Bhargavi ChMSc II – Semester

Seminar on Progeria Syndrome

Department of Human Genetics

ANDHRA UNIVERSITY

GOOD MORNING

AGING is the accumulation of changes in an organism over time.

POPULATION : 1.2 BILLIONGROWTH IS 2.4% PER ANNUM INCLUDING NET DEATHS. IE, 27 MILLION PER

ANNUM. THIS IS 540,000 PER WEEK OR 78,000 PER WEEK. GIVE OR TAKESOME THIS IS A GROWTH OF 10,000 PER DAY - THAT IS 400 PER HOUR AND 62

MINTE OR APPROXIMATELY 1 PER SECOND!

TELOMERE THEORYTelomeres (structures at the ends of chromosomes) haveexperimentally been shown to shorten with each successive celldivision.

PROGERIA SYNDROME

“Progeria” also known as“Progeria of Childhood” or

“Hutchinson Gilford ProgeriaSyndrome (HGPS)” is an extremely

rare, severe genetic conditionwherein symptoms resembling

aspects of aging are manifested at an early age.

Mode of InheritanceDe novo dominant mutation.

INCIDENCEThe disorder has a very low incidence and occurs in one per eight million live births and male predominance with M:F ratio of 1.5:1 and a strong racial susceptibility for Caucasians who represent 97% of patients.

CLINICAL DIAGNOSIS/ CharacteristicsThe diagnosis of Hutchinson-Gilford progeria syndrome (HGPS,progeria) is based on recognition of common clinical features and thepresence of the LMNA p.Gly608Gly mutation.

Growth Body fat

CharacteristicsSkin/Teeth

Characteristics - Skeletal system

CVS. Severe, progressiveatherosclerosis withwidely variable age ofclinical manifestationresulting in myocardialinfarction and stroke Other/ Characteristics

The following features are frequently present:

• Body fat. Prominent superficial veins• Skin• Thin, taut, dry, wrinkled skin that is brown-spotted invarious areas• "Sclerodermatous" skin over lower abdomen and proximalthighs, in which irregular bumps reflect underlyinglipodystrophy• Loss of eyebrows and sometimes eyelashes• Dystrophic nails• Skeletal system. Persistently patent anterior fontanel• Other• Pinched nose, beaked nasal tip• Faint nasolabial cyanosis• Thin lips• Protruding ears; lack of ear lobes• Thin, high-pitched voice

TESTINGThe clinical diagnosis of HGPS is based on recognition ofcommon clinical features and detection of the p.Gly608Gly mutationin exon 11 of the LMNA gene, which is present in all individuals withHGPS. Molecular genetic testing for this mutation is clinicallyavailable.

Urinary hyaluronic acid. Although urinary hyaluronic acid hasbeen reported to be increased in most children with HGPS, the measurement is now regarded as unreliable and is not recommended for diagnosis.

Gene.The p.Gly608Gly mutation in exon 11 of the LMNA gene is presentin all individuals with HGPS.Clinical methods• Confirmatory diagnostic testing• Prenatal diagnosisClinical testing• Targeted mutation analysis and sequence analysis can be used toidentify p.Gly608Gly, the recurrent de novo LMNA mutation inexon 11 that defines HGPS.

Test MethodMutations Detected

Mutation Detection Rate1 Test availability

Sequence analysis/ Target Mutation analysis

LMNAp.Gly608Gly point mutation

100% Clinical Testing

Molecular Genetic Testing Used in Hutchinson-GilfordProgeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS, progeria) is defined by the presence of the LMNA p.Gly608Gly mutation.

LMNA Gene is located on chromosomal locus 1q21.2 and the protein name is LAMIN A/C.

PRENATAL TESTINGPrenatal diagnosis for HGPS is possibleby analysis of DNA extracted from fetalcells obtained by amniocentesis usuallyperformed at approximately 15 to 18weeks' gestation or chorionic villussampling (CVS) at approximately ten to12 weeks' gestation. The disease-causingallele of an affected family member mustbe identified before prenatal testing canbe performed.

MANAGEMENTA regular diet is recommended; however, if the lipid profilebecomes abnormal, treatment includes exercise, diet modification, andmedication as warranted.Age-appropriate schooling is usually recommended. Appropriatemedication dosage is based on body weight or body surface arearather than age. Anesthetics should be used with caution.Nitroglycerin is frequently of benefit if angina develops. Routine anti-congestive therapy is appropriate if congestive heart failure (CHF) ispresent.Hip dislocation is best managed conservatively with physical therapyand body bracing; surgery involving bones should be avoided ifpossible.Dental extractions may be required to avoid dental crowding. Routinephysical and occupational therapy, active stretching and strengtheningexercises, and hydrotherapy are recommended.

GENETIC COUNSELINGGenetic counseling is the process of providing individuals andfamilies with information on the nature, inheritance, and implicationsof genetic disorders to help them make informed medical and personaldecisions.

The following section deals with genetic risk assessmentand the use of family history and genetic testing to clarify geneticstatus for family members. This section is not meant to address allpersonal, cultural, or ethical issues that individuals may face or tosubstitute for consultation with a genetics professional. To find agenetics or prenatal diagnosis clinic, see the GeneTests ClinicDirectory.

RISK TO FAMILY MEMBERSParents of a proband• All probands with HGPS have the disorder as the result of a denovo mutation.• Parents of probands are not affected.Sibs of a proband• Because HGPS is caused by a de novo mutation, the risk to thesibs of a proband is small.

Offspring of a proband. Individuals with HGPS do not reproduce.Other family members of a proband. Because HGPS occurs as theresult of a de novo mutation, other family members of a proband arenot at increased risk.

GENETICALLY RELATED (ALLELIC) DISORDERSMore than ten other diseases and conditions with mutations or

variations in the LMNA gene have been identified.

Penetrance - Penetrance is complete.

Differential Diagnosis

• Neonatal progeroid syndrome (Weidemann-Rautenstrauchsyndrome)• Acrogeria• allermann-Streif syndrome• Gerodermia osteodysplastica• Petty-Laxova-Weidemann progeroid syndrome• Ehlers-Danlos syndrome, progeroid form• Werner syndrome.

EVALUATIONS FOLLOWING INITIAL DIAGNOSIS

• Establishement of vascular status using baselineelectrocardiogram (ECG), echocardiogram, and carotid duplexscans for stenosis and for intimal thickness• Skeletal x-ray to evaluate for characteristic findings:acroosteolysis, clavicular resorption, and coxa valga• Dual-energy x-ray absorptiometry (DEXA) to assess bonemineral density• Standard goniometry to assess global joint mobility• Nutritional assessment to optimize caloric intake

TREATMENT OF MANIFESTATIONSThere is no conclusive treatment for Progeria that can beeffective. Treatments can only reduce complications likecardiovascular diseases, with a possible heart bypass operation or low-dose medicines. A high-calorie diet can probably prolong the life-span. There is a growth hormone treatment being tested to find out if itcan cure progeria.

Medications. Dosages should be based on body weight or bodysurface area and not on age. Anesthetics should be used with particularcaution. Nitroglycerin is frequently of benefit if angina develops.

Injuries. Children are susceptible to fractures; treatment is routine.

Hips. Children are particularly susceptible to hip dislocation becauseof the coxa valga malformation.

Teeth. Delayed loss of primary teeth is common.

Physical therapy. Routine physical and occupational therapy isrecommended to help maintain range of motion in large and smalljoints.

Surveillance• ECG, echocardiogram.• Yearly lipid profiles• Yearly dental examination and x-ray• Physical and occupational therapy multiple times per week• Hip x-rays every few years

Agents/Circumstances to AvoidChildren should avoid being in the midst of large crowds with muchtaller and larger peers because of the increased risk of injury.

“Progerin” is present at low levels in the cells of healthy people.

One could envision a scenario in which

progerins effects on the notch path way and by extension on adult stem cells could over time lead to many of the tissue changes we commonly associate with the aging process

CASE-1

This beautiful little boyCameron froms stevensville,Michigan, was diagnosed inMarch 2007 at 5 months of age.

CASE-2

Meet Hayley from England, oneof the very special children withProgeria who has captured thehearts of many. Hayley has wonthe prestigious Children ofCourage Award and appeared inseveral documentariesand other media stories aboutProgeria.

CASE-3Zach Pickard was diagnosedwith Progeria in December2007 at the age of 11 months.His family and their friendstook immediate action, holdingfundraisers, speaking with themedia and organizing aKentucky chapter, to help find acure for Zach and the otherchildren with Progeria.

CASE-4

Leslie Gordon was a physician who didn't know anything about progeria until her own son , Sam, was diagnosed at 21 months. Gordon and her husband, pediatrician Scott Berns, founded the

Progeria Research Foundation.

CASE-5

The series of portraits depictsthe 24 year old Leon Botha, oneof the world’s longest survivingProgeria sufferers.

He is an Artist.

CASE-6

While the average life expectancy of a child with Progeria is less than14 years, it is believed that the oldest case ever recorded 26 years ofage. Not true.

The oldest case ever recorded was a Japanese man wholived with this Syndrome for 45 years.

In this particular case, the child did not show signs of growthretardation until around 12 years of age. It was noted, however, thathis head was larger than normal at the age of one and he didexperience hair loss in childhood, but enjoyed a rather normal life for12 years. By age 20, this particular subject had total Alopecia andaging began to accelerate. The subject died at the age of 45 frommyocardial infarction.

The disease which infects one in four lakh people, is present in India too. Bisul khan and Razia Khatooon,’s family in Chhapra, Bihar; has seven children, of which five areProgeria patients.HERE PARENTS ARE FIRST DEGREE COUSINS

Out Of the five, three daughters,Are dead; having passed away at theages of 17, 24 and 13.

Two sons Ikramul (23) and AliHosain (22) are still alive, buttheir medical ages are 70 and 66.Two children are normal.

The sad thing is that the villagersostracized the Progeria-strickenfamily from Chhapra in 2003because the children wereconsidered bad omen.

PROGERIA CASE IN INDIA

There is a trust called by S B Devi Charity home which takes care ofthe Progeria family’s needs, financial problems and medicalrequirements.

Ikramul and Ali suffer from astro-arthritis and cannot bend their legsor sit properly. Their bodies are very weak and their liver and heart areunder-developed. The longest lifespan for progeria in the world is 23.Unfortunately, both the kids are nearing that age.

Razia's family is the only family in the world, which had five cases ofProgeria.She has already lost her two sons and a daughter to this disease and is hoping for a miracle to save her two sons.

PAA is a Progeria Based Hindi Movie, Starring Amitab Bachchan playing a 12 year old boy, AURO, a progeria victim.

nature is a mutable cloud which isalways and never the same

THANK YOUTHANK YOU