobilize iron from the reticuloendothelial cell to plasma.[6] Ceruloplasmin also oxidizes iron from its ferrous state to the ferric form that is required for iron binding.[4] Impairment in these copper dependent enzymes that transport iron may cause the secondary iron deficiency anemia.[6] Another speculation for the cause of anemia is involving the mitochondrial enzyme cytochrome c oxidase (complex IV in the electron transport chain). Studies have shown that animal models with impaired cytochrome c oxidase failed to synthesize heme from ferric iron at the normal rate.[6] The lower rate of the enzyme might also cause the excess iron to clump, giving the heme an unusual pattern.[6] This unusual pattern is also known as ringed sideroblastic anemia cells.

Cell Growth Halt   

The cause of neutropenia is still unclear; however, the arrest of maturing myelocytes, or neutrophil precursors, may cause the neutrophil deficiency.[6][3]

Zinc Intoxication   

Zinc intoxication may cause anemia by blocking the absorption of copper from the stomach and duodenum.[2] Zinc also upregulates the expression of chelator metallothionein in enterocytes, which are the majority of cells in the intestinal epithelium.[2] Since copper has a higher affinity for metallothionein than zinc, the copper will remain bound inside the enterocyte, which will be later eliminated through the lumen.[2] This mechanism is exploited therapeutically to achieve negative balance in Wilson’s disease, which involves an excess of copper.[2]

Treatment    

Copper deficiency is a very rare disease and is often misdiagnosed several times by physicians before concluding the deficiency of copper through differential diagnosis (copper serum test and bone marrow biopsy are usually conclusive in diagnosing copper deficiency). On average, patients are diagnosed with copper deficiency around 1.1 years after their first symptoms are reported to a physician.[2] Copper deficiency can be treated with either oral copper supplementation or intravenous copper.[7] If zinc intoxication is present, discontinuation of zinc may be sufficient to restore copper levels back to normal, but this usually is a very slow process.[7] People who suffer from zinc intoxication will usually have to take copper supplements in addition to ceasing zinc consumption. Hematological manifestations are often quickly restored back to normal.[7] The progression of the neurological symptoms will be stopped by appropriate treatment, but often with residual neurological disability.

References    

Jump up ^ Scheiber, Ivo; Dringen, Ralf; Mercer, Julian F. B. (2013). "Chapter 11. Copper: Effects of Deficiency and Overload". In Astrid Sigel, Helmut Sigel and Roland K. O. Sigel. Interrelations between Essential Metal Ions and Human Diseases. Metal Ions in Life Sciences 13. Springer. pp. 359–387. doi:10.1007/978-94-007-7500-8_11.

^ Jump up to: a b c d e f g h i j k l m n o p q r s t u v Jaiser, S. R., & Winston, G. P. (2010). Copper deficiency myelopathy. [Review]. Journal of Neurology, 257(6), 869-881.

^ Jump up to: a b c d e f g h Halfdanarson, T. R., Kumar, N., Li, C. Y., Phyliky, R. L., & Hogan, W. J. (2008). Hematological manifestations of copper deficiency: a retrospective review. [Article]. European Journal of Haematology, 80(6), 523-531.

^ Jump up to: a b c d e Kodama, H., & Fujisawa, C. (2009). Copper metabolism and inherited copper transport disorders: molecular mechanisms, screening, and treatment. Metallomics, 1(1), 42-52.

Jump up ^ Copper Information: Benefits, Deficiencies, Food Sources. http://www.healthvitaminsguide.com/minerals/copper.htm

^ Jump up to: a b c d e f g h i j Klevay, L. M. (2006). "Myelodysplasia," myeloneuropathy, and copper deficiency. Mayo Clinic Proceedings, 81(1), 132-132.

^ Jump up to: a b c d e f g h i j k l m n o Kumar, N. (2006). Copper deficiency myelopathy (human swayback). Mayo Clinic Proceedings, 81(10), 1371-1384.

^ Jump up to: a b Fong T, Vij R, Vijayan A, DiPersio J, Blinder M. (2007). Copper deficiency: an important consideration in the differential diagnosis of myelodysplastic syndrome. Haematologica 92(10):1429-30.

^ Jump up to: a b c d e f g Jaiser, S. R., & Winston, G. P. (2008). Copper deficiency myelopathy and subacute combined degeneration of the cord: why is the phenotype so similar? Journal of Neurology, 255, P569.

Jump up ^ Ataxic Gait Demonstration. Online Medical Video. http://www.youtube.com/watch?v=FpiEprzObIU&feature=related

^ Jump up to: a b Bolamperti, L., Leone, M. A., Stecco, A., Reggiani, M., Pirisi, M., Carriero, A., et al. (2009). Myeloneuropathy due to copper deficiency: clinical and MRI findings after copper supplementation. [Article]. Neurological Sciences, 30(6), 521-524.

^ Jump up to: a b c d e f Pineles, S. L., Wilson, C. A., Balcer, L. J., Slater, R., & Galetta, S. L. (2010). Combined Optic Neuropathy and Myelopathy Secondary to Copper Deficiency. [Review]. Survey of Ophthalmology, 55(4), 386-392.

^ Jump up to: a b Jaiser, Stephan R. and Duddy, R. Copper Deficiency Masquerading as Subacute Combined Degeneration of the Cord and Myelodysplastic Syndrome. Advances in clinical neuroscience and rehabilitation, http://www.acnr.co.uk/JA07/ACNR_JA07_abnwinner.pdf

^ Jump up to: a b c Spinazzi, M., De Lazzari, F., Tavolato, B., Angelini, C., Manara, R., Armani, M. (2007). Myelo-optico-neuropathy in copper deficiency occurring after partial gastrectomy. Do small bowel bacterial overgrowth syndrome and occult zinc ingestion tip the balance? Journal of Neurololgy,254, 1012-1017.

^ Jump up to: a b Hedera, P., Peltier, A., Fink, J. K., Wilcock, S., London, Z., & Brewer, G. J. (2009). Myelopolyneuropathy and pancytopenia due to copper deficiency and high zinc levels of unknown origin II. The denture cream is a primary source of excessive zinc. [Article]. Neurotoxicology (Amsterdam), 30(6), 996-999.

Jump up ^ Dhawan, S. S., Ryder, K. M., & Pritchard, E. (2008). Massive penny ingestion: The loot with local and systemic effects. [Article]. Journal of Emergency Medicine, 35(1), 33-37.

^ Jump up to: a b c Kaler, S. G., Liew, C. J., Donsante, A., Hicks, J. D., Sato, S., & Greenfield, J. C. (2010). Molecular correlates of epilepsy in early diagnosed and treated Menkes disease. Journal of Inherited Metabolic Disease, 33(5), 583-589.

Jump up ^ Vest, Katherine E.; Hashemi, Hayaa F.; Cobine, Paul A. (2013). "Chapter 13 The Copper Metallome in Eukaryotic Cells". In Banci, Lucia (Ed.). Metallomics and the Cell. Metal Ions in Life Sciences 12. Springer. doi:10.1007/978-94-007-5561-10_12. ISBN 978-94-007-5560-4. electronic-book ISBN 978-94-007-5561-1 ISSN 1559-0836 electronic-ISSN 1868-0402