fragile x syndrome

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a genetic disorder causing mental retardation

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By: tallguy72 (9 month(s) ago) Private Comment

Really interesting and would ask that you send me a copy of the power point. A small care company have asked for something on it and said that I would reseach. info@training2care.co.uk Thank you

By: muneerazhar (28 month(s) ago) Private Comment

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By: amreeta (27 month(s) ago)

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By: amreeta (27 month(s) ago)

Presentation Transcript

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SYNDROME A CASE STUDY AMRITA NANDI B.Sc (H) GENETICS 6 th SEMESTER

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"I got very excited when we first discovered the fragile X gene," "I think it was the first triumph of the Human Genome Project. With fragile X we've got just one protein missing, so it's a simple problem. So, you know, if I were going to work on something with the thought that I were going to solve it, oh boy, I'd work on fragile X." - Dr. James D. Watson Nobel Laureate and co-discoverer of the structure of DNA.

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WHAT FRAGILE X IS…??? Fragile X syndrome is the leading cause of inherited developmental and mental impairment. Fragile X is a genetic disorder that is caused by a break or weakness on the long arm of the X chromosome. The gene where the break or weakness has occurred has been named FMR1 (Fragile X Mental Retardation-1). Fragile X is estimated to occur in 1 in 1,200 males and 1 in 2,500 females. Most common genetic diseases and is the most common inherited cause of learning disabilities and mental retardation known to exist just after DOWN’S SYNDROME.

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HISTORY Martin-Bell syndrome or marker X syndrome 1943-Martin and Bell investigated a family with multiple male relatives who had mental retardation and link the cognitive disorders to an unidentified mode of X-linked inheritance. 1969-Lubs discovered excessive genetic material extending beyond the long arm of the X chromosome in affected males and in their unaffected female relatives. Since the 1960s and early 1970s, progress toward mapping the gene has been steady and rewarding. FRAGILE X

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CAUSES

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WHAT CAUSES THIS…??? Fragile X syndrome (FXS) is caused by a change (mutation) in a gene on the X chromosome. Genes contain codes, or recipes, for proteins. Proteins are very important biological components (parts) in all forms of life. The gene on the X chromosome that causes FXS is called the Fragile X Mental Retardation 1 (FMR1) gene. The FMR1 gene makes a protein that is needed for normal brain development. In FXS, the protein is not made. FMRI 1 GENE

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HOW IT IS DIFFERENT….??? FXS is one of a small class of genetic disorders, called trinucleotide repeat disorders, which is caused by a more complicated change in the gene. In the case of FXS, this complex change turns off the gene so no protein product is made. Trinucleotide repeat disorders have a chain of three nucleotides that are repeated over and over again. In most people, the number of repeats is small. If the number of repeats is large, the gene does not work properly. CGG is repeated over and over again in the FMR1 gene, and when it reaches a certain number of repeats, the gene is turned off. THE X CHROMOSOME

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THREE + 1 STAGES…. NORMAL:~ A normal FMR1 gene has between about 6 and 45 CGG repeats. FULL MUTATION:~ When there are over 200 CGG repeats, this is referred to as a full mutation. The gene turns off because of a process called methylation. When the gene is turned off, no protein is made. PREMUTATION:~ CGG repeats falls between the normal range and the full mutation, about 55-200 repeats People who have a this do not have FXS because the FMR1 gene still works learning disabilities. INTERMEDIATE , GRAY ZONE :~ 45 to 55 CGG repeats with learning disabilities 3 + 1 STAGES

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FMR1 THE PHYSIOLOGY FXTAS ASSOCIATED WITH TREMOR ATAXIA SYNDROME FRAGILE X SYNDROME Wakeley, A., Rivera, S.M. (2006). M.I.N.D INSTITUTE

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ANTICIPATION Anticipation causes subsequent generations in a family to be more severely affected by a disease. increasing the number of triplet repeats in the fragile area through the generations. strike with a greater frequency. This is called Sherman Paradox . 1st GEN 2nd GEN 3rd GEN

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KARYOTYPE… Kryotype of a fragile x male. With the X chromosome having fragile tail. FMR1 gene on X chromosome at Xq27.3 was sequenced in 1991

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FRAGILE SITES ON ‘X’ CHROMOSOME FRA-A (q) FRA-E (q) FRA-B (p) FRA-C (q) FRA-D (q) FRA-F (q) FOLATE SENSITIVE FRAGILE SITES ON X Only the FRAX-E mutation is associated with intellectual disability Detected by improved techniques fluorescent in situ hybridization (FISH).

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INHERITANCE PATTERN… A carrier woman has a 50%chance of passing on the fragile X chromosome to her children. males are likely to be affected by the syndrome, while daughters have a 1 in 3 chance of being clinically affected. Men can also be unaffected carriers of the fragile X chromosome. In such cases the genetic change is passed to all daughters, but to none of the sons. These daughters will themselves be unaffected but at risk of having affected children. Any sons of carrier males will be completely unaffected as they do not receive their X chromosome from their father.

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SYMPTOMS

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CHARACTERISTICS…… PHYSICAL:~ Growth: Childhood growth spurt. adult height average Craniofacial: Adolescent patients have long thin face with prominent ears, facial asymmetry, and a prominent forehead and jaw. Mouth: dental overcrowding and high-arched palate. Ears: large and protrude. Eyes: Strabismus is frequently noted. Extremities: Hands and feet nonspecific findings, hyperextensible finger joints, hand calluses, double-jointed thumbs, a single palmar crease, and pes planus. Back and chest: Pectus excavatum and scoliosis Genitals: Macroorchidism . testicular volume is more than 25 mL and can be high as 120 mL. Cardiac: A heart murmur or click consistent Testicular Volume

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CHARACTERISTICS….. BEHAVIOUR:~ Hyperactivity disorder (ADHD) or attention deficit disorder (ADD). Hand flapping and chewing on skin, clothing, or objects, connected to sensory processing problems and anxiety. Perseverative speech and self-talk Shyness, anxiety, depression and difficulties with social contacts are most often mentioned as characteristics of girls with fragile X. Behavioural aspects

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EFFECT VARIES ON MALE N FEMALE The characteristics seen in males can also be seen in females females often have milder intellectual disability and a milder presentation of the behavioral or physical features. About 1/3 of the females have a significant intellectual disability Others may have more moderate or mild learning difficulties. the physical and behavioral characteristics are often expressed to a lesser degree. A GIRL AND A BOY

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REPEAT SIZE MOSAICISM Individuals with mosaicism perform at a higher intellectual level than individuals with completely methylated full mutations, these individuals are usually mentally retarded. (Average IQ 60) patients with methylation mosaicism or completely unmethylated full mutations are normal intellect Mosaicism is present in about 15% to 20% of individuals with FMR1 mutations. Presumably these individuals produce at least some FMR1 protein because the FMR1 gene is unmethylated. The existence of these exceptional patients suggests that repeat expansion and methylation of the gene are not absolutely coupled. A PATIENT

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Risk that a Mother with a Premutation will have an Affected Child with a Full Mutation

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SEVERITY OF FRAGILE X SYNDROME The severity of Fragile X Syndrome varies between males and females Vary based on the number of triplet repeats in the FMR1 gene Males are most often moderately to severely affected Females are most often mildly to moderately affected. FRAGILE XX AND XY

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ADULT WITH FRAGILE X Hyperactivity tends to improve Anxiety, (particularly social anxiety) is present Aggressive outbursts Possibly up to 50% of adult males experience mitral valve prolapse Mild aortic root dilation may also occur Hypertension is relatively common, but may be the result of anxiety. ADULTS WITH FRAGILE X

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ASSOCIATION WITH OTHER DISEASES MR, ADHD, autistic like features can be seen in Asperger, FAS, and autism Coffin-Lowery shares features of prominent ears, coarse features Lujan Fryns syndrome - marfanoid habitus and machroorchidism Atkin syndrome - large ears, short stature, machroorchidism Fragile X has been seen in conjunction with chromosomal aneuploidy syndromes A PATIENT

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PROGNOSIS OF FRAGILE X SYNDROME Prognosis for this disease varies, Less affected individuals may be able to have a job and live on their own, severe retardation will need to be supervised for their entire life. These individuals may be able to live to 60 years of age. Those affected with the disease do have a capacity to learn, and can attend special schools that cater to their needs. WORKING BOYS

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FRAGILE X AND AUTISM Autism is a pervasive developmental disorder Characterized by a lack of social responsiveness, a typical communication skills, and a limited and repetitive range of behaviors and interests. Fragile X syndrome is one of the known genetic causes of autism. The association of fragile X in persons with autism range from 3% to 6%. In recent studies - 20% of individuals with fragile X meet criteria for autism. BOY WITH AUTISM

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DIFFERENCE BETWEEN FRAGILE X AND AUTISM :~ GENETIC THEORY :- Fragile X is caused by a single gene disorder Autism is caused by multiple genes (3-15) Autism in fragile X syndrome comes from a second hit or background genes, which predispose persons with fragile X syndrome to autism. kids with fragile X syndrome display more autistic behaviors , while others have not found this relationship.

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SCREENING ‘N’ THERAPY

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INTERVENTION While there is no cure for fragile X syndrome as yet, there are many areas of intervention that can improve the lives of those affected and their families. Cognitive Development Intervention Intervention for Sensory Integration Disorders Speech and language therapy Therapy for Behavior Disorders Daily living skill ACTIVITIES

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COMPUTERS IN FRAGILE X THERAPY USEFULL TO ENHANCE BRAIN DEVELOPMENT BRAIN DEVELOPMENT IS DONE BY INCREASING SYNAPTIC ACTIVITY. SHOWN HERE IS A MRI SCAN OF A GIRL WITH SYNDROME

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CLINICAL MEDICATIONS Treatments specifically directed at the underlying brain defects in fragile X syndrome are not presently available. FMRP may play an important role in allowing normal levels of AMPA receptor proteins AMPA receptors mediate the level of excitability of brain cells at synapses and maintain strength Altered synaptic shape and reduced synaptic strength are observed in fragile X and are associated with a reduction in AMPA-receptors in certain brain areas. Thus, medication that increases AMPA receptors might partially correct a defined neurochemical defect in fragile X which will result in improved cognitive and behavioral functioning. RECENT RESEARCH :~ Ampakine CX516 on Cognition and Functioning in Fragile X Syndrome and Autism MEDICINES

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VITAMIN AND FOLIC ACID THERAPY “Orthomolecular therapy” or vitamin supplements and other biomedical treatments, like folic acid, vitamin B6, and magnesium to treat children with disabilities like autism and fragile X. “Orthomolecular therapy" is defined by its proponents as "the treatment of disease by varying the concentrations of substances normally present in the human body. Main complements are vitamin and folic acid. SUPLIMENTS INJECTIONS

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GENETIC TESTING FOR FRAGILE X A DNA test for Fragile X was developed in 1992. This blood test is accurate and can detect both carriers and fully-affected individuals. THE CONCEPT-> Testing is based primarily on measuring the length of the FMR1 gene region containing the CGG repeat stretch and then calculating the CGG repeat number. Analysis of the gene's methylation status is often performed simultaneously. Categorization of the mutation type is based on CGG repeat number and in some cases also on the methylation status of the gene. Methylation information is useful for delineating premutations from full mutations. DNA ANALYSIS

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SOUTHERN BLOTT ANALYSIS Male, normal: A single band of normal size, unmethylated Female, normal: Two bands of normal size, one unmethylated (on the active X chromosome) and one methylated (on the inactive X chromosome). Male, premutation: A single band of increased size, unmethylated. This premutation has 75 repeats Female, premutation: A four-band pattern with an unmethylated (on the active X) and a methylated (on the inactive X) form of both the premutation and normal bands. This premutation has 92 repeats Male, full mutation: >200 repeats, methylated. Absence of a normal unmethylated band. Female, full mutation: >200 repeats, methylated. The two normal bands from the normal allele are also present. 355 repeats Male, mosaic: Full mutation and premutation. In this case the full mutation has 510 repeats and the premutation has 84 repeats BANDS ON GEL

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POLYMERASE CHAIN REACTION (size indicates approximate number of repeats present) It is very accurate in sizing normal and premutation alleles. The efficiency is inversely related to number of CGG repeats present Large permutations and mutations difficult to analyze and may fail to yield detectable product. It also does not give information about FMR1 methylation

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DETECTION BY ANTIBODY More recently, an FMRP antibody test has been developed to measure expression in lymphocytes. This can detect the full mutation in males. It is not useful in mosaic males or females as some FMRP is still formed. FMRP ANTIBODY

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PRENATAL DIAGNOSIS Prenatal diagnosis (testing for the fragile X mutation in a baby before it is born) is available to any person shown to be a carrier of a fragile X mutation. Prenatal fragile X testing is usually performed on the developing baby using one of two methods: either chorionic villus sampling (CVS), performed at approximately 10 weeks of pregnancy: amniocentesis, performed between 16-20 weeks of pregnancy. All couples considering prenatal diagnosis should meet with a genetic counselor before becoming pregnant in order to discuss the most current prenatal techniques, their limitations and benefits. AMNIOCENTESIS

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A CASE OF FMR PATIENT A BOY WITH FRAGILE X Age : 6 years Height : 2’10” Weight : 22 Kg SAME BOY WITH A NORMAL BOY

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FAMILY PEDIGREE OF THE PATIENT

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CYTOGENETICS PREPARATION DONE AT LAB BLOOD/BONE MARROW (SAMPLE COLLECTED) INNOCULATE IN CULTURE MEDIUM WITH STIMULANT (medium=10ml, sample=1 ml) INCUBATE AT 37C FOR 69-70 HOURS ADD MITOTIC INHIBITOR AND INCUBATE FOR 1 HOUR CENTRIFUGE CELLS AND REMOVE MEDIUM, RESUSPEND CELL BUTTON IN 5ml PREWARMED HYPOTONIC SOLUTION (KCl OR SODIUM CITRATE) AT 37C. INCUBATE WATER BATH AT 37C FOR 15 MIN. ADD 4-5 DROPS OF FRESH, CHILLED FIXATIVE, RESUSPEND AND CENTRIFUGE AT 1000 RPM FOR 10 MIN. ALLOW DRYING PREPARE SLIDES BY DROPPING CELL SUSPENSION ON TO CHILLED, WET SLIDES. STAIN THE SLIDES USING GEIMSA STAIN COUNT AND ANALYSE AND PHOTOGRAPH METAPHASE ARRANGE THE CHROMOSOME TO MAKE THE KARYOTYPE.

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KARYOTYPE LABORATORY PROTOCOL

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WORK DONE AT LAB INOCULATION IN CULTURE MEDIUM WITH STIMULANTS ( medium= 10 ml , sample = 1 ml )

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WORK DONE AT LAB HARVESTING OF CELL CULTURES

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WORK DONE AT LAB PREPARATION OF SLIDES DROPPING OF CELL SUSPENSION ON TO WET , CHILLED SLIDE

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WORK DONE AT LAB ANALYSIS OF SLIDES METAPHASE PLATES

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METAPHASE PLATE

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RESULTS + PRESENT - ABSENT Hand Flapping + Hand biting - Hyperactivity + Poor Eye Contact - Large Ears + Long Face + Hand calluses +

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ORGANISATIONS NATIONAL FRAGILE X FOUNDATION FRAGILE X ASOCIATION -CALIFORNIA FRAXA ORGANISATION

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REFERENCES www.frgilex.org - NFXF en.wikipedia.org/wiki/Fragile_X_syndrome - WIKI www.nlm.nih.gov/medlineplus/fragilexsyndrome.html - MEDLINE PLUS www.omim.org - OMIM WEBSITES JOURNALS AND PAPERS QUATERLY JOURNALS OF NFXF RESEARCH PAPERS

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CONCLUSION FRAGILE X is the most common cause of mental impairment among child nowadays For the family, the diagnosis of a child is very much needed. Knowledge of the diagnosis can direct the family to appropriate information and to fragile X support groups. Results of fragile X DNA testing allow accurate genetic counseling to be provided. Carrier testing for at-risk individuals and prenatal testing empowers families to make informed reproductive decisions.

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ACKNOWLEDGEMENT I AM VERY GRATE FULL TO Prof. AMIT CHAKRAVARTY AND Prof. SUDIPA CHAKRAVARTY AND ALL THE FACULTY OF THE “ INSTITUTE OF GENETIC ENGINEERING” FOR THEIR VALUABLE GUIDANCE TO COMPLETE THIS PROJECT EFFICIENTLY