Transcript Neurodegenerative Disorders

Neurodegenerative
Disorders
AR ALTAHAN FRCP
KKUH
Neurodegenerative Disorders
Evolved concept
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Ambigous concept!
What is meant by degeneration?
Gowers 1902  Abiotrophy
 Lack of vital endurance
 Premature death
This embodied the unproven concept that
aging & ND share similar processes
Neurodegenerative Disorders
Evolving concepts
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Many NDD were conisdered idiopathic,
found to have specific etiology…inherited
Many are familial…!
Basic pathogenetic mechanism of cell
death…is it ?
Apoptosis Versus Degeneration
APOPTOSIS
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Genetically Programmed cell death
Deletion of individual cells by
fragmentation into membrane-bound
particles, which are phagocytized.
apoptosis elicits no inflammatory response
in adjacent cells and tissues.
APOPTOSIS
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Besides being genetically programmed,
apoptosis can be:
Induced by injury to cellular DNA, as by
irradiation and cytotoxic agents
Suppressed by naturally occurring
factors (e.g., Prot. Kinase AKT) and by
some drugs (e.g., prostaglandin E2).
Neurodegenerative Disorders
Basic pathogenetic mechanism
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Degeneration V Apoptosis:
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Apoptosis:
Characteristic, gradual neuron loss, not
preceded by accumulation of degenerative
products & is associated with sparse gliosis
Degeneration:
More rapid neuronal breakdown/loss,
associated with deposition of degenerative
products and evokes vigorous phgocytosis
and gliosis
Neurodegenerative Disorders
Degenerative products
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NDD appear to have common cellular and
molecular mechanisms including degenerative
products:
protein aggregation and inclusion body
formation
Most likely represent a later stage of a molecular
cascade leading to cell death.
Earlier steps in the cascade may be more
directly tied to pathogenesis than the inclusions
themselves.
Nature Medicine 10, S10–S17 (2004)
Neurodegenerative Disorders
Degenerative products
Disease
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Parkinson
Alzhimer
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FTDP17
Huntington
SCA
ALS
CJD
Inclusios
Protein
component
Locus of mutation in familial case
Lewy body
a-synuclein
locus ?
Senile plaque
NFT
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Nuclear&cytop.
inclusions
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Amyloid plaque
Amyloid beta
Tau
Tau
Huntigtin
APP
Presenilin1,2
Tau
Huntigtin
Ataxin
SOD1
Prion
Ataxin
NF-H
Prion
Tau & Taupathies
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Tau is a neuronal Microtubule stabilizing protein,
It contribute to axonal transport, growth &
morphology.
Tau misregulation and deposition correlates with
neuronal cell death in:
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Frontotemporal dementia & Parkinsonism associated
with Chr.17(FTDP-17)
Alzheimer’s neurofibrillary tangles are composed of
phosphrylated Tau. Its role however in pathogenesis
is controversial
a-Synuclein
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a-Synuclein is a tubular-filamentous
nonsoluble protein, with important role in
the maintenance of synaptic pool
misfolded a-synuclein is part of the
abnormal protein aggregate found in Lewy
bodies
Synucleinopathies
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NDD characterized by intracellular
aggregation of alpha-synuclein:
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Parkinson’s Disease
Dementia with Lewy Bodies
Lewy Body Variant of AD
Multiple System Atrophies
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OPCA & SND & Shy-Drager Syndrome
Neurodegeneration with brain iron
accumulation type 1( Hallervorden-Sp.)
Role of Tau and a-synuclein in
neurodegenerative diseases
Triplet Repeat Expansions
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This is characterized by dynamic
expansion of tandem nucleotide repeats.
These stretches of repeats tend to be
inherently unstable, and this instability
favors expansion.
When the length of the repeat expansion
exceeds the range in the general
population, a symptomatic state may
result.
Triplet Repeat Expansions
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Genetic anticipation:
The clinical phenomenon of increasing severity
and earlier age of onset in successive
generations, noted in many of these disorders
that includes:
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fragile X syndrome
myotonic dystrophy
oculopharyngeal muscular dystrophy
dominantly inherited spinocerebellar ataxias.
Friedreich ataxia
Huntington disease
Protein misfolding diseases
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Prions
Diseases caused by mutations in
α-crystallin:
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α-crystallin belongs to the class of molecular
chaperones , present in all tissue types
Functions include maintaining microfilament
stability
Neurodegenerative Disorders
Degenerative products deposition
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Abnormal protein tends to aggregates
and accumulate as a consequence of:
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Deficient disposal/degradation
Deficient recycling
Neurodegenerative Disorders
Proteasome-Ubiquitin system
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Proteasome is a barrel-shaped enzyme,
labelled “the master controller of the cell”:
It breaks down protein molecules and abnormal
“misfolded” proteins, and recycles regulatory
proteins.
Ubiquitin is a tiny molecule that latches onto the
damaged protein and carries it to the
proteasome, where the protein is sliced and
diced.
Kopito & Bence, Science 2004
Neurodegenerative Disorders
Proteasome-Ubiquitin system
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Defective proteins clump together into
aggregates  aggregates build up
(defective protein may clog proteasome)
 interfere with proteasome function
 accumulation of more aggregates that
further impair the proteasome….
A viscious circle!
Kopito & Bence, Science 2004
Neurodegenerative Disorders
Proteasome-Ubiquitin system
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Onset of the disease occurs when
aggregates build up ( slow course…)
reaches significant level.
In Huntington diseases, the ubiquitinproteasome system breaks down.
Huntingtin aggregates are noted to
contain thousands of misfolded proteins
with ubiquitin flags attached to them.
Kopito & Bence, Science 2004
Neurodegenerative Disorders
Etiology
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Several factors combined are
implicated:
Genetic predisposition
 Environmental toxins
 Oxidative stress
 Aging
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Neurodegenerative Disorders
General clinical features
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Insidious onset
Progressive, relentless clinical course
De novo ! No apparent evoking factor ?
(long pre-clinical phase)
Selective involvement of neuronal
systems, that are anatomically or
physiologically related
Bilateral symmetry clinically
“Earlier may be unilateral”
Neurodegenerative Disorders
General tests features
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Minimal CSF changes:
Little cellular reaction
Radiologically; tissue loss (atrophy), no
reaction, no enhancement
Neurodegenerative Disorders
General Conclusions
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NDD is a group of disorders that share
similar general clinical and pathological
characteristics
Genetic factors/predisposition is at the
heart of its pathogenesis
Until this “genetic pathogenesis” is defined
in all disorders, classification continue to
depend on clinical/pathologic features
Neurodegenerative Disorders
General Conclusions
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A group of disorders that share similar
general clinical and pathological
characteristics
Genetic factors/predisposition is at the
heart of its pathogenesis
Until this “genetic pathogenesis” is defined
in all disorders, classification continue to
depend on clinical/pathologic features
Neurodeg-Disorders Classification
Syndromes of Dementia
1-Progressive dementias
 Diffuse cerebral atrophy:
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Alzheimer disease
Non-Alzheimer
Lewy-body dementia
Circumscribed cortical atrophy;
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Picks disease
Mesolimbocortical dementia (non-Alzheimer)
Thalamic degeneration
Neurodeg-Disorders Classification
Syndromes of Dementia
2-Progressive dementias with other
neurological abnormality
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Huntington disease
Other dementias & Chorea disorders
Cortico-Striato-Spinal deg. & dementiaParkinson-ALS complex (Guamian..)
Cotico-basal-ganglionic deg.
Dentato-rubro-pallido-luysian deg.
Cerebro-cerebellar deg.
Familial dementia & spas….& myoclonus
Lewy-body disease
Polyglucosan body disease
Neurodeg-Disorders Classification
Syndromes of Movement disorders
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Parkinson disease
Striato-nigral degeneration.
Striato-nigral degen. & autonomic failure
Progressive supranuclear palsy
Dystonia muscularum deformans
Restricted Dystonia (Spa-Torticollis & Meige)
Guill de la Tourette Syndrome
Hallervorden-Spatz disease
Acanthosis chorea
Neurodeg-Disorders Classification
Syndromes of Progressive Ataxia
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Predominantly Spinal:
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Freidrex ataxia
Non-Freidrex ataxia
Pure cerebellar ataxia
(familial & late onset)
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Complicated cerebellar ataxia:
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Olivo-ponto-cerebellar atrophy (MSA)
Gertsman-Straussler-Sheinker disease
Machado-Joseph disease
Paraneoplastic & alcohol related ataxia
Neurodeg-Disorders Classification
Synd. of Progressive weekness & Atrophy
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Without sensory changes:
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Progressive SMA
ALS
Progressive bulbar palsy
Primary lateral sclerosis
Hereditary progressive atrophy & Spastic
paraplegia
With Sensory changes:
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HSN
HMSN (CMT, Dejerene Sottas, Refsum
disease)
Neurodeg-Disorders Classification
Synd. of Spastic paraplegia without
amyotrophy
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Hereditary Spastic paraplegia
Primary lateral sclerosis
Neurodeg-Disorders Classification
Syndrome of Progressive blindness or
ophthalmoplegia with/whithout neurodisorder
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Leber’s optic atrophy
Retinitis pigmentosa
Karne-Sayer Syndrome
Stanfort?? Disease
Neurodeg-Disorders Classification
Syndromes Characterized by
neuro-sensory deafness
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Pure sensory deafness
Hereditary hearing and retinal disease
Hereditary hearing loss with system
atrophy
DEMENTIA
Causes
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Alzheimer's disease
Fronto-temporal dementia
Vascular dementia
Parkinson's disease with dementia
Lewy body dementia
Progressive supranuclear palsy (PSP)
Normal pressure hydrocephalus
Creutzfeldt-Jacob Disease
Huntington's disease
Others
ALZHEIMER DISEASE
Epidemiology
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Worldwide: 5-10% of people over the age
of 65 are affected, and the number
doubles every 5 years over age 65  50%
in over 80 yrs
ALZHEIMER DISEASE
Plaques and Tangles
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The two most significant physical findings
in Alzheimer's disease are:
neuritic plaques and neurofibrillary tangles
are these the cause or the result of the
disease process?
Alzheimer disease & Amyloid-Beta
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Evidence suggests a central role for the
A-Beta peptide in AD pathogenesis.
Amyloid plaques are primarily composed
of A-Beta peptides which are produced by
cleavage of amyloid precursor protein.
Mutations in APP lead to overproduction of
insoluble Amyloid peptide and its
deposition in the neuritic plaques.
Alzheimer disease & Amyloid-Beta
& ApoE
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Apo E is a protein found with beta amyloid
in neuritic plaques, and may be involved in
modifying the age of onset.
ApoE genotype is the most important
genetic risk factor for AD.
ALZHIMER DISEASE
Genetics…
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Alzheimer disease occur more among
relatives
A clear inherited pattern of AD exists in
< 10% of cases. Around 40 % are
inherited as an autosomal dominant.
ALZHEIMER DISEASE
Genetics
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APP gene / chr. 21 is implicated in the
occurrence of AD in:
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Down's syndrome patients who survive
beyond 40 years.
Some families with a history of early-onset AD
Mutation in the presenilin-1 gene (PS-1)
/chr.14.
Apo E gene on chromosome 19.
ALZHEIMER DISEASE
Risk Factors
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Age.
Apo E
Chronic hypertension in older people.
Treatment reduces the risk.
Head injury adults are three times more
likely to develop Alzheimer's disease.
The evidence for role of gender is
inconclusive
ALZHIMER DISEASE
Investigations…
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EEG:
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SPECT:
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usually normal
symmetrical reduction in grey matter blood perfusion.
PET:
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bilateral reduction of oxygen utilization and glucose
uptake principally in the parietal and temporal lobes
in the early stages & later in the frontal lobes.
ALZHIMER DISEASE
Investigations
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CT scanning:
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exclusion of other pathological processes.
Correlation between severity of mental
changes and
cortical atrophy was not strong,
but ventricular size provided a better correlation
Serial scanning provides evidence of progressive
ventricular dilatation .
MRI scanning:
provides little additional information.
ALZHEIMER DISEASE
Treatment…
Symptomatic and include:
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Acetylcholin-esterase inhibitors
donepezil (Aricept)
galantamine (Reminyl)
rivastigmine (Exelon)
ALZHEIMER DISEASE
Treatment…
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Glutamate antagonist:
Memantine approved for moderate-tosevere disease. Can be used alone or in
combination with AChEI.
Side effects include headache,
constipation, confusion, and dizziness.
ALZHEIMER DISEASE
Treatment
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Antidepressants:
Helps concomitant (early) depression.
Have no effect on cognitive function.
ALZHEIMER DISEASE
Prognosis
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Patients may survive 8 to 10 years.
Some lived up to 25 years.
Death usually occurs due to secondary
infections, heart disease, or malnutrition.
Fronto-Temporal Dementia
PICKS DISEASE
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The condition occurs both sporadically and
in a familial form inherited as an
autosomal dominant.
It generally presents in the sixth decade of
life.
The atrophic process concentrates on the
frontal and temporal lobes
Parkinson Disease
Pathology
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Proteinacious inclusion bodies:
Lewy bodies & Lewy neurits
Lewy bodies are:
Fibrillar deposits of alpha synuclein
Parkinson’s Disease
Etiology
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In sporadic Parkinson's disease,
1/5th of patients have at least one relative
with parkinsonian symptoms,
 genetic factor
Several genes are identified in hereditary
cases!
The role for Park3 gene in sporadic form
was questioned
Parkinson's disease
Summary of genes
Gene
Park 1
Park 2
Park 3
Park 4
Mode Chromosome Gene product
AD
4q21-23
a- synuclein
AR
6q25.2-27
Parkin
AD
2p13
Unknown
AD
4p14-16 .3
Unknown
MOTOR NEURON DISEASE
Epidemiology
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Approximately 30,000 patients in the
United States currently have ALS.
The disease has no racial, socioeconomic,
or ethnic boundaries.
ALS is most commonly diagnosed in
middle age and affects men more often
than women.
MOTOR NEURON DISEASE
Risk Factors
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Sporadic ALS (90–95% ) appears to be
increasing worldwide. Causes:
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viruses
neurotoxins (Guamanian ALS)
heavy metals
DNA defects (familial ALS)
immune mechanism
MOTOR NEURON DISEASE
Familial ALS(FALS)
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FALS ( 5-10%) is linked to a genetic
defect on chr. 21 (only in 40% of cases).
This gene codes for superoxide dismutase
(SOD), an antioxidant.
More than 60 different mutations for SOD
have been found.
Neurodegenerative disease of
Guam & Environment
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There is a high prevalence of long-latency
neurodegenerative disorder (parkinsonism,
dementia, and motor neuron disease complex)
on the western Pacific island of Guam.
Epidemiological studies show that the ALS
variant develops after heavy exposure to the
raw or incompletely detoxified seed of
neurotoxic cycad plants.
cycads may harbor a "slow toxin Cycasin”
that causes the post-mitotic neuron to undergo
slow irreversible degeneration.
MOTOR NEURON DISEASE
Treatment & Prognosis
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Neurotrophins:
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Human trials  Failed
Animal Experiment:
Vascular endothelial growth factor (VEGF) in a
SOD1 G93A rat model of ALS delays onset of
paralysis, improves motor performance and
prolongs survival
The life expectancy of ALS patients is
usually 3 to 5 years after diagnosis.
ATAXIA
Classification…
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Early classification was based on anatomic
localization of pathologic changes:
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Predominantly spinal ( Spinocerebellar)
Pure Cerebellar ataxias
Anita Harding 1993:
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Congenital
Inherited metabolic syndromes with known
genetic/biochemical defects
Degenerative ataxias of unknown cause:
early onset (<20 y) & late-onset (>20 y)
ATAXIA
Classification/Trinucleotide repeat
Advances in the molecular pathology of the
trinucleotide repeat NDD has allowed
re-classification into:
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Translated polyglutamine diseases, which are
due to CAG repeat expansions:
Toxic gain of function of mutant expanded
misfolded proteins  activation of apoptosis.
Heterogenous group where trinucleotide
repeat remains untranslated.
ATAXIA with identified genetic/
biochemical deficit
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Acute intermittent ataxia
Ataxias with spinocerebellar dysfunction
Progressive ataxias plus (i.e., prominent
cerebellar dysfunction with additional
neurological signs)
Ataxias with polymyoclonus and seizures
Acute Intermittent Ataxias
Intermittent/Episodic Ataxia in association
with a known inherited disorders:
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Maple syrup urine disease AR, 112p13.
Episodic ataxia1 Intermittent ataxia AD,19p13
point mutations affecting the voltage-gated
potassium channel (KCNA1),
Episodic ataxia 2 AD associated with mutations that
affect the calcium channel (CACNA1A) gene at the
19p13 locus.. Also allelic with SCA-6 and hemiplegic
migraine
Hartnup disease & Intermittent ataxia AR, 11q13
Altered calcium channel function
Others
ATAXIA with identified genetic/
biochemical deficit
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Acute intermittent ataxia
Ataxias with spinocerebellar dysfunction
Progressive ataxias plus (i.e., prominent
cerebellar dysfunction with additional
neurological signs)
Ataxias with polymyoclonus and seizures
Ataxias with Spinocerebellar
Dysfunction/SCA
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A wide range of molecular defects,
but overlap in the clinical presentation
because of limited pathologic responses
within the system.
Most have a heritable basis; mainly AD or
AR
AR group is expanding constantly as the
genetic defects are discovered
Ataxias with Spinocerebellar
Dysfunction-Classification
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AD Cerebellar Ataxias
Friedreich Ataxia/AR
Ataxia With Selective Vitamin E Deficiency
Abetalipoproteinemia
Hypobetalipoproteinemia
Autosomal-Dominant SCA…
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At least 12 forms have been described and
labeled sequentially from SCA1 to SCA12.
Position 9 has been reserved for a unknown
variety.
Clinical:
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A great degree of overlap in phenotype is present
Mainly symptoms of cerebellar and spinocerebellar
pathway dysfunction.
Neuroimaging studies are nonspecific.
Autosomal-Dominant SCA…
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SCA-1: Peripheral neuropathy,Pyramidal signs, 6p23
Ataxin-1, CAG exp.39-83 (6-36 normal range)
SCA-2: Abnormal ocular saccades,Hyporeflexia,
dementia,Peripheral neuropathy 12q24.1
Ataxin-2, CAG exp.34-400 (15-31 normal range)
SCA-3: Pyramidal, extrapyramidal, and ocular
movement abnormalities
Amyotrophy and sensory neuropathy14q24.3-q32.2
CAG exp.55-86 (12-40 normal range)
SCA-4: Sensory axonopathy 16q22.1
SCA-5: Myokymia, nystagmus, and altered vibration
sense 11p11.q11
CAG exp. not demonstrated as yet
Autosomal-Dominant SCA
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SCA-6: Slowly progressive ataxia, 19p13
CAG exp.20-33 (4-16 normal range)
with altered alpha1A subunit of the voltagedependent calcium channel (CACLN1A4)
SCA-7: Visual loss retinopathy 3p21.1-p12
Ataxin-7, CAG exp.37 to>300 (4-19 normal
range)
SCA-8…….SCA-10…SCA-11…SCA-12.
Dentato-rubro-pallido-luysian atrophy
(DRPLA)
Dentato-Rubro-Pallido-Luysian
Atrophy
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DRPLA is another triplet-repeat disorder
AD, CAG repeat exp. from 49-75. The
mutation affect a protein product
"atrophin-1," 12p13.31.
Clinical features include:
Progressive ataxia , chorea, seizures,
myoclonus, and dementia.
Friedreich Ataxia
Genetics
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The first identified AR SCA with a
mutation involving a triplet repeat
expansion.
GAA repeats 7-38 in normal alleles
and 66 to over 1700 in disease-causing
alleles. Most affected carry > 600 repeats.
The mutation leads to formation of the
abnormal protein “frataxin”.
Friedreich Ataxia
Clinical features…
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Variable age of onset when younger than
20 years
Neurological:
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By 5-10 years cerebellar ataxia, dysarthria,
nystagmus,
impaired proprioception.
Hypoactive knee and ankle DTR’s,
Babinski sign
Friedreich Ataxia
Clinical features
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Cardiac: Hypertrophic cardiomyopathy;
congestive heart failure; and subaortic
stenosis
Skeletal: Pes-cavus, and scoliosis
GI: Malabsorptive state in the early years
with steatorrhea and abdominal distension
Metabolic: Abnormal GTT/ diabetes
mellitus
Friedreich Ataxia
Inevstigations
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NCS…Axonal neuroapthy
EKG
MRI – Cerebellar & spinal cord atrophy
Abetalipoproteinemia…
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Rare autosomal-recessive disorder is
characterized by low levels of (LDLs) and
(VLDLs).
It features defective assembly and secretion of
apolipoprotein B (Apo-B)–containing lipoproteins
by the intestines and the liver.
Mutations affect the microsomal triglyceride
transfer protein (MTP) gene, which results in
dysfunction.
Abetalipoproteinemia
Clinical features
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Areflexia, proprioceptive dysfunction, and
Babinski sign
By 5-10 years, gait disturbances and
cerebellar signs
Malabsorptive state in the early years with
steatorrhea and abdominal distension
Pes cavus and scoliosis present in most
patients
Pigmentary retinopathy
Abetalipoproteinemia
Laboratory features
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Acanthocytosis on peripheral blood smears
(constant finding)
Decreased serum cholesterol
Increased high-density lipoprotein
cholesterol levels
Low levels of LDL and VLDL
Low triglyceride levels
Abetalipoproteinemia
Treatment
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High-dose supplementation of vitamin E
has a beneficial effect on neurological
symptoms.
Administer other fat-soluble vitamins (D,
A, K).
Ataxia with Selective Vitamin E
Deficiency
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A rare AR disorder due to a mutation in
the gene for alpha-tocopherol transfer
protein.
Clinical features:
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Onset 2-52 years and usually < than 20 yrs;
slowly progressive.
Phenotypically similar to Friedreich ataxia ,
Skin is affected by xanthelasmata and tendon
xanthomas.
Ataxia with Selective Vitamin E
Deficiency
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Investigations:
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Low-to-absent serum vitamin E and
high serum cholesterol, triglyceride, and betalipoprotein.
Treatment
Vitamin E supplement, of 400-1200 IU/d
for life.
ATAXIA with identified genetic/
biochemical deficit
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Acute intermittent ataxia
Ataxias with spinocerebellar dysfunction
Progressive ataxias plus Systemic features
Ataxias with polymyoclonus and seizures
ATAXIAS WITH PROGRESSIVE
CEREBELLAR DYSFUNCTION PLUS
SYSTEMIC FEATURES…
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The mode of inheritance includes both
mendelian and nonmendelian patterns.
Many of these disorders involve defects in
DNA repair that involve a complex
sequence of events. In disorders involving
these pathways, multiple gene defects are
involved.
ATAXIAS WITH PROGRESSIVE
CEREBELLAR DYSFUNCTION PLUS
SYSTEMIC FEATURES
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These disorders present with progressive
ataxia combined with other neurological
and systemic features:
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Cognitive delay or decline, seizures
Movement disorders and abnormalities of
muscle tone.
ATAXIAS WITH PROGRESSIVE
CEREBELLAR DYSFUNCTION PLUS
SYSTEMIC FEATURES
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Cockayne Syndrome
Xeroderma Pigmentosum
Ataxia Telangiectasia
Refsum Disease
Cerebrotendinous Xanthomatosis
Late-Onset Sphingolipidoses
L-2-hydroxyglutaricaciduria
Carbohydrate Deficient Glycoprotein Syndrome
Leukoencephalopathy With Vanishing White Matter
Succinic-Semialdehyde Dehydrogenase Deficiency
Neuropathy, Ataxia and Retinitis Pigmentosa syndrome
Leigh Disease
Ataxia Telangiectasia
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AR ataxia presents in early childhood
(Onset 1-3 years) .
A defective truncated protein results from
mutations of the ATM gene locus. .
Ataxia Telangiectasia
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Clinical features
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Progressive ataxia and slurred speech
Choreoathetosis
Oculomotor apraxia
Cutaneous and bulbar telangiectasia
Immunodeficiency and increased susceptibility
to infections
Susceptibility to cancer (e.g., leukemia,
lymphoma)
Ataxia Telangiectasia
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Laboratory features
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Molecular-genetic testing for
mutations
affecting the ATM gene locus (11q22.3),
& Breakpoints involved in translocation at the 14q11
and 14q32 sites
Elevated (>10 ng/mL) serum alphafetoprotein in 90-95% of patients
Refsum Disease
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AR disorder, associated with impaired
oxidation of phytanic acid & elevated
phytanic acid levels in CNS.
Refsum Disease
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Clinical features, relapsing-remitting
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Onset in second to third decade of life
Cerebellar ataxia
Polyneuropathy with elevated CSF protein
Night blindness and retintis pigmentosa
Sensorineural deafness
Ichthyosis
Cardiac arrhythmia.
Refsum Disease
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Laboratory features
Elevated phytanic acid levels in the
plasma and urine are diagnostic.
 Cultured fibroblasts show reduced ability
to oxidize phytanic acid.
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Treatment
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Reduction in dietary phytanic acid
& plasmapheresis at onset can
ameliorate the neuropathy.
ATAXIA with identified genetic/
biochemical deficit
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Acute intermittent ataxia
Ataxias with spinocerebellar dysfunction
Progressive ataxias plus (i.e., prominent
cerebellar dysfunction with additional
neurologic signs)
Ataxias with polymyoclonus and seizures
Ataxia With Progressive
Myoclonic Epilepsy
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A group of seizure disorders with
phenotypic features of myoclonic and
other generalized seizures, ataxia, and
cognitive defects. These features occur in
variable combinations that progress over
time.
Differential diagnosis is difficult on purely
clinical grounds.
Ataxia With Progressive
Myoclonic Epilepsy
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Unverricht-Lundborg Disease
Lafora Body Disease
Neuronal Ceroid Lipofuscinosis
Myoclonic Epilepsy With Ragged Red
Fibers
Multiple System Atrophy
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MSA is defined as:
A sporadic, progressive, NDD of
undetermined etiology, characterized by
extrapyramidal, pyramidal, cerebellar, and
autonomic dysfunction in any combination.
MSA is an alpha-synucleinopathy
Multiple System Atrophy
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Shy-Drager syndrome :
autonomic failure predominates.
Striatonigral degeneration or MSA-P:
extrapyramidal features predominate
sporadic olivopontocerebellar atrophy or
MSA-C:
cerebellar features predominate
Multiple System Atrophy
Pathology
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Neuronal loss, extensive demyelination
and gliosis
Oligodendroglial cytoplasmic inclusions
(GCIs) :
abnormal tubular structures in the
cytoplasm and nucleus of oligodendrocytes and neurons mainly in the basal
ganglion, cerebellum, and intermediolateral columns of the spinal cord.
Multiple System Atrophy
Pathogenesis
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Oligodendroglial cytoplasmic inclusions
(GCIs) indicates that damage is primarily
in the white matter.
Autoimmune ? , toxic agents ?
Multiple System Atrophy
Clinical features
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Parkinsonism, ataxia, autonomic failure, or
pyramidal signs, in various combinations:
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predominantly parkinsonism
predominantly ataxia, or as
A combination of parkinsonism, ataxia, and
autonomic failure
it is a relatively rapidly progressive and
fatal (average of 9.5 years from onset.
Multiple System Atrophy
Investigations
MRI:
 Hyperintensity in pons, peduncles, and
cerebellum on T2
 The slit hyperintensity of the lateral margin of
the putamen in T2-weighted MRI is a
characteristic finding in patients with MSA
involving the extrapyramidal system.
To differente between MSA and PD,
fluordeoxyglucose dopa PET imaging may help.
Olivo-Ponto-Cerebellar Atrophy
? On classification
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OPCA describe a form of progressive ataxia
distinguished by pontine flattening and cerebellar
atrophy on brain imaging studies and at autopsy.
Thus defined, OPCA also may qualify as an SCA or as an
MSA.
While MSAs are sporadic by definition, the genetic bases
of the SCAs are increasingly well defined.
Since OPCA may exist as a sporadic or inherited disease,
categorizing sporadic OPCA as MSA and inherited OPCA
as SCA may be appropriate.
Differences between sporadic and inherited OPCA in
microscopic pathology support this division.
Neuroacanthocytosis Syndromes
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The classic neuroacanthocytosis syndrome
It is AR disorder due to a single gene
locus defect on chromosome 9.
Pathologic features include atrophy of the
caudate and putamen
Manifests in adults with combined features
of: acanthocytosis (i.e., spiked red blood
cells), chorea, orofacial tics, amyotrophy &
norm-betalipoproteinemia.
Neuroacanthocytosis Syndromes
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Bassen-Kornzweig syndrome (BK):
Abetalipoproteinemia, ataxia, and retinitis
pigmentosa typically in a child with
acanthocytosis.
McLeod syndrome:
Acanthocytosis and high CPK level (due to a
benign skeletal myopathy),
occasionally
with cardiomyopathy, involuntary movements,
and/or dementia.
Occasional NA syndromes in children, with only
acanthocytosis and decreased betalipoproteins.
Hallervorden-Spatz Disease
Clinical Features
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Onset in commonly in late childhood or
early adolescence.
Progressive extrapyramidal dysfunction
and dementia.
Hallervorden-Spatz Disease
Etiology
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The disease can be familial or sporadic
Familial HSD is AR inherited, chr. 20
a mutation in the pantothenate kinase
(PANK2) gene 20p13
Zhou et al, 2001.
Hallervorden-Spatz Disease
Pathophysiology
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Pathophysiology is not known:
? abnormal peroxidation of lipofuscin to
neuromelanin and deficient cysteine
dioxygenase  abnormal iron
accumulation in the brain ( globus pallidus
and pars reticulata of substantia nigra)
Protein misfolding diseases
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Prion encephalopathies
Huntington’s disease
Diseases caused by mutations in
chaperones
α-crystallinopathy
Prion Encephalopathies
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Prion protein PrP;
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Is a normal abundant protein in the brain. The
function is unknown. It has a normal secondary
structure dominated by alpha-helical formations
Abnormal prion protein PrPSc
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Results from conformational conversion of PrP, as its
secondary structure becomes dominated by betapleated sheets, which makes it more prone to
aggregate and resistant to protease digestion
Prion Encephalopathies
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PrPSc transmissibility:
PrPSc “recruits” normal prion to the abnormal
shape thus allowing for “propagation” and
accounting for transmissibility
PrPSc forms amyloid fibrils in the brain;
injection of this material into the brains of
normal mice leads to disease
Prion Encephalopathies
in Man
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Kuru (historical)
Creutzfeldt-Jakob disease
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Sporadic
Transmitted
Familial
New variant of CJD
Gerstmann-Straussler-Scheinker disease
Fatal familial insomnia
α-crystallin and disease
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α-crystallin belongs to the class of
molecular chaperones
Functions include maintaining
microfilament stability and perhaps actin
and tubulin
Present in all tissue types & makes up
nearly 1/3 of the eye lens protein
Associated with: Cataract, Alexander d.
Neurodegenerative disorders
Huntington’s disease
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Huntington’s disease is caused by the
expansion of CAG trinucleotide repeats
6-39 180 (encoding polyglutamine)
within a large protein huntingtin :
Mutant huntingtin form nuclear and
cytoplasmic aggregates
The function of huntingtin is unclear;
evidence points to trafficking