Pathophysiology of nervous system II:
Control of motor function and its disorders – part 2
Role of basal ganglia and cerebellum (extrapyramidal system) in the control of movement
Disorders of BG (incl. Parkinson's and Huntington's diseases as examples)
Disorders of cerebellum
Neuromuscular junction and its disorders (myasthenia syndromes)
Muscle diseases (muscular dystrophy)
Functional Segregation and Hierarchical Organization
• (1) Functional Segregation
• motor system is divided into a number of
different areas throughout the nervous
system that control different aspects of
movement (a “divide and conquer” strategy)
• understanding of the functional roles played by
each area is necessary for understanding various
motor disorders
• (2) Hierarchical Organization
• higher-order areas can concern themselves
with more global tasks regarding action, such
as deciding when to act, devising an
appropriate sequence of actions, and
coordinating the activity of many limbs
• i.e. „go“ signal
• they do not have to concern the activity of
individual muscles, or coordinate movements
with changes in posture
• these low-level tasks are performed by the lower
levels of the hierarchy
• i.e. micro-management of movement
final
common
path
Disorders of muscle tone and movement
• paralysis (UMND or LMND)
• incl. spasticity or flaccidity
• basal ganglia and cerebellum disorders (i.e.
extrapyramidal system)
• incl. rigidity and abnormal movements
• abnormal electric activity of the brain
• epilepsy
• disorders of neuromuscular junction
• skeletal muscle disorders
• muscle atrophy
• muscle dystrophy
Anatomy and physiology of the NS in the BG context
• peripheral nervous system
• spinal and cranial nerves
• central nervous system
• spinal cord
• receives and processes sensory information from skin, joints,
and muscles (dorsal horns)
• passes motor commands on to the muscles (ventral horns)
• brain
• brainstem (hindbrain)
• medulla oblongata
• digestion, breathing, heart-beat
• pons
• passes information about movements from the
cerebrum and the cerebellum
• midbrain
• controls many sensory and motor functions, e.g. eye
movements, and the coordination of visual and acoustic
reflexes
• reticular formation
• runs along the whole brainstem, and contains the
summary of all incoming information
• cerebellum
• controls force and movements, and is involved in motor learning
• forebrain
• diencephalon
• thalamus - processing most incoming (sensory)
information, on its way to the cerebrum
• hypothalamus - regulates the autonomous system,
controls the glands
• cerebral hemispheres (telencephalon) incl. BG
Anatomy of BG (should be basal nuclei in fact) and thalamus
Divisions of BG (should be basal nuclei in fact)
Divisions of BG (should be basal nuclei in fact)
• forebrain
• telencephalon
• striatum
• caudate nucleus
• putamen
• n. accumbens = ventral striatum
• pallidum
• globus pallidus - internal segment (GPi)
• globus pallidus - external segment (Gpe)
• diencephalon
• subthalamic nucleus
• midbrain = mesencephalon
• substantia nigra
• pars compacta
• pars reticularis
How are BG integrated into the control of movement - why we need them?
• We can perform many various movements with our
limbs and facial musculature and certain motoric plan
can be executed by multiple ways
• but for given situation (plus experience, context, …) only
one might be appropriate
• we are choosing best one with the help of BG
• How does the BG receive information above the
desired/planned movement?
• be widespread connections with cerebral cortex
• How does the BG output influence the movement?
• via motoric thalamus
• BG execute an inhibitory control over the motoric thalamus
• this keeps our movement under the check
• temporary removal of the inhibition (= disinhibition) allows to
perform optimal movement and not all sorts of unwanted and
competing movements
• Therefore, BG operate in the circuit of cerebral
cortex  BG (multiple processing)  thalamus 
cerebral cortex
• there are also outputs to brainstem
BG functions – still quite a lot of hypotheses to prove
• (A) motor functions
• voluntary movements are not initiated in the BG (they are
initiated in the cortex); however, proper functioning of the
BG appears to be necessary in order for the motor cortex to
relay the appropriate motor commands to the lower levels of
the hierarchy
• control of cortical activity
• selection form learned and stereotypical movements (motor
programmes)
• movement coordination, precision, appropriateness and
smoothness
• influence on and the modulation of the activity of motor
cortex and the descending motor pathways in ways that
cause distinct symptoms when different BG structures are
damaged
• disorders of BG comprise motor disturbances, not paralysis!
• tremor
• involuntary movements
• changes of muscle tone
• slowness/too high velocity of movement
• BG are heavily inter-connected with cortical structures and
brainstem
• see further
BG process several parallel cortico-basal ganglia-thalamocortical
loops (CBGTC loops)
• clinical relevance to
• motor disorders
• hyperkinetic – hypo-dystonic
movement disorders
• such as Huntington's
disease
• hypo-/akinetic – hypertonic
movement disorders
• such as Parkinson's disease
• mental disorders
• of control
• such as attention deficit
hyperactivity disorder
(ADHD)
• obsessive–compulsive
disorder (OCD)
• Tourette syndrome
• addictions
Dale Purves et al. (eds.) – Neuroscience 6th e (2018)
BG functions – still quite a lot of hypotheses to prove
• BGs are involved in cognitive functions
• there are a number of cortical loops
through the BG that involve prefrontal
association cortex and limbic cortex
• the loops comprise the motor,
associative, and limbic domains, which
respectively transit through the
posterior, anterior, and ventral striatum,
thus segregated functionally and
anatomically
• BG are involved in selecting and enabling
various cognitive, executive, or
emotional programs that are stored in
these other cortical areas
• BG appear to be involved in certain types
of learning
• BG may have a major role in learning
what motor acts result in rewards for
the organism
• enhance the firing of cortical motor
programs that produce rewarding
outcomes
• connections with the limbic system and
other structures
BG loops controlling body movements
• BG select/modulate motor programs
stored in the motor cortex
• BG and motor cortex form a processing loop
whereby the basal ganglia enables initiation
of the proper motor program stored in
motor cortex circuits via the direct pathway
and inhibits competing motor programs via
the indirect pathway
• The proper motor programs are selected
based on the desired motor output
relayed from cortex
Thalamus
• an ovoid, paired grey matter
structure found in the centre of the
brain, just superior to the brainstem
• each side of the thalamus contains
six groups of nuclei
• anterior nuclei
• lateral nuclei
• medial nuclei
• intralaminar nuclei
• paraventricular (midline) nuclei
• reticular nucleus
• The thalamic nuclei relay and
modulate information incoming
from the periphery to the cerebral
cortex.
• almost all ascending neural pathways
synapse within a thalamic nucleus,
where the information is sorted,
integrated, and analysed before sent
further to the cerebral cortex
• This fact makes the thalamus a socalled
“gateway” to the cerebral
cortex for limbic, motor, and all
sensory modalities besides olfaction,
including vision, hearing, taste, and
somatic sensation
Thalamus – „motoric “ nuclei related to movement
Summary of levels (5-6): Control of voluntary movement
• Commands for voluntary movement originate in cortical association areas
• The cortex, basal ganglia, and cerebellum work cooperatively to plan and optimise movements
• Movement executed by the cortex is relayed via the corticospinal tracts and corticobulbar tracts to spinal motor
neurons
• The cerebellum provides feedback to adjust and smoothen the movement
Thalamus
Direct pathway through BG and disinhibition of thalamus
- GPi has a tonic (= permanent) inhibitory effect on
thalamus and therefore cerebral cortex
- should we move, this inhibitory effect has to
transiently removed (inhibited)
- positive feed-back
- 2nd and 3rd neurons/ connections are inhibitory,
therefore inhibition of inhibition (= disinhibition)
causes excitation
Direct () vs. indirect () pathways through BG
- GPi has a tonic (permanent) inhibitory effect on
thalamus and therefore cerebral cortex
- should we move, this inhibitory effect has to
transiently removed
- positive feed-back
- 2nd and 3rd neurons/ connections are inhibitory,
therefore inhibition of inhibition (= disinhibition)
causes excitation
- reinforcement of tonic inhibitory effect of GPi on thalamus and
therefore cerebral cortex
- negative feed-back
- the subthalamic nucleus receives an inhibitory input from GPe,
and in turn the subthalamic nucleus has an excitatory
(glutamate) projection to both GPe and GPi
The critical role of dopamine in the activity of BG
• These two pathways have opposite net effects on thalamic target structures
• how come we ever move?
• the normal functioning of the basal ganglia apparently involves a proper balance
between the activity of these two pathways
• the direct pathway
• the net effect is the cortex exciting (positive feedback loop)
• direct pathway striatal neurons have D1 dopamine receptors, which depolarize
the cell in response to dopamine
• the indirect pathway
• the net effect is to inhibit the cortex (negative feedback loop)
• indirect pathway striatal neurons have D2 dopamine receptors, which
hyperpolarize the cell in response to dopamine
• nigrostriatal projection from the substantia nigra pars compacta to the
striatum is an important pathway in the modulation of the direct and indirect
pathways via dopamine
• it amplifies the effect of direct and deepens the inhibition of indirect pathway on
cortex
• see Parkinson´s disease as an example/confirmation
BG have a somatotopic organisation similar to motor cortex
Functional contribution of different parts of BG to movement
• input - striatum
• CN receives projections from prefrontal
cortex and visual areas =
movement of eyes (oculomotor
loop) and cognitive faculty
• PU receives projections from motor
and sensory cortex = movement of
the body (body movement loop)
• n. accumbens (not shown in the
cross-section) receives projections
from ventro-medial parts of
forebrain processing emotions =
modulation of affect
• output - pallidum
Inputs to the BG and intrinsic pathways
• There are two main
inputs to the BG
terminating in the
striatum
• (1) from multiple regions
of the cerebral cortex
(corticostriatal pathways)
• excitatory – glutamate
• from intralaminar
nuclei of the thalamus
(thalamostriatal
pathway)
• (2) from the substantia
nigra pars compacta
(nigrostriatal pathway)
• excitatory –
dopaminergic
• NOTE dopaminergic
connection from
ventral tegmental area
to n. accumbens in
limbic loop
Dale Purves et al. (eds.) – Neuroscience 6th e (2018)
Outputs from the BG and intrinsic pathways
• Striatum communicates via inhibitory GABAergic projections with
• substantia nigra pars reticulata
• with GPi
• and with GPe also – see further
• The two major outputs of the BG (both are inhibitory GABAergic)
projecting from
• GPi to the thalamus
• to a number of thalamic structures by way of two fibre tracts:
• the ansa lenticularis and the lenticular fasciculus
• substantia nigra pars reticulata to the superior colliculus, which is involved
in eye movements, as well as to the VA/VL thalamic nuclei
Dale Purves et al. (eds.) – Neuroscience 6th e (2018)
Cortical Afferents and Efferents and cytoarchitecture
• efferent pathways
• directly to alpha motor neurons via the corticospinal
tract
• the corticorubral tract to modulate the rubrospinal tract
• the corticotectal tract to modulate the tectospinal tract
• the corticoreticular tract to modulate the reticulospinal
tracts
• the corticostriatal tract to the caudate nucleus and
putamen of the basal ganglia
• the corticopontine tract and cortico-olivary tract to the
cerebellum
• the corticocortical pathways to other brain areas (bi-
directional)
• afferent pathways
• the corticocortical pathways from other brain areas (bi-
directional)
• indirectly via the corticothalamic pathways (from the
cerebellum and basal ganglia)
Disorders of
extrapyramidal motor system
The two brain structures considered as “side loops” in the motor hierarchy:
- Level (5) basal ganglia and thalamus
- Level (6) cerebellum
BG loops in controling body movements
Extrapyramidal syndromes related to BG
• (1) hypo-/akinetic syndromes
• hyperfunction of the BG inhibitory loop (inhibition of cortical function)
• slow beginning of the movement
• reduced range and force
• resting tremor
• muscle rigidity (“cog-wheel” phenomenon)
• resistance to passive movement of the limb – competing programmes
• Parkinson disease
• (2) dys-/hyperkinetic syndromes
• excessive, involuntary motor activity due to the reduced BG inhibitory loop
• chorea
• athetosis
• ballism
• dystonia
• tardive dyskinesia (drug induced)
• Huntington disease/chorea
• Sydenham chorea (usually reversible)
• neurological disorder of childhood resulting from infection via Group A beta-hemolytic
streptococcus (GABHS), the bacterium that causes rheumatic fever
• Wilson disease
• degeneration of the putamen, a part of the lenticular nucleus
• motor disturbances include “wing-beating” tremor or asterixis, dysarthria, unsteady gait,
and rigidity
• hemiballism
• instructive videos to watch on
https://www.thelancet.com/journals/lancet/article/PIIS0140-
6736(13)62418-6/fulltext#sec1 and many other internet resources
Parkinson´s disease – etiology
• degenerative condition due to the loss of cells
producing dopamine (SNpc)
• progressive destruction of the nigrostriatal pathway with
subsequent reduction of the dopamine in the striatum
• manifest at loss of 70 to 85 percent of dopaminergic neurons
• because the nigrostriatal pathway excites the direct
pathway and inhibits the indirect pathway, the loss of this
input tips the balance in favour of activity in the indirect
pathway
• GPi neurons are abnormally active, keeping the thalamic
neurons inhibited
• without the thalamic input, the motor cortex neurons are not
as excited, and therefore the motor system is less able to
execute the motor plans in response to the patient’s volition
• etiology
• idiopathic – degeneration of the substantia nigra
• autooxidation of catecholamines during melanin synthesis?
• another hallmark is the presence of Lewy bodies—oligomeric
deposits of a protein called alpha-synuclein inside the neurons
• cerebral vascular disease
• toxic (e.g. CO poisoning)
• early-onset – genetic
• mutations in the -synuclein and parkin gene
Etiopathogenesis of PD
• familial forms – implicated genes indicate
likely etiopathogenesis
• (1) impaired intracellular protein homeostasis
• dysfunction of ubiquitin-proteasome system
• PINK-1 (parkin) = ubiquitin E3 ligase
• misfolding of proteins and their aggregation
• -synuclein  Lewy bodies
• (2) mitochondrial dysfunction (LRRK2)
• defect of complex 1
• experimentally by MPTP (1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine)
• oxidative stress (DJ-1 – antioxidant enzyme)
• (4) role of dopamine metabolites
• formation of ROS
• (5) others
• iron homeostasis
• Ca metabolism
Parkinson´s disease - etiology
• Parkinson's disease (PD) is characterised by selective and severe
degeneration of the substantia nigra pars compacta and the locus
coeruleus (LC), which underlies the most prominent symptoms
• An α-synuclein deposition at synaptic sites can impair synaptic
dopamine release and induces the death of nigrostriatal neurons
• Although α‐synuclein accumulation has long been established to play
a causal role in the disease, it alone cannot explain the selective
degenerative pattern
• Recent evidence shows that the selective vulnerability could arise
due to the large presence of cytosolic catecholamines and Ca2+ ions
in the substantia nigra pars compacta and LC specifically that can be
aberrantly affected by α‐synuclein accumulation
• Moreover, each has its own toxic potential, and disturbance of one
can exacerbate the toxic effects of the others
• This presents a mechanism unique to these areas that can lead to a
vicious degenerative cycle
• Interestingly, in familial variants of PD, the exact same brain areas
are affected, implying the underlying process is likely the same
• however, the exact disease mechanisms of many of these genetic
variants remain unclear. Here, we review the effects of the PD‐related
genes Parkin, PINK1 and DJ‐1.
Monomeric, oligomeric, and fibrillary α-synuclein at
the synaptic terminal • (a) Monomeric α-synuclein modulates synaptic
function by controlling synaptic vesicle release.
This form of the protein can be released in
association with exosomes, activates microglial
cells, and can be internalized at postsynaptic sites.
• (b) Oligomeric α-synuclein formation is enhanced
by interaction of monomeric protein with DA.
Alpha-synuclein oligomers can form a stable
adduct with the toxic dopamine metabolite
DOPAL. Oligomers can be released in association
with extracellular vesicles and then activate
microglia. Alpha-synuclein oligomers can disrupt
synaptic vesicles membranes as well as
presynaptic and postsynaptic membranes.
Exogenous α-synuclein oligomers can damage lipid
rafts and affect LTP by activating NMDA receptors.
Intracellular α-synuclein oligomers with
endogenous or exogenous origin impair
mitochondrial functions and cytoskeletal
architecture.
• (c) Fibrillary-aggregated α-synuclein alters synaptic
vesicle release by clustering synaptic vesicles and
by perforating plasma membrane. Extracellular
fibrils deriving from degenerating neurons in the
PD brain can activate microglial cells and actively
contribute to alpha-synuclein pathology spreading.
The formation of endogenous α-synuclein fibrils
can reduce seeding activity and toxicity although
exogenous α-synuclein fibrils function as a seed
for the aggregation of endogenous α-synuclein in
recipient cells.
Francesca Longhena, Gaia Faustini, Cristina Missale, Marina Pizzi, PierFranco Spano, Arianna Bellucci, "The Contribution of α-Synuclein Spreading to Parkinson’s Disease Synaptopathy",
Neural Plasticity, vol. 2017, Article ID 5012129, 15 pages, 2017. https://doi.org/10.1155/2017/5012129
Neurodegeneration pathways in Parkinson's disease
• The discovery of Mendelian inherited genes has enhanced our understanding
of the pathways that mediate neurodegeneration in Parkinson's disease.
• One main pathway of cell toxicity arises through a-synuclein, protein misfolding
and aggregation.
• These proteins are ubiquitinated and initially degraded by the ubiquitin–proteasome
system (UPS), in which parkin has a crucial role. However, there is accumulation and
failure of clearance by the UPS over time, which leads to the formation of fibrillar
aggregates and Lewy bodies. Synuclein protofibrils can also be directly toxic, leading
to the formation of oxidative stress that can further impair the UPS by reducing ATP
levels, inhibiting the proteasome, and by oxidatively modifying parkin. This leads to
accelerated accumulation of aggregates. Phosphorylation of a-synuclein-containing or
tau-containing aggregates might have a role in their pathogenicity and formation, but
it is not known whether leucine-rich repeat kinase 2 (LRRK2) mediates this.
• Another main pathway is the mitochondrial pathway.
• There is accumulating evidence for impaired oxidative phosphorylation and decreased
complex I activity in Parkinson's disease, which leads to reactive oxygen species (ROS)
formation and oxidative stress. In parallel, there is loss of the mitochondrial
membrane potential. This leads to opening of the mitochondrial permeability
transition pore (mPTP), release of cytochrome c from the intermembrane space to the
cytosol, and activation of mitochondrial-dependent apoptosis resulting in caspase
activation and cell death. There is evidence that recessive-inherited genes, such as
phosphatase and tensin homologue (PTEN)-induced kinase 1 (PINK1), Parkinson's
disease (autosomal recessive, early onset) 7 (DJ1) and HtrA serine peptidase 2
(HTRA2, also known as OMI), might all have neuroprotective effects against the
development of mitochondrial dysfunction, although the exact site of their action
remains unknown. Parkin has also been shown to inhibit the release of cytochrome c
following ceramide-induced stress, and is itself modified by the interacting protein
BCL2-associated athanogene 5 (BAG5).
• Dysfunction of both pathways leads to oxidative stress, which causes further
dysfunction of these pathways by feedback and feedforward mechanisms,
ultimately leading to irreversible cellular damage and death.
• I–IV, mitochondial electron transport chain complexes I–IV; -syn(PO4)n, phospho--
synuclein; A30P, alanine to proline substitution at -synuclein amino acid residue 30;
A53T, alanine to threonine subsitution at -synuclein residue 53; E1, ubiquitin
activating enzyme; E2, ubiquitin conjugating enzyme; E46K, glutamic acid to lysine
substitution at -synuclein residue 46; NO, nitric oxide; 3n/4n, 3 or 4 copies of asynuclein;
Tau(POi)n,Tau (POi)n, phospho-Tau; UCHL1, ubiquitin carboxyl-terminal
esterase L1.
Parkinson´s disease – pathophysiology
Parkinson´s disease - symptoms
• resting tremor
• characteristically disappears with purposeful movement but is evident when the extremities are motionless
• often unilateral
• slow turning motion (pronation– supination) of the forearm and the hand and a motion of the thumb against the fingers as if rolling
a pill
• rigidity
• passive movement of an extremity may cause the limb to move in jerky increments referred to as cogwheeling
• increases when another extremity is engaged in voluntary active movement
• bradykinesia (slow movements)
• take longer to complete most activities and have difficulty initiating movement, such as rising from a sitting position or turning in
bed
• freezing phenomenon
• shuffling gait with decreased arm swings
• loss of postural reflexes
• standing with the head bent forward due to forward flexion of the neck, hips, knees, and elbows
• difficulty in pivoting and loss of balance places the patient at risk for falls
• speech and swallowing problems
• dysphonia (soft, slurred, low-pitched, and less audible speech)
• dysphagia, drooling and risk for choking and aspiration
• loss of facial mimics
• masklike and expressionless and the frequency of blinking decreases
• psychiatric symptomatology
• depression
• sleep disturbances
• hallucinations
• dementia (late onset, in 20% patients)
• vegetative dysbalances
• excessive and un-controlled sweating, paroxysmal flushing, orthostatic hypotension, gastric and urinary retention, constipation, and
sexual disturbances
Parkinson´s disease - symptoms
• usually occurs over the age of 50
• characterized by slowness or absence of movement
(bradykinesia or akinesia), rigidity, and a resting
tremor (especially in the hands and fingers)
Parkinson´s disease - treatment
• pharmacotherapy – restoration of the
dopaminergic system
• L-DOPA or dopamine agonists
• other drugs prolonging the dopamine half live
• cathechol-O-methyltransferase (COMT) inhibitors
• monoamine oxidase B (MAO-B) inhibitors
• deep brain stimulation
Huntington's disease (chorea)
• prevalence 4-10/100 000 in Caucasoid population
• manifestation
• onset of symptoms typically between 35 – 50 yrs of age, but it depends on genetics
• dead after 15 - 20 let from diagnosis (~12% commit suicide)
• progressive neurodegeneration due to a loss of D2-positive (GABA-ergic) neurons of
striatum (destruction of indirect pathway) and then in cortex
• GPi constitutively disinhibited and leads to dyskinesia symptoms/movements - chorea
• etiopathogenesis
• genetics - expansion of CAG (= glutamine) trinucleotide repetition in exon 1 (in total 67 exons)
of the gene encoding huntingtin (ch. 4p16.3 ) leading to expansion of the polyglutamine tract
in the N‐terminus of this protein
• htt is 350kDa protein encoded by gene with normal number (6 - 35) of CAG repetitions
• in HD there are 36 – 121 repetitions
• late manifestation when CAG <60
• early manifestation CAG >60
• in subjects with 36-40 repetitions < 100% penetrance !!
• the number of repetitions increases with generations in paternal transmission – phenomenon of anticipation
• the mutation is most prominent in the striatal part of the basal ganglia, and progressive
differential dysfunction and loss of striatal projection neurons and interneurons account for
the progression of motor deficits seen in this disease
• misfolded htt is contained in inclusion bodies, mutant htt negatively affects critical gene expression and thus function of
striatum and cortex
• symptoms
• early – clumsiness, loss of balance, involuntary movements, lack of concentration, depression,
irritability
• late – chorea, dyskinesia, dysarthria, cognitive impairment to dementia
• MORPHOLOGICALLY a generalised brain atrophy (25-30%)
Simplified scheme of the HD pathophysiology
Pathology in the indirect pathway is a key to HD
Cerebellum = error correction
How is cerebellum integrated into the control of movement why
we need it?
• although the cerebellum accounts for
approximately 10% of the brain’s volume, it
contains over 50% of the total number of
neurons in the brain!!!
• its surface area is about 75% of that of the
cerebral cortex
• does not initiate motor activity, rather, the
cerebellum modifies the motor commands of
the descending pathways to make movements
more adaptive and accurate
• major functions
• coordination of voluntary multi-joint movements
to improve stability
• necessary for maintenance of balance and posture
• subsequent balance disorders require postural
strategies to compensate for this problem (e.g., a
wide-based stance)
• motor learning to improve motor performance
• cognitive functions
Functional divisions of
cerebellum
Inputs and outputs of the cerebellum
conveying info on proprioception
and position of the head
note: given side of the
body is represented
contra- laterally in the
cerebral hemisphere
but ipsi-laterally in
cerebellum
VA/VL motoric
nuclei
Disorders of cerebellum
• damage to cerebellum produces movement
disorders not associated with the visual control
(persist with closed eyes)
• vestibulocerebellar disorders
• fixation of gaze when moving a head
• cerebellar ataxia
• gait
• adiadochokinesis
• dysmetria
• cerebellar tremor
• Friedrich ataxia
• FA (similar to HD) is one of an increasing number of
human genetic diseases affecting the nervous
system that are characterized by trinucleotide
repeat expansion
• all in exons with exception of Friedrich ataxia
• frataxin gene – mitochondrial dysfunction
• susceptibility to oxidative damage
• neurological symptoms combined with sensory loss,
diabetes and cardiomyopathy
Disorders of neuromuscular junction
• drug effects
• curare-type
• block Ach receptor activation
• botulotoxin type
• affect Ach release (irreversibly)
• organophosphates
• block Ach-esterase
• myasthenia gravis
• onset between 20 – 30 yrs, 2x more women
• etiology
• unknown
• in 75% cases MG associated with thymoma or thymus hyperplasia
• pathogenesis - autoimmune
• production of blocking Ab against Ach receptors
• autoantibodies also induce complement-mediated degradation of
the AchR, resulting in progressive weakening of the skeletal
muscles
• symptoms
• muscle weakness (ptosis, diplopia, chewing, speech, respiration)
• fatigue
• Lambert-Eaton syndrome
• blockade of presynaptic Ach release
• paraneoplastic (lung carcinoma)
Disorders of neuromuscular junction
Muscular diseases
• (A) Muscular dystrophies
• characterised by muscle degeneration and weakness
• there are about 60 different forms of muscular dystrophy, ranging from the most
common Duchenne MD, which often causes death by the age of thirty, to rarer, more
slowly-progressing or later-onset forms
• All types of MD are caused by mutations in genes implicated in muscle structure and
function
• dystrophinopathies (most common) – Duchenne and Becker MD (different type of mutation)
• dystrophin is actually part of a complex of molecules situated in the membrane encircling muscle
cells
• (B) Mitochondrial myopathies
Muscular dystrophies
NOTE: women could be manifesting carries since one copy of X
ch gets inactivated (lyonisation) and if this happens with majority
of non-mutated X ch. symptoms develop in a carrier female