Degenerative Diseases Flashcards
T or F: The proportion of change of Alzheimer pathologic change decreases continuously from age 70 to age 100
T
What percentage of AD patients have a dominant inheritance pattern?
<1%
High degree of penetrance
What is the Ribot law of memory?
The remote memories are preserved while the recent ones are lost
T or F in the late stages of AD the patient is left in a state of paraplegia in extension
F. In flexion.
What % of patients in the late stages of AD develop seizures?
5
What are the five main symptomatologies un AD?
Which one is the most prominent?
Amnesia-- MOST PROMINENT Naming Paranoia and personality changes Executive function Visuospatial orientation
Microscopically early in the disease loss of nerve cells is seen where?
What lobes are usually involved in Alzheimer’s disease?
Layer 2 of the entorhinal cortex
Frontal, temporal and parietal–
Most affected: hippocampus, parahippocampus and subiculum
What are the 3 pathological hallmarks of AD?
- Neurofibrillary tangles (hyperphosphorylated form of the microtubular protein tau)
- Amyloid spherical deposits seen with PAS stating (neuritic plaques)
- Granulovacuolar degeneration of neurons in the pyramidal layer of the hippocampus
What particular part of the hippocampus is affected in AD?
What do astrocytes look like in AD?
CA1 and CA2 (of Lorente de No)
Compensatory hypertrophy is seen most in layer 3 and 4
What is tau composed of? what does it form?
beta 2 transferrin –> tau –> tangles
Tau is a discrete cytoskeleltal protein that promotes assembly of the microtubules and stabilizes their structure
What sequence of events favor amyloid toxicity?
Amyloid precursor protein (APP)–> cleaved by beta then by gamma –> Abeta 40 (non toxic) AND Abeta42 (toxic) protein favors fibrillogenesis; amyloid aggregation–> neuronal toxicity
Non toxic route is cleavage by alpha secretase cleavage followed by gamma cleavage
The cholinergic synthetic capacity of demented brains is decreased on account of reduction in cells in?
Basal forebrain nuclei or nucleus basalis of Meynert
What chromosome is the errant amyloid precursor protein seen? How about mutated presenellin genes?
Chromosome 21
Chromosome 14 and 1
T or F. Apo E a regulator of lipid metabolism in its E4 isoform doubles the risk of developing SPORADIC AD.
F. triples the risk!
having 2 e4 alleles guarantees the development of AD if the individual lives until 80
e4 actas a SUSCEPTIBILITY RISK FACTOR– it accelerates the appearance of AD by about 5 years
What 3 genes are responsible for early AD?
APP, PS1, PS2
What is the EEG and CSF in AD?
Late in the disease diffuse slowing on EEG
Occasionally elevated protein
Which areas exhibit diminished activity with SPECT (blood flow) and PET (metabolism) in AD?
- Medial temporal lobes
2. Parietal association regions
T or F the ratio of A beta 42 to tau is IN THE CSF is LOW in AD
What areas in neuropsychologic testing do patients with AD score low in?
T
Memory and verbal access skills
What is the CNS disorder usually seen in the context of alcoholism and malnutrition. The condition classically involves the corpus callosum with necrosis and demyelination.
What are the 3 types of FTLD?
Marchiafava-Bignami disease
- Behavioural variant (frontal lobe involvement)
- The language variant (left frontal or temporal lobe involvement) presenting with apraxia and aphasia
- Posterior cortical atrophy: Progressive loss of the ability to understand and use visual information with relative sparing of memory
T or F. Amyloid plaques and tangle deposition are far more common in the brains of patients with PD 20-30% than in AD
In FTD what are argyrophilic cytoplasmic inclusions called? Diffusely staining ballooned cells?
T
Pick bodies
Pick cells
What percentage of Primary Progressive Aphasias (FTD variant) have Pick bodies? Have AD histopath?
40-40
60% HAVE NO CHARACTERISTIC PATHOLOGIC CHANGE
What are the two types of primary progressive aphasia (a variant of FTLD)?
What are the main components of lewy bodies?
Progressive nonfluent aphasia: Characterized by decreased verbal output and difficulty finding words but the language system is intact
Semantic dementia: The patient retains fluency. Initial sxs characterized by difficulty naming and generating a list of words.
Logopenic aphasia
ubiquitin and synuclein
What is the essential criteria for DLB diagnosis?
What are the 4 core clinical criteria for DLB?
What are the indicative biomarkers?
CRITERIA:
Probable DLB can be diagnosed if:
a. Two or more core clinical features of DLB are present, with or without the presence of
INDICATIVE biomarkers, or
b. Only one core clinical feature is present, but with one or more indicative biomarkers.
Probable DLB should not be diagnosed on the basis of biomarkers alone.
Supportive biomarkers include: Generalized low uptake on SPECT/PET perfusion/metabolism scan with reduced occipital
activity 6 the cingulate island sign on FDG-PET imaging.
ESSENTIAL CRITERIA: Progressive cognitive decline sufficient magnitude to interfere with normal social and occupational function
CLINICAL
1. Fluctuating cognition with pronounced variations in attention and alertness.
2. Recurrent visual hallucinations that are typically well formed and detailed.
3. REM sleep behavior disorder, which may precede cognitive decline.
4. One or more spontaneous cardinal features of parkinsonism: these are bradykinesia (defined as
slowness of movement and decrement in amplitude or speed), rest tremor, or rigidity.
BIOMARKERS
- Reduced dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET.
- Abnormal (low uptake) 123iodine-MIBG myocardial scintigraphy.
- Polysomnographic confirmation of REM sleep without atonia.
What drug reduces delusions, hallucinations and anxiety for lewy body dementia?
Rivastigmine
What is the triad of Huntington disease?
- Dominant inheritance
- Choreoathethosis
- Dementia
Identify which gene:
- Huntington
- Alzheimer’s disease
- Chromosome 4, CAG repeats
2. Chromosome 21
What is the critical number of CAG repeats before Huntington symptoms invariably manifest?
What number for a late onset mild form of the disease “senile chorea”?
More than 42
35-39
at 39 to 42 disease may not manifest if the person does not live long enough
T or F. In Huntington dementia, there is relative sparing of memory, aphasia, agnosia apraxia because it is a “subcortical dementia”.
T
Inability to manage household, diminished work performance, difficulty with concentration and assimilating new material
In huntington chorea, what comes first? cognitive impairmaent or movement disorder
How to distinguish from PD on the basis of blink rate?
Cognitive impairment
High blink rate in HD low in PD
What is the characteristic pathology of the brain of HD patients?
What is the Westphal variant of HD?
Atrophy of the head of the caudate and putamen + also of the frontal and temporal regions
Westphal– rigid variant with mostly parkinsonism sxs
Why does expansion the polyglutamine portion of huntingtin result in neuronal loss?
How long before HD patients become vegetative?
Makes the cells undult sensitive to glumate induced toxicity
10-15 years of symptoms
What drug can be used for huntington?
What are the finding sin neuroimaging of HD?
Dopamine antagonist, haloperidol
Gross bilateral atrophy of the caudate nucleus and putamen with diffusely enlarged ventricles
What is the usual blink rate?
Normal is 12-20
in parki it is less than normal 5-10
in huntington it is more than normal
What are the 2 common tremors of PD?
- 4 per second pill rolling tremor of the thumb, tremor in a position of repose
- 7-8 per second slighly irregular action tremor of the outstretched finger and hands that PERSISTS throughout voluntary movement and on outstretched fingers and hands NOT present in the resting position
What is the froment sign?
What are the 4 core features of Parkinson disease?
Rigidity is elicited by having the opposite hand engage in a motor activity that require concentration– like touching each finger to the thumb on the opposite limb
BRIT
Bradykinesia, Rigidity, Instability of Posture, Tremors
What is camptocormia?
What is kinesis paradoxica?
Extreme forward flexion of the spine and corresponding severe stooping occurs
Remarkably effective movement during unusual circumstances (danger) in usually bradykinetic and rigid PD patients
What is the myerson sign?
What is the average time before PD patients acquire dyskinesia from mediation use?
inability to inhibit blinking as a response to a tap over the bridge of the nose or glabella
3-5 years
What is the average time in PD from inception of the disease to a chairbound state?
7.5 years BUT THIS HAS A WIDE RANGE
10% remain mild or relatively only gradually progressive
In the ddx of PD what alternative diagnoses the ff symptoms suggest?
- Early falls and vertical gaze impairment
- Dysautonomia with fainting, bladder or vocal cord dysfunction
- Early and rapidly evolving dementia or intermittent psychosis
- Apraxia
- PSP
- MSA
- LBD
- Corticobasal ganglionic degeneration
- Early falls and vertical gaze impairment
- Dysautonomia with fainting, bladder or vocal cord dysfunction
- Early and rapidly evolving dementia or intermittent psychosis
- Apraxia
What is the typical clinical phenotype of vascular dementia patients?
“Lower half parkinsonsim” whereby predominant symptoms are shuffling gait, stickiness on turning and falling with little or no response to levodopa
How does essential tremor differ from PD?
- Disappears at rest present on movement
2. Faster
Besides the substantia nigra what other areas of the brain lose their pigmented nuclei?
Locus ceruleus and dorsal motor nucleus of the vagus
What are lewy bodies?
Eosinophilic cytoplasmic inclusions containing ubiquitin and synuclein found in all cases of idiopathic parkinson disease.
ALPHA SYNUCLEIN IS THE MAIN COMPONENT OF LEWY BODIES
According to Braak and Braak, where does the earliest change in the brain occur in PD?
- Dorsal glossopharyngeal-vagal nuclei
2. Anterior olfactory nuclei
What neurotoxin produces pyridinium MPP that binds to melanin in dopaminergic cells in enough concentration to initiate destruction of these cells
What is the % of familial occurrence with Parkinson Disease?
MPTP
1 methyl 1,4 phenyl 1,2,3,6 tetrahydropyridine
15%
What genetic defect
- Accounts for 50% of early onset inherited PD and 20% of sporadic early onset ones, AR
- 2 main mutations A53T and A30P promote oligomerization of alpha synuclein, AD (early onset as well)
- In ashkenazi jews protein is also called dadarin– aka LRRK2 protein, AD (late onset), 5-8% of familial PD
- Mitochondrial gene with AR inheritance
- Late onset dystonia parkinsonism unknown mode of inheritanec
- Park 2, parkin
- Park 1, SCNA alpha synuclein
- Park 8, LRRK2, leucine rich repeat kinase 2
- PINK1/ Park 6
- Park14 PLA2G6
What phenomena underlies dyskinesias in the treatment of PD with levodopa?
Denervation hypersensitivity of striatal target neurons
What are the 3 side effects of levodopa?
Nausea
Hypotension
Confusion
What does entacapone do to levodopa?
How about carbidopa?
COMT inhibitor that extends plasma half life and duration of levodopa effect by preventing its breakdown
Prevent peripheral decarboxylation of L-dopa to dopaine permitting a greater proportion of L-dopa to reach nigral neurons
What group of PD meds can be given early in the disease where tremor is the only manifestation?
Anticholinergics: Trihexyphenidyl and Benztropine
T or F: Patients give levodopa early in the disease survived longer and with less disability than those who began the medication late in the course
T
What antipsychotic may be used for levodopa induced psychosis?
Clozapine because of its additional benefit of suppressing dyskinesias in advanced PD
What diet may help control motor fluctuations in patients with PD and levodopa?
Low protein diet because amino acids compete for Levodopa absorption
What parts of the brain are stimulated with DBS for PD?
Subthalamic nucleus and Globus pallidus
What are the parts of the nervous system that degenerate in MSA
- Substantia Nigra, zona compacta
- Striatum
- Autonomic nervous system
- Cerebellum
CODE: SNAC
NO LEWY BODIES OR NF TANGLES
What are the 4 characteristics of MSA that distinguish it from idiopathic PD?
- Symmetry of signs
- Rapid course
- Lack of response to L-dopa
- Absence of minimal amount of tremor
- Early presence of autonomic disorders
Contrast with LBD that has tremor
What does the hot cross bun sign signify in MSA?
The high t2 signal intensity of the pontocerebellar fibers in an atrophic pons– SELECTIVE degeneration of the pontocerebellar tracts
T or F The presence of glial cytoplasmic inclusions that CONTAIN ALPHA SYNUCLEIN are specific to MSA.
F. Found in practically all degenerative diseases
What is the most common early complaint in patients with he Richardson Steele Olszewski syndrome?
Undsteadiness of gait and unexplained falling without LOC
T or F the bell phenomenon, doll’s eyes and convergence are eventually lost in PSP
T
What 3 characteristics of PSP distinguish it from PD?
- Tonic grimace (furrowed brow with a stare)
- Erect rather than stooped posture
- Prominence of oculomotor abnormalities
- LACK of tremor
ADD: Applause sign: The “applause sign” (a tendency
to initiate an automatic program of applause
when one is asked to initiate a voluntary program of
three claps) was described some years ago and regularly
observed in PSP
Contrast with LBD that has tremor
What areas of the brain have gliosis and loss of neurons in PSP?
- Periaqueductal gray matter
- Superior colliculus
- Subthalamic nucleus
- Red nucleus
- Pallidum
- Dentate nucleus
- Pretectal nuclei
- Vestibular nuclei
What is the histopathological hallmark of CBD?
Neuronal achromasia, ballooned and chromatolytic neurons with eccentric nuclei that stain for tau protein
PSP has NF tangles!!!! linking it to CBD and FTD
What treatments are avaliable for PSP
Levodopa SLIGHT AND UNSUSTAINED BENEFIT
Zolpidem for rigidity
Benztropine for dystonia
What is the earliest manifestation of CBD?
Asymmetrical clumsiness of the limbs with rigidity or tremor in 1/5– as the illness progressed almost all had asymmetric or unilateral akinetic rigid syndrome
What are the histopath changes in CBD?
What does imaging in CBD reveal?
Cortical atrophy in the frontal
motor-premotor area and anterior partietal lobes with assosicated degeneration of the SN– there is neuronal achromasia (ballooned and chromatolytic neurons with eccentric nuclei in the frontoparietal areas
Asymmetrical cerebral and pontine atrophy
What is the function and name of the mutated protein in Friedrich ataxia?
What is the inheritance?
Frataxin a mitochondrial matrix protein whose function is to prevent iron overloading in the mitochondria
AR: Chromosome 9q13-2
NB: GAA trinucleotide repeat is seen within a gene that codes for frataxin
What does the foot of someone with friedrich ataxia look like?
Hammertoes with pes cavus
What does the heart of of someone with friedrich ataxia look like?
hypertrophic with IRON REACTIVE GRANULES in the fibers
A tabetocerebellar gait is seen in? What is characterizes the gait?
Friedrich ataxia (spinocerebellar ataxias)
MIXED sensory and cerebellar type gait
T or F TENDON REFLEXES are ABOLISHED IN NEARLY EVERY CASE of Friedrich ataxia
T
BABINSKI IS POSITIVE
What is the imaging abnormality in FA and its corresponding histopathology?
The cord is thin– the corticospinal tracts degenerated beyond the medullocervical junction. Posterior columns and corticospinal tracts are deplete of myelinated fibers and thre is mild gliosis.
REDUCED dorsal root ganglia
SELDOM IS CEREBELLAR ATROPHY FOUND
Deficiency if what vitamin causes a spinocerebellar syndrome?
E
What medication modifies cereballar symptoms in FA?
5-hydroxytryptophan
What SCA is most common representing 25% of dmoinant ataxias manifesting as spasticity, neuropathy, and extrapyramidal features?
SCA 3 Machado-Joseph
Ataxin-3 AD Onset at teens
What are the top 3 SCA?
25% SCA 3 Machado Joseph
10-25% SCA 1 (ataxin 1, AD) with ophthalmoparesis, polyneuropathy and dementia
20% SCA 6 (CACNA1A alpha calcium channel, AD) dysarthria
What differentiates primary lateral sclerosis from amyotrophic lateral sclerosis?
When UMN signs predominate with LMN signs coming in late in the disease
What are the 4 cardinal features of ALS?
What is the singular genetic discovery in relation to ALS?
Atrophic weakness
Fasciculations
Slight spasticity
Hyperreflexia
ALL IN THE ABSENCE OF SENSORY CHANGE
Superoxide dismutase (SOD1)
T or F. Before diagnosing primary lateral sclerosis, there should be progression for 3 years without evidence of LMN dysfunction
T
How do motor units of ALS look like?
Enlarged
What are the mechanisms by which alpha synuclein accumulate in PD?
- alpha synuclein gene mutation or duplication that generate excessive alpha syuclein
- Parkin and UCH-L1 mutation that reduce the normal removal of the alpha synuclein via the ubiquitin proteosome system
The two systems result in excess alpha synculein that form fibrils and eventually lewy bodies that are cytotoxic to dopamine secreting cells in the SN
What is Parkin?
A ubiquitin protein ligase that participates int eh removal of unnecessary proteins from cells through the proteosomal system
What is also known as Segawa disease?
Dopa responsive dystonia
What PD drugs can cause cardiac valvular damage?
Pergolide and cabergoline
What PD symptoms respond least well to surgical lesioning?
Postural imbalance Paroxysmal akinesia Bladder and bowel disturbances Dystonia Speech
EVEN FOR DBS LITTLE IS IMPROVEMENT IS MADE IN GAIT AND BALANCE
What is the diagnostic criteria for MSA?
A sporadic, progressive, adult (>30 years of age)-onset disease characterized by:
Autonomic failure involving urinary incontinence (inability to control the release of urine from the bladder, with erectile dysfunction in males) or an orthostatic decrease of blood pressure within 3 min of standing by at least 30 mmHg systolic or 15 mmHg diastolic and
Poorly levodopa-responsive parkinsonism (bradykinesia with rigidity, tremor, or postural instability) or
A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction)
What characteristic vocal problems do MSA patients have?
Dysphonia or stridor
What percentage of patients with MSA will be wheel chair bound in 5 years?
4 years
What are the eye signs observed in PSP?
- Difficulty in voluntary vertical movement of eyes– often downwards but sometimes only upward progressing to impairment
- Hypometric saccades in response to OK drum
- Doll’s eye during fixation are STILL INTACT at the start but also lost eventually
- Saccadic choppiness of pursuit movements
- At the end both Bell’s and convergence are also lost
Also with furrowed brow due contraction of the procerus muscle
What are the main taupathies?
AD
FTD
CBD
PSP
What is the criteria for the CBD phenotypes: possible CBS, FBS, naPPA, PSPS?
Research Criteria: Insiduous onset and gradual progression 1 year duration >= 50 years old No family history (2 or more relatives) 1. Probably CBS 2. FBS or NAV plus at least 1 CBS feature No genetic mutation affecting tau
if Clinical criteria:
Possible CBS
naPPA
PSPS plus one CBS feature
Probable CBS, characterized by an asymmetric presentation and at least two of: a) limb rigidity or akinesia, b) limb dystonia, c) limb myoclonus,
plus two of: d) orobuccal or limb apraxia, e) cortical sensory deficit, f) alien limb phenomena (more than simple levitation)
Possible CBS is same but 2–>1
Frontal behavioral-spatial syndrome (FBS), characterized by two of: a) executive dysfunction, b) behavioral or personality changes, c) visuospatial deficits
Nonfluent/agrammatic variant of primary progressive aphasia (naPPA), characterized by effortful, agrammatic speech plus at least one of: a) impaired grammar/sentence comprehension with relatively preserved single word comprehension, or b) groping, distorted speech production (apraxia of speech)
Progressive supranuclear palsy syndrome (PSPS), characterized by three of: a) axial or symmetric limb rigidity or akinesia, b) postural instability or falls, c) urinary incontinence, d) behavioral changes, e) supranuclear vertical gaze palsy or decreased velocity of vertical saccades
What is the most common inherited dystonia and what protein is affected?
DYT 1, aka TOR1A on chromosome 9q, dystonia musculorum deformans, AD
Like other inherited dystonias starts in one limb then generalizes as opposed to sporadic dystonia that confines themselves to one region of the body only
T or F Segawa syndrome has NO symptoms of parkinsonism just dystonia.
F. Some have PD sxs as well– juvenile dysonia parkinsonism syndrome
Low dopamine levels due to defect in the synthesis of tetrahydrobiopterin a cofactor for tyrosine hydroxylase in the production of dopamine
For segawa sydrome
- Age of onset?
- Body part onset?
- Starting dose of levodopa?
- What activity makes the symptoms disappear or subside?
- When dose tolerance to levodopa set in?
- Age of onset? 4-8 years old
- Body part onset? Lower extremities– intermittent stiffening with frequent falls and posturing, equinovarus position
- Starting dose of levodopa? 10mg/kg/day
- What activity makes the symptoms disappear or subside? Sleep
- It doesn’t– no wearing off or dyskinesias
Pantothenate kinase-associated neurodegeneration (PKAN) is a type what group of diseases that cause extrapyramidal symptoms?
Pantothenate kinase-associated neurodegeneration (PKAN), also known as neurodegeneration with brain iron accumulation 1 (NBIA1), also called Hallervorden–Spatz syndrome
Which SCA?
- Neuropathy with ophthalmoparesis– SLOWED SACCADES, ataxin 2
- Olivopontocerebellar atrophy with retinal degeneration, hearing loss, ophthalmoplegia, spasticity and generational anticipation
- Slowly progressive sensory neuropathy and spasticity
- Machado joseph disease comprising 25% of dominant ataxias, gaze evoked nystagmus
- Slowed saccades
- Neuropathy with ophthalmoparesis– SLOWED SACCADES, ataxin 2: 2
- Olivopontocerebellar atrophy with retinal degeneration, hearing loss, ophthalmoplegia, spasticity and generational anticipation: 7
- Slowly progressive sensory neuropathy and spasticity: 8
- Machado joseph disease comprising 25% of dominant ataxias, gaze evoked nystagmus: 3
- Slowed saccades: 1,2,3,7
What is also known as the Azorean disease of the nervous system? Autosomal striatonigral degeneration causing ataxia,, dysmetric horizontal and vertical saccades, parkinsonsian syndrome with a cerebellar ataxia
Machado Joseph disease SCA 3
SCA 3 IS VERY SIMILAR TO MSA. What sets it apart?
Early age of onset, prominence of dystonia and ophthalmoplegia
In dentatorubropallidoluysian atrophy
- What are the 3 main sxs?
- What is the trinucleotide repeat and the protein that it codes for
- Inheritance pattern
- What are the 3 main sxs? Ataxia, Choreoathetosis and Dementia
- What is the trinucleotide repeat and the protein that it codes for? CAG Atrophin
- Inheritance pattern: AD
What can ameliorate paroxysmal ataxia from a mutation of the calcium channel in chromosome 19?
Oral acetazolamide
Another channelopathy caused by K channel on C12 IS NOT relived by acetazolamide
Which inherited ataxias have expanded CAG trinucleotide repeats?
SCA 1, 3, 6, 7, 12, 17
DRPLA
What % of ALS is familial?
10%
What countries have the ALS dementia parkinsonism syndrome?
Guam and Japan
What is the revised el escorial criteria for ALS?
Weakness, atrophy, hyperreflexia, spasticity, progression over time, EMG/NCV/ Biopsy/Neuropathology
LMN + UMN in 3 regions
Probable 2 regions
Possible 1 region
UMN and LMN not in the same region but present: Suspected
Caveat even if 1 region only with genetic testing confirming familial ALS we may diagnose
Regions are: Cranial, Cervical, Thoracic, Lumbosacral
Triad of ALS?
1 Atrophic weakness of hands and forearms
2 Fasciculations with spasticity of arms and legs
3 Hyperreflexia
NO SENSORY CHANGE
What is the Mills variant of ALS?
Hemiplegic variant
Cranial MRI in ALS can show?
Hyperintensities in the posterio limb of the IC on FLAIR, motor brainstem and SC. Atrophy of the motor cortex can also be seen
Which has a better prognosis? (Slower pace of development surviving 15 years of more) Progressive muscular atrophy or ALS or Primary lateral sclerosis?
PMA
Progressive and asymmetrical amyotrophy of the hand traced to ligamentous hypertrophy and buckling in the ventral spinal canal– compression of the cervical spinal cord gray matter causes a chronic ischemic effect.
What disease?
Hirayama disease
Nucleotide expansion in what gene is associated with 40% of the inherited forms of ALS?
C9orf72– causes mishandling of RNA binding proteins
Also associated with 4-8% of sporadic cases!
TARDBP
FUS
C9orf72
Are genes that are associated with what 2 neurodegenerative conditions?
ALS
FTD
In ALS, what has emerged from genetic studies is that the common feature is accumulation of _____ and _____ in neurons which leads to cell death.
FUS
TDP43
What kind of agent is riluzole and how can does it affect ALS outcomes?
Anti glutamate
Can extend life by 3 months
Counting to 25 corresponds to a vital capacity of how many liters?
2.5
Which genetic defect associated with ALS?
- ALS with FTD
- Prominent spasticity
- VERY slowly progressive with juvenile onset
- ALS with FTD FUS
- Prominent spasticity
CytoC - VERY slowly progressive with juvenile onset
ALS2 and SETX
ALS2 has prominent corticospinal signs
At what site do mutations affect the chromosome 5q11.2-13.3 gene to produces the SMA phenotype?
SMN site
Survival motor neuron site
Identify the type of SMA:
- Werdnig-Hoffman
- Dubowitz
- Kugelberg-Welander
- Onset after 30 years old
- Two copies of SMN2 gene
- 4 copies of smn 2 gene
- X-linked CAG repeat expansion in the AR gene
- Onset at 6-12 months
- Onset from 1 year to adolescence
- Werdnig-Hoffman: 1
- Dubowitz: 2
- Kugelberg-Welander: 3
- Onset after 30 years old: 4
- Two copies of SMN2 gene: 1
- 4 copies of smn 2 gene: 4
- X-linked CAG repeat expansion in the AR gene: Kennedy syndrome aka bulbospinal atrophy
- Onset at 6-12 months: 2
- Onset from 1 year to adolescence: 3
What allele of SMN is LOST in SMA?
SMN1
So it is the remaining copies of SMN2 which makes a truncated and partially functional form of SMN determines the severity of the disease
What are the histopathologic features of SMA?
- Denervation atrophy (group atrophy)
- Reduced nerve cells
- Degenerating cells: chromatolytic with cytoplasmic inclusions
- Replacement gliosis
2 3 4 apply to anterior horn cells and motor nuclei in the lower brainstem
What are the genetic hallmarks of Kennedy syndrome?
Defect is a CAG expansion in the gene that codes for the androgen receptor on the the X chromosome
What is AKA as Strumpell-Lorrain disease? Most common genetic defect?
Hereditary spastic paraplegia
40-50% from Spastin protein
What are the “added features” of these variants of hereditary spastic paraplegia?
- Ferguson
- Behr
- Kjellin
- Ferguson: Ataxia
- Behr: Optic atrophy
- Kjellin: Macular degeneration
Re: Leber optic neuropathy
- When does visual loss set in?
- What type of vision is lost first?
- When does visual loss set in? Between 18 to 25 years old
2. What type of vision is lost first? Central
Re: Retinitis pigmentosa
- What retinal layers are affected?
- What is the first symptom?
- What are the ophtha findings? TRIAD
- How is it different from Stargardt disease?
- What retinal layers are affected? ALL
- What is the first symptom? Nyctalopia
- What are the ophtha findings? TRIAD Pigments that look like bony corpuscles, Vascular attenuation, Optic pallor
- How is it different from Stargardt disease? S affects primarily cones while RP goes for the rods first– hence the nyctalopia
What protein aggregates in HD?
Huntingtin protein accumulating in the striatum
What are treatment options for HD?
Dopamine antagonists, Blockers of dopamine receptors, dopamine delpeleters
- Haloperidol
- Clozapine
- Reserpine
- Tetrabenazine
In the Pipeline: Ionis-HTTRx
Phase 1 study of the intrathecal drug lowers the levels of huntingtin protein
What do RBCs in acanthocytosis look like?
A rounded projection, as on the margin of a shell. The condition or state of being crenate. A process resulting from osmosis in which red blood cells, in a hypertonic solution, undergo shrinkage and acquire a notched or scalloped surface.
THORNY AND SPIKY RBCs
Besides chorea, mental retardation what neurophysiologic feature characterizes neuroacanthocytosis?
Decreased or absent tendon reflexes and evidence of chronic axonal neuropathy
What disease in Guam is a corticostriatospinal degeneration?
Guamanian PD Dementia ALS complex
