Chapter 28 part 5 Flashcards
1
Q
Atypical parkinsonism syndromes
A
- minimally responsive to L-DOPA
- distinguished from PD through presence of additional signs and symptoms
2
Q
PSP (progressive supranuclear palsy)–symptoms
onset? hallmark?
A
-taupathy
-trunkal rigidity, disequilibrium with frequent falls and difficulty with voluntary eye movements
-nuchal dystonia, pseudobulbar palsy, mild progressive dementia
-onset– 5th to 6th decade–males 2X
fatal–5-7 years of onset
-hallmark- presence of tau containing inclusions in neurons and glia
3
Q
CBD (corticobasal degeneration)- clinical
A
- progressive taupathy
- extrapyramidal rigidity, asymmetric motor disturbances (jerkings movments of limbs), impaired higher cortical function
- cognitive decline may occur later in illness
- same tau variant linked to PSP
- CBD- tau lesions more toward cerebral cortical involvement (In PSP- in brainstem and deep gray matter
4
Q
MSA (multiple system atrophy)- different from other degenerative diseases why?
A
-hallmark is observed in glial cells and degeneration of white matter tracts
5
Q
MSA (multiple system atrophy)– 3 distinct neuroanatomic circuits involved?
A
- striatonigral circuit (parkinsonism)
- olivopontocerebellar circuit (ataxia)
- autonomic NS (autonomic dysfunction–orthostatic hypotension)
6
Q
MSA pathogenesis
A
- alpha-synuclein is major component of inclusions
- sporadic disease
- glial cytoplasmic inclusions- primary pathologic event
- alpha-synuclein in onligodendrocytes–become more sensitive to oxidative stress
7
Q
MSA diagnosis
A
-glial cytoplasmic inclusions (in oligodendrocytes)- contain alpha synuclein
8
Q
HD (huntington disease)- characterized by?
A
- autosomal dominant
- progressive movement disorders and dementia caused by degeneration of strial neurons
- jerky, hyperkinetic, dystonic movements (chorea)
- later may develop bradykinesia and rigidity
- fatal in 15 years
9
Q
HD- prototype for?
A
-polyglutamine trinucleotide repeat expansion diseases
10
Q
gene for HD
A
- HTT-encodes huntingtin
- CAG repeat–encodes polyglutamine region
- normal HTT genes- 6-35 copies of CAG repeat
- if above 35 copies=disease
- longer repeats=earlier onset
- polyglutamine region expansion–toxic gain of function on huntingtin-protein aggregation and intranuclear inclusions containing huntingtin
- mutated huntingtin binds various transcriptional regulators
11
Q
pathologic hallmarks of HD
A
-intranuclear inclusions containing huntingtin
12
Q
HD morphology
A
atrophy of caudate nucleus, ventricular dilation
- profound loss of striatal neurons (esp in caudate nucleus)
- protein aggregates containing huntingtin in neurons
13
Q
HD clinical features caused by?
A
- loss of striatal neurons leads to dysregulation of basal ganglia circuitry that modulates motor output
- these neurons normally function to dampen motor activity; their degeneration results in increased motor output (choreoathetosis)
- 4-5 decade
14
Q
HD clinical features
A
- -movement disorder-choreiform, increased/involuntary jerky movements, writhing movements of extremities
- early symptoms of higher cortical dysfunction–forgetfulness and though disorders–progress to dementia
- intercurrent infection– most common cause of death
15
Q
spinocerebellar degenerations–clinical
A
-cerebellar and sensory ataxia, spasticity, sensorimotor peripheral neuropathy
16
Q
2 common autosomal recessive disorders characterized by spinocerebellar degeneration?
A
- friedreich ataxia
- ataxia telangiectasia
17
Q
SCA (spinocerebellar ataxia
A
- autosomal dominant
- neuronal loss and secondary degeneration of white matter tracts
18
Q
SCA (spinocerebellar ataxia) –3 mutations
A
- polyglutamine diseases–expansion of CAG repeat
- expansion of non-coding region repeats
- point mutations
19
Q
Friedreich Ataxia–characterized by? when?
A
- autosomal recessive
- progressive ataxia, spasticity, weakness, sensory neuropathy, cardiomyopathy!!
- 1st decade of life–gait ataxia, followed by hand clumsiness and dysarthria
- joint position and vibratory sense impaired
- sometimes loss of pain and temperature
- pes cavus, kyphoscoliosis
- wheelchair bound within 5 years of onset
- life expectancy- 40-50 age
- cardiomyopathy!!
20
Q
Friedreich Ataxia caused by?
A
- expansion of GAA trinucleotide repeat in a gene that encodes frataxin- found in mitochondrial inner membrane where its involved in assembly of iron-sulfur cluster enzymes of complex I and II
- reduced mitochondrial frataxin–decreased mitochondrial ox phos and increased free iron
- free iron- ox stress!
21
Q
Friedreich ataxia morphology
A
- spinal cord- loss of axons and gliosis in posterior columns, CSTs, spinocerebellar tracts
- degeneration of neurons in spinal cord, brainstem (CN7, 8, 9), cerebellum, motor cortex
22
Q
Ataxia telangiectasia characterized by?
A
- autosomal recessive
- ataxic-dyskinetic syndrome early in childhood, with development of telangiectasias in conjuctiva, and skin along with immunodeficiency
23
Q
Ataxia-Telangiectasia-gene?
A
-ATM (ataxia-telangiectasia mutated) gene–encodes a kinase- role in cellular response to double stranded DNA breaks
24
Q
Ataxia-Telangiectasia morphology
A
- loss of purkinje and granule cells- cerebellum
- degeneration of dorsal columns, spinocerebellat tracts, anterior horn cells, peripheral neuropathy
- amphicytes–enlargement of nucleus 2-5X
- LNs, thymus, gonads hypoplastic
25
Ataxia-Telangiectasia clinical features
- death in 2nd decade
- initial-recurrent sinopulmonary infections, unsteadiness in walking
- later- dysarthric speech, eye movement abnormalities
- many develop lymphoid neoplasms, especially T-cell leukemias
26
ALS--loss of?
- loss of UMNs in cerebral cortex
- loss of LMNs in spinal cord and brainstem
- results in denervation of muscles--produces weakness
- onset in 5th decade
- sporadic ALS moree common than familial
27
ALS genetics
- autosomal dominant
- 20% of cases--mutation in gene encoding SOD1
- mutated SOD1-gain of function misfolds/forms aggregations-cell injury
- aggregated SOD1 also in sporadic ALS
28
most common mutation that gives rise to ALS and FTLD
-expansion of a hexanucleotide repeat-C90rf72
29
ALS morphology
- anterior roots of spinal cord are thin--loss of LMN fibers
- reduction in anterior horn neurons throughout spinal cord, associated with reactive gliosis
- skeletal muscles innervated by degenerated LMNs--show neurogenic atrophy
- degeneration of corticospinal tracts
30
ALS--clinincal symptoms--early, later
- early--asymmetric weakness of hands, cramping, spasticity of arms/legs
- later- m strength and bulk diminish, fasciculations
31
progressive muscular atrophy
-LMN predominantly
32
primary lateral sclerosis
-UMN predominantly
33
progressive bulbar palsy (bulbar ALS)
- degeneration of lower brainstem cranial motor nuclei
| - deglutition, phonation abnormalities
34
spinal and bulbar muscular atrophy (kennedy disease) characherized by?
- X-linked polyglutamine repeat expansion disease
- distal limb amyotrophy and bulbar signs (atrophy, fasciculations of tongue, dysphagia)--degeneration of LMNs
- expanded repeat in androgen R--androgen insensitivity, gynecomastia, testicular atrophy, oligospermia
- intranuclear inclusions
35
SMA (spinal muscular atrophy)
- childhood--marked loss of LMNs--weakness
- most severe=SMA type 1
- later onset--SMA type III
- severity related to level of protein (SMN)
36
genetic metabolic disease--3 classifications
- neuronal storage diseases (autosomal recessive)--def in enzyme in catabolism of sphigolipids, mucopolysaccharides, or mucolipids
- leukodystrophies (autosomal recessive)--deficincy in enzymes in myelin synthesis or catabolism
- mitochondrial encephalomyopathies--ox phos
37
Neuronal storage diseases
- autosomal recessive
- Tay-sachs, Niemann- Pick diseases, mucopolysaccharidoses
- accumulation of substrate in neurons
38
Leukodystrophies--different from demylinating disease because?
- insidious, progressive loss of cerebral function
- younger ages
- associated with diffuse, symmetric changes on imaging
39
leukodystrophies--diseases
- Krabbe disease
- metachromatic leukodystrophy
- adrenoleukodystrophy
40
Krabbe disease--what is it?
- autosomal recessive
- deficiency of galactocerebroside-B galactosidase
- galactocerebroside shunted to galactosylsphinosine--toxic at elevated levels
41
Krabbe disease--clinincal symptoms
- rapidly progressive
- onset-ages 3-6 months; death by age 2
- loss of myelin and oligodendrocytes in the CNS and in peripheral nerves
- neurons and axons spared
42
Krabbe disease--diagnostic features
-aggregation of engorged macrophages (globoid cells) in the brain parenchyma and around blood vessels
43
metachromatic leukodystrophy--what is it?
- autosomal recessive
- deficiency of lysosomal enzyme arylsulfatase A (cleaves sulftate from sulfatides)
- enzyme deficiency--accumulation of sulfatides, especially cerebroside sulfate
- white matter injury, inhibiting differentiation of oligodendrocytes, proinflammatory response
44
metachromatic leukodystrophy-diagnosis
-urine-metachromasia--sulfatides shift the absorbance spectrum dye
45
adrenoleukodystrophy--what is it?
- x-linked recessive disease
- mutations in ABCD1 (ATP binding cassette transporter proteins)-involves in transport of molecules into peroxisomes
- inability to catabolize VLCFAs (very long chain FAs) within peroxisomes--results in VLCFAs in serum
- progressive loss of myelin in CNS and peripheral nerves, adrenal insufficiency
46
Pelizaeus--Merzbacher disease
mutations in genes that encode proteins required for myelin formation
47
alexander disease
-mutations in genes that encode proteins for GFAP (intermediate filament proteins)
48
vanishing white matter leukoencephalopathy
-mutations in genes that encod proteins required for subunits of translation initiation factor eIF2B
49
mitochondrial encephalomyopathies--characteristics, selectively target?
- present as m diseases
- heteroplasmy--cells have a mix of normal and abnormal mitochondria
- selectively target neurons, gray matter
- elevated tissue lactate levels
50
MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke like episodes)--characteristics, gene?
- recurrent episodes of acute neurologic dysfunction, cognitive changes, m weakness, lactic acidosis
- stroke-like episodes--reversible deficits (dont correspond to specific vascular areas)
- infarction areas
- altered expression of cytochrome c oxidase
- most common mutation--MTTL1 (mitochondrial tRNA-leucine)
51
MERRF (myoclonic epilepsy and ragged red fibers)
- maternally transmitted
- myoclonus, seizure disorder, myopathy
- myopathy--ragged red fibers
- ataxia--neuronal loss from cerebellar system
- mutations in tRNAs often
52
Leigh syndrome characterized by?
- disease of infancy
- lactic acidemia, arrest of psychomotor development, feeding problems, seizures, extraocular palsies, weakness with hypotonia
- death 1-2 years
- regions of destruction of brain tissue associated with spongiform appearance, proliferation of blood vessels
53
Thiamine deficiency causes
- Wernicke encephalopathy--acute appearance of psychotic symptoms and opthalmoplegia
- symptoms reversible if treated
54
korsakoff syndrome
- thiamine (B1) deficiency--can be due to gastric disorders
- disturbances of short term memory, confabulation (dosomedial nucleus of thalamus)
- chronic alcoholism
55
wernicke encephalopathy--morphology--early, later lesions
- foci of hemorrhage and necrosis in mamillary bodies and walls of 3/4 ventricles
- early--dilated capillaries--leaky hemorrhages
- later--macrophages, cystic space
56
vitamin B12 deficiency causes? symptoms?
- subacute combined degeneration of spinal cord--degeneration of asc and desc spinal tracts
- defect in myelin formation
- early-bilateral symmetrical numbness, tingling, ataxia in LE
- complete paraplegia may occur
- axons degenerate
57
Adrenoleukodystrophy--clinical
--young males, behavioral changes, adrenal insufficiency
