neurodegenerative disorders postgraduate course human genetics 13-11-2015 bart dermaut center for...
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Neurodegenerative disorders
Postgraduate Course Human Genetics 13-11-2015
Bart Dermaut
Center for Medical Genetics Ghent
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Outline
Triplet repeat disorders
Alzheimer disease (AD)
Introduction
Diseases of mitochondrial DNA (mt DNA)
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General introduction
AD: senile plaques, neurofibrillary ‘tangles’ neuronal lossPD: Lewy bodies, depletion of dopamineALS: cellular inclusions, axon swelling of motor neurons HD: nuclear inclusions, loss of striatal neurons
Martin J.B., NEJM 340:1970-1980 (1999)
Chronic and progressive disorders
Progressive and selective loss of neuronsMotor, sensorial and cognitive system
Nosological classification following pattern of neuronal loss and disease specific cellular markers
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General introduction
Genetic factors
Environment: toxic or metabolic processes, infection, unknown
-Mendelian inheritance – monogenic: rare familial forms of common disordersclassic monogenic e.g. repeat expansion disorder
-Multifactorial - common disorders: several genes contribute to diseasevariation in age of onset and progression point to
different pathogenetic mechanismse.g. AD
Causes
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Outline
Triplet repeat disorders
Alzheimer disease (AD)
Introduction
Diseases of mitochondrial DNA (mt DNA)
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Prevalence strongly increases with age
70% are Alzheimer’s disease cases(860,000 cases in France in 2005)
Alzheimer’s disease (AD) => characterised in the brain by :
Neurofibrillary degeneration Amyloid deposition
0
10
20
30
40
60 70 80 90 100
Age (years)
Cas
es /
100
CVD
Dementia
Parkinson
0
10
20
30
40
60 70 80 90 100
Age (years)
Cas
es /
100
CVD
Dementia
Parkinson
Intraneuronal accumulation of hyperphosphorylated Tau
Extracellular accumulation of amyloid peptides
Alzheimer disease
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Alzheimer disease
http://www.whonamedit.com/doctor.cfm/177.html
Alois Alzheimer (1864-1915)Described AD in 1907
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Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde Allgemeine Zeitschrift fur Psychiatrie und Psychisch-gerichtliche Medizin. 1907 Jan ; 64:146-8.
“Die Sektion ergab ein gleichmäßig atrophisches Gehirn ohne makroskopische Herde. Die größeren Hirngefäße sind arteriosklerotisch verändert.An Präparaten. die mit der Bielschowskyschen Silbermethode angefertigt sind, zeigen sich sehr merkwürdige Veränderungen der Neurofibrillen. Im Innern einer im übrigen noch normal erscheinenden Zelle treten zunächst eine oder einige Fibrillen durch ihre besondere Dicke und besondere Imprägnierbarkeit stark hervor. Im weiteren Verlauf zeigen sich dann viele nebeneinander verlaufende Fibrillen in der gleichen Weise verändert. Dann legen sie sich zu dichten Bündeln zusammen und treten allmählich an die Oberfläche der Zelle. Schließlich zerfällt der Kern und die Zelle, und nur ein aufgeknäueltes Bündel von Fibrillen zeigt den Ort, an dem früher eine Ganglienzelle gelegen hat.Da sich diese Fibrillen mit anderen Farbstoffen färben lassen als normale Neurofibrillen, muß eine chemische Umwandung der Fibrillensubstanz stattgefunden haben. Diese dürfte wohl die Ursache sein, daß die Fibrillen den Untergang der Zelle uberdauern. Die Umwandlung der Fibrillen scheint Hand in Hand zu gehen mit der Einlagerung eines noch nicht näher erforschten pathologischen Stoffwechselproduktes in die Ganglienzelle. Etwa 1/4 bis 1/3 aller Ganglienzellen der Hirnrinde zeigt solche Veränderungen. Zahlreiche Ganglienzellen, besonders in den oberen Zellschichten. sind ganz verschwunden.”
“Über die ganze Rinde zerstreut, besonders zahlreich in den oberen Schichten, findet man miliare Herdchen, welche durch Einlagerung eines eigenartigen Stoffes in die Hirnrinde bedingt sind. Er läßt sich schon ohne Färbung erkennen. ist aber Färbungen gegenüber sehr refractär.”
Amyloid plaques
Tau tangles
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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
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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: 1- 25 yrs
• post mortem: macroscopic - microscopic
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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)
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Alzheimer disease - neuropathology
Diagnosis/testing
histological findings (neuropathological hallmarks) in brain tissue of ß-amyloid (senile) plaques and intraneuronal neurofibrillary tangles
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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
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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 senileplaques led to cloning of the -amyloid gene
-amyloid gene (chromosome 21q21.2): • encodes large protein, amyloid precursor protein
(APP) -, - and -secretases (proteases) cleave APP into
smaller fragments A40 (normal) en A42 (toxic -amyloid)
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Alzheimer disease - APP
• APP: transmembrain protein -amyloid motif extracellular to the middle of membrane
• mutations cause increased production of specific -amyloid fragment (A42) • APP mutations in less than 1% of all early-onset cases
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Alzheimer disease - APP
normal AA
AA substitutions
normal function APP: neuronal survival, neurite outgrowth,synaptic plasticity,cell adhesion
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Alzheimer disease - APPmutations in APP influence proteolytic - and -secretases
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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• rare missense mutations in PS-2
• new protein family, transmembranary, 450 AA, 8 transmembranary domains
• genomic organization of PS genes is similar (10 exons)
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Alzheimer disease - genetics
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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
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2° lic Biomedische Wetenschappen 2006 - 2007
AD – genetic testing
Other risk genes recently identified
PresenileFamilial AD
SenileFamilial AD
Sporadic AD
Presenilin 1gene
(chr 14)Age: 25-60 y
APPgene
(chr 21)Age: 40-65 y
Presenilin 2gene
(chr 1)Age: 45-84 y
Inheritance of e4 alleleof ApoE
gene(chr 19)
Age: > 50 y
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Meta-analysis: 74.000 individuals!Consortium: > 200 authors, >250 collaborators!
Lambert et al, Nat Genet 2013
AD risk loci
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Clear! Unclear!
AD risk loci: causal gene, causal variant?
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Genetics of Alzheimer’s disease: a paradigm
APP, PS1 PS2
ABCA7, APOE, BIN1, CASS4, CD2AP, CELF1, CLU, CR1, EPHA1, FERMT2, HLA-DRB1, INPP5D, MEF2C, MS4A6A, NME8, PICALM, PTK2B, SLC24A4, SORL, ZCWPW1
TREM2
APOE
Less than 1% of the cases are monogenic forms.
The majority of other forms are defined as without obvious mendelian inheritance. The genetic attributable risk has been estimated between 60 and 80% and to date, 22 loci have been associated with AD risk.
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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%
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AD genes – therapy
Current (symptomatic) therapy
• cholinergic replacement (cholinesterase inhibitors)
Therapies under development
• inhibit of -secretases (PS1)
• inhibit -secretase
• stimulate -secretase
• Inhibit fibril formation and disaggregate amyloid
-Immunization against -amyloid
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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)
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Triplet repeat expansions
5’UTR coding 3’UTR
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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 retardationintronic in Friedreich ataxia (FRDA) putative antisense sequences in SCA8
CAG repeats in coding regions of following disease genes: Huntington diseasedentatorubropallidoluysian atrophy (DRLPA)spinal and bulbar muscular atrophySCA 1,2,3,6,7,12 and 17
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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 carriersexception: FRAXA, FRDA, MD en SCA8
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(*) 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
Disease Inher Triplet(*)
Location Genderbias
Nl Unstable Affected
Huntington AD CAG exon pat <36 27-35 >35
Fragile X XL CGG 5’UTR mat <60 59-200(premut)
>200
Myotonic dystrophy
AD CTG 3’UTR mat <38 38-49
(premut)
50-2000
Friedreich ataxia
AR AAG intron mat <34 36-100 >100
Unique for humans (repeat stable in transgenic mice)
Triplet repeat disease
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Huntington disease (HD)
“On Chorea” 1872 – Huntington’s choreaLatin ‘choreus’ = dance Uncontroled, dance-like movements
Chorea not obligate, a lot of other featuresCorrect name: Huntington disease (HD)
Clinical characteristics progressive disorder with motor, cognitive and psychiatric symptoms (www.genetests.org)
first signs mostly in 4° decademovement- and behavioural changes
progressive chorea, abnormal eye movements
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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
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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
Huntington disease (HD) – basal ganglia
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Huntington disease (HD)
From disease to gene: a long journey…
Linkage IT15 gene
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HD – IT15 gene
CAG triplet repeat expansion in coding region, exon 1
10-26 CAGs : normal27-35 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
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HD – genetic testing
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Slipped mispairing mechanism
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Pathogenesis: toxic gain-of-function due to nuclear inclusions
Gain-of function due to CAG repeat mutations
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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 in 4.000 males. 30% of female mutation carriers: mild to moderate retardation (1/8.000)
“fragile site”: chromatin does not condense adequately during meiosis (visible when X chromosome cultured in folium-deficient medium)
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Fragile-X syndrome
FMR1-gene (Fragile-X Mental Retardation-1) (Xq27.3)
expanding CGG-repeat in 5’ UTR (promotor region) FMR1normal 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
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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
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Fragile-X syndrome vs FXTAS
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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)
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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 myotoniaclassic: muscle weakness and dystrophy,
myotonia, cataract, cardiac conduction abnormalitiescongenital: severe hypotonia and muscle weakness
neonatal respiratory insufficiency with early death mental retardation
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Myotonic dystrophy
CTG expansion in 3’ UTR of DMPK gene: genotype-phenotype correlation
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Myotonic dystrophy
mild form60 CTG
adult form150 CTG
congenital form2000 CTG
adult form180 CTG
juvenile form500 CTG
CTG expansion in 3’ UTR of DMPK gene: genotype-phenotype correlation
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Outline
Triplet repeat disorders
Alzheimer disease (AD)
Introduction
Diseases of mitochondrial DNA (mt DNA)
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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
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- 900 gene products- mtDNA: 37 genes, no introns, very compact, 16.6 kb, 22 tRNAs, 2 rRNAs, 13 subunits of the RC- each cell contains hundreds to thousands of mitochondria, 3-10 genomes per mitochondrion
Diseases of mt DNA
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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
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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
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Genotype-phenotype correlations
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Mutations in tRNA genes: MELAS
Mitochondrial Encephalopathy Lactic Acidosis and Stroke-like lesions
Mutation in mitochondrial tRNALeu (3243)
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Mutations in tRNA genes: MELAS and MERFF
mutations leading to MELAS mutation leading to MERFF