Types of Mutations Myotonic Dystrophy Anticipation probabilistic

Types of Mutations Myotonic Dystrophy Anticipation probabilistic www.phwiki.com

Types of Mutations Myotonic Dystrophy Anticipation probabilistic

Pasmore, Scott, Host has reference to this Academic Journal, PHwiki organized this Journal Trinucleotide repeat disorders: Huntington Disease You MUST know material on course page objectives Review pages 217-220 in Gelerhter/Collins/Ginsburg text “We used to think our fate is in the stars. Now we know, in large measure, our fate is in our genes.” – James Watson Types of Mutations Single base pair substitutions missense, nonsense, splice site Deletions Duplications Inversions Insertions Repeat Expansions

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Outline of Lecture Overview of types of trinucleotide repeat disorders Huntington disease Molecular testing as long as trinucleotide repeat disorders Ethical, legal, in addition to social implications of predictive testing Pathophysiology of trinucleotide disorders Discussion with visiting patient in addition to her family Trinucleotide repeat: a type of short t in addition to em repeat The size of repeat region varies between individuals in addition to is polymorphic in normal individuals For some trinucleotide repeats, when the number of repeats exceeds a certain threshold, a neurological disease results 7 repeats 8 repeats Timeline of Gene Discoveries as long as Trinucleotide Repeat Disorders 1991 Fragile X MR syndrome, SBMA 1992 Myotonic dystrophy 1993 Huntington disease, SCA1, FRAXE, DRPLA/HR 1994 Machado-Joseph disease/SCA3 1996 SCA2, Friedreich ataxia, SCA6 1997 SCA7 1999 SCA10, SCA5, SCA4 2000s Other SCAs, Psychiatric disorders

Major Features of Most Trinucleotide Repeat Disorders Neurological/cognitive symptoms Many are autosomal dominant with variable expression (exceptions: Friedreich ataxia (recessive); Spinobulbar muscular atrophy, Fragile X syndrome, FRAXE MR – X-linked recessive) Later age of onset (exceptions: congenital myotonic dystrophy, Fragile X syndrome, FRAXE) Meiotic in addition to mitotic instability with some degree of anticipation in many of the conditions Why Know About Trinucleotide Repeat Disorders Over 15 genetic different disorders that cause a significant proportion of inherited neurological disease in adults in addition to the most common cause of inherited mental retardation in males (Fragile X syndrome) Molecular diagnosis is available as long as diagnostic confirmation, predictive testing, prenatal testing, preconception testing, in addition to preimplantation diagnosis. Genetic counseling issues are complex in addition to important to underst in addition to as are related ethical issues FMR1 in FRAXA Mental Retardation 17 exon FMR1 gene cloned in 1991 Highest FMR1 expression in neurons in addition to spermatogonia FMR1P associates with translating ribososmes in addition to is involved in nucleocytoplasmic shuttling Approximate repeat ranges: 6-45 CGGs (0-3 AGGs) Unmethylated, Stable, Normal 46-60 CGGs (0-2 AGGs) Unmethylated, +/- Instability, Normal 60-200 CGGs Unmethylated, Premutation – Unstable, Normal > 200 CGGs – Methylated, no FMR1, Unstable, Affected

Myotonic Dystrophy Common adult-onset muscular dystrophy (1 in 8000 in Caucasians, 1 in 475 in Quebec Autosomal dominant – 19q13.2-.3 Expansion of 3’ UTR CTG repeat in 15 exon myotonic dystrophy protein kinase gene (DMPK) 5 – 37 normal 50 – 90 mild – cataract, balding, limited muscle involvement, > 50 years 90 – 1000 classic muscle weakness, myotonia, cataracts, onset 20-30 years > 1000 often congenital,hypotonia, developmental delays Instability of repeats – 10% expansion, 3% contraction. Congenital DM always due to maternal expansion Anticipation Increasing severity in addition to /or decreasing age of onset of an inherited disease in successive generations within a family. Friedreich Ataxia: Autosomal recessive progressive neurological disorder, onset < 25 years with ataxia due to expansion of GAA repeat in intron of FRATAXIN gene Spinocerebellar Ataxia (many types): Autosomal dominant progressive neurological disorder characterized by ataxia usually in the 3rd or 4th decade due to exp in addition to ed CAG repeat in coding exons of SCA genes Myotonic Dystrophy: Autosomal dominant progressive neurological disorder with variable expression in addition to anticipation due to expansion of 3’ UTR region of DMPK gene Fragile X syndrome: X-linked recessive mental retardation syndrome due to expansion of CGG repeat in 5’ UTR region of FRAXA gene 5’ UTR exon intron exon intron exon 3’ UTR CGG FRAXA FRAXE GAA FA CAG HD SCAs SMBA DRLPA CTG MD Trinucleotide repeat disorders can involve expansions of various repeats in coding in addition to non-coding regions of the gene Dr. George Huntington (1850 -1916) Became interested in hereditary chorea in 1871 Wrote his seminal paper on this disease when he was 22 in 1872 Was a general practitioner - never on a medical faculty Individual with Huntington Disease Huntington Disease Average age of onset 40 years (range 2- >80 years); Progression over 10-25 years. Movement disorder: choreic movements, twitching, balance problems, tracking problems, slowing of voluntary movement. In juvenile HD in addition to in late stages of HD, rigidity in addition to dystonia. Cognitive dysfunction: problem solving, cognitive flexibility, short term memory, visuospatial functioning; progression to a global subcortical dementia Personality changes: depression, apathy, irritability, impulsive behavior, affective disorders, rarely psychoses, increased alcohol use in early stages, increased suicide rate

Incidence of Huntington Disease per 100,000 People African Blacks 0.06 South African Whites 2.4 Japan 0.38 Finl in addition to 0.5 Hong Kong 2.5 American Blacks 3-7 Western Europeans 7 American Whites 7-10 North Sweeden 144 Tasmania, Australia 174 Moray Firth, Scotl in addition to 560 (5 people in <1000) Zulia, Venezuela 700 Woodrow Wilson Guthrie Woody Guthrie Diagnosed in 1952, age 40 years Died15 years later at age 55 years During 17 year career wrote more than 1,000 songs in addition to left behind 2,500 lyrics. Near the end of his life he could only use “yes” in addition to “no” cards to communicate. Woody Arlo Abe mood swings behavioral disturbances, hyperreflexia, memory impairment, increased clumsiness, impairment of voluntary movements, eye movement abnormalities dysarthria chorea gait abnormalities bradykinesia, rigidity global dementia, dystonia, dysphagia incontinence, wasting, aspiration, bed ridden death Transitional Early Middle Late 0-3 3-5 8-10 15-25 Phase Years Symptoms Pathology of Huntington Disease Brain atrophy involving caudate nucleus in addition to putamen with loss of striatal neurons in addition to secondary atrophy of globus pallidus Dilation of lateral in addition to third ventricles Additional atrophy throughout cortex, especially frontal in addition to parietal lobes Loss of small neurons precedes larger neurons with neurons utilizing GABA in addition to enkephalin or substance P preferentially Fibrillary gliosis Huntington disease Huntington Disease IT15/Huntingtin gene on 4p16.3 cloned in 1993 Disease mutation - CAG expansion in exon 1 Repeat number Outcome 10-28: normal, no transmission of HD 29-35: normal, paternal meiotic instability 36-39: reduced penetrance (25%: 36 repeats, 90%: 39 repeats) 40-100+: will develop HD if person lives long enough Increased meiotic instability in males - Paternal transmission of exp in addition to ed allele associated with over 3/4 of juvenile disease Encodes 348 kD huntingtin protein which is a target as long as caspase 3, a protease associated with neuronal apoptosis Pasmore, Scott Good Morning Arizona - KTVK-TV Host www.phwiki.com

N N N HD N N So the HD disease was cloned now what Provide precise, rapid diagnosis including prenatal in addition to predictive testing Improve molecular underst in addition to ing of pathophysiology Increase ethical, psychosocial, in addition to legal concerns Improve medical management Develop novel, targeted therapies HD DNA testing: Diagnosis confirmation Prenatal diagnosis Predictive diagnosis psychosocial impact employment concerns insurance issues

A. A normal nerve cell newly-injected with mutant HD genes B. The dying nerve cell with disappearance of the fingerlike processes C. Dying cells rescued by adding functional protein. A B C 5’ UTR exon intron exon intron exon 3’ UTR CGG FRAXA FRAXE GAA FA CAG HD SCAs SMBA DRLPA CTG MD Trinucleotide repeat disorders are neurological disorders involving expansions of various repeats in coding in addition to non-coding regions of the gene Summary Trinucleotide repeat disorders account as long as a large proportion of inherited neurological in addition to mental retardation conditions Sensitive in addition to specific DNA based diagnosis may be used as long as diagnostic, predictive, in addition to prenatal testing if desired Genetic counseling in addition to education is useful as long as at-risk individuals to make in as long as med choice about testing options Huntington Disease is an autosomal dominant later onset progressive neurodegenerative disorder due to expansion of a CAG repeat in coding region Guidelines as long as predictive in addition to prenatal HD testing are well-established in addition to serve as prototype as long as predictive testing as long as adult onset conditions

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