Progeria

1. Progeria By Ann Lehto and Lekha Nair

2. History “Progeria” is derived from the Greek word meaning 'prematurely old‘ It is also known as Hutchinson-Gilford syndrome, because Jonathan Hutchinson and Hastings Gilford discovered the syndrome in 1886 Around 100 cases have been identified since its discovery

3. Onset and Signs of Progeria • At birth, the child appears normal. The first symptoms of Progeria are generally presented at 6-12 months, when the child fails to gain weight, lose hair and have changes in skin conditions. • The child begins to look old – having narrowed face, conspicuous scalp veins and a pinched nose. • There is high risk of delayed tooth formation. Generally, the limbs shows fragility accompanied with joint stiffness.

4. Symptoms of Progeria Growth failure during the first year of life Narrow, shrunken or wrinkled face with beaked nose Baldness, in addition to loss of eyebrows and eyelashes Prominent eyes Short stature Large head for size of face (macrocephaly) Open soft spot (fontanelle) Small jaw (micrognathia) Dry, scaly, thin skin Limited range of motion Teeth - delayed or absent formation High pitched voice All children have a similar appearance, regardless of ethnic background.

5. Treatment and Prognosis • There is no cure for Progeria. • Regular monitoring for cardiovascular disease may help with managing your child's condition. Some children undergo coronary artery bypass surgery or dilation of cardiac arteries (angioplasty) to slow the progression of cardiovascular disease. • Certain therapies may ease some of the signs and symptoms. They include: • Low-dose aspirin – a daily dose may help prevent heart attacks and stroke • Physical and occupational therapy - to help with joint stiffness and hip problems, and allow the child to remain active • High-calorie dietary supplements - including extra calories in the child's daily diet may help prevent weight loss and ensure adequate nutrition • Extraction of primary teeth - the child's permanent teeth may start coming in before his or her baby teeth fall out. Extraction may help prevent overcrowding and developing a second row of teeth when permanent teeth come in.

6. Prognosis • Progeria is associated with a short lifespan • The average patient survives to the early teens (around 13), however some patients have lived up to 30 years • The cause of death is usually caused by stroke or heart problems, as a result of the progressive atherosclerosis (hardening of arteries)

7. Diagnosis • Some signs of Progeria that can be tested: • Insulin-resistant diabetes: doesn’t respond readily to insulin injections • Skin changes where connective tissue becomes hard and tough • Cardiac stress testing can show signs of atherosclerosis of blood vessels- where fatty material collects along walls of arteries. This disorder is commonly associated with Progeria, and can be life threatening. • The symptoms are unique to the disorder, and often it is diagnosed when the symptoms are shown at a young age. John Tacket, 15

8. Inheritance • Caused by a mutation of the LMNA gene • Lamin A/C- produces proteins called lamins • Lamins- structural proteins called intermediate filament proteins, which is important in the structure of the nuclear lamina • Because the disorder is caused by a genetic mutation it is usually not inherited, and because the individual usually dies in their teens it cannot be passed on further. • The disorder is rarely inherited from parents, but it can occur in children of consanguineous parents as a recessively inherited gene

9. The Mutation • Mutation changes nucleotide in DNA sequence in gene- changes the cytosine to thymine in nucleotide 1824 • Mutation in lamin A results in abnormal lamin protein called progerin, which is missing 50 amino acids on the end • When mutated protein is incorporated into nuclear lamina, it prevents normal assembly of nuclear lamins- causes abnormal nuclear shapes • Buildup of damaged protein can cause cells to die prematurely

10. Pedigree This pedigree of a girl from Italy with consanguineous parents (second cousins)

11. Interesting Facts There are 54 known children in 30 countries with Progeria, and 97% of the children are Caucasian. Progeria is a rare sporadic disorder with an incidence of 1 per 8 million live births. 90 percent of progeria patients die by age 13 from fatal heart attacks or strokes. The mutation is believed to occur in the father’s sperm before conception. In spite of their physical ailments, children with Progeria have normal intellectual development. At school they are bright and inquisitive children. A child with Progeria, Mickey Hays, appeared in a movie playing an alien character - http://www.youtube.com/watch?v=llHgPR2wie8 Researchers have discovered that the toxic protein responsible for progeria is actually produced at low levels in all humans, possibly accumulating as we age. Bystudying children with progeria, we can further our understanding of a major mechanism of human aging and maybe find new ways to slow the process.

12. Questions What is Progeria, essentially? What are some of the signs and symptoms of Progeria? What can a child with Progeria anticipate about his or her life? How does a child get Progeria? What is another disorder that is often associated with Progeria and can be tested?

13. Works Cited "Progeria." MayoClinic.com. 24 Apr 2009. Mayo Foundation for Medical Education and Research (MFMER), Web. 10 Jan 2010. <http://www.mayoclinic.com/health/progeria/DS00936>. "About Progeria." 2006. The Progeria Research Foundation, Web. 10 Jan 2010. <http://www.progeriaresearch.org/about_progeria.html>. "Learning About Progeria." 10 Apr 2009. National Human Genome Research Institute, Web. 9 Jan 2010. <http://www.genome.gov/11007255>. "LMNA". Genetics Home Reference. January 7, 2010 <http://ghr.nlm.nih.gov/gene=lmna>. Paradisi, Mauro. "Dermal fibroblasts in Hutchinson-Gilford progeria syndrome with the lamin A G608G mutation have dysmorphic nuclei and are hypersensitive to heat stress". BMC Cell Biology. January 7, 2010 <http://www.biomedcentral.com/1471-2121/6/27>. "Hutchinson-Gilford Progeria". eMedicine. January 8, 2010 <http://emedicine.medscape.com/article/1117344-overview>. "Progeria". The New York Times. January 8, 2010 <http://health.nytimes.com/health/guides/disease/progeria/overview.html>. Juncosa, Barbara. "New Hope for Progeria: Drug for Rare Aging Disease". Scientific American. January 9, 2010 <http://www.scientificamerican.com/article.cfm?id=new-hope-for-progeria-drug-for-rare-aging-disease >.