Bhargavi Saragadam MSC II Semester

Seminar on Progeria Syndrome Department of Human Genetics ANDHRA UNIVERSITY

AGING is the accumulation of changes in an organis m or object over time. Ageing in humans refers to a multidimensional process of physical, psychological, and social change. Roughly 100,000 people worldwide die each day of age-related causes.

the scientific technique for the extraction of a solution which will reintroduce Telomere Lengthening Enzymes is available to current day researchers and has been shown in studies to reset cellular functionality and there by, in theory, prolong a healthy individual's life span! THE EXACT NUMBER IS CALCULATED AS FOLLOWS;
POPULATION : 1.2 BILLION GROWTH 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 TAKE SOME THIS IS A GROWTH OF 10,000 PER DAY - THAT IS 400 PER HOUR AND 62 MINTE OR APPROXIMATELY 1 PER SECOND!

TELOMERE THEORY Telomeres (structures at the ends of chromosomes) have experimentally been shown to shorten with each successive cell division.

Shortened telomeres activate a mechanism that prevents further cell multiplication. This may be an important mechanism of ageing in tissues like bone marrow and the arterial lining where active cell division is necessary. In model organisms and laboratory settings, researchers have been able to demonstrate that selected alterations in specific genes can extend lifespan. At present, the biological basis of aging is unknown.

PROGERIA SYNDROME
Progeria also known as Progeria of Childhood or Hutchinson Gilford Progeria Syndrome (HGPS) is an extremely rare, severe genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. Progeria was first described in 1886 by Jonathan Hutchinson and also described independently in 1897 by Hastings Gilford. The condition was later named Hutchinson Gilford Progeria Syndrome. Scientists are particularly interested in Progeria because it might reveal clues about the normal process of aging. It is a genetic condition that occurs as a new mutation and is not usually inherited, although there is a uniquely inheritable form. This is in contrast to another rare but similar premature aging syndrome, Dyskeratosis congentia (DKC), which is inheritable and will often be expressed multiple times in a family line.

Mode of Inheritance Hutchinson-Gilford progeria syndrome (HGPS) is caused by a de novo dominant mutation.

INCIDENCE The 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. DISEASE CHARACTERISTICS Clinical features develop in childhood and resemble some features of accelerated aging. Children with HGPS appear normal at birth. Profound failure to thrive occurs during the first year. Characteristic faces, partial alopecia, loss of subcutaneous fat, stiffness of joints, bone changes and abnormal tightness of the skin. Death usually occurs as a result of complications of cardiac or cerebrovascular disease generally between 6 and 20 years of age, with an average life span of approximately 13 years.

CLINICAL DIAGNOSIS The diagnosis of Hutchinson-Gilford progeria syndrome (HGPS, progeria) is based on recognition of common clinical features and the presence of the LMNA p.Gly608Gly mutation. The clinical manifestations include the following abnormalities, which are almost always present after age three years: Growth Short stature stunted growth and

Weight distinctly low for height Head disproportionately large for face Body fat Diminished subcutaneous fat Prominent veins scalp

 Skin/Teeth Generalized alopecia Delayed and crowded dentition

Skeletal system Distal phalangeal osteolysis Delayed anterior fontanelle closure Pear-shaped thorax Micrognathia Short, dystrophic clavicles "Horse-riding" stance Coxa valga Thin limbs Tightened ligaments joint

 CVS. Severe, progressive atherosclerosis with widely variable age of clinical manifestation resulting in myocardial infarction and stroke Other Prominent eyes Lagophthalmos Wide-based, shuffling gait Failure to complete secondary sexual development

The

following features are frequently present: Body fat. Prominent superficial veins Skin Thin, taut, dry, wrinkled skin that is brown-spotted in various areas "Sclerodermatous" skin over lower abdomen and proximal thighs, in which irregular bumps reflect underlying lipodystrophy 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

Individuals having most of these features are considered to have the classic Hutchinson-Gilford progeria syndrome. Individuals with either more or less severe features are considered to have atypical progeria.

TESTING: The clinical diagnosis of HGPS is based on recognition of common clinical features and detection of the p.Gly608Gly mutation in exon 11 of the LMNA gene, which is present in all individuals with HGPS. Molecular genetic testing for this mutation is clinically available. Urinary hyaluronic acid. Although urinary hyaluronic acid has been reported to be increased in most children with HGPS [Brown et al 1990], the measurement is now regarded as unreliable [Gordon et al 2003] and is not recommended for diagnosis. Molecular Genetic Testing GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

Table 1. Molecular Genetic Testing Used in Hutchinson-Gilford Progeria Syndrome Test Method Sequence analysis Targeted mutation analysis Mutations Detected Mutation Detection Rate1 Test Availab ility Clinical Testing

LMNA p.Gly608Gly point mutation

100%

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

Gen e Sym bol

Chromos omal Locus

Prot ein Na me

Locus Specific

H G M D

Human Intermediate Filament Database LMNA (lamin C1) Human Intermediate Filament Database LMNA (lamin A) L Lam LM Human Intermediate M 1q21.2 inNA Filament Database LMNA N A/C (lamin C2) A The LMNA mutations database IPN Mutations, LMNA Leiden Muscular Dystrophy pages (LMNA) Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt.

PRENATAL TESTING Prenatal diagnosis for HGPS is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed. Note: (1) Because HGPS has thus far not been reported to recur in families, prenatal testing would only be performed because of the (unlikely) possibility of germline mosaicism in one of the parents. (2) Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD. Note: Because HGPS has thus far not been reported to recur in families, PGD would only be performed because of the (unlikely) possibility of germline mosaicism in one of the parents.

MANAGEMENT A regular diet is recommended; however, if the lipid profile becomes abnormal, treatment includes exercise, diet modification, and medication as warranted. Age-appropriate schooling is usually recommended. Appropriate medication dosage is based on body weight or body surface area rather than age. Anesthetics should be used with caution. Nitroglycerin is frequently of benefit if angina develops. Routine anticongestive therapy is appropriate if congestive heart failure (CHF) is present. Hip dislocation is best managed conservatively with physical therapy and body bracing; surgery involving bones should be avoided if possible. Dental extractions may be required to avoid dental crowding. Routine physical and occupational therapy, active stretching and strengthening exercises, and hydrotherapy are recommended. Surveillance includes: annual or semi-annual electrocardiogram (ECG), echocardiogram, and carotid duplex scans; annual lipid profiles and dental examination and x-ray; physical and occupational therapy multiple times per week; and hip x-ray every few years to evaluate for avascular necrosis and progressing coxa valga. Children with HGPS should avoid being in the midst of large crowds with much taller/larger peers because of the risk of injury.

GENETIC COUNSELING Almost all individuals with HGPS have the disorder as the result of a de novo dominant mutation. Because HGPS is caused by a de novo mutation, the risk to the sibs of a proband is small. One instance of apparent somatic and germline mosaicism has been reported. Thus, the recurrence risk may be on the order of one in 500, as in other de novo dominant mutations. Prenatal testing is available; however, because of the low risk of recurrence, prenatal testing would only be performed because of the (limited) possibility of germline mosaicism in one of the parents. Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.

RISK TO FAMILY MEMBERS Parents of a proband All probands with HGPS have the disorder as the result of a de novo mutation. Parents of probands are not affected. Sibs of a proband Because HGPS is caused by a de novo mutation, the risk to the sibs of a proband is small. One instance of apparent somatic and germline mosaicism has been reported [Wuyts et al 2005]. Therefore, the recurrence risk may be on the order of one in 500, as in other de novo dominant mutations. With the exception of two sets of identical twins with HGPS, the authors are unaware of any convincing cases of a family with more than one sib with classic HGPS. Offspring of a proband. Individuals with HGPS do not reproduce. Other family members of a proband. Because HGPS occurs as the result of a de novo mutation, other family members of a proband are not at increased risk.

GENETICALLY RELATED (ALLELIC) DISORDERS More than ten other diseases and conditions with mutations or variations in the LMNA gene have been identified. See OMIM 150330. Progeroid laminopathy. The term "progeroid laminopathy" can be used to describe phenotypes that resemble HGPS in which an LMNA mutation other than p.Gly608Gly has been identified. Approximately 10% of individuals with clinically diagnosed HGPS have uniparental isodisomy (UPD) of chromosome 1 (including the LMNA gene), a mosaic rearrangement of chromosome 1, and a deletion involving the LMNA gene locus [Eriksson et al 2003]. These individuals are hypothesized to have somatic changes that occur in vivo or in vitro, deleting the mutated LMNA and providing a growth advantage to that clone of cells. Penetrance: Penetrance is complete. Differential Diagnosis The following are other syndromes that include some features of premature aging: Neonatal progeroid syndrome) Acrogeria allermann-Streif syndrome Gerodermia osteodysplastica

syndrome

(Weidemann-Rautenstrauch

Berardinelli-Seip lipodystrophy ( generalized lipodystrophy)

Petty-Laxova-Weidemann progeroid syndrome Ehlers-Danlos syndrome, progeroid form Werner syndrome.

EVALUATIONS FOLLOWING INITIAL DIAGNOSIS To establish the extent of disease in an individuals diagnosed with Hutchinson-Gilford progeria syndrome (HGPS), the following evaluations are recommended: Establishement of vascular status using baseline electrocardiogram (ECG), echocardiogram, and carotid duplex scans for stenosis and for intimal thickness Skeletal x-ray to evaluate for characteristic acroosteolysis, clavicular resorption, and coxa valga findings:

Dual-energy x-ray absorptiometry (DEXA) to assess bone mineral density Standard goniometry to assess global joint mobility Nutritional assessment to optimize caloric intake

TREATMENT OF MANIFESTATIONS There is no conclusive treatment for Progeria that can be effective. Treatments can only reduce complications like cardiovascular diseases, with a possible heart bypass operation or lowdose medicines. A high-calorie diet can probably prolong the lifespan. There is a growth hormone treatment being tested to find out if it can cure progeria.No evidence exists that a low-cholesterol, low-fat, or other special diet influences the course of progeria. In general, serum cholesterol and triglyceride concentrations are not elevated and HDL concentrations may decrease with age. Thus, a regular diet is indicated unless the lipid profile becomes abnormal, at which point appropriate treatment includes exercise, diet modification, and medication as warranted. Prior to decline in cardiovascular or neurologic status (resulting from strokes, angina, or heart attacks), children should be encouraged to be physically active as possible, taking in to account joint mobility and possible hip problems limiting their ability to exercise. Because intellect and maturity are normal, age-appropriate schooling is usually indicated. Infections are generally handled as for unaffected children. Medications. Dosages should be based on body weight or body surface area and not on age. Anesthetics should be used with particular caution. Nitroglycerin is frequently of benefit if angina develops. Routine anti-congestive therapy is appropriate if congestive heart failure (CHF) is present. Injuries. Children are susceptible to fractures; treatment is routine. Hips. Children are particularly susceptible to hip dislocation because of the coxa valga malformation. Conservative management with physical therapy and body bracing and avoidance of surgical procedures on bones are recommended when possible. Teeth. Delayed loss of primary teeth is common. Extractions may be required to avoid crowding and development of two rows of teeth. Physical therapy. Routine physical and occupational therapy is recommended to help maintain range of motion in large and small joints. Active stretching and strengthening, along with hydrotherapy, are recommended.

Surveillance The following are appropriate: ECG, echocardiogram, and carotid duplex scans annually or semi-annually to monitor for cardiovascular disease (Children may experience severe carotid artery atherosclerotic blockage prior to any significant ECG changes.) Yearly lipid profiles Yearly dental examination and x-ray Physical and occupational therapy multiple times per week Hip x-rays every few years to evaluate for avascular necrosis and progressing coxa valga Agents/Circumstances to Avoid Children should avoid being in the midst of large crowds with much taller and larger peers because of the increased risk of injury.

CASES: This beautiful little boy Cameron froms stevensville, Michigan, was diagnosed in March 2007 at 5 months of age. Meet Hayley from England, one of the very special children with Progeria who has captured the hearts of many. Hayley has won the prestigious Children of Courage Award and appeared in several documentaries and other media stories about Progeria.

Zach Pickard was diagnosed with Progeria in December 2007 at the age of 11 months. His family and their friends took immediate action, holding fundraisers, speaking with the media and organizing a Kentucky chapter, to help find a cure for Zach and the other children with Progeria.

The series of portraits depicts the 24 year old Leon Botha, one of the worlds longest surviving Progeria sufferers. He is an Artist.

While the average life expectancy of a child with Progeria is less than 14 years, it is believed that the oldest case ever recorded 26 years of age. Not true. The oldest case ever recorded was a Japanese man who lived with the disease for 45 years. In this particular case, the child did not show signs of growth retardation until around 12 years of age. It was noted, however, that his head was larger than normal at the age of one and he did experience hair loss in childhood, but enjoyed a rather normal life for 12 years. By age 20, this particular subject had total Alopecia and aging began to accelerate. The subject died at the age of 45 from myocardial infarction.

PROGERIA CASES IN INDIA Progeria is a debilitating, rare illness and genetic disorder with just 45 odd cases in the world. 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 are Progeria patients. Out Of the five, three daughters, Guriya, Rehana and Rubina are dead; having passed away at the ages of 17,24 and 13 respectively. Two sons Ikramul (23) and Ali Hosain (22) are still alive, but their medical ages are 70 and 66. Two children Sanjita (21 year old) and Gulab Shah(7 year old) are normal. The sad thing is that the villagers ostracized the Progeria-stricken family from Chhapra in 2003 because the children were considered bad omen. Doctors Apurba Ghosh, director of the Institute of Children Health, Kolkata and Dr Chandan Chatterjee from Switzerland, were the first to diagnose this disorder. Rubenas Pneumonia treatment convinced the medical team that the kids are affected with Progeria. Bisul Khans family in India, is the ONLY FAMILY in the world that has more than one case of progeria (five to be prescise). Dr. Ghosh says, There are only 40 known cases world-wide, all isolated and seemingly random.On average, a progeria child will die by 17. They develop striking physical symptoms - premature baldness, heart disease, thinning bones and arthritis.The family of Progeria was a curious case to the medical team of ICH and Chandan Chattopadhyay, who found out that the family had a defective gene, known as Amino AC.T

There is a trust called by S B Devi Charity home which takes care of the Progeria familys needs, financial problems and medical requirements. It is to the credit of good medication and regular psychological sessions that Ali and Ikramul have been able to survive for so long. Though death is imminent, the children enjoy their lives and have fun. They can eat only in small measure(like 3-4 year olds do). Paa is a Progeria based movie. Ikramul and Ali suffer from astro-arthritis and cannot bend their legs or sit properly. Their bodies are very weak and their liver and heart are under-developed. The longest lifespan for progeria in the world is 23. Unfortunately, both the kids are nearing that age. They are born in an extremely poor father, who earns Rs 2,500 a month as a security guard, in a private company. They are dependent on their mother, Rajia, for eating, bathing and virtually their every need. Razia's family is the only family in the world, which had five cases of Progeria. She has already lost her two sons and a daughter to this disease and is hoping for a miracle to save her two sons.

Nature is a mutable cloud which is always and never the same

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