Ehlers-Danlos Syndrome

From Science Online

Contents 1 History 2 Genetics and Etiology 3 Protein Involved 4 Classification and Symptoms 5 Diagnosis 6 Medical Treatment Available 7 Prevention

History

This condition was first noted in the writings titled 'Airs, Waters and Places' by Hipprocates in 400 BC observing the Nomads and Scythians. He found them to contain lax joints and multiple scars. In the year 1657, a Dutch surgeon named Job Janszoon van Meek'ren observed a case thought to be this disorder of a boy named George Albes. This patient was observed at the Academy of Leyland and was found to have abnormalities within his skin including extreme flexibility. Another case was found with the famous violin player known as the 'Virtuso in Excelsis' named Paganini who lived from 1782 to 1840. Due to his hypermobile joints, slender physique, thoracic deformity, and joint laxity, he was able to perform in extreme ways musically. The first comprehensive observation and record of EDS was published in 1892 by Dr. Tschernogobow. He had been working with two patients at the Moscow Venereology and Dermatology Society. Throughout the 1800's many individuals containing symptoms of EDS went on to use this abnormality in circus performances such as 'The India Rubber Man' or the 'elastic lady'. (Parapia, 2008)

The condition today known as Ehlers-Danlos Syndrome was first officially diagnosed by two doctors named Edvard Ehlers and Henri-Alexandre Danlos. At the time, Ehlers, a danish dermatologist, was specializing in dermatology medical research and Danlos was working as a doctor in Paris France at Hospital Tenon. These two medical professionals classified the condition based on a grouping of symptoms. In 1936 Frederich Parkes-Weber, an English physician, established the name of the disorder, naming it after the two doctors. Until the year 1967 this single classification served to cover the disorder characterized by a group of particular symptoms. (Parapia, 2008)This broad classification was then split into eleven unique classification types organized based on distinct symptoms. These eleven classifications were then altered again in 1997 when EDS was reclassified into six major subclasses. Today EDS is diagnosed based on these six subtypes. (Wikipedia)

Genetics and Etiology

Ehlers-Danlos is a heterogeneous group of heritable connective tissue disorders caused by a variation of different genetic mutations. These alterations in the genes disturb healthy production and development of collagen within the human body. Collagen is a fibrous protein that serves as one of the major constituents of connective tissue, giving these tissues strength and elasticity by acting as a sort of 'glue'. These proteins are the most abundant in the human body, existing as trimers with a central triple helical region as can be seen in the collagen type-III picture displayed under the protein category. Patients with EDS have bodies that are unable to go through proper collagen synthesis, which causes their connective tissues in their systems to become weak and unstable. Today, EDS is classified into six subtypes, each distinguished by its manifestation of symptoms and signs. All of these subtypes involve defects in different genes and are considered distinct genetic disorders. (Byers, 1994)

Although every one of the six subtypes of EDS is inherited from the parent passed onto the child as a specific or group of genetic alterations, inheritance patterns of the subtypes differ by each classification. Each the arthrochalasia, classic, hypermobility, and vascular forms of EDS are inherited through an autosomal dominant inheritance pattern. This means that only one copy of an altered gene in a cell is sufficient enough to lead to the syndrome in the child. This pattern of inheritance of a genetic trait is expressed whenever the gene is present regardless of the gender of the person. (MedicineNet)These make up the majority of the cases of EDS. The minority other two types of EDS, dermatosparaxis and kyphoscoliosis, and occasionally seen in rare cases with the previously discussed classic and hypermobility subclasses, are inherited through an autosomal recessive inheritance pattern in which two copies of a gene in each cell are altered leading to the development of the disorder within the child. One chromosome making up the pair is inherited from each of the parents. In most cases, both parents of the individual that contain the autosomal recessive disorder will be carriers of a copy of the mutated gene but not actually exhibit symptoms of the disorder in that they have one mutated copy and one normal copy making up the chromosome pair. Because EDS is passed on by the parent's genes, family history plays a huge risk factor in many cases.

The majority of cases of classic EDS are found to contain mutations within the genes COL5A1 or COL5A2 both serving in the production of collagen V. Both the Collagen type V, alpha 1 and collagen, type V, alpha 2 genes serve to encode for one alpha chain for fibrillar collagens which are comprised of one or more varieties of alpha chains in the form of a trimer. Collagen V is a protein located in tissues also found to contain collage I and has been discovered to hold the job of regulating the assemblage of heterotypic fibers which are comprised of both type I collagen as well as type V collagen. Different types of collagen vary from one another through their functions. Type-1 collagen is the main component of bones in the body, while type-5 collagen serves to control and regulate the assemblage and initiation of collagen fibrils. Through clinical studies, it is shown that not all that are afflicted with EDS classic subtype contain a mutation within their COL5A1 gene or their COL5A2 gene. For this reason, research continues as COL1A1, COL1A2, and DCN genes have been ruled out.

The hypermobility subclass of EDS is caused by mutations in the COL3A1 gene and the TNXB gene. The collagen, type III, alpha 1 gene encodes instructions for the creation of pro-alpha 1 (III) chains which serve as components and leads to the formation of type III collagen by joining together in threes to make the molecule III procollagen. III procollagen then goes through a process involved with enzymes outside of the cell in which protein segments from the ends are removed. After this, collagen III molecules form in cross-linked long, thin fibrils, which create strong and mature collagen III fibrils located in spaces around cells. Mutations within this COL3A1 gene lead to alterations within the production of type III procollagen molecules leading the incorrect assemblage of or lack of collagen type-III. It is this lack of the correct form collagen III that leads to the symptoms of EDS hypermobility. The other gene, TNXB also known as tenascin XB, can hold mutations leading to EDS hypermobility. This gene encodes production of the protein tenascin-X found between the structures of cells. It is important in this location for the organization and mantinace of normal tissue structure for support for the body. Tenascin-X also helps to determine the deposition of collagen fibrils within the extracellular matrix and may be involved in the stability and strength of elastic fibers providing support for the body. Elastic fibers are structures composed of branches that give the skin the characteristic of being able to maintain and return to its original shape after it has undergone distortion by deforming forces. Unlike in hypermobility cases of EDS due to mutations in COL3A1, mutations in TNXB affect elastic fibers. Mutations of the TNXB gene which lead to EDS hypermobility are rare but occur when the mutation prevents a copy of TNXB from producing functioning protein which leads to the reduction of tenascin-X levels in the body. This reduction of tenascin-X disrupts the deposit of collagen and the network of elastic fibers located in tendons and joint ligaments and leads to the alterations in the structure of connective tissues.

The Vascular subtype of Ehlers-Danlos Syndrome is a result of a variety of mutations in the COL3A1 human gene which contains the code for the production of type III procollagen, previously discussed for its role in EDS hypermobility type. Type-III collagen is a fibrous protein, also known as scleroproteins which make up bone, cartilage, bone marrow stroma, tendon, and connective tissues within the body. EDS vascular subtype is a result of a point mutation within the gene which produce substitution of glycine residues in the triple helical structure of collagen III. In this case, glycine residues of the alpha 1 (III) chain of collagen type-III being disrupted, as glycine at position 135 is replaced by arginine within the triple helix collagen structure. This subclass can also be caused from exon-skipping mutations and multi-exon deletions. Each of these mutations within the human gene affect and lead to malformation within the areas of structure, synthesis, and the secretion process of type III procollagen. This causes the body to produce a thin dermis layer, small fiber bundles of collagen, and inconsistent or small fibril diameters. These lead to the symptoms and signs of Vascular EDS including thin, translucent skin; arterial, intestinal, or uterine fragility or rupture, and extensive bruising.

Kyphoscoliosis, another subclass of EDS, is caused by an autosomal recessive condition resulting from abnormalities in lysyl hydroxylase which is also known as procollagen-lysine 5-dioxygenase. Lysyl hydroxylase serves a critical purpose as an oxygenase enzyme serving to catalye the process of hydroxylation of lysine into hyoxylysine. This process is required in the development and stabilization of collagen. This reaction of hydroxylation of lysyl residues within collagen type-1 is needed in the process of developing standard crosslinks within molecules of the collagen protein. Crosslinks derived from lysine are less stable than crosslinks aquired from hydroxylysine. In addition these crosslinks also are not able to mature as quickly within the multi-component intermolecular links which serve to make molecular interactions stable. This subtype's signs are a result of the lack of healthy, more complicated and intricate crosslinks within collagen.

Another subclass of EDS is known as arthrochalasia and is identified by a defect within the process of converting type I procollagen into collagen. Procollagen is a precursor to collagen which is made up of procollagen peptide chains which contain lysine and proline which are yet to be hydroxylated or, in definition, introduced to a hydroxyl group. The genes involved with this subclass are COL1A2 and COL1A1. Within cases of arthrochalasia, patients have been found to contain mutations within the cleavage sites of substrate proalpha1 (1) [type A] and proalpha2(1) [type B] chains which lead to deficient processing of amino terminal ends within these chains of type-1 collagen. The mRNA coming from the mutant allele lack a portion or lack completely the domain that is responsibly for producing the cleavage site for N-proteinase known as exon 6. This eradication of a portion or all of exon 6 can lead to deletion of the cleavage site in a chain, disarry of the amino-terminal site of cleavage on molecules involved with the irregular chain, and the removal of a lysyl residue in telopeptide extensions which are involved in the hydroxylation process and in intermolecular crosslinks.

The final type of subclass of EDS is called dermatosparaxis. This subclass is the result of mutations within the ADAMTS2 gene or the ADAM metallopeptidase with throbospondin type 1 motif, 2 gene. This gene holds the service of providing directions for the production of a specific enzyme which processes multiple types of procollagen molecules within their development to collagen. This gene's enzyme cuts a small portion of amino acids off of one of the terminals of the procollagen molecule which in result leads to collagen molecules which are able to assemble into slender, strong fibrils and then into cross-links. In the case of dermatosparaxis EDS, mutations within the ADAMTS2 gene lead to the reduction of development or interaction of the produced enzyme. Without this enzyme functioning properly, molecules of procollagen are unable to be processed accurately leading to the incorrect assemblage of collagen fibrils and the disruption of cross-links and chemical interactions with the collagen fibrils. Overall these results cause connective tissue within the body to become weak, leading to this specific classification of EDS. (Byers, 1994)(Grahame, 2007)

(Byers, 1994) (Parapia, 2008) (Hermanns-Le, 2007) (MayoClinic)(Wikipedia) (Genetics Home Reference) (MedicineNet) (Ehlers Danlos National Foundation)

Protein Involved

This disease is caused by mutations within the ADAMTS2, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, PLOD1, and TNXB genes which all are involved in the processing or production of collagen or proteins interacting with collagen. Collagen is important to the body as it is the main protein of connective tissue. It is also the most abundant protein found in mammals making up approximately a quarter of all protein in the human body. This protein is unique in that it contains high tensile strength. There are 28 types of collagen known, but over 90% of collagen in the body are types I, II, III, and IV. Mutations in the processing or production of collagen can harm the body by weakening connective tissue in the skin, bones, blood vessels, and organs. Collagen type III and type V are the characteristic collagen types in which defects can cause Ehlers-Danlos syndrome. Those that are afflicted with Ehlers-Danlos syndrome lack appropriate collagen synthesis which causes connective tissues to be weak and unstable. (Genetics Home Reference)

The picture above is of a synthetic peptide containing a region from human type III collagen. This particular collagen type is found in artery walls, skin, intestines, and the uterus and is the collagen of granulation tissue. This particular type of Collagen is a homotrimer that with collagen type I is able to form 67 nm axially periodic fibrils in blood vessels, skin, and other tissues that require extensibility. Collagen type III is associated with the Hypermobility classification of Ehlers-Danlos.

Within this picture we are able to see the structure of collagen. Collagen structure is made up of an atypical composition of amino acids in a polypeptide chain containing great amounts of the amino acids glycine and proline. It also is distinct in that collagen contains two other amino acids in great quantity that are not inserted directly by RNA during protein synthesis known as hydroxyproline and hydroxylysine which are each derived from the amino acids proline and lysine respectively. These two amino acids are important in the stabilisation of the tropocollagen globular structure. (3Dchem.com)The collagen crystal structure consists of a rod-like triple-helical structure which is made up of three supercoiled polyproline II-like chains and requires Gly as every third residue. All residues in the X and Y positions are highly exposed to solvent which makes the triple helical structure very well suited in interacting with other molecules and in self-association. The triple helix geometrical features prohibit intrachain hydrogen bonding. Collagen III contains distinct binding domains located on the collagen triple-helix including unique collagenase cleavage site and binding sites for integrins.(3Dchem.com)

(Kramer, 1999)

Classification and Symptoms

Ehlers-Danlos syndrome is divided into six different classifications based on signs and symptoms.

The most common form of Ehlers-Danlos syndrome is the Hypermobility type (formerly known as type III). This particular type of EDS affects roughly about one in every 10,000 to 15,000 people and is characterized by the symptoms of loose, unstable joints, easy bruising, velvety-smooth skin, mildly hyperextensible skin, advanced premature osteoarthritis, heart valve problems, and chronic joint pain. This particular classification is caused by an autosomal dominant mechanism.

Classical EDS is diagnosed in approximately 2 to 5 in 100, 000 people or overall around 20,000 to 40,000 people and produces symptoms including losse joints prone to dislocation and lack of development, elastic, velvety skin, fragile skin, poor wound healing, scarring, noncancerous fibrous growths located on areas of pressure, fatty growths located on the forearm and shin areas, hernias, , scoliosis, and heart valve problems.

Vascular EDS, effecting about 1 in 100,000 people, is the result of a autosomal dominant defect leading to symptoms including spontaneous ruptures of arteries and bowels due to fragile blood vessels and organs that are prone to tearing, clubfoot present at time of birth, skin laxity, thin and fragile skin, loose joints, facial appearance with protruding eyes, thin nose and lips, sunken in cheeks, small chin, and visible veins through skin. This form of EDS is the most serious and can lead to death due to complications. For those diagnosed with this classification, life expectancy is approximately 48 years.

The classification of Kyphoscoliosis type EDS is a very uncommon diagnosis which causes symptoms including progressive curvature of the spine, respiratory problems, fragile, damage prone eyes, thin sclera, weakness in muscles, and increased risk of medium-sized artery rupture. This type of EDS is extremely rare with only approximately sixty reported cases.

Arthrochalasis, another are form of EDS with only approximately thirty cases reported causes symptoms including loose and unstable joints, fragile skin, early-onset arthritis, and increased risk of bone loss and fracture. Patients with this classification of EDS are characteristically short in height.

The most rare form of EDS, Dermatosparaxis, has only been diagnosed in approximately ten cases worldwide. Patients inflicted with this classification show symptoms including loose, unstable joints, fragile, sagging skin that loses elasticity, short stature, delayed closure of the fontanels which are the soft areas of the skull of a newborns head, facial appearance with swollen eyelids and bluish tinge to whites of eyes, umbilical hernia, and short fingers.

Throughout medical research and practice other extremely rare forms of EDS have been discovered. Overall, much more research needs to be conducted on this particular syndrome in order for scientists to fully gain an understanding of EDS.(MayoClinic)(Ehlers Danlos National Foundation)

(MayoClinic)

Diagnosis

In order to diagnose EDS, a medical doctor will begin with a full physical medical examination paying specific attention to joints and skin conditions. A careful record will also be taken of the patients medical and family history. In addition, any of the following tests may be conducted in order to lead to a thorough conclusion.

One type of testing available to diagnose classical, vascular, kyphoscoliosis, and arthrochalasis types of EDS is Genetic testing. This is done as prenatal DNA testing and preimplantation genetic diagnosis which tests embryos obtained by in vitro fertilization. This is done and is available for families with family histories containing the EDS gene.

Another type of testing available which can lead to the diagnosis of kyphoscoliosis class of EDS is urine testing. This particular test is used to observe and measure the levels of a specific enzyme that is produced by the specific gene that is in association with this particular subclass of EDS. Within this process, the levels of this specific enzyme are noted in which abnormal levels may indicate the kyphoscoliosis class of EDS.

A third option for diagnosis of EDS is a skin biopsy. This test is used to diagnose the Vascular subclass of EDS. This involves the process of the removal of a skin sample which is then observed under a microscope where the skin is scanned for any abnormalities within the composition of collagen fibers in the skin.

A fourth option for those undergoing testing for the diagnosis of EDS is a heart ultrasound that can lead to the diagnosis of the classical or hypermobility EDS subtypes. This checks for mitral valve prolapse with is a symptom of these two subclasses of EDS. This procedure creates a image of the heart beating that can show abnormalities in heart function such as in the muscles and valves of the heat or any sort of fluid that may be surrounding the heart.(MayoClinic)

Medical Treatment Available

There is no known cure for Ehlers-Danlos syndrome because there is no way in which medicine knows today to reverse genetic alterations that cause Ehlers-Danlos syndrome. (Genetics Home Reference)Medical treatment focuses on finding ways to manage the signs and symptoms of each of the six particular types depending on each person. Much of treatment procedures are of self-care and protection strategies to stop effects such as excessive bruising and injuries and to protect joints. In most cases, evaluation of condition by a physician who specializes in rehabilitation medicine or physical therapy is needed.(MayoClinic) Overall the symptoms of each particular subclass of EDS are treated on a individual basis based on the manifestations present in the patient. (MedicineNet)

Due to the lack of a cure for EDS, most individuals inflicted with this syndrome rely on self-care and protection. This involves avoiding contact sports or dangerous activities that may lead to injuries. Those with EDS must use protective gear such as padding, guards, and protective clothing to protect the individuals afflicted from injury. Other ways in which injury is prevented are by keeping a tidy home free of clutter and using assistive devices to reduce stress on joints. In addition sunscreen is a must to protect skin from premature aging from exposure to UV rays. (MayoClinic)

Prevention

For those whom hold a family history of the mutated allele, genetic counseling is recommended. Through testing and evaluation, results can show the chances of EDS being passed on from parent to child. This sort of process can aid in comprehension not only of the disorder but of the genetics of EDS.(Genetics Home Reference)

(MayoClinic) (Ehlers Danlos National Foundation) (MedicineNet) (Genetics Home Reference) (UW Medicine: Orthopaedics and Sports Medicine) (Grahame, 2007) (Hermanns-Le, 2007) (Roulet, 2007) (Horii, 2006) (Byers, 1994)

References