neurodegenerative disorders ar altahan frcp kkuh

Neurodegenerative Neurodegenerative DisordersDisorders

AR ALTAHAN FRCPAR ALTAHAN FRCP

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Neurodegenerative Disorders DisordersEvolved conceptEvolved concept

Ambigous concept!Ambigous concept!

What is meant by degeneration?What is meant by degeneration?

Gowers 1902 Gowers 1902 AbiotrophyAbiotrophy

Lack of vital enduranceLack of vital endurance

Premature deathPremature death

This embodied the This embodied the unprovenunproven concept concept that that aging & ND share similar aging & ND share similar processesprocesses

Neurodegenerative DisordersNeurodegenerative Disorders Evolving Evolving conceptsconcepts

Many NDD were conisdered Many NDD were conisdered idiopathic, found to have specific idiopathic, found to have specific etiology…inherited etiology…inherited

Many are familial…Many are familial…!! Basic pathogenetic mechanism of cell Basic pathogenetic mechanism of cell

death…is it ?death…is it ?

Apoptosis Apoptosis Versus Versus DegenerationDegeneration

APOPTOSISAPOPTOSIS

Genetically Programmed cell deathGenetically Programmed cell death Deletion of individual cells by Deletion of individual cells by fragmentation into membrane-bound fragmentation into membrane-bound particles, which are phagocytized. particles, which are phagocytized.

apoptosis elicits no inflammatory apoptosis elicits no inflammatory responseresponse in adjacent cells and in adjacent cells and tissues. tissues.

APOPTOSISAPOPTOSIS

Besides being genetically Besides being genetically programmed, apoptosis can be: programmed, apoptosis can be:

InducedInduced by injury to cellular DNA, as by injury to cellular DNA, as by iby irradiationrradiation and and cytotoxic cytotoxic agentsagents

SuppressedSuppressed by naturally occurring by naturally occurring factors (e.g., Prot. Kinase AKT) and factors (e.g., Prot. Kinase AKT) and by some drugs (e.g., prostaglandin by some drugs (e.g., prostaglandin E2). E2).

Neurodegenerative DisordersNeurodegenerative Disorders Basic pathogenetic mechanismBasic pathogenetic mechanism

Degeneration V Apoptosis:Degeneration V Apoptosis: Apoptosis: Apoptosis:

Characteristic, gradual neuron loss, not Characteristic, gradual neuron loss, not preceded by accumulation of preceded by accumulation of degenerative productsdegenerative products & is associated & is associated with sparse gliosiswith sparse gliosis

DegenerationDegeneration: : More rapid neuronal breakdown/loss, More rapid neuronal breakdown/loss, associated with deposition of associated with deposition of degenerative productsdegenerative products and evokes and evokes vigorous phgocytosis and gliosis vigorous phgocytosis and gliosis

Neurodegenerative Disorders Neurodegenerative Disorders Degenerative productsDegenerative products

NDD appear to have common cellular and NDD appear to have common cellular and molecular mechanisms including molecular mechanisms including degenerative products: degenerative products: protein aggregationprotein aggregation and and inclusion inclusion body body formationformation

Most likely represent a later stage of a Most likely represent a later stage of a molecular cascade leading to cell death. molecular cascade leading to cell death.

Earlier steps in the cascade may be more Earlier steps in the cascade may be more directly tied to pathogenesis than the directly tied to pathogenesis than the inclusions themselves.inclusions themselves.

Nature MedicineNature Medicine 1010, S10–S17 (2004), S10–S17 (2004)

Neurodegenerative Disorders Neurodegenerative Disorders Degenerative productsDegenerative products

DiseaseDisease InclusiosInclusios Protein Protein Locus of mut-Locus of mut- component ation in familial component ation in familial

casecase ParkinsonParkinson

Lewy bodyLewy body a-synuclein a-synuclein locus ? locus ? AlzhimerAlzhimer

Senile plaqueSenile plaque Amyloid beta APP Amyloid beta APP======== NFTNFT Tau Tau Presenilin1,2 Presenilin1,2

FTDP17FTDP17 ================ Tau Tau Tau Tau HuntingtonHuntington Nuclear&cytop.Nuclear&cytop. Huntigtin Huntigtin

HuntigtinHuntigtininclusionsinclusions

SCASCA ================ Ataxin Ataxin Ataxin Ataxin ALSALS ================ SOD1 SOD1 NF-H NF-H

CJDCJD Amyloid plaqueAmyloid plaque Prion Prion

PrionPrion

Tau & TaupathiesTau & Taupathies

Tau is a neuronal Microtubule stabilizing Tau is a neuronal Microtubule stabilizing protein, protein,

It contribute to axonal transport, growth & It contribute to axonal transport, growth & morphology.morphology.

Tau misregulation and deposition correlates Tau misregulation and deposition correlates with neuronal cell death in:with neuronal cell death in: Frontotemporal dementia & ParkinsonismFrontotemporal dementia & Parkinsonism

associated with Chr.17(FTDP-17)associated with Chr.17(FTDP-17) Alzheimer’sAlzheimer’s neurofibrillary tangles are composed neurofibrillary tangles are composed

of phosphrylated Tau. Its role however in of phosphrylated Tau. Its role however in pathogenesis is controversialpathogenesis is controversial

a-Synucleina-Synuclein

a-Synuclein is a tubular-filamentous a-Synuclein is a tubular-filamentous nonsoluble protein, with important nonsoluble protein, with important role in the maintenance of synaptic role in the maintenance of synaptic poolpool

misfolded a-synuclein is part of the misfolded a-synuclein is part of the abnormal protein aggregate found in abnormal protein aggregate found in Lewy bodiesLewy bodies

SynucleinopathiesSynucleinopathies

NDD characterized by intracellular NDD characterized by intracellular aggregation of alpha-synuclein:aggregation of alpha-synuclein: Parkinson’s DiseaseParkinson’s Disease Dementia with Lewy BodiesDementia with Lewy Bodies Lewy Body Variant of ADLewy Body Variant of AD Multiple System AtrophiesMultiple System Atrophies

OPCA & SND & Shy-Drager SyndromeOPCA & SND & Shy-Drager Syndrome Neurodegeneration with brain iron Neurodegeneration with brain iron

accumulation type 1( Hallervorden-Sp.)accumulation type 1( Hallervorden-Sp.)

Role of Tau and a-synuclein in neurodegenerative diseases

Triplet Repeat ExpansionsTriplet Repeat Expansions

This is characterized by This is characterized by dynamic dynamic expansion of tandem nucleotide expansion of tandem nucleotide repeatsrepeats. These stretches of repeats . These stretches of repeats tend to be tend to be inherently unstableinherently unstable, and , and this instability favors expansion.this instability favors expansion.

When the When the length length of the repeat of the repeat expansion exceeds the range in the expansion exceeds the range in the general population, a symptomatic general population, a symptomatic state may result. state may result.

Triplet Repeat ExpansionsTriplet Repeat Expansions

Genetic anticipation:Genetic anticipation:

The clinical phenomenon of The clinical phenomenon of increasing increasing severity and earlier age of onset in severity and earlier age of onset in successive generationssuccessive generations, noted in many of , noted in many of these disorders that includes:these disorders that includes: fragile X syndrome fragile X syndrome myotonic dystrophymyotonic dystrophy oculopharyngeal muscular dystrophy oculopharyngeal muscular dystrophy dominantly inherited spinocerebellar ataxias. dominantly inherited spinocerebellar ataxias. Friedreich ataxiaFriedreich ataxia Huntington diseaseHuntington disease

Protein misfolding diseasesProtein misfolding diseases

Prions Diseases caused by mutations in

α-crystallin: α-crystallin belongs to the class of

molecular chaperones , present in all tissue types

Functions include maintaining microfilament stability

Neurodegenerative Disorders Neurodegenerative Disorders Degenerative products depositionDegenerative products deposition

Abnormal protein tends to Abnormal protein tends to aggregatesaggregates

and accumulate as a consequence and accumulate as a consequence of:of: Deficient Deficient disposal/degradationdisposal/degradation Deficient Deficient recyclingrecycling

Neurodegenerative Disorders Neurodegenerative Disorders Proteasome-Ubiquitin systemProteasome-Ubiquitin system

ProteasomeProteasome is a barrel-shaped enzyme, is a barrel-shaped enzyme, labelled “the master controller of the labelled “the master controller of the cell”: cell”:

It breaks down protein molecules and It breaks down protein molecules and abnormal “misfolded” proteins, and recycles abnormal “misfolded” proteins, and recycles regulatory proteins. regulatory proteins.

Ubiquitin Ubiquitin is a tiny molecule that latches onto is a tiny molecule that latches onto the damaged protein and carries it to the the damaged protein and carries it to the proteasome, where the protein is sliced and proteasome, where the protein is sliced and diced.diced.

Kopito & Bence, Science 2004 Kopito & Bence, Science 2004


Defective proteins clump together into Defective proteins clump together into aggregates aggregates aggregates build up aggregates build up (defective protein may clog (defective protein may clog proteasome)proteasome)

interfere with proteasome functioninterfere with proteasome function

accumulation of more aggregates accumulation of more aggregates that further impair the proteasome….that further impair the proteasome….

A viscious circle! A viscious circle! Kopito & Bence, Science 2004Kopito & Bence, Science 2004


Onset of the disease occurs when Onset of the disease occurs when aggregates build up ( slow course…) aggregates build up ( slow course…) reaches significant level.reaches significant level.

In Huntington diseases, the ubiquitin-In Huntington diseases, the ubiquitin-proteasome system breaks down. proteasome system breaks down. Huntingtin aggregates are noted to Huntingtin aggregates are noted to contain thousands of misfolded contain thousands of misfolded proteins with ubiquitin flags attached to proteins with ubiquitin flags attached to them.them.

Kopito & Bence, Science 2004Kopito & Bence, Science 2004

Neurodegenerative Disorders Neurodegenerative Disorders EtiologyEtiology

Several factors combined are Several factors combined are implicated: implicated: Genetic predispositionGenetic predisposition Environmental toxinsEnvironmental toxins Oxidative stressOxidative stress Aging Aging

Neurodegenerative DisordersNeurodegenerative DisordersGeneral clinical featuresGeneral clinical features

Insidious onsetInsidious onset Progressive, relentless clinical courseProgressive, relentless clinical course De novo ! No apparent evoking factor De novo ! No apparent evoking factor

? (long pre-clinical phase)? (long pre-clinical phase) Selective involvementSelective involvement of neuronal of neuronal

systems, that are anatomically or systems, that are anatomically or physiologically relatedphysiologically related

Bilateral symmetry clinicallyBilateral symmetry clinically““Earlier may be unilateral”Earlier may be unilateral”

Neurodegenerative DisordersNeurodegenerative DisordersGeneral tests featuresGeneral tests features

Minimal CSF changes:Minimal CSF changes:

Little cellular reactionLittle cellular reaction Radiologically; tissue loss (atrophy), Radiologically; tissue loss (atrophy),

no reaction, no enhancementno reaction, no enhancement

Neurodegenerative DisordersNeurodegenerative DisordersGeneral ConclusionsGeneral Conclusions

NDD is a group of disorders that NDD is a group of disorders that share similar general clinical and share similar general clinical and pathological characteristicspathological characteristics

Genetic factors/predisposition is at Genetic factors/predisposition is at the heart of its pathogenesisthe heart of its pathogenesis

Until this “genetic pathogenesis” is Until this “genetic pathogenesis” is defined in all disorders, classification defined in all disorders, classification continue to depend on continue to depend on clinical/pathologic features clinical/pathologic features

Neurodegenerative DisordersNeurodegenerative DisordersGeneral ConclusionsGeneral Conclusions

A group of disorders that share A group of disorders that share similar general clinical and similar general clinical and pathological characteristicspathological characteristics

Genetic factors/predisposition is at Genetic factors/predisposition is at the heart of its pathogenesisthe heart of its pathogenesis

Until this “genetic pathogenesis” is Until this “genetic pathogenesis” is defined in all disorders, classification defined in all disorders, classification continue to depend on continue to depend on clinical/pathologic features clinical/pathologic features

Neurodeg-Disorders Classification Neurodeg-Disorders Classification Syndromes of DementiaSyndromes of Dementia

1-Progressive dementias1-Progressive dementias Diffuse cerebral atrophy:Diffuse cerebral atrophy:

Alzheimer diseaseAlzheimer disease Non-AlzheimerNon-Alzheimer Lewy-body dementiaLewy-body dementia

Circumscribed cortical atrophy;Circumscribed cortical atrophy; Picks diseasePicks disease Mesolimbocortical dementia (non-Mesolimbocortical dementia (non-

Alzheimer)Alzheimer) Thalamic degenerationThalamic degeneration

Neurodeg-Disorders Classification Neurodeg-Disorders Classification Syndromes of DementiaSyndromes of Dementia

2-Progressive dementias with 2-Progressive dementias with other neurological abnormalityother neurological abnormality

Huntington diseaseHuntington disease Other dementias & Chorea disordersOther dementias & Chorea disorders Cortico-Striato-Spinal deg. & dementia-Cortico-Striato-Spinal deg. & dementia-

Parkinson-ALS complex (Guamian..)Parkinson-ALS complex (Guamian..) Cotico-basal-ganglionic deg.Cotico-basal-ganglionic deg. Dentato-rubro-pallido-luysian deg.Dentato-rubro-pallido-luysian deg. Cerebro-cerebellar deg.Cerebro-cerebellar deg. Familial dementia & spas….& myoclonusFamilial dementia & spas….& myoclonus Lewy-body diseaseLewy-body disease Polyglucosan body diseasePolyglucosan body disease

Neurodeg-Disorders Classification Neurodeg-Disorders Classification Syndromes of Movement disordersSyndromes of Movement disorders

Parkinson diseaseParkinson disease Striato-nigral degeneration.Striato-nigral degeneration. Striato-nigral degen. & autonomic failureStriato-nigral degen. & autonomic failure Progressive supranuclear palsyProgressive supranuclear palsy Dystonia muscularum deformansDystonia muscularum deformans Restricted Dystonia (Spa-Torticollis & Restricted Dystonia (Spa-Torticollis &

Meige)Meige) Guill de la Tourette SyndromeGuill de la Tourette Syndrome Hallervorden-Spatz diseaseHallervorden-Spatz disease Acanthosis choreaAcanthosis chorea

Neurodeg-Disorders Classification Neurodeg-Disorders Classification Syndromes of Progressive AtaxiaSyndromes of Progressive Ataxia

Predominantly Spinal:Predominantly Spinal: Freidrex ataxiaFreidrex ataxia Non-Freidrex ataxia Non-Freidrex ataxia

Pure cerebellar ataxiaPure cerebellar ataxia(familial & late onset)(familial & late onset)

Complicated cerebellar ataxia:Complicated cerebellar ataxia: Olivo-ponto-cerebellar atrophy (MSA)Olivo-ponto-cerebellar atrophy (MSA) Gertsman-Straussler-Sheinker diseaseGertsman-Straussler-Sheinker disease Machado-Joseph diseaseMachado-Joseph disease

Paraneoplastic & alcohol related ataxiaParaneoplastic & alcohol related ataxia

Neurodeg-Disorders Classification Neurodeg-Disorders Classification Synd. of Synd. of Progressive weekness & AtrophyProgressive weekness & Atrophy

Without sensory changes:Without sensory changes: Progressive SMAProgressive SMA ALSALS Progressive bulbar palsyProgressive bulbar palsy Primary lateral sclerosisPrimary lateral sclerosis Hereditary progressive atrophy & Hereditary progressive atrophy &

Spastic paraplegiaSpastic paraplegia With Sensory changes:With Sensory changes:

HSNHSN HMSN (CMT, Dejerene Sottas, Refsum HMSN (CMT, Dejerene Sottas, Refsum

disease)disease)

Neurodeg-Disorders Classification Neurodeg-Disorders Classification Synd. of Spastic paraplegia without Synd. of Spastic paraplegia without

amyotrophyamyotrophy

Hereditary Spastic paraplegiaHereditary Spastic paraplegia Primary lateral sclerosisPrimary lateral sclerosis

Neurodeg-Disorders Classification Neurodeg-Disorders Classification Syndrome of Progressive blindness or Syndrome of Progressive blindness or ophthalmoplegia with/whithout neuro-ophthalmoplegia with/whithout neuro-

disorderdisorder

Leber’s optic atrophyLeber’s optic atrophy Retinitis pigmentosaRetinitis pigmentosa Karne-Sayer SyndromeKarne-Sayer Syndrome Stanfort?? DiseaseStanfort?? Disease

Neurodeg-Disorders Classification Neurodeg-Disorders Classification Syndromes Characterized by Syndromes Characterized by

neuro-sensory deafnessneuro-sensory deafness

Pure sensory deafnessPure sensory deafness Hereditary hearing and retinal Hereditary hearing and retinal

diseasedisease Hereditary hearing loss with system Hereditary hearing loss with system

atrophyatrophy

DEMENTIADEMENTIACausesCauses

Alzheimer's disease Alzheimer's disease Fronto-temporal dementia Fronto-temporal dementia Vascular dementia Vascular dementia Parkinson's disease with dementia Parkinson's disease with dementia Lewy body dementia Lewy body dementia Progressive supranuclear palsy (PSP) Progressive supranuclear palsy (PSP) Normal pressure hydrocephalus Normal pressure hydrocephalus Creutzfeldt-Jacob Disease Creutzfeldt-Jacob Disease Huntington's diseaseHuntington's disease Others Others

ALZHEIMER DISEASEALZHEIMER DISEASEEpidemiologyEpidemiology

Worldwide: 5-10% of people over the Worldwide: 5-10% of people over the age of 65 are affected, and the age of 65 are affected, and the number number doubles every 5 years over doubles every 5 years over age 65 age 65 50% in over 80 yrs 50% in over 80 yrs

ALZHEIMER DISEASEALZHEIMER DISEASE Plaques and TanglesPlaques and Tangles

The two most significant physical The two most significant physical findings in Alzheimer's disease are:findings in Alzheimer's disease are:

neuritic plaquesneuritic plaques and and neurofibrillary tanglesneurofibrillary tangles are these the are these the cause or the result of the disease cause or the result of the disease process?process?

Alzheimer disease & Amyloid-BetaAlzheimer disease & Amyloid-Beta

Evidence suggests a central role for the Evidence suggests a central role for the A-Beta peptide in AD pathogenesis. A-Beta peptide in AD pathogenesis.

Amyloid plaques are primarily composed Amyloid plaques are primarily composed of A-Beta peptides which are produced of A-Beta peptides which are produced by cleavage of amyloid precursor by cleavage of amyloid precursor protein. protein.

Mutations in APP lead to overproduction Mutations in APP lead to overproduction of insoluble Amyloid peptide and its of insoluble Amyloid peptide and its deposition in the neuritic plaques.deposition in the neuritic plaques.

Alzheimer disease & Amyloid-BetaAlzheimer disease & Amyloid-Beta& ApoE& ApoE

Apo E is a protein found with beta Apo E is a protein found with beta amyloid in neuritic plaques, and may amyloid in neuritic plaques, and may be involved in modifying the age of be involved in modifying the age of onset.onset.

ApoE genotype is the most important ApoE genotype is the most important genetic risk factor for AD.genetic risk factor for AD.

ALZHIMER DISEASEALZHIMER DISEASEGenetics…Genetics…

Alzheimer disease occur more among Alzheimer disease occur more among relatives relatives

A clear inherited pattern of AD exists A clear inherited pattern of AD exists in < 10% of cases. Around 40 % are in < 10% of cases. Around 40 % are inherited as an autosomal dominant. inherited as an autosomal dominant.

ALZHEIMER DISEASEALZHEIMER DISEASEGeneticsGenetics

APP gene / chr. 21 is implicated in APP gene / chr. 21 is implicated in the occurrence of AD in: the occurrence of AD in: Down's syndrome patients who survive Down's syndrome patients who survive

beyond 40 years.beyond 40 years. Some families with a history of early-Some families with a history of early-

onset ADonset AD Mutation in the presenilin-1 gene (PS-Mutation in the presenilin-1 gene (PS-

1) /chr.14. 1) /chr.14. Apo E gene on chromosome 19. Apo E gene on chromosome 19.

ALZHEIMER DISEASEALZHEIMER DISEASERisk FactorsRisk Factors

Age. Age. Apo E Apo E Chronic hypertension in older people. Chronic hypertension in older people.

Treatment reduces the risk. Treatment reduces the risk. Head injury adultsHead injury adults are three times are three times

more likely to develop Alzheimer's more likely to develop Alzheimer's disease. disease.

The evidence for role of gender is The evidence for role of gender is inconclusiveinconclusive

ALZHIMER DISEASEALZHIMER DISEASEInvestigations…Investigations…

EEG: EEG: usually normalusually normal

SPECT: SPECT: symmetrical reduction in grey matter blood symmetrical reduction in grey matter blood

perfusion. perfusion. PET: PET:

bilateral reduction of oxygen utilization and bilateral reduction of oxygen utilization and glucose uptake principally in the parietal and glucose uptake principally in the parietal and temporal lobes in the early stages & later in temporal lobes in the early stages & later in the frontal lobes.the frontal lobes.

ALZHIMER DISEASEALZHIMER DISEASEInvestigationsInvestigations

CT scanning: CT scanning: exclusion of other pathological processes. exclusion of other pathological processes. Correlation between severity of mental Correlation between severity of mental

changes changes and and

cortical atrophycortical atrophy was not strong,was not strong,

but but ventricular sizeventricular size provided a better provided a better correlation correlation

Serial scanning provides evidence of Serial scanning provides evidence of progressive ventricular dilatation .progressive ventricular dilatation .

MRI scanning:MRI scanning:

provides little additional information. provides little additional information.

ALZHEIMER DISEASEALZHEIMER DISEASETreatment…Treatment…

Symptomatic and include:Symptomatic and include: Acetylcholin-esterase inhibitorsAcetylcholin-esterase inhibitors

donepezil (Aricept)donepezil (Aricept)

galantamine (Reminyl) galantamine (Reminyl)

rivastigmine (Exelon) rivastigmine (Exelon)

ALZHEIMER DISEASEALZHEIMER DISEASETreatment…Treatment…

Glutamate antagonist:Glutamate antagonist:

Memantine Memantine approved for moderate-approved for moderate-to-severe disease. Can be used alone to-severe disease. Can be used alone or in combination with AChEI. or in combination with AChEI.

Side effectsSide effects include headache, include headache, constipation, confusion, and constipation, confusion, and dizziness.dizziness.

ALZHEIMER DISEASEALZHEIMER DISEASETreatmentTreatment

Antidepressants:Antidepressants:

Helps concomitant (early) Helps concomitant (early) depression. Have no effect on depression. Have no effect on cognitive function.cognitive function.

ALZHEIMER DISEASEALZHEIMER DISEASE PrognosisPrognosis

Patients may survive 8 to 10 years. Patients may survive 8 to 10 years. Some lived up to 25 years. Some lived up to 25 years. Death usually occurs due to Death usually occurs due to secondary infections, heart disease, secondary infections, heart disease, or malnutrition. or malnutrition.

Fronto-Temporal Dementia Fronto-Temporal Dementia PICKS DISEASEPICKS DISEASE

The condition occurs both The condition occurs both sporadicallysporadically and in a and in a familial formfamilial form inherited as an autosomal dominant. inherited as an autosomal dominant.

It generally presents in the sixth It generally presents in the sixth decade of life. decade of life.

The atrophic process concentrates on The atrophic process concentrates on the the frontal frontal and temporal lobesand temporal lobes

Parkinson DiseaseParkinson DiseasePathologyPathology

Proteinacious inclusion bodies:Proteinacious inclusion bodies:

Lewy bodies & Lewy neuritsLewy bodies & Lewy neurits Lewy bodies are:Lewy bodies are:

Fibrillar deposits of alpha Fibrillar deposits of alpha synucleinsynuclein

Parkinson’s DiseaseParkinson’s Disease Etiology Etiology

In sporadic Parkinson's disease, In sporadic Parkinson's disease, 1/51/5thth of patients have at least one of patients have at least one relative with parkinsonian symptoms, relative with parkinsonian symptoms, genetic factorgenetic factor

Several genes are identified in Several genes are identified in hereditary cases!hereditary cases!

The role for Park3 gene in sporadic The role for Park3 gene in sporadic form was questioned form was questioned

Parkinson's diseaseParkinson's diseaseSummary of genesSummary of genes

Gene Mode Chromosome Gene Gene Mode Chromosome Gene product product

Park 1 AD 4q21-23 a- synuclein Park 1 AD 4q21-23 a- synuclein

Park 2 AR 6q25.2-27 ParkinPark 2 AR 6q25.2-27 Parkin

Park 3Park 3 AD 2p13 Unknown AD 2p13 Unknown

Park 4 AD 4p14-16 .3 UnknownPark 4 AD 4p14-16 .3 Unknown

MOTOR NEURON DISEASEMOTOR NEURON DISEASEEpidemiologyEpidemiology

Approximately 30,000 patients in the Approximately 30,000 patients in the United States currently have ALS. United States currently have ALS.

The disease has no racial, The disease has no racial, socioeconomic, or ethnic boundaries. socioeconomic, or ethnic boundaries.

ALS is most commonly diagnosed in ALS is most commonly diagnosed in middle age and affects men more middle age and affects men more often than women. often than women.

MOTOR NEURON DISEASEMOTOR NEURON DISEASE Risk FactorsRisk Factors

Sporadic ALSSporadic ALS (90–95% ) appears to (90–95% ) appears to be increasing worldwide. Causes:be increasing worldwide. Causes: viruses viruses neurotoxins (Guamanian ALS) neurotoxins (Guamanian ALS) heavy metalsheavy metals DNA defects (familial ALS) DNA defects (familial ALS) immune mechanismimmune mechanism

MOTOR NEURON DISEASEMOTOR NEURON DISEASE Familial ALS(FALS)Familial ALS(FALS)

FALS ( 5-10%) is linked to a genetic FALS ( 5-10%) is linked to a genetic defect on chr. 21 (only in 40% of defect on chr. 21 (only in 40% of cases). cases).

This gene codes for superoxide This gene codes for superoxide dismutase (SOD), an antioxidant. dismutase (SOD), an antioxidant.

More than 60 different mutations for More than 60 different mutations for SOD have been found. SOD have been found.

Neurodegenerative disease of Neurodegenerative disease of Guam & EnvironmentGuam & Environment

There is a high prevalence of There is a high prevalence of long-latency long-latency neurodegenerative disorder neurodegenerative disorder (parkinsonism, dementia, and motor (parkinsonism, dementia, and motor neuron disease complex) on the western neuron disease complex) on the western Pacific island of Guam.Pacific island of Guam.

Epidemiological studies show that the ALS Epidemiological studies show that the ALS variant develops after heavy exposure to variant develops after heavy exposure to the raw or the raw or incompletely detoxified seed of incompletely detoxified seed of neurotoxic neurotoxic cycad cycad plants. plants.

cycads may harbor a cycads may harbor a "slow toxin"slow toxin Cycasin”Cycasin” that causes the post-mitotic that causes the post-mitotic neuron to undergo slow irreversible neuron to undergo slow irreversible degeneration.degeneration.

MOTOR NEURON DISEASEMOTOR NEURON DISEASE Treatment & PrognosisTreatment & Prognosis

Neurotrophins:Neurotrophins: Human trials Human trials Failed Failed Animal Experiment: Animal Experiment:

Vascular endothelial growth factorVascular endothelial growth factor (VEGF) in a (VEGF) in a SOD1SOD1 G93A rat model of ALS G93A rat model of ALS delays onset of paralysis, improves delays onset of paralysis, improves motor performance and prolongs motor performance and prolongs survivalsurvival

The life expectancy of ALS patients is The life expectancy of ALS patients is usually 3 to 5 years after diagnosis.usually 3 to 5 years after diagnosis.

ATAXIAATAXIAClassification…Classification…

Early classification was based on anatomic Early classification was based on anatomic localization of pathologic changes:localization of pathologic changes: Predominantly spinal ( Spinocerebellar)Predominantly spinal ( Spinocerebellar) Pure Cerebellar ataxias Pure Cerebellar ataxias

Anita Harding 1993: Anita Harding 1993: Congenital Congenital Inherited metabolic syndromes with known Inherited metabolic syndromes with known

genetic/biochemical defects genetic/biochemical defects Degenerative ataxias of unknown cause:Degenerative ataxias of unknown cause:

early onset (<20 y) & late-onset (>20 y) early onset (<20 y) & late-onset (>20 y)

ATAXIAATAXIAClassification/Classification/Trinucleotide repeatTrinucleotide repeat

Advances in the molecular pathology of Advances in the molecular pathology of the the trinucleotide repeattrinucleotide repeat NDD has NDD has allowed re-classification into:allowed re-classification into:

Translated polyglutamine diseasesTranslated polyglutamine diseases, which , which are due to CAG repeat expansions:are due to CAG repeat expansions:

Toxic gain of function of mutant expanded Toxic gain of function of mutant expanded misfolded proteins misfolded proteins activation of activation of apoptosis. apoptosis. Heterogenous group where trinucleotide Heterogenous group where trinucleotide

repeat remains untranslated.repeat remains untranslated.

ATAXIA with identified genetic/ ATAXIA with identified genetic/ biochemical deficitbiochemical deficit

Acute intermittent ataxiaAcute intermittent ataxia Ataxias with spinocerebellar Ataxias with spinocerebellar

dysfunction dysfunction Progressive ataxias plus (i.e., Progressive ataxias plus (i.e.,

prominent cerebellar dysfunction prominent cerebellar dysfunction with additional neurological signs) with additional neurological signs)

Ataxias with polymyoclonus and Ataxias with polymyoclonus and seizures seizures

Acute Intermittent AtaxiasAcute Intermittent Ataxias

Intermittent/Episodic Ataxia in Intermittent/Episodic Ataxia in association with a known inherited association with a known inherited disorders:disorders: Maple syrup urine diseaseMaple syrup urine disease AR, AR, 1112p13. 12p13. Episodic ataxia1Episodic ataxia1 Intermittent ataxia AD, Intermittent ataxia AD,19p1319p13

point mutations affecting the point mutations affecting the voltage-gatedvoltage-gatedpotassium channel (potassium channel (KCNA1KCNA1), ),

Episodic ataxia 2Episodic ataxia 2 AD associated with mutations AD associated with mutations that affect the calcium channel (that affect the calcium channel (CACNA1ACACNA1A) gene ) gene at the 19p13 locus.. Also allelic with at the 19p13 locus.. Also allelic with SCA-6 and SCA-6 and hemiplegic migrainehemiplegic migraine

Hartnup diseaseHartnup disease & Intermittent ataxia AR, & Intermittent ataxia AR, 11q1311q13Altered Altered calcium channel functioncalcium channel function

OthersOthers


Acute intermittent ataxia Acute intermittent ataxia Ataxias with spinocerebellar Ataxias with spinocerebellar

dysfunctiondysfunction Progressive ataxias plus (i.e., Progressive ataxias plus (i.e.,

prominent cerebellar dysfunction prominent cerebellar dysfunction with additional neurological signs) with additional neurological signs)

Ataxias with polymyoclonus and Ataxias with polymyoclonus and seizures seizures

Ataxias with Spinocerebellar Ataxias with Spinocerebellar Dysfunction/SCADysfunction/SCA

A wide range of molecular defects, A wide range of molecular defects, but but overlap in the clinical presentationoverlap in the clinical presentation because of because of limited pathologic limited pathologic responsesresponses within the system. within the system.

Most have a heritable basisMost have a heritable basis; mainly ; mainly AD or ARAD or AR

AR group is AR group is expanding constantlyexpanding constantly as as the genetic defects are discovered the genetic defects are discovered

Ataxias with Spinocerebellar Ataxias with Spinocerebellar Dysfunction-Dysfunction-ClassificationClassification

AD Cerebellar Ataxias AD Cerebellar Ataxias Friedreich Ataxia/AR Friedreich Ataxia/AR Ataxia With Selective Vitamin E Ataxia With Selective Vitamin E

DeficiencyDeficiency Abetalipoproteinemia Abetalipoproteinemia HypobetalipoproteinemiaHypobetalipoproteinemia

Autosomal-Dominant SCA…Autosomal-Dominant SCA…

At least 12 forms have been described and At least 12 forms have been described and labeled sequentially from SCA1 to SCA12. labeled sequentially from SCA1 to SCA12. Position 9 has been reserved for a Position 9 has been reserved for a unknown variety. unknown variety.

Clinical:Clinical: A great degree of A great degree of overlap in phenotypeoverlap in phenotype is is

presentpresent Mainly Mainly symptoms of cerebellar and symptoms of cerebellar and

spinocerebellar pathway dysfunctionspinocerebellar pathway dysfunction. . Neuroimaging studies are nonspecific. Neuroimaging studies are nonspecific.

Autosomal-Dominant SCA…Autosomal-Dominant SCA…

SCA-1:SCA-1: Peripheral neuropathy,Pyramidal signs, Peripheral neuropathy,Pyramidal signs, 6p23 6p23 Ataxin-1Ataxin-1, , CAG exp.39-83CAG exp.39-83 (6-36 normal range) (6-36 normal range)

SCA-2:SCA-2: Abnormal ocular saccades,Hyporeflexia, Abnormal ocular saccades,Hyporeflexia, dementia,Peripheral neuropathy 12q24.1 dementia,Peripheral neuropathy 12q24.1 Ataxin-2Ataxin-2, , CAG exp.34-400CAG exp.34-400 (15-31 normal range) (15-31 normal range)

SCA-3:SCA-3: Pyramidal, extrapyramidal, and ocular Pyramidal, extrapyramidal, and ocular movement abnormalitiesmovement abnormalitiesAmyotrophy and sensory neuropathy14q24.3-Amyotrophy and sensory neuropathy14q24.3-q32.2 q32.2 CAG exp.55-86CAG exp.55-86 (12-40 normal range) (12-40 normal range)

SCA-4:SCA-4: Sensory axonopathy 16q22.1 Sensory axonopathy 16q22.1 SCA-5:SCA-5: Myokymia, nystagmus, and altered Myokymia, nystagmus, and altered

vibration sense 11p11.q11 vibration sense 11p11.q11 CAG exp.CAG exp. not demonstrated as yet not demonstrated as yet

Autosomal-Dominant SCAAutosomal-Dominant SCA

SCA-6:SCA-6: Slowly progressive ataxia, Slowly progressive ataxia, 19p1319p13

CAG exp.20-33CAG exp.20-33 (4-16 normal range) (4-16 normal range) with altered alpha1A subunit of the with altered alpha1A subunit of the voltage-dependent calcium channel voltage-dependent calcium channel ((CACLN1A4CACLN1A4))

SCA-7:SCA-7: Visual loss retinopathy Visual loss retinopathy 3p21.1-p12 3p21.1-p12

Ataxin-7Ataxin-7, , CAG exp.37 to>300CAG exp.37 to>300 (4-19 normal (4-19 normal range) range)

SCA-8…….SCA-10…SCA-11…SCA-12.SCA-8…….SCA-10…SCA-11…SCA-12. Dentato-rubro-pallido-luysian atrophy Dentato-rubro-pallido-luysian atrophy

(DRPLA)(DRPLA)

Dentato-Rubro-Pallido-Luysian Dentato-Rubro-Pallido-Luysian AtrophyAtrophy

DRPLA is another DRPLA is another triplet-repeat triplet-repeat disorder disorder

AD, CAG repeat exp. from 49-75. The AD, CAG repeat exp. from 49-75. The mutation affect a mutation affect a protein product protein product "atrophin-1,""atrophin-1," 12p13.3112p13.31..

Clinical features include:Clinical features include:

Progressive ataxia , chorea, seizures, Progressive ataxia , chorea, seizures, myoclonus, and dementia.myoclonus, and dementia.

Friedreich AtaxiaFriedreich AtaxiaGeneticsGenetics

The first identified The first identified AR SCAAR SCA with a with a mutation involving a triplet repeat mutation involving a triplet repeat expansion. expansion.

GAAGAA repeats 7-38 in normal alleles repeats 7-38 in normal alleles

and and 66 to over 1700 66 to over 1700 in disease-in disease-causing alleles. Most affected carry > causing alleles. Most affected carry > 600 repeats. 600 repeats.

The mutation leads to formation of the The mutation leads to formation of the abnormal protein abnormal protein “frataxin”.“frataxin”.

Friedreich AtaxiaFriedreich AtaxiaClinical features…Clinical features…

Variable age of onset when younger Variable age of onset when younger than 20 years than 20 years

Neurological:Neurological: By 5-10 years cerebellar ataxia, By 5-10 years cerebellar ataxia,

dysarthria, nystagmus, dysarthria, nystagmus, impaired proprioception.impaired proprioception. Hypoactive knee and ankle DTR’s, Hypoactive knee and ankle DTR’s, Babinski sign Babinski sign

Friedreich AtaxiaFriedreich AtaxiaClinical featuresClinical features

Cardiac: Cardiac: Hypertrophic Hypertrophic cardiomyopathy; congestive heart cardiomyopathy; congestive heart failure; and subaortic stenosis failure; and subaortic stenosis

Skeletal:Skeletal: Pes-cavus, and scoliosis Pes-cavus, and scoliosis GI:GI: Malabsorptive state in the early Malabsorptive state in the early

years with steatorrhea and abdominal years with steatorrhea and abdominal distensiondistension

Metabolic:Metabolic: Abnormal GTT/ diabetes Abnormal GTT/ diabetes mellitusmellitus

Friedreich AtaxiaFriedreich Ataxia InevstigationsInevstigations

NCSNCS…Axonal neuroapthy …Axonal neuroapthy EKG EKG MRI MRI – Cerebellar & spinal cord – Cerebellar & spinal cord

atrophyatrophy

Abetalipoproteinemia…Abetalipoproteinemia…

Rare autosomal-recessive disorder is Rare autosomal-recessive disorder is characterized by low levels of (LDLs) and characterized by low levels of (LDLs) and (VLDLs). (VLDLs).

It features It features defective assembly and defective assembly and secretion of apolipoprotein B (Apo-B)–secretion of apolipoprotein B (Apo-B)–containing lipoproteins by the intestines containing lipoproteins by the intestines and the liver. and the liver.

Mutations affect the microsomal Mutations affect the microsomal triglyceride transfer protein (MTP) gene, triglyceride transfer protein (MTP) gene, which results in dysfunction. which results in dysfunction.

AbetalipoproteinemiaAbetalipoproteinemiaClinical featuresClinical features

Areflexia, proprioceptive dysfunction, Areflexia, proprioceptive dysfunction, and Babinski sign and Babinski sign

By 5-10 years, gait disturbances and By 5-10 years, gait disturbances and cerebellar signs cerebellar signs

Malabsorptive state in the early years Malabsorptive state in the early years with steatorrhea and abdominal with steatorrhea and abdominal distension distension

Pes cavus and scoliosis present in Pes cavus and scoliosis present in most patients most patients

Pigmentary retinopathy Pigmentary retinopathy

AbetalipoproteinemiaAbetalipoproteinemiaLaboratory featuresLaboratory features

Acanthocytosis on peripheral blood Acanthocytosis on peripheral blood smears (constant finding) smears (constant finding)

Decreased serum cholesterol Decreased serum cholesterol Increased high-density lipoprotein Increased high-density lipoprotein

cholesterol levels cholesterol levels Low levels of LDL and VLDL Low levels of LDL and VLDL Low triglyceride levels Low triglyceride levels

AbetalipoproteinemiaAbetalipoproteinemiaTreatmentTreatment

High-dose supplementation of High-dose supplementation of vitamin E has a beneficial effect on vitamin E has a beneficial effect on neurological symptoms. neurological symptoms.

Administer other fat-soluble vitamins Administer other fat-soluble vitamins (D, A, K). (D, A, K).

Ataxia with Selective Vitamin E Ataxia with Selective Vitamin E DeficiencyDeficiency

A rare AR disorder due to a mutation A rare AR disorder due to a mutation in the gene for in the gene for alpha-tocopherol alpha-tocopherol transfer protein. transfer protein.

Clinical features: Clinical features: Onset Onset 2-52 2-52 years and usually < than 20 years and usually < than 20

yrs; slowly progressive. yrs; slowly progressive. Phenotypically similar to Friedreich Phenotypically similar to Friedreich

ataxia ,ataxia , Skin is affected by xanthelasmata and Skin is affected by xanthelasmata and

tendon xanthomas.tendon xanthomas.

Ataxia with Selective Vitamin E Ataxia with Selective Vitamin E DeficiencyDeficiency

Investigations:Investigations: Low-to-absent Low-to-absent serum vitamin Eserum vitamin E and and high serum cholesterol, triglyceride, and high serum cholesterol, triglyceride, and

beta-lipoprotein. beta-lipoprotein. TreatmentTreatment

Vitamin E supplement, of 400-1200 Vitamin E supplement, of 400-1200 IU/d for life. IU/d for life.



dysfunction dysfunction Progressive ataxias plus Systemic Progressive ataxias plus Systemic

featuresfeatures Ataxias with polymyoclonus and Ataxias with polymyoclonus and

seizures seizures

ATAXIAS WITH PROGRESSIVE ATAXIAS WITH PROGRESSIVE CEREBELLAR DYSFUNCTION PLUS CEREBELLAR DYSFUNCTION PLUS

SYSTEMIC FEATURES…SYSTEMIC FEATURES…

The mode of inheritance includes The mode of inheritance includes both mendelian and nonmendelian both mendelian and nonmendelian patterns. patterns.

Many of these disorders involve Many of these disorders involve defects in DNA repairdefects in DNA repair that involve a that involve a complex sequence of events. In complex sequence of events. In disorders involving these pathways, disorders involving these pathways, multiple gene defects are involved. multiple gene defects are involved.


SYSTEMIC FEATURESSYSTEMIC FEATURES

These disorders present with These disorders present with progressive ataxiaprogressive ataxia combined with combined with other neurological and systemic other neurological and systemic features: features: Cognitive delay or decline, seizuresCognitive delay or decline, seizures Movement disorders and abnormalities Movement disorders and abnormalities

of muscle tone. of muscle tone.


SYSTEMIC FEATURESSYSTEMIC FEATURES Cockayne Syndrome Cockayne Syndrome Xeroderma Pigmentosum Xeroderma Pigmentosum Ataxia Telangiectasia Ataxia Telangiectasia Refsum Disease Refsum Disease Cerebrotendinous XanthomatosisCerebrotendinous Xanthomatosis Late-Onset Sphingolipidoses Late-Onset Sphingolipidoses L-2-hydroxyglutaricaciduria L-2-hydroxyglutaricaciduria Carbohydrate Deficient Glycoprotein Syndrome Carbohydrate Deficient Glycoprotein Syndrome Leukoencephalopathy With Vanishing White Matter Leukoencephalopathy With Vanishing White Matter Succinic-Semialdehyde Dehydrogenase DeficiencySuccinic-Semialdehyde Dehydrogenase Deficiency Neuropathy, Ataxia and Retinitis Pigmentosa Neuropathy, Ataxia and Retinitis Pigmentosa

syndromesyndrome Leigh Disease Leigh Disease

Ataxia TelangiectasiaAtaxia Telangiectasia

AR ataxia presents in early childhood AR ataxia presents in early childhood (Onset 1-3 years) . (Onset 1-3 years) .

A defective truncated protein results A defective truncated protein results from mutations of the ATM gene from mutations of the ATM gene locus. . locus. .


Clinical featuresClinical features Progressive ataxia and slurred speech Progressive ataxia and slurred speech Choreoathetosis Choreoathetosis Oculomotor apraxia Oculomotor apraxia Cutaneous and bulbar telangiectasia Cutaneous and bulbar telangiectasia Immunodeficiency and increased Immunodeficiency and increased

susceptibility to infections susceptibility to infections Susceptibility to cancer (e.g., leukemia, Susceptibility to cancer (e.g., leukemia,

lymphoma) lymphoma)


Laboratory featuresLaboratory features Molecular-geneticMolecular-genetic testing for testing for

mutations affecting the ATM gene locus mutations affecting the ATM gene locus (11q22.3), (11q22.3),

& Breakpoints involved in translocation at the & Breakpoints involved in translocation at the 14q11 and 14q32 sites 14q11 and 14q32 sites

Elevated (>10 ng/mL) serum Elevated (>10 ng/mL) serum alpha-alpha-fetoprotein fetoprotein in 90-95% of patientsin 90-95% of patients

Refsum DiseaseRefsum Disease

AR disorder, associated with AR disorder, associated with impaired oxidation of impaired oxidation of phytanic acidphytanic acid & & elevated phytanic acid levels in CNS. elevated phytanic acid levels in CNS.


Clinical featuresClinical features,, relapsing-remittingrelapsing-remitting Onset in second to third decade of life Onset in second to third decade of life Cerebellar ataxia Cerebellar ataxia Polyneuropathy with elevated CSF protein Polyneuropathy with elevated CSF protein Night blindness and retintis pigmentosa Night blindness and retintis pigmentosa Sensorineural deafness Sensorineural deafness Ichthyosis Ichthyosis Cardiac arrhythmia.Cardiac arrhythmia.


Laboratory featuresLaboratory features Elevated phytanic acid levels in the Elevated phytanic acid levels in the

plasma and urine are plasma and urine are diagnostic.diagnostic. Cultured fibroblasts show reduced Cultured fibroblasts show reduced

ability to oxidize phytanic acid. ability to oxidize phytanic acid. Treatment Treatment

Reduction in dietary phytanic acid Reduction in dietary phytanic acid & plasmapheresis at onset can & plasmapheresis at onset can ameliorate the neuropathy. ameliorate the neuropathy.



dysfunction dysfunction Progressive ataxias plus (i.e., Progressive ataxias plus (i.e.,

prominent cerebellar dysfunction prominent cerebellar dysfunction with additional neurologic signs) with additional neurologic signs)

Ataxias with polymyoclonus and Ataxias with polymyoclonus and seizuresseizures

Ataxia With Progressive Ataxia With Progressive Myoclonic EpilepsyMyoclonic Epilepsy

A group of seizure disorders with A group of seizure disorders with phenotypic features of phenotypic features of myoclonic and myoclonic and other generalized seizures, ataxia, other generalized seizures, ataxia, and cognitive defectsand cognitive defects. These features . These features occur in variable combinations that occur in variable combinations that progress over time. progress over time.

Differential diagnosis is difficult on Differential diagnosis is difficult on purely clinical grounds. purely clinical grounds.

Ataxia With Progressive Ataxia With Progressive Myoclonic EpilepsyMyoclonic Epilepsy

Unverricht-Lundborg Disease Unverricht-Lundborg Disease Lafora Body Disease Lafora Body Disease Neuronal Ceroid LipofuscinosisNeuronal Ceroid Lipofuscinosis Myoclonic Epilepsy With Ragged Red Myoclonic Epilepsy With Ragged Red

Fibers Fibers

Multiple System Atrophy Multiple System Atrophy

MSA is defined as:MSA is defined as:

AA sporadic sporadic, progressive, NDD of , progressive, NDD of undetermined etiology, characterized undetermined etiology, characterized by extrapyramidal, pyramidal, by extrapyramidal, pyramidal, cerebellar, and autonomic cerebellar, and autonomic dysfunction in any combination.dysfunction in any combination.

MSA is an MSA is an alpha-synucleinopathy alpha-synucleinopathy

Multiple System AtrophyMultiple System Atrophy

Shy-Drager syndrome :Shy-Drager syndrome : autonomic failure predominates. autonomic failure predominates.

Striatonigral degeneration or MSA-P:Striatonigral degeneration or MSA-P: extrapyramidal features predominateextrapyramidal features predominate

sporadic olivopontocerebellar sporadic olivopontocerebellar atrophy or MSA-C: atrophy or MSA-C:

cerebellar features predominatecerebellar features predominate

Multiple System AtrophyMultiple System AtrophyPathologyPathology

Neuronal loss, Neuronal loss, extensive extensive demyelinationdemyelination and gliosis and gliosis

Oligodendroglial cytoplasmic Oligodendroglial cytoplasmic inclusions (GCIs) :inclusions (GCIs) :

abnormal tubular structures in the abnormal tubular structures in the cytoplasm and nucleus of oligodendro-cytoplasm and nucleus of oligodendro-cytes and neurons mainly in the basal cytes and neurons mainly in the basal ganglion, cerebellum, and intermedio-ganglion, cerebellum, and intermedio-lateral columns of the spinal cord.lateral columns of the spinal cord.

Multiple System AtrophyMultiple System AtrophyPathogenesisPathogenesis

Oligodendroglial cytoplasmic Oligodendroglial cytoplasmic inclusions (GCIs) indicates that inclusions (GCIs) indicates that damage is primarily in the white damage is primarily in the white matter. matter.

Autoimmune ? , toxic agents ?Autoimmune ? , toxic agents ?

Multiple System AtrophyMultiple System AtrophyClinical featuresClinical features

Parkinsonism, ataxia, autonomic Parkinsonism, ataxia, autonomic failure, or pyramidal signs, in various failure, or pyramidal signs, in various combinations:combinations: predominantly parkinsonismpredominantly parkinsonism predominantly ataxia, or as predominantly ataxia, or as A combination of parkinsonism, ataxia, A combination of parkinsonism, ataxia,

and autonomic failure and autonomic failure it is a relatively rapidly progressive and it is a relatively rapidly progressive and

fatal (average of 9.5 years from onset.fatal (average of 9.5 years from onset.

Multiple System AtrophyMultiple System AtrophyInvestigationsInvestigations

MRI:MRI: Hyperintensity in pons, peduncles, and Hyperintensity in pons, peduncles, and

cerebellum on T2 cerebellum on T2 The The slit hyperintensityslit hyperintensity of the lateral of the lateral

margin of the putamen in T2-weighted MRI margin of the putamen in T2-weighted MRI is a is a characteristic findingcharacteristic finding in patients with in patients with MSA involving the extrapyramidal system.MSA involving the extrapyramidal system.

To differente between MSA and PD, To differente between MSA and PD, fluordeoxyglucose dopa PET imaging may fluordeoxyglucose dopa PET imaging may help. help.

Olivo-Ponto-Cerebellar AtrophyOlivo-Ponto-Cerebellar Atrophy? On classification? On classification

OPCA describe a form of progressive ataxia OPCA describe a form of progressive ataxia distinguished by distinguished by pontine flattening and cerebellar pontine flattening and cerebellar atrophyatrophy on brain imaging studies and at autopsy. on brain imaging studies and at autopsy. Thus defined, OPCA also may qualify as an SCA Thus defined, OPCA also may qualify as an SCA or as an MSA. or as an MSA.

While MSAs are sporadic by definition, the genetic While MSAs are sporadic by definition, the genetic bases of the SCAs are increasingly well defined. bases of the SCAs are increasingly well defined.

Since OPCA may exist as a sporadic or inherited Since OPCA may exist as a sporadic or inherited disease, disease, categorizing sporadic OPCA as MSA and categorizing sporadic OPCA as MSA and inherited OPCA as SCA may be appropriateinherited OPCA as SCA may be appropriate. .

Differences between sporadic and inherited OPCA Differences between sporadic and inherited OPCA in microscopic in microscopic pathologypathology support this division. support this division.

Neuroacanthocytosis SyndromesNeuroacanthocytosis Syndromes

The classic neuroacanthocytosis The classic neuroacanthocytosis syndromesyndrome

It is AR disorder due to a single gene It is AR disorder due to a single gene locus defect on chromosome 9. locus defect on chromosome 9.

Pathologic features include atrophy of the Pathologic features include atrophy of the caudate and putamencaudate and putamen

Manifests in adults with combined Manifests in adults with combined features of: features of: acanthocytosisacanthocytosis (i.e., spiked (i.e., spiked red blood cells), red blood cells), chorea, orofacial tics, chorea, orofacial tics, amyotrophy & norm-betalipoproteinemiaamyotrophy & norm-betalipoproteinemia..

Neuroacanthocytosis SyndromesNeuroacanthocytosis Syndromes

Bassen-Kornzweig syndrome (BK): Bassen-Kornzweig syndrome (BK): Abetalipoproteinemia, ataxia, and retinitis Abetalipoproteinemia, ataxia, and retinitis pigmentosa typically in a childpigmentosa typically in a child with with acanthocytosis.acanthocytosis.

McLeod syndrome: McLeod syndrome: Acanthocytosis and high CPK levelAcanthocytosis and high CPK level (due to (due to a benign skeletal myopathy), a benign skeletal myopathy), occasionally with cardiomyopathy, occasionally with cardiomyopathy, involuntary movements, and/or dementia. involuntary movements, and/or dementia.

Occasional NA syndromes in children, with Occasional NA syndromes in children, with only acanthocytosis and decreased only acanthocytosis and decreased betalipoproteins.betalipoproteins.

Hallervorden-Spatz DiseaseHallervorden-Spatz DiseaseClinical FeaturesClinical Features

Onset in commonly in late childhood Onset in commonly in late childhood or early adolescence.or early adolescence.

Progressive extrapyramidal Progressive extrapyramidal dysfunction and dementia. dysfunction and dementia.

Hallervorden-Spatz DiseaseHallervorden-Spatz DiseaseEtiologyEtiology

The disease can be familial or The disease can be familial or sporadicsporadic

Familial HSD is AR inherited, chr. 20 Familial HSD is AR inherited, chr. 20

a mutation in the a mutation in the pantothenate pantothenate kinasekinase (PANK2) gene 20p13 (PANK2) gene 20p13

Zhou et al, 2001Zhou et al, 2001. .

Hallervorden-Spatz DiseaseHallervorden-Spatz DiseasePathophysiologyPathophysiology

Pathophysiology is not known: Pathophysiology is not known:

? abnormal peroxidation of lipofuscin ? abnormal peroxidation of lipofuscin to neuromelanin and deficient to neuromelanin and deficient cysteine dioxygenase cysteine dioxygenase abnormal abnormal iron accumulation in the brainiron accumulation in the brain ( globus pallidus and pars reticulata ( globus pallidus and pars reticulata of substantia nigra) of substantia nigra)

Protein misfolding diseasesProtein misfolding diseases

Prion encephalopathies Huntington’s disease Diseases caused by mutations in

chaperonesα-crystallinopathy

Prion EncephalopathiesPrion Encephalopathies

Prion proteinPrion protein PrP;PrP; Is a normal abundant protein in the brain. The Is a normal abundant protein in the brain. The

function is unknown. It has a normal function is unknown. It has a normal secondary structure dominated by alpha-secondary structure dominated by alpha-helical formations helical formations

Abnormal prion protein PrPScAbnormal prion protein PrPSc Results from conformational conversion of PrP, Results from conformational conversion of PrP,

as its secondary structure becomes dominated as its secondary structure becomes dominated by beta-pleated sheets, which makes it more by beta-pleated sheets, which makes it more prone to aggregate and resistant to protease prone to aggregate and resistant to protease digestiondigestion

Prion EncephalopathiesPrion Encephalopathies

PrPSc PrPSc transmissibility:transmissibility:

PrPSc “recruits” normal prion to the PrPSc “recruits” normal prion to the abnormal shape thus allowing for abnormal shape thus allowing for “propagation” and accounting for “propagation” and accounting for transmissibility transmissibility

PrPSc forms amyloid fibrils in the brain; injection of this material into the brains of normal mice leads to disease

Prion EncephalopathiesPrion Encephalopathiesin Manin Man

Kuru (historical)Kuru (historical) Creutzfeldt-Jakob diseaseCreutzfeldt-Jakob disease

SporadicSporadic TransmittedTransmitted FamilialFamilial

New variant of CJDNew variant of CJD Gerstmann-Straussler-Scheinker Gerstmann-Straussler-Scheinker

diseasedisease Fatal familial insomniaFatal familial insomnia

αα-crystallin and disease-crystallin and disease

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 disordersNeurodegenerative disorders Huntington’s diseaseHuntington’s disease

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

neurodegenerative disorders ar altahan frcp kkuh

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concept ambigous concept

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