Presentation is loading. Please wait.

Presentation is loading. Please wait.

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

Similar presentations


Presentation on theme: "Neurodegenerative disorders Postgraduate Course Human Genetics 12-12-2013 Bart Dermaut Center for Medical Genetics Ghent."— Presentation transcript:

1 Neurodegenerative disorders Postgraduate Course Human Genetics Bart Dermaut Center for Medical Genetics Ghent

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

3 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: (1999) 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

4 General introduction Genetic factors Environment: toxic or metabolic processes, infection, unknown -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 Causes

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

6 2° lic Biomedische Wetenschappen Alzheimer disease Alois Alzheimer ( ) Described AD in 1907

7 2° lic Biomedische Wetenschappen 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, /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 2° lic Biomedische Wetenschappen 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 yrs range: yrs post mortem: macroscopic - microscopic

9 2° lic Biomedische Wetenschappen Alzheimer disease Near and connected to hippocampus Learning processes, short term memory and conversion to long term memory in other parts (olfactory bulb, amygdala, nucleus basalis)

10 2° lic Biomedische Wetenschappen Alzheimer disease - neuropathology Diagnosis/testing histological findings (neuropathological hallmarks) in brain tissue of ß-amyloid (senile) plaques and intraneuronal neurofibrillary tangles

11 2° lic Biomedische Wetenschappen 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 2° lic Biomedische Wetenschappen 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 2° lic Biomedische Wetenschappen 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 2° lic Biomedische Wetenschappen Alzheimer disease - APP normal AA AA substitutions normal function APP: neuronal survival, neurite outgrowth, synaptic plasticity, cell adhesion

15 2° lic Biomedische Wetenschappen Alzheimer disease - APP mutations in APP influence proteolytic - and -secretases

16 2° lic Biomedische Wetenschappen 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 (10 exons)

17 2° lic Biomedische Wetenschappen APOE gene apolipoprotein E variant 4 4th locus on 19q involved in late-onset AD homozygotes develop AD 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 2° lic Biomedische Wetenschappen

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

20 2° lic Biomedische Wetenschappen CLU and CR1 associated with AD -CLU (Cx 8): amyloid clearance -CR1 (Cx 1): inflammation

21 2° lic Biomedische Wetenschappen AD – genetic testing Other genes yet to be identified Presenile Familial AD Senile Familial AD Sporadic AD Presenilin 1 gene (chr 14) Age: y APP gene (chr 21) Age: y Presenilin 2 gene (chr 1) Age: y Inheritance of e4 allele of ApoE gene (chr 19) Age: > 50 y

22 2° lic Biomedische Wetenschappen 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%

23 2° lic Biomedische Wetenschappen 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

24 Outline 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 Alzheimer disease (AD) Introduction Diseases of mitochondrial DNA (mt DNA)

25 Triplet repeat expansions 5’UTRcoding3’UTR

26 Class I: Very large expansions of repeats outside coding sequences -> L-O-F e.g. methylation of FMR1 promoter region (FRAXA) Class III: Modest expansions of CAG repeats within coding sequences -> G-O-F Late onset (mid-life) neurodegenerative No mutations in genes / genes not related Expanded allele is transcribed/translated Polyglutamine aggregates (Huntington disease) Triplet repeat disease: pathogenic pathways

27 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

28 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

29 (*) 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 DiseaseInherTriplet (*) LocationGender bias NlUnstableAffected HuntingtonADCAGexonpat< >35 Fragile XXLCGG5’UTRmat< (premut) >200 Myotonic dystrophy ADCTG3’UTRmat< (premut) Friedreich ataxia ARAAGintronmat< >100 Unique for humans (repeat stable in transgenic mice) Triplet repeat disease

30 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

31 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

32 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 Huntington disease (HD) – basal ganglia

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

34 HD – IT15 gene CAG triplet repeat expansion in coding region, exon CAGs : normal CAGs : intermediary allele, carrier normal, next generation ‘at risk’ CAGs : ‘reduced penetrance’, check family history > 40: 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

35 HD – genetic testing

36 Slipped mispairing mechanism

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

38 Fragile-X syndrome 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 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)

39 Fragile-X syndrome 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: 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

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

41 Fragile-X syndrome vs FXTAS

42 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)

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

44 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

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

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

47 Myotonic dystrophy- pathogenesis hypothesis 1: large CTG expansion in 3’-UTR of DMPK gene (dystrophia myotonica-protein kinase) leads to haploinsufficiency hypothesis 2: effect on other genes in environment hypothesis 3: pathologic effects of expanded mRNA

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

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

50 Diseases of mt DNA 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 mitochondrial genome (mt DNA): circular, ds

51 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

52 mt DNA mutation: in 1 mt DNA-molecule homoplasmy: cell contains same mt DNA-molecules (normal or mutant mt DNA) heteroplasmy: cell contains mixed mt DNA-molecules (normal and mutant) 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 Diseases of mt DNA proportion normal/mutant underlies phenotypic expression and variability of mt DNA disorders

53 Genotype-phenotype correlations

54 Mutations in tRNA genes: MELAS Mitochondrial Encephalopathy Lactic Acidosis and Stroke-like lesions Mutation in mitochondrial tRNA Leu (3243)

55 Mutations in tRNA genes: MELAS and MERFF mutations leading to MELAS mutation leading to MERFF

56

57 AD genes – therapy


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

Similar presentations


Ads by Google