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Neurodegenerative disorders

Postgraduate Course Human Genetics 12-12-2013. Neurodegenerative disorders. Bart Dermaut Center for Medical Genetics Ghent. Triplet repeat disorders. Diseases of mitochondrial DNA (mt DNA). Alzheimer disease (AD). Introduction. Outline. Chronic and progressive disorders.

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Neurodegenerative disorders

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  1. Postgraduate Course Human Genetics 12-12-2013 Neurodegenerative disorders Bart Dermaut Center for Medical Genetics Ghent

  2. Triplet repeat disorders Diseases of mitochondrial DNA (mt DNA) Alzheimer disease (AD) Introduction Outline

  3. Chronic and progressive disorders Selective and symmetric loss of neurons Motor, sensorial and cognitive system Nosological classification following pattern of neuronal loss and disease specific cellular markers General introduction AD: senile plaques, neurofibrillar ‘tangles’ neuronal loss, acetylcholine deficiency PD: Lewy bodies, depletion of dopamine ALS: cellular inclusions, axon swelling of motor neurons HD: loss of striatal neurons Martin J.B., NEJM 340:1970-1980 (1999)

  4. Causes Genetic factors Environment: toxic or metabolic processes, infection, unknown General introduction -Mendelian inheritance – monogenic: rare familial forms of common disorders classic monogenic e.g. repeat expansion disorder -Multifactorial - common disorders: several genes contribute to disease variation in age of onset and progression point to different pathogenetic mechanisms e.g. AD

  5. Triplet repeat disorders Diseases of mitochondrial DNA (mt DNA) Alzheimer disease (AD) Introduction Outline

  6. Alzheimer disease Alois Alzheimer (1864-1915) Described AD in 1907 http://www.whonamedit.com/doctor.cfm/177.html

  7. Alzheimer disease • Disease characteristics • adult-onset slow progressive dementia (memory, • cognition, personality) • most frequent form of dementia • >60 y: 5-10%, >85 y: 45% • 4 mill/y, 100.000 +/y in US, cost 60 miljard US dollar • 25% of cases familial • - mostly late onset • - < 2% early-onset familial AD (EOFAD) • symptoms always < 65 y

  8. Alzheimer disease • Clinical features • dementia, typically begins with subtle and poorly recognized failure of memory • slowly becomes more severe and, eventually, incapacitating • other common symptoms:anxiety, confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations • occasional symptoms: seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, mutism • death usually results from general inanition, malnutrition, • pneumonia • typical clinical duration of the disease: 8-10 yrsrange: 1- 25 yrs • post mortem: macroscopic - microscopic

  9. Alzheimer disease Learning processes, short term memory and conversion to long term memory in other parts (olfactory bulb, amygdala, nucleus basalis) Near and connected to hippocampus

  10. Alzheimer disease - neuropathology Diagnosis/testing histological findings (neuropathological hallmarks) in brain tissue of ß-amyloid (senile) plaques and intraneuronal neurofibrillary tangles

  11. Alzheimer disease - tau Although tau neurofibrillary tangles appear to be one of the causes of the neuronal degeneration in AD, mutations in the tau gene are associated not with AD, but with another autosomal dominant dementia, FTD

  12. Alzheimer disease - genetics • mid-80s: • older patients with Down syndrome have neurofibrillary tangles and senile plaques • suggests that extra copies of a gene on chromosome 21 induce the pathologic spectrum of AD • finding of a protein fragment, -amyloid, in senile • plaques led to cloning of the -amyloid gene • -amyloid gene (chromosome 21q21.2): • encodes large protein, amyloid precursor protein (APP) • -, - and -secretases (proteases) split APP in smaller fragments A40 (normal) en A42 (toxic -amyloid)

  13. Alzheimer disease - APP • APP: transmembranary protein • -amyloid motif extracellular to the middle of membrane • mutations cause increased production of specific • -amyloid fragment (A42) • APP mutations in less than 1% of all early-onset cases

  14. Alzheimer disease - APP normal AA AA substitutions normal function APP: neuronal survival, neurite outgrowth, synaptic plasticity, cell adhesion

  15. Alzheimer disease - APP mutations in APP influence proteolytic - and -secretases

  16. Alzheimer disease - genetics • < 1% of EOFAD caused by APP mutations, other genes ??? • linkage to locus 14q in 50% of all EOFAD!! • positional cloning PS-1 on 14q24.3 • identification PS-2 on 1q31-q42 • through sequence homology with PS-1 • mostly missense mutations in PS-1 • two missense mutations in PS-2 • new protein family, transmembranary, 450 AA, 8 • transmembranary domains • genomic organization of PS genes is similar (10exons)

  17. APOE gene • apolipoprotein E variant 4 • 4th locus on 19q • involved in late-onset AD • homozygotes develop AD 10-20 years earlier than carriers of 2, 3 • mainly produced in astrocytes • uptake in neurons through LDLR • part of LDL particle • apolipoprotein E4 increases deposition of -amyloid • second modifier on chromosome 10

  18. CLU and PICALM associated with AD -CLU (Cx 8): amyloid clearance -PICALM (Cx 11): function in synapses

  19. CLU and CR1 associated with AD -CLU (Cx 8): amyloid clearance -CR1 (Cx 1): inflammation

  20. AD – genetic testing Presenile Familial AD Senile Familial AD Sporadic AD Presenilin 1 gene (chr 14) Age: 25-60 y Presenilin 2 gene (chr 1) Age: 45-84 y Inheritance of e4 allele of ApoE gene (chr 19) Age: > 50 y APP gene (chr 21) Age: 40-65 y Other genes yet to be identified

  21. AD – genetic counseling • Genetic counseling • first degree relatives of individuals with sporadic AD • have about a 20% lifetime risk of developing AD • presumably, when several individuals in a family have • AD, the risk is further increased • EOFAD is inherited in an autosomal dominant manner • The risk to offspring of individuals with EOFAD is • 50%

  22. AD genes – therapy • Current (symptomatic) therapy • cholinergic replacement (anticholinesterase) • Therapies under development • inhibit of -secretases (PS1) • inhibit -secretase • stimulate -secretase • Block immune response • Inhibit fibril formation and disaggegate amyloid • - Proteoglycans to inhibit amyloid formation • - Immunization against -amyloid

  23. Triplet repeat disorders - Class I: non-coding repeat, loss of protein function - Class II: non-coding repeat, novel protein function - Class III: coding repeat expansions Diseases of mitochondrial DNA (mt DNA) Alzheimer disease (AD) Introduction Outline

  24. Triplet repeat expansions 5’UTR coding 3’UTR

  25. Dynamic mutations in NDD 10 hereditary NDD have polyglutamine expansions different genes but specific neuropathological characteristics: same pathogenesis ? new paradigm for genetic disease - anticipation repeats in non-coding regions of disease genes 3’ UTR in myotonic dystrophy, 5’ in fragile X mental retardation intronic in Friedreich ataxia (FRDA) putative antisense sequences in SCA8 CAG repeats in coding regions of following disease genes: Huntington disease dentatorubropallidoluysian atrophy (DRLPA) spinal and bulbar muscular atrophy SCA 1,2,3,6,7,12 and 17

  26. Dynamic mutations in NDA often autosomal dominant or X-linked inheritance FRDA: autosomal recessive somatic and germline instability rather prone to expansions than contractions during transmission increase in severity phenotype associated with repeat expansion parental origin can influence degree of anticipation increased risk for anticipation in male carriers exception: FRAXA, FRDA, MD en SCA8

  27. (*) 64 possible trinucleotide sequences; however only 10 different ones if you take into account permutations (CAG)n=(AGC)n=(GCA)n and reading from either strand 5’(CAG)n=5’(CTG)n Triplet repeat disease Unique for humans (repeat stable in transgenic mice)

  28. Huntington disease (HD) • “On Chorea” 1872 – Huntington’s chorea • Latin ‘choreus’ = dance • Uncontroled, dance-like movements • Chorea not obligate, a lot of other features • Correct name: Huntington disease (HD) • Clinical characteristics • progressive disorder with motor, • cognitive and psychiatric symptoms (www.genetests.org) • first signs mostly in 4° decade • movement- and behavioural changes • progressive chorea, abnormal eye movements

  29. Huntington disease (HD) • Clinical characteristics • end stage: dementia, personality changes, • irritability, depression, hearing loss • death due to swallowing problems, infection, suicide… • (15-18 y after ‘onset’) • juvenile form, first symptoms before age of 20

  30. Huntington disease (HD) – basal ganglia 1. Gyrus cinguli 2. Gyrus frontalis superior 3. Gyrus frontalis medius 4. Gyrus frontalis inferior 5. Corpus callosum 6. Cornu frontale ventriculi lateralis 7. Nucleus caudatus 8. Capsula interna 9. Putamen 10. Polus temporalis 11. Septum pellucidum 12. Corpus striatum 13. Arteria cerebri media 14. Gyri orbitales http://www.neuropat.dote.hu/anastru/anastru.htm

  31. Huntington disease (HD) From disease to gene: a long journey… Linkage IT15 gene

  32. HD – IT15 gene • CAG triplet repeat expansion in coding region, exon 1 • 10-26 CAGs : normal • 27-35 CAGs : intermediary allele, carrier normal, next generation • ‘at risk’ • 36-39 CAGs : ‘reduced penetrance’, check family history • > 40: 40-150 glutamine residues: HD • >70 repeats: juvenile HD (children, adolescents) • protein: 348 kDa, huntingtin, ubiquitously expressed • anticipation: increase of repeats and severity disease • in successive generations

  33. HD – genetic testing

  34. Slipped mispairing mechanism

  35. Gain-of function due to CAG repeat mutations Pathogenesis: toxic gain-of-function due to nuclear inclusions

  36. frequent cause of X-linked mental retardation (males) clinical diagnosis: long face with prominent ears, chin, ogival palate; macroorchidism, mild joint hyperlaxity. Behavioural changes in children. MR milder in women than men 1 op 4.000 males. 30% of female mutation carriers: mild to moderate retardation(1/8.000) “fragile site”: chromatine does not condense adequately during meiosis(visible when X chromosome cultured in folium-deficient medium) Fragile-X syndrome

  37. FMR1-gene (Fragile-X Mental Retardation-1) (Xq27.3) expanding CGG-repeat in 5’ UTR (promotor region) FMR1 normal alleles: 6-43 CGG premutation alleles: 59-200 CGG. -premutation carriers: normal intelligence full mutation: > 200 CGG -hypermethylation of FMR1 promotor, leading to loss of function -male mutation carriers: Fragile-X syndrome -females: 30% mild to moderate mental retardation and 50%-70% IQ < 85 deletion or point mutation in FMR1, also leading to loss of function Fragile-X syndrome

  38. FXTAS: Fragile X associated Tremor-Ataxia syndrome FXTAS -25-30% of male carriers premutation: FXTAS -> 50 years -intentional tremor -ataxia -Parkinson-like manifestations -MRI: white matter lesions in cerebellum

  39. Fragile-X syndrome vs FXTAS

  40. Fragile-X syndrome meiotic instability: maternal transmission premutation > mutation: in female premutation carriers risk of expansion premutation to mutation: ~ number CGG-repeats male premutation carriers: transmission premutation to daughters without expansion (normal transmitting males or NTM) Sherman paradox (anticipation)

  41. CGG-repeats meiotically and mitotically unstable Fragile X syndrome – genetic testing

  42. Myotonic dystrophy (MD1, Steinert disease) • multisystem disorder • multi-organ involvement: muscles, eye, heart,endocrine • system, CNS • variable expression: mild to severe (congenital) • mild: cataract and mild myotonia • classic: muscle weakness and dystrophy, myotonia,cataract, cardiac conduction abnormalities • congenital: severe hypotonia and muscle weakness • neonatal respiratory insufficiency • with early death • mental retardation

  43. Myotonic dystrophy CTG expansion in 3’ UTR of DMPK gene: genotype-phenotype correlation

  44. mild form 60 CTG adult form 150 CTG adult form 180 CTG congenital form 2000 CTG juvenile form 500 CTG Myotonic dystrophy CTG expansion in 3’ UTR of DMPK gene: genotype-phenotype correlation

  45. Myotonic dystrophy- genetic testing Small expansions: PCR; large expansions: Southern blot

  46. Triplet repeat disorders Diseases of mitochondrial DNA (mt DNA) Alzheimer disease (AD) Introduction Outline

  47. mitochondrial genome (mt DNA): circular, ds 16.5 kb, intronless, 37 genes, transcription in mitochondria -13 encode enzymes < 5 enzyme complexes involved in oxydative phosphorylation and apoptosis -22 encode tRNAs and 2 rRNA’s necessary for synthesis of these enzymes energy supply (ATP) of nearly all systems dependent of oxydative phosphorylation -mutations in mitochondrial genome: a wide variety of symptoms (pleiotropy) -affect mainly organs that are highly energy-dependent: brains, skeletal muscles, eye (retina), ears (inner ear), kidney, heart Diseases of mt DNA

  48. one mitochondrion: several mt DNA-molecules; most cells: more than 1000 mt DNA-molecules divided over 100 mt; in mature oocytes: number is higher mt DNA: higher mutation frequency than nuclear genome (10 x) cause: no repair mechanisms inheritance: maternal (mt DNA exclusively maternally transmitted) - female with mutation in mt DNA: transmitted to 100% of offspring - male: no transmission of mt DNA mutations Diseases of mt DNA

  49. mt DNA mutation: in 1 mt DNA-molecule mitochondrial division: replication of each mt DNA-molecule. At random division of new mt DNA-molecules over new organels cell division: at random division of mitochondria over daughter cells homoplasmy: cell contains same mt DNA-molecules (normal or mutant mt DNA) heteroplasmy: cell contains mixed mt DNA-molecules (normal and mutant) Diseases of mt DNA proportion normal/mutant underlies phenotypic expression and variability of mt DNA disorders

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