Degenerative Diseases Flashcards
what has been established re: inheritance in Alzheimer disease
familial occurrence <1 percent there is a dominant inheritance pattern with a high degree of penetrance and appearance of disease at a younger age
T/F Women in general are at slightly higher risk for AD
True p1064
major symptom in AD
gradual development of forgetfulness
Ribot law of memory
Remote memories are preserved and recent ones lost. this is only relatively true.
repetition of every spoken phrase
echolalia
in AD, most prominent finding visible on MRI
extreme atrophy of hippocampus p1067
Microspcopic findings in AD
widespread loss of nerve cells
Early: most pronounced in layer II of entorhinal cortex marked neuronal loss in hippocampus, affected also are parahippocampal gyri, subiculum
other parts affected: anterior nuclei of thalamus, septal nuclei, diagonal band of Broca, amygdala, brainstem parts of the monoaminergic systems
cholinergic neurons of nucleus basalis of Meynert (substantia innominata) and locus ceruleus are reduced in number cerebral cortex:
cell loss affects pyramidal neurons
astrocytic hypertrophy which is compensatory prominent in layers III and V
3 Microscopic changes that make AD distinct
- neurofibrillary tangles - presence within the nerve cell cytoplasm of thick, fiber-like strands of silver-staining material, also in the form of loops, coils or tangled masses
- neuritic plaques - spherical deposits of amorphous material scattered through the cerebral cortex and easily seen with Periodic acid-Schiff
the core of aggregates is amyloiud, surrounded by degenerating nerve terminals
- Granulovacuolar degeneration of neurons most evident in the pyramidal layer of hippocampus
a discrete cytoskeletal protein, made of B2 transferrin, that promotoes assembly of microtubules, stabilizes their structure, and participates in synaptic plasticity
Tau
Conditions wherein there is aggregation of Tau
Alzheimer Disease
PSP
FTD
Picks
CBD
It is believed that the cleavage of the amyloid precursor protein by the B and gamma secretase results in 40- and 42-amino-acid by products. Which of these two forms is toxic?
AB42
the ratio of AB42 to AB40 is critical to neuronal toxicity of amyloid
True or False
The ratio of AB42 to AB40 is increased in Down syndrome.
True
genes encoding for endosomal proteins which are also implicated in Alzheimer
presenilin 1 and 2
the presenilins interact or maybe a component of gamma secretase, the enzyme that produces the AB42 fragment
Mutations of the APP and presenilin genes explain a very small proportion of Alzheimer cases
protein product from an inadequate functioning progranulin gener, deposited in neurons and may play a substantial role in the severity of expression of AD
this protein has been implicated in the pathogenesis of FTD and motor neuron disease
TDP-43
True or False
Studies showed that the presence of cerebral infarctions, small or large, and nondescript ischemic white matter disease accelerates the deposition of amyloid and the development of neurofibrillary tangles in the brains of AD patients.
True
p1069
Neurotransmitter abnormality in AD
reduction in choline acetyltransferase (ChAT) and acetycholine in the hippocampus and neocortex
loss of cholinergic synthetic capacity was attributed to a reduction in the number of cells in the basal forebrain nuclei (mainly the nucleus basalis of Meynert) from which the majorportion of neocortical cholinergic terminals originate
50% reduction in ChAT activity has been found in caudate nucleus
Mutations and Modulating factors associated with AD
APP - amyloid precursor protein bound to neuronal membranes
presenilin 1 and 2 - endosomal proteins
ApoE - regulator of lipid metabolism that has an affinity for AB alzheimer plaques; presence of E4 is associated with tripling the risk of developing sporadic AD (not a mendelian trait but a susceptibility risk
TREM2 - TREM2 polymorphism causes inadequate phagocytic clearance of amyloid
UBQLN1 - ubiquilin1 - interacts with PS1 and PS2 and participates in proteasomal degrradation
Coronal MRI, EEG in AD shows
disproportionate atrophy of hippocampi and corresponding enlargement of temporal horns of lateral ventricles
EEG: mild diffuse slowing (late in the illness)
SPECT and PET scan in AD
diminished activity in the parietal association regions and the medial temporal lobes
ratio of AB42 to tau in CSF in Alzheimer
Low
medications for Alzheimer
donepezil - acetylcholinesterase inhibitor for mild to moderately affected patients
SE: nausea, vomiting, insomnia, incraesed confusion
Memantine - NMDA glutaminergic antagonist- for use in the late-stage AD
True or False
The combination of memantine and donepezil in moderately to severely affected patients offered modest benefit over either drug alone.
FALSE
NO BENEFIT
p1073
a variant of lobar atrophy presenting with behavioral changes - apathy, disinhibition, perseveration, poor judgment, limited ability for abstraction, loss of empathy, bizarre affect, eating disorders
Insight is impaired, some subjects become euphoric or display repetitive compulsive behaviors
MRI: disproportionate atrophy and hypofunction in the frontal lobes usually asymmetric
a proportion presents with parkinsonian features
many cases shows deposition of progranulin consisting of ubiquitin neuronal inclusion consisting of TDP-43
Behavioral Variant of FTLD
Types of Primary Progressive Aphasia
progressive nonfluent - initially speaks less and has word finding difficulty, language stucture is intact
semantic - difficulty naming items, people and words followed by verbal perseveration; difficulty in generating lists of words of a given category
logophenic - shares most aspects of nonfluent aphasia but the meaning of words is retained
variant of lobar degenertaion with progressive loss of the ability to understand and use visual information
-progressive and ultimately severe visuospatial difficulty with a relative preservation of memory
Prosopagnosia, achromatopsia, dyslexia
difficulty with depth perception, reaching for objects and an inordinate sensitivity to bright light
Posterior Cortical Atrophy
defined by diffuse involvement of cortical neurons with Lewy-body inclusions and by an absence or inconspicuous number of neurofibrillary tangles and amyloid plaques
aggregated a-synuclein
typical form: parkinsonian features, dementia and a tendency to episodic delirium, especially nocturnally, rapid eye movement (REM) sleep behavior disorder
Lewy-body dementia
Diffuse Lewy-body Disease
Diagnostic Criteria for Lewy-body Dementia
requires 2 of 3 of the following:
- parkinsonian syndrome (usually symmetric)
- fluctuations in behavior and cognition
- recurrent hallucinations
psychotic features in LBD
episodic confusion, hallucinations, paranoid delusions
True or False
In LBD, the parkinsonian features may respond favorably to L-Dopa but only for a limited time and sometimes at the expense of causing an agitated delirum or hallucinations, uncharacteristic of early PD.
True
p1075
medication for LBD helps reduce delusions, hallucination and anxiety
Rivastigmine, anticholinesterase inhibitor
distinguished by the triad: dominant inheritance, choreoathetosis, dementia
Huntington Disease
True or False
The length of the nucleotide repeats CAG in Huntington determines not only the presence of the disease but also the age of onset wherein longer repeat length is associated with an earlier appearance of signs.
True
p 1077
CAG codon codes for what amino acid
glutamine
rare alternative mutation for Huntington
termed HDL2 (huntington diseae like-2) is associated with what repeat expansion of what gene
CATCG
juntophilin-3-gene
True or False
The first symptoms to appear in half the cases of Huntington are alterations in personality.
true
p 1077
True or False
The dementia in Hutington Disease is described as subcortical dementia, that is, the elements of aphasia, apraxia, and agnosia are observed only rarely and meomry loss is not profound.
true
p1077
Huntington
The abnormality of movement is subtle at first and most evident in the leg.
False
evident in the hands and face
Slowness of movementof the fingers and hands, reduced rate of finger tapping, difficulty in performing a sequence of hand movements are early signs.
True or False
As in parkinsonism, the frequency of blinking in Huntington is decreased.
False
Blinking is increased!
p1077
and voluntary protrusion of the tongue, like other attempt at sustained posture is constantly interrupted by unwanted darting movements
In huntington, about how many years in which most patients deteriorate to a vegetative state
10-15 years of ymptoms
True or False
Suicidal rate in Huntington is high.
True
p1077
True or False
Huntington. The dementia is generally more severe in cases of early (15-40) onset and with correspondingly longer repeat lengths than in those of later onset (55-60).
True
p1077
Pathology in Huntington
gross atrophy of the bilateral caudate nuclei and putamen is characteristic
moderate degree of gyral atrophy in the frontal and temporal regions
PET findings in Huntington
low glucose metabolism in the caudate nuclei
which precedes the volumetric loss of tissue. The striatal degeneration begins in the medial part of the caudate nucleus and spreads, tending to spare the nucleus accumbens.
True or False
Huntington. The anterior parts of the putamen and caudate are more affected than the posterior parts.
True
p1078
in the cerebral cortex there is a slight neuronal loss in layers 3,5,6 with replacement gliosis
Anticipation is well described in huntington and is known to be attributable to increasing lengths of CAG repeat sequence. What is anticipation?
earlier onset of disease in successive generations
Huntington.
where does huntingtin protein accumulate
striatum and affected cortex
drugs that can occasionally cause chorea
amphetamines
cocaine
tricyclic antidepressants
lithium
isoniazid
linezolid
Treatment for huntington
haloperidol - dopamine antagonist - in dialy doses of 2-10mg
effective partially in suppressing movement disorder
other drugs that deplete dopamine or block dopamine receptors which suppress the chorea in huntington to some degree but their side effctes (drowsiness, akathisia, tardive dyskinesia) outweigh their desired effects
reserpine, clozapine, tetrabenazine
disease has been linked to chromosome 9q
there is mutation in gene encoding protein chorein - involved in cellular protein sorting and trafficking
atrophy and gliosis of caudate nuclei BUT NO NEURONAL LOSS
neuroacanthocytosis
2 categories
- defect in red cell lipid membrane (bassen-Kornzweig disease) and HARP hypobetalipoproteinemia, acanthocytosis, retinitis pigmentosa, pallidal degeneration
- second group that lacks lipid abnormality
disorder with acanthocytosis and gradual development of chorea in the middle to late life, degeneration of caudate and putamen
with myopathy (elevated CPK)
fewer facial tic and orofacial features
arise from mutations on the X-chromosome that encodes KX protein which binds to surface Kell antigens on red cells
diminished kell antigen expression on the red-cell surface
McLeod Disease
tetrad of hypo/bradykinesia, resting tremor, postural instability, rigidity
Parkinson Disease
True or False
Volitional movememt dampens the resting tremor momentarily.
True
p1083
True or False
Tremor in PD is aggravated by walking and excitement.
True
p1083
pill-rolling tremor frequency
4-per second
axial dystonia in PD
extreme forward flexion of the spine, severe stooping occurs
camptocormia
kinesis paradoxica
in PD, in the excitement of some unusual circumstance, e.g. escapinf from fire, the paient with all but advanced disease is capable of bried but remarkably effective movement
Myerson sign
inability to inhibit blinkingin response to a tap over the bridge of nose or glabella
dyskinesias after treatment with levodopa usually appears when?
3-5 years of treatmentwith levodopa
In parkinsons, how many fail to display the characteristic tremor? not responsive to L-dopa?
25% for tremor
10% do not respond to L-dopa
most constant and pertinent finding in idiopathic and postencephalitic PD
loss of pigmented cells in substantia nigra and other pigmented nuclei (locus ceruleus, dorsal motor nucleus of the vagus
Rate limiting enzyme for the synthesis of dopamine
Tyrosine hydroxylase
True or False
PD. The earliest changes in the brain occur in the dorsal glossopharyngeal-vagal and anterior olfactory nuclei.
True
p1086
neurotoxin which produces irreversible signs of parkinsonism and selective destruction of cells in the subtantia nigra
analogue of meperidine
MPTP
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine transformed by monoamine oxidase to a toxic metabolite pyridinium MPP
what protein/PARK gene accounts for 50% of earl-onset inherited PD, 20% of sporadic early-onset cases,
Autosomal recessive
PARK 2/parkin
what protein/PARK gene resembles idiopathic PD
late onset, autosomal dominant
PARK 3
what protein/PARK gene accounts for those seen in Ashkenazic Jews, protein also called dardarin, related to Gaucher disease
Autosomal dominant, late onset
Park8/ LRRK2
leucine rich repeat kinase 2
the main component of Lewy bodies in both the sporadic and inherited forms of PD
a-synuclein
CT scan and MRI finding in CBD
asymmetrical cerebral and pontine atrophy
Elderly patients in whom the essential abnormality was a progressive asymmetrical extrapyramidal rigidity combined with signs of corticospinal disease with the ffg postmortem findings: cortical atrophy (mainly in the frontal motor-premotor, anterior parietal lobes) was associated with degeneration of the substantia nigra, and in one instance, of the dentatorubrothalamic fibers
Corticobasal degeneration
Group of disorders characterized by neuronal degeneration mainly in the substantia nigra, striatum, autonomic nervous system, and cerebellum
multiple system atrophy
orthostatic hypotension in Multiple System Atrophy has been attributed to
loss of intermediolateral horn cells and pigmented nuclei of brainstem
other autonomic changes aside from orthostatic hypotension
erectile dysfunction, loss of sweating, dry mouth, miosis, urinary retention, incontinence
MRI finding in MSA
hot cross bun sign - reflects atrophy of the pontocerebellar fibers that manifest high T2 signal intensity in an atrophic pons
other findings: atrophied cerebellum and pons
Hypointense putamen, may have increased deposition of iron in the parkinsonian form
CT and MRI: atrophy of cerebellum and pons in those with cerebellar features
Pathology in MSA
Abnormal staining material in the cytoplasm of astrocytes and oligodendrocytes and in some neurons call Glial cytoplasmic inclusions they contain a-synuclein
prototype of all forms of progressive spinocerebellar ataxias
autosomal recessive, mutation is in the expansion of a GAA trinucleotide repeat with a gene that codes for the protein frataxin
- reduction in the levels of frataxin and loss of its function
features: ataxia of gait, hands become clumsy years after gait disorder, half of patients have cradiomyopathy (myocardial fibers are hypertrophic, contain iron-reactive granules, some die of CHF or arrhythmia), 10% have DM, gait abnormality is mized sensory and cerebellar, (+) Romberg sign, horizontal nystagmus may be present
Friedreich Ataxia
Pathology in Friedreich Ataxia
- spinal cord is thin
- posterior columns and CST, spinocerebellar tracts are all depleted of myelin fibers
- mild gliosis
- nerve cells in the Clarke column, large neurons of the dorsal root ganglia esecially at the LS area are reduced in number
- nuclei of cranial nerves VIII, X, XII all exhibit reduction of cells
- moderate neuronal loss is seen also in the dentate nuclei, middle and superior cerebellar peduncles
- some depletion of Purkinje cells in the superior vermis, inferior olivary nuclei
- myocardial muscle fibers degenerate
SCA3
- Machado-Joseph
- ATXN3 ataxin-3
- age of onset: teens
- 25% of dominant ataxias, spasticity, neuropathy, extrapyramidal symptoms
Dentatorubropallidoluysian atrophy (DRPLA)
- onset: childhood
- gene ATN1
- protein: atrophin1
- presents with chorea, dystonia, seziures, dementia
- a special form of hereditary ataxia with brainstem and extrapyramidal signs
- autosomal dominant
- slowly progressive ataxia beginning in adolescence and early adult life
- hyperreflexia, extrapyramidal features (rigidity and slowness), dystonia, bulbar signs, distal motor weakness, opthlamoplegia
- no impairment of intellect
SCA3
Machado-Joseph-Azorean Disease
Pathologic findings in SCA3
Machado-Joseph-Azorean Disease
degeneration of dentate nuclei, spinocerebellar tracts, loss of anterior horn cells and neurons of the pons, substantia nigra, and oculomotor nuclei
- rare familial disorder, described mostly in Japan and some in Europe
- cerebellar ataxia, choreoathetosis and dystonia
- parkinsonisms, myoclonus, epilepsy or dementia
- gene defect: unstable CAG repeat gene that codes for atrophin
- autosomal dominant
- anticipation
Dentatorubropallidoluysian atrophy (DRPLA)
The earliest manifestation of the lower motor neuron component of ALS is sometimes
volitional cramping
Prognosis in ALS
half the patients succumb within 3 years of onset
90 percent within 6 years
- lower motor neuron syndrome
- more common in men
- tends to progress at a lower pace, about 15 yrs or longer
- younger patients had a more benign course
- mutation in SOD1 gene
- wasting of muscles, fascicular twitchings and crampings, tendon reflexes are diminished or absent
Progressive Muscular Atrophy
- first and dominant symptoms relate to weakness and laxity of muscles innervated by the motor nuclei of the lower brainstem
- defective modulation
- mastication and deglutition become impaired
- jaw jerk may be exaggerated
- pseudobulbar signs (pathologic laughing and crying)
- progressive course
- patient may die 2-3 years after onset from inanition and aspiration pneumonia
Progressive Bulbar Palsy
- With certainty: on average, the appearance of e4 allele acceerates the appearance of AD by about ____ years
*
5 years
- the product of inadequate functionning of progranulin gene
- deposited in neurons and may play a substantial role in teh severity of expression of AD
- this protein has been implicated the pathogenesis of frontotemporal dementia and motor neuron disease
TDP-43
major symptom in AD
gradual development of forgetfulness
T/F
Alzheimer.
Occasionally, widespread myoclonic jerks or mild choreoathetotic movements are observed late in the illness.
True
p1065
T/F
In Huntington Disease, memory is relatively spared.
True
p1077
Alzheimer
Neuronal lass in the hippocampus specifically in
layer II of entorhinal cortes
in Alzheimer:
astrocytic hypertrophy is an evidence of compensatory or reparative process most prominent in which layers
Layers III and V
T/F
Neuritic plaques and neurofibrillary changes are found in all the association areas of the cerebral cortex.
True
p 1067
Correlate best with the severity of dementia
Neurofibrillary tangles and quantitative neuronal loss
p1067
define “subcortical dementia” as described in Huntington
elements of aphasia, apraxia, and agnosia are observed only rarely and memory loss is not profound
T/F
in AD, PSP, FTD
tau is hyperphosphorylated and aggregates resultign in PAIRED HELICAL FILAMENTS that makeup the neurofibrillary tangles
True
p1068
T/F
AD
Elevation of the levels of B42 leads to aggregation of amyloid and then to neuronal toxicity.
True
p 1068
T/F
Huntington.
once the movement disorder is fully established, there is nearly always some degree of cognitive abnormality.
True
p 1077
APP or amyloid precursor protein is located in chromosome
chrom 21
T/F
low suicide rate in Huntington
False
High suicide rate
p1077
T/F
In the westphal variant of Huntington, functional decline is much faster in children than it is in adults.
True
p 1077
Loss of cholinergic capacity in AD was attributed to
a reduction in number of cells in the basal forebrain nuclei (mainly the nucleus basalis of Meynert)
from which the major portion of neocortical cholinergic terminals originate
presenilin genes 1 and 2 are located in chromosome
chrom 14 and 1, respectively
T/F
Huntington
Dementia is severe in cases of early onset and with correspondingly longer repeath lengths.
True
p1077
T/F
Alzheimer
Possession of the e4 allele correlates with increased deposition of AB protein in the brain.
True
p1070
The presence of e4 allele accelerated the appearance of Alzheimer disease by about ____ years.
5 years
Mutations and Modulating factors associated with Alzheimer
APP
Presenilin 1 nd 2
UBQLN1
TREM2
ApoE
T/F
A form of motor neuron disease is also linked to frontotemporal dementia in a small number of cases.
true
p1074
huntington gene is localized in chromosome
chromosome 4
T/F
The pathologic change in lobar atrophy is circumcscribed and often asymmetrical. The parietal lobes are involved less frequently than the frontal and temporal lobes.
True
p1073
T/F
Huntington
In adult patients with early onset, the chorea and intellectual loss tend to be more prominent initially.
In the patients with older age of onset, the emotional disturbance is more often the initial complaint.
False
early onset: emotional disturbance precedes chorea
older oage of onset: chorea is more prominent initially
T/F
In Huntington, levodopa and other dopamin agonists may improve chorea.
False
p1079
LD and other dopa agonists make the chorea worse, and in the rigid form of the disease, evoke chorea.
Drugs that deplete dopamin or block dopamine receptors - clozapine, reserpine, tetrabenazine suppress the chorea to some degree, but their side effects usually outweigh their desired effects. (drowsiness, akathisia, tardive dyskinesia)
T/F
PD
The 4-per-second “pill-rolling” tremor of the thumb and fingers, although most characteristic, is seen in only about half the patients.
True
p1082
indicate the gene/protein and notation:
Two main mutations A53T, A30P
promote oligomerization of a-synuclein
Park1 and 4
SCNA (a-synuclein)
indicate the gene/protein and notation:
Accounts for 50% of early-onset inherited PD; 20% of sporadic early onset cases
Park 2
parkin
indicate the gene/protein and notation:
rese,bles idiopathic PD
Park3
indicate the gene/protein and notation:
PD
mitochondrial gene
PINK1
PTEN-induced putative kinase 1
indicate the gene/protein and notation:
gene is implicated in the formation and identity of dopaminergic neurons
NR4A2
NURR1
nuclear-receptor related protein 1
PD
Dopamine Agonists
Ropinirole
Pramipexole
PD
Glutamate antagonist
Amantadine
PD
Anticholinergics
Benztropine
Trihexyphenidyl
COMT inhibitors
Entacapone
MAO-inhibitors
Rasagiline
Selegiline
Symptoms in PD that responded least well to surgical therapy
postural imbalance and instability
aproxysmal akinesia
bladder and bowek disturbances
dystonia and speech difficulties
T/F
in PD
The anticholinergic drugs have limited effect on postural, hypokinetic, and other manifestations of diseas.
True
p1092
DBS in Parkinson disease
the electrodes are placed in:
posterior and ventral (medial) parts of the subthalamic nucleus
OR
internal segment of gobus pallidus
PET findings in MSA
impairment of glucose metabolism in striatum and to a lesser extent in the frontal cortex
due to loss of functioning neuronal elements in the said parts
onset 6th decade
combination of difficulty of balance, abrupt falls, visual and ocular disturbances, slurred speech, dysphagia and sometimes vague changes in personality, apprehensiveniess, fretfulness,
difficulty in voluntary verticla movement of the eyes, often downward but sometimes only upward, and later impairment of voluntary saccades in all directions
Progressive Supranuclear Palsy
in PSP
most common early complaint
unsteadiness of gait and unexplained falling without loss of consciousness
other degenerative conditions that can manifest with a supranuclear vertical gaze disorder although never to the extent in PSP
CBD
LBD
PD
whipple disease
MRI findings in PSP
atrophy of the dorsal mesencephalon
(superior colliculi, red nuclei)
giving rise to “mouse ears” configuration
pathology in PSP
Postmortem examinations have disclosed a bilateral loss of neurons and gliosis in the periaqueductal gray matter, superior colliculus, subthalamic nucleus, red nucleus, pallidurn, dentate nucleus, and pretectal and vestibular nuclei, and to some extent in the oculomotor nucleus
this drug has been reported to ameliorate the akinesia and rigidity of PSP
zolpidem
described mostly in Japan
symptoms of cerebellar ataxia coupled with choreoathetosis, dystonia, parkinsonism, myoclonus, dementia
unstable CAG repeat in the gene that codes for atrophin
Machado-Joseph-Azorean Disease
The most common early symptom was an asymmetrical clumsiness of the limbs, in half of the patients, with rigidity and, in one-fifth, with tremor
asymmetric or unilateral akinetic-rigid syndrome, which may be considered the essential motor disorder of this disease and various forms of gait disorder and dysarthria
cannot effectively direct their voluntary actions. Attempts to move a limb to accomplish some purposeful act might result in a totally inappropriate movement, always with great enhancement of rigidity in the limb and in other affected parts, or the limb may drift off and assume an odd posture, such as a persistent elevation of the arm without the patient’s awareness-a kind of catalepsy
“alien hand”
Corticobasal degeneration
pathology in CBD
cortical atrophy - mainly frontal motor-premotor and anterior parietal lobes
degeneration of substantia nigra
dentatorubrothalamic fibers
CT and MRI in CBD
cerebral and pontine atrophy
gene that codes for torsine A which is found in most cases of dystonia musculorum deformans
DYT1
T/F
in Torsion Dystonia
recumbency initially relieves the spasms but later on position has no influence.
True
p1100
dystonia that is responsive to L-dopa
found a linkage to the gene on chromosome 14q for the protein GTP cyclohydrolase 1 (GCH1 gene) that is implicated in the synthesis of tetrahydrobiopterin, a cofactor for tyrosine hydroxylase
mutation impairs the generation of dopamine
no cell loss in substantia nigra
A remarkable feature is the disappearance or marked subsidence of the symptoms after a period of sleep and worsening as the day progresses.
Hereditary Dystonia-Parkinsonism
(Segawa syndrome, Juvenile Dopa-Responsive Dystonia)
men are affected twice as often as women
pts older than 45 at onset of symptoms
weakness in a distal part of one limb
unexplained tripping from slight foot-drop, awkwardness in tasks reuiring fine finger movements
stiffness of the fingers
slight weakness or wasting of hand muscles on one side
cramping beyond what is natural, fasciculations of muscles of the upper arm, shoulder girdle
atrophic weakness, fasciculations, slight spasticity of arms and legs, generalized hyperreflexia
ALS
GAA trinucleotide repeat in Friedreich ataxia codes for what protein
frataxin
mutation is a missense, reduction in levels of frataxin and loss of its function
nearly always the initial symptom in Friedreich ataxia
ataxia of gait
T/F
Tendon reflexes are abolished in almost all cases of Friedreich ataxia.
True
p1104
may be obtainable when the patient is examined early in teh illness
Plantar reflexes are extensor and flexor spasms may occur even with complete absence of tendon reflexes.
Diagnostic tests in Friedreich ataxia
NCV
ECG/Echo
CT/MR
CSF
genetic testing
sensory nerve conduction velocities and amplitudes - normal because peripheral neuropathy is not a component
ECG/Echo - heart block and ventricular hypertrophy
CT and MRI - seldom reveal a significant degree of cerebellar atrophy but the spinal cord is small
CSF and blood - no consistent abnormality
genetic testing for the length of GAA is available
first and dominant manifestations of motor neuron disease may be
spastic weakness of legs
friedreich ataxia
serum may be submitted for an assay of which vitamin?
deficiency of a certain vitamin transport protein can cause a similar spinocerebellar syndrome
vitamin E
- progressive, degenerative disease of upper motor neurons characterized by progressive spasticity
- 5th or 6th decade
- stiffness of one leg then in the other
- slowing of gait with spasticity predominating over weakness
- over the years finger movements become slower, arms become more spastic
- no sensory symptoms or signs
- half the patients acquire spasticity of the bladdder
- diagnostic criterion: progression for 3 years without evidence of LMN dysfunction
Primary Lateral Sclerosis
Laboratory Features of Motor Neuron Disease
EMG
CSF
Motor Evoked Potentials
MRI
- EMG - widespread fibrillations (evidence of activer denervation) and fasciculations and enlarged motor units (denoting reinnervation)
- motor nerve conduction studies reveal only slight slowing
- WITHOUT FOCAL motor conduction block
- SNAPs are normal
- CSF protein usually normal or marginally elevated
- motor evoked potentials are prolonged
- slight atrophy of the motor cortices
pathology: principal finding in ALS
loss of nerve cells in the anterior horn cells in the Spinal Cord and motor nuclei of the brainstem
Large alpha motor neurons tend to be affected before small ones
slight gliosis and proliferation of microglia cells
noted a finding of a cytoplasmic inclusion in ALS
most studies indicate that these are made up of
TDP-43 and ubiquitin
most frequent form og spinal muscular atrophies, the severe infantile type
occur once in every 20,000 live births
Werdnig-Hofmman SMA type I
Spinal Muscular Atrophy
genetic aspects
- autosomal recessive
- mutations affect the gene at the “survival of motor neuron”
function of SMN gene
how does the presence/absence correlate with the severity of the disease in SMA?
- SMN protein participates in forming protein-RNA complexes (small nuclear ribonucleoproteins and RNA) that are essential for gene splicing
- 2 alleles in SMN locus
- SMN1 - generates a full-length fully functional form of SMN
- SMN2 - tuncated partially functional SMN
latter can partially compensate for loss of SMN1
disease due to loss of both copies of SMN1 causes very severe SMA in individuals who carry only one copy of SMN2 while those with multiple copies of SMN 2 have milder disease
Characteristics of SMA type I
Werdnig-Hoffman Disease
- at birth, weakn and limp, floppy
- fetal movement in utero are less than expected
- arthrogryposis at the ankles and wrists or dislocation of the hips
- muscle weakness in these children is generalized form the beginning, death comes early usually in the first yr
- hypotonic
- tendon reflexes unobtainable
- respiratory movements become paradoxical - abdominal protrusion, chest retraction
- legs in “frog position”
EMG findings in SMA type I
- fibrillations - denervation process
- MUP are diminished in number, some are larger than normal (giant or polyphasic potentisls reflecting reinnervation)
- Motor nerve conduction velocities are normal or fall in the low normal range
- age of onset 1 yera to adolescence
- weakness and atrophy of the pelvic girdle and proximal leg muscles, followed by involvement of the shoulder girdle and upper arm muscles
- Bulbar musculature and corticospinal tracts are spared
Chronic Childhood and Juvenila Proximal Spinal Muscular Atrophy
Wohlfart-Kugelberg-Welander Syndrome
Type of SMA s
Number of SMNs
Age of onset
- SMA I - infantile, Werdnig-Hoffman, auotosomal recessive, Two copies of SMN2, preterm to 6 months
- SMA II - intermediate type, Dubowitz Disease, autosomal recessive, at least 3 copies of SMN2, 6-16 months
- SMA III - Wohlfart-Kugelber-Welander, AR, or dominants, at least 3 copies of SMN2, 1 year to adolescence
- SMA IV - AR, at least 4 copies of SMN2, after age 3
- distal muscualr atrophy with prominent bulbar signs
- onset: childhood to adult age
- symptoms on 3rd decade
- X-linked pattern
- dysarthria, dysphagia
- tendon reflexes become depressed
- 2/3 gynecomastia, oligospermia, diabetes
- Ck is leevated
- genetic defect: CAG expansion, that codes for androgen receptor on the X-chromosome
Kennedy syndrome
X-linked Bulbospinal Muscular Atrophy
- progressive paralysis of the facial, lingual, pharyngeal, laryngeal and sometimes ocular muscle
- stridor and respiratory symptoms, followed by facial diplegia, dysarthria, dysphagia, and dysphonia
- mutation in SLC52A3, a riboflavin trasnporter, and some beneficial effect is derived from administration of riboflavin (vitamin B2)
Progressive Bulbar Palsy of Childhood
(Fazio-Londe Syndrome)
