Progeria

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Progeria is a disorder that occurs once in every four million births, making it one of the rarest genetic disorders studied (National Human Genome Research Institute 2010). It is nearly impossible to diagnose at birth because as a newborn there are no symptoms. Within the first year of their childhood, victims stop showing signs of normal growth, but exhibit normal intelligence for children their age. Once symptoms begin to show, some that are exhibited are baldness, aged-looking skin, and loss of subcutaneous fat. Although there is no way to rid someone from Progeria, there are ways to suppress the symptoms. It is caused by a point mutation in the Lamin A gene, which creates an unusable form of the Lamin A protein. Children with this disease normally do not exceed the age of thirteen.

"http://www.youtube.com/embed/xCSzysu_flY?rel=0" A video showing the life story of a young boy with Progeria.

History

Progeria was first described by Dr. Jonathan Hutchinson in 1886 and then was elaborated on in 1904 by Dr. Hastings Gilford (Walton et al. 1994). This disease was so rare that it was hard to fully understand what was happening to these progeria victims until later when more advanced research was conducted. Doctors could only try to develop explanations as to why this disease affected only certain individuals. Hutchinson first came into contact with a progeria diseased victim by documenting the medical features of a six year old boy who lost his hair and had skin that was almost transparent. Gilford then followed Hutchinson’s discoveries years later by interacting with a patient with the same symptoms. Gilford came up with the name progeria from a Greek word meaning “prematurely old.” He followed this patient from infancy until the age of 17 years and showed characteristics continually getting worse as the patient aged.

Symptoms

Progeria starts out with no signs or symptoms. As a newborn child, progeria victims usually appear perfectly normal. It is within the first year of their childhood development that the symptoms start to become apparent. The child’s growth rate will be suppressed drastically and they will weigh much less than a normal child of their age. Children with progeria, however, will typically show normal intelligence. Their physical appearance as they age consists of baldness, aged-looking skin, a pinched nose, loss of subcutaneous fat, high serum lipid levels, early atherosclerotic changes in vessels, and a small face and jaw relative to their head size. They also experience symptoms on average seen in much older people such as stiffness of joints, hip dislocations, and severe, progressive cardiovascular diseases. Progeria victims usually do not exceed the age of thirteen (Walton et al. 1994).

Symptoms.jpg

(medchrome.com)

Mechanism Behind Progeria

Progeria is caused by a point mutation of the Lamin A (LMNA) gene. Lamin A is the protein that helps to form the nuclear envelope. A point mutation is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide. In the case of Progeria, cytosine is replaced with thymine in position 1824 of the LMNA gene, which creates an unusable form of the Lamin A protein, because the cells of the body become unstable (McClintock et al. 2007). This truncated version of Lamin A is also referred to as "progerin." This mutation is generally not inherited, but is thought to have developed at the time of conception. This mutation in the Lamin A gene results in the premature aging symptoms of progeria, although the mechanism connecting the misshapen nucleus to the symptoms is not known.

Current Treatments

There are many different treatment options for those suffering from the effects of progeria. Although there is no cure, there are different techniques that can be followed to relieve the symptoms. Having a child participate in physical therapy and occupational therapy can help increase mobility and relieve joint stiffness, as well as coordination and range of motion (Mayo Clinic 2009). Children suffering from progeria are more susceptible to injuries and fractures, especially in the hips, so necessary precautions should be taken (The Progeria Handbook 2010). There has not been any evidence that says that a special diet including low-cholesterol or low-fat food choices influences symptoms, however supplements are recommended to reduce weight loss in children suffering from progeria. A high calorie diet can also alter the weight loss, and it also allows for the correct amount of nutrients to be met. Feeding tubes may be necessary for infants in order for them to get the nutrients needed to remain healthy (Mayo Clinic 2009).

Infections are treated in progeria patients the same way as in healthy patients, and medication doses should be given based on body weight and type, and not rely on age as a factor. A daily low dose of aspirin can be taken to reduce the chances for a heart attack or stroke and other cardiovascular problems even if no signs of problems have occurred. Once signs of seizures, blood clots, strokes and heart attacks are seen, doses should be altered (The Progeria Handbook 2010). Surgery can be used to relieve certain symptoms as well, however surgery on bones is not recommended because of the possibility of brittleness. A surgery to remove baby teeth may be necessary because of the chance of overcrowding when the primary teeth start to come in before the baby teeth are lost completely (Mayo Clinic 2009). One other type of surgical technique used is an angioplasty, which is an artery bypass surgery that can reduce the chances of cardiovascular disease (The Progeria Handbook 2010). Having the child see a therapist can help them cope with the thoughts of the disease, as well as the thought of death at a young age. Support groups for patients and parents alike may help relieve the stresses of coping with, and taking care of a patient with the disease (Mayo Clinic 2009).

Outlook of Progeria

The average life span of a patient suffering from Progeria is thirteen years old, however there have been cases in which patients live to be as old as twenty one (Progeria Research Foundation). Most children die from complications of atherosclerosis, including heart attack and stroke (Progeria Research Foundation). No treatments have been proven effective for curing progeria. However, there have been some therapies used that may reduce the signs and symptoms of the disease (Mayo Clinic 2009)

It has been determined that patients with Progeria have mental development that is not affected. Children can still participate in daily activities, such as going to school, and possibly participating in sports (The Progeria Handbook).

Dr. Maria Eriksson created an abnormal mouse model with modified teeth and skin. The Progeria gene present in the mice was engineered to be turned off and on. After the mice showed signs of symptoms for Progeria, the gene was then turned off. After weeks of taking part in the study, it was determined that the Progeria affected mice cells showed skin that was indistinguishable to that of normal skin cells. The purpose of this study was to show that the damage that Progeria can do to cells of the skin and other organs is not irreversible. With the correct treatment, many symptoms can be reversed (Eriksson 2008).

Human trials have been conducted using a medicine that consists of three drugs: Pravastatin, Zoledronic acid, and Lonafarnib. Although results cannot yet be determined, the treatment seems to be promising in obtaining a cure for Progeria.

Trial Medications (Progeria Research Foundation 2010):

- Pravastatin A statin drug that has been mostly used for lowering cholesterol and preventing cardiovascular disease.

- Zoledronic acid A bisphosphonate drug that is mostly used to prevent skeletal fractures in cancer patients by minimizing the effects of osteoporosis.

- Lonafarnib A farnesyltransferase inhibitor (FTI) drug that is under recent study that has seemed to reverse abnormality in Progeria cells. This drug has improved the abnormalities in mice with Progeria in laboratory settings.

All three of these drugs affect different points of progerin, a truncated version of the Lamin A gene which causes Progeria. If these three drugs used human trial can be administered in a way that effectively blocks the farnesyl group attachment, the progression of progerin may cease and Progeria could possibly be improved.

A study presented by Dr. Carlos Lopez-Otin showed that two new drugs, Pravastatin and Soledronic acid, showed improvement in Progeria cells and extended the lifespan of mice with Progeria. The results of this study show that medicines for Progeria have a promising future.

Prgeria cells.jpg

Current Research

Farnesyltransferase inhibitors (FTIs), are medications being evaluated to help with the cell structure damage that children with Progeria may face. Although these types of drugs were developed for cancer symptoms, studies have shown that they could reduce the damage seen to cells. In 2005, Mallampalli et al. published a study that stated that the cancer drugs reverse the abnormalities of Progeria affected cells, and return them to the normal cell state in the laboratory.

In August and October of 2008, it was noted that gene therapy and the use of the FTIs can reverse the effects of Progeria in mice. The cardiovascular system was the main priority to treat because Progeria affects it and causes heart disease. If the drugs were to reverse the effects of Progeria in children, it would be a large breakthrough in the understanding of the disease (Progeria Research Foundation 2010).

In January 2009, a new technique was developed to determine the amount of progerin in Progeria affected cells, as well as normal healthy cells. It was determined that the normal cells have the protein, just not in the large quantities as in Progeria cells. The cells both create more progerin as the cells get older, the Progeria cells just have a build up much more quickly (Rodriguez et al. 2009).

February 2010 brought along more information regarding Farnesyltransferase inhibitors. It was determined that the drugs do not inhibit proteins, but that FTIs act on the part of progerin that is affected (Yang et al. 2010). Davies et al. (2010) introduced new evidence that a farnesyl group on the progerin protein is the main cause of the symptoms of Progeria. A normal mouse progerin protein was studied, and it was noted that the farnesyl group on the affected cells was not present in the normal proteins. The step that causes the disease is the inability to remove the farnesyl group from the proteins.

In 2010, research showed that the progerin protein ages in everyone, whether sick or healthy, and this brought along new questions about whether or not this protein is another factor for heart disease in aging adults. Also studied was the effects an insulin-like growth factor would have on symptoms, and it was determined that the life of an Progeria protein infected mouse was extended to a certain point (Progeria Research Foundation 2010).

Researchers are developing ways to determine the effects of the LMNA gene on aging. DNA is being examined to determine the changes. Another method of research involves using the affected gene to see the effects it has on blood vessels in mice, as well as humans (National Institutes of Health 2007).

Literature Cited

Davies, B., R. Barnes, Y. Tu, S. Ren, D. Andres, H. Spielmann, J. Lammerding, Y. Wang, S. Young, L. Fong. 2010. An accumulation of non-farnesylated prelamin A causes cardiomyopathy but not progeria. Human Molecular Genetics, 19:2682-2694.

Eriksson, M. 2008. Reversible phenotype in a mouse model of Hutchinson-Gilford Progeria syndrome. J. Med. Genet. doi:10.1136/jmg.2008.060772.

Mallampalli, M., G. Huyer, P. Bendale, M. Gelb, S. Michaelis. 2005. Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson–Gilford progeria syndrome. PNAS, 102: 14416–14421.

Mayo Clinic. 2009. Progeria. [Online] http://www.mayoclinic.com/health/progeria/DS00936.

McClintock, D., D. Ratner, M. Lokuge, D. Owens, L. Gordon, F. Collins, K. Djabali. 2007. The mutant form of lamin A that causes Hutchinson-Gilford Progeria is a biomarker of cellular aging in human skin. PLoS ONE, 12: e1269. doi:10.1371/journal.pone.0001269.

National Human Genome Research Institute. 2010. Learning about progeria. [Online] http://www.genome.gov/11007255.

National Institutes of Health. 2007. Fact Sheet:Progeria. [Online] http://www.nih.gov/about/researchresultsforthepublic/Progeria.pdf.

The Progeria Handbook; A Guide for Families and Health Care Providers of Children with Progeria. 2010. [Online] http://www.progeriaresearch.org/assets/files/PRFhandbook_0410.pdf.

Progeria Research Foundation. 2010. [Online] http://www.progeriaresearch.org/.

Rodriguez, S., F. Coppedè, H. Sagelius, M. Erikson. 2009. Increased expression of the Hutchinson-Gilford progeria syndrome truncated lamin A transcript during cell aging. European Journal of Human Genetics, 17 (1):1-10.

Walton, J., J. Barondess, and S. Lock. 1994. Progeria. The Oxford Medical Companion, 797.

Yang, S., S. Chang, D. Andres, H. Spielmann, S. Young, L. Fong. 2010. Assessing the efficacy of protein farnesyltransferase inhibitors in mouse models of progeria. Journal of Lipid Research, 51:400-405.