4.

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10 Feb 2016

Sentais Angels and Demons| Seminar Report: Neuropsychiatric Disorders

Myasthenia Gravis (MG)

from Greek and Latin words meaning serious muscle

weakness
caused by antibodies attacking acetylcholine receptors
(AchR) comprising the end-plate potential
o reduces effective synaptic transmission
most common form: chronic autoimmune neuromuscular
disorder characterized by fluctuating weakness of voluntary
muscle groups
Biochemical Basis

Normal Physiology of Synaptic Transmission

(pahap a

a la g to a. )

Myasthenia Gravis - as much as 80% reduction in Ach

receptors

Pathophysiology

a prototypical antibody-mediated, T-helper cell dependent

autoimmune disease

majority of MG patients: presence of auto-Ab directed

against the alpha-subunit of the nicotinergic acetylcholine
receptor (AchR) of skeletal muscles
o result: loss of receptors and destruction of the
postsynaptic membrane
o auto-Ab produced in the thymus and lymphatic
system by AchR-specific auto-reactive T and B
lymphocytes

healthy individual: auto-Ab eliminated or

adequately controlled by regulatory T cells

other causes: blocking of Ab which bind at or in the

immediate vicinity of the Ach binding sites

primary triggering event: poorly understood

AchR antibodies detected in 80% to 90% of patients with

generalized MG and in about 50% of patients with ocular
MG.

Figure X. Signal Transduction of the Action Potential located at the

NMJ.

voluntary muscles - controlled by nerve impulses arising from

the corticospinal (pyramidal) descending tracts
o nerve impulse are carried by nerve fibers down to the
muscle fibers they innervate
neuromuscular junction (NMJ) space between the nerve
ending and muscle fiber
acetylcholine chemical released by the nerve fibers upon
receiving nerve impulses
generation of action potential

Figure X. Different mechanisms on how Ab affects the NMJ.

activation of

voltage-gated Ca2+

channel

Signs and Symptoms

increase in intracellular

Ca2+

release of acethylcholine from the nerve fibers (through vesicles) to the

NMJ
binding of Ach to its receptor

Hallmarks of MG: Muscle weakness and fatigability

severity of muscle weakness - varies greatly among patients
o localized weakness e.g. eye muscles only
o severe/generalized weakness many muscles affected

symptoms vary from day to day and from hour to hour,

typically increasing toward evening

muscle contraction

Transcribers: Partners in Crime Biochem Trans Team + Sentais Angels and Demons

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muscles commonly affected, in order of decreasing
frequency:
o Levator palpebrae superioris
o Extraocular muscles
o Proximal limb muscles
o Muscles of facial expression
o Neck extensors
eye muscles first most commonly affected
o ptosis (drooping of eyelids)
o diplopia (double vision)
o blurred vision
o Ocular Myasthenia only eye muscles are affected
facial and throat muscles if affected, individuals may have
problems in:
o speaking (dysarthria)
o swallowing (dysphagia)
o facial expression
limbs when limb muscles are affected, it generally occurs in
conjunction with other muscles in the body
Treatment and Management

1. Anticholinesterase (AChE) inhibitors

initial treatment for mild MG

Pyridostigmine: maintenance therapy

Cyclosporine A, methotrexate and cyclophosphamide: for

severe cases
2. Intravenous immune globulin (IVIg)

moderate or severe MG worsening into crisis

most commonly used in elderly patients and those with

comorbid diseases (e.g. with acute respiratory failure)
3. Plasmapharesis

reserved for myasthenic crisis and refractory cases

used if other treatments a t control the disease

4. Thymectomy

proposed as a first-line therapy in most patients with

generalized myasthenia

not recommended in patients with antibodies to musclespecific kinase (MuSK)

Stroke
rapid developing loss of brain function due to disturbances in
the blood vessels supplying the brain
causes:
o Ischemia due to thrombosis/embolism
o Hemorrhage
affected area of the brain unable to function, leading to:
o inability to move one or more limbs on one side of the
body
o inability to understand or formulate speech
o inability to see one side of the visual field
major risk factors:
o HPN, blood disorders
o tobacco use, illegal drugs
o atrial fibrillation, heart failure, heart attack
o age, gender
o race

Transcribers: Partners in Crime Biochem Trans Team + Sentais Angels and Demons

African American highest risk

Hispanics, American Indies lowest risk
Post stroke depression (PSD) most common
neuropsychiatric disorder after stroke
o serotonin implied to play a great role in the onset of
depression

Types of Stroke
HEMORRHAGIC Stroke

rupture of one of the major blood vessels supplying the brain

blood accumulates in the:
o sub-arachoid space sub-arachnoid hemorrhage (SAH)
o intra-cerebral space intra-cerebral hemorrhage (ICH)
ISCHEMIC/THROMBOEMBOLIC Stroke

lack of blood supply in the small perforating arteries of the

brain ischemia

Subtypes of Ischemic Stroke

A. Small Vessel Disease (SVD)
B. Large Vessel Disease (LVD)
C. Cardioembolic Stroke

Small Vessel Disease (SVD) - consequence of fatty deposits

building up on the blood vessel wall, causing blockage of the
small perforating blood vessels
o atherosclerosis fatty build-up in all the vessels
throughout the body; consequence of high fat diet

Large Vessel Disease (LVD) ischemia is a consequence of

large vessel occlusion/emboli

Cardioembolic Stroke ischemia as a result of an emboli

with cardiac origin
o can be due to cervical artery dissection
Biochemical Basis

cerebral ischemia occurs when oxygen and other nutrients

supplied by blood flow is insufficient to meet the metabolic
demands of brain tissue.
final event in cerebral ischemia death of neurons
(irreversible loss of neurologic function)
2 pathways that occurs after ischemia (leading to death of
neurons):
o Necrotic Pathway
o Apoptotic Pathway
NECROTIC CELL DEATH
characterized by energy failure leads to inhibition of
protein synthesis cell death
primary pathology: depletion of energy stores
hypoxia and hyperglycemia

mitochondria fail to produce ATP

membrane ion pumps stop functioning

neurons depolarize, increasing intracellular

[Ca2+] and [glutamate]

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Glutamate
o normal condition: participate in neurological functions
such as memory, movement, sensation, cognition,
synaptic plasticity
o increased amount: CYTOTOXIC
o activates N-methyl-D-aspartate (NMDA) and nonNMDA channels mediating further increase in
2+
intraneuronal Ca
2+
To i e e tsof[Ca ]:
o activation of Calpain 1 converts xanthine
dehydrogenase to xanthine oxidase

xanthine oxidase metabolize xanthine to

superoxide
o activation of phospholipase A2 releases arachidonic
acid from injured cell membrane, metabolized by
cyclooxygenase to produce prostaglandin and
superoxide (by-product)
2+
o activation of Ca -dependent isoforms of NO
production of NO

NO + superoxides (from xanthine oxidase and

cyclooxygenase) = peroxynitrite (highly reactive
ROS)

NOTE: I short, [Ca ] RO I e plai la g u g

mechanisms kung paano nagincrease ang ROS.
2+

ga

APOPTOSIS
Internal Pathway

key event in triggering apoptosis: release of cyt c from the

mitochondria

binding of death ligands to Fas and TNF-

receptors
activation of caspase 8
cleavage of Bcl-2 protein
cleaved Bcl translocated from cytoplasm to
mitochondria
release of Cyt C
Internal Pathway

Treatment and Management

Ischemic stroke

dissolution of thrombus/emboli

Tx: Aspirin, IV injection of tissue plasminogen activator (TPA)

Hemorrhagic stroke

repair of ruptured vessels

Tx: surgical blood vessel repair, surgical clipping

Neuropsychiatric

Tx: antidepressants fluoxetine (a serotonin selective

reuptake inhibitor)

release of Cyt C from the mt

Fragile X Syndrome (FXS)
cleavage of procaspase 9 to caspase 9

caspase 9 cleaves and activates caspase 3,6,7

caspase 3-mediated programmed cell death thru

cleavage of cytoskeletal and DNA repair proteins

hallmark of apoptosis: cleavage of cytoskeletal and DNA

repair proteins
release of cyt c controlled by:
o anti-apoptotic bcl-2 family (inhibition)
o pro-apoptotic proteins such as bax and bak

NOTE: e all a la g to, gu s. Balance between anti-apoptotic

and pro-apoptotic proteins determine the release of cyt c.
External Pathway

mediated by Fas and TNF- e epto s ellsu fa e e epto s

DNA base oxidation + other DNA damage can initiate

apoptosis via activation of p53
rd
*differe t e ha is
to a. Recall 3 shifting oncogenes.
Mentioned for comparison purposes.

Transcribers: Partners in Crime Biochem Trans Team + Sentais Angels and Demons

also known as Martin-Bell Syndrome , Es ala te s

Syndrome
most common form of inherited mental retardation
o occurs more in males
Inheritance Pattern: X-linked recessive
children with FXS often diagnosed with autism
prominent signs and symptoms:
o elongated face
o large/protruding ears
o large testes (macroorchidism)
o premature menopause
Biochemical Basis

Genetic Basis

expansion of CGG t i u leotide epeatsi the u t a slated

region
o once expanded, it becomes methylated, leading to
silencing of the gene
o methylated part of the chromosome appears
constricted / fragile under the microscope; hence, the
name of the disease

occurs in the fragile X mental retardation 1 (FMR1) gene

located on the X chromosome

failure to express the fragile X mental retardation protein

(FMRP)

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o FMRP required for normal neural development
can also occur due to point or spontaneous mutations
affecting FMR1 gene (only 2% of all FXS cases)

Table X. Comparison of the different alleles of FMR1 gene depending

on the length of their CGG trinucleotide repeats.
# of CGG repeats
Normal
<30
Pre-mutation
55-200
Full mutation
>200

Treatment and Management

no current treatment or cure

medication: symptom-based
o Anti-depressants: SSRIs (Selective Serotonin Reuptake
Inhibitors)
o Anti-psychotics: Risperdal, Seroquel
o Anti-convulsions
genetic counseling

*45 to 54 grey area ; close to permutation state but is still normal

Sherman Paradox unusual inheritance pattern of FXS

o occurrence of non-penetrant male carrying the mutated
gene

explains the presence of pre-mutation alleles

o non-penetrant male non-penetrant daughter
affected son
NOTE: They have the mutated gene kaso hindi pa nagmamanifest (pre-mutation alleles). As these pre-mutation alleles
di ide, as hu aha a u g e pa ded repeats kasi highly
unstable ang genome ng pre-mutant alleles (lalo na sa
female meiosis) kaya nagiging full mutation. Once it becomes
full utatio , ag a a ifest a u g disease.

molecular mechanism of CGG repeat expansion slippage

of Okazaki fragments
o normal: CGG repeats interrupted by 2 AGG

CGG repeats + interruptions of AGG = repeat

number: <30

almost same length as that of mammalian Okazaki

fragment
o with FXS: no interruption as reference

CGG repeat number: >30

Result: Okazaki fragments slip due to increased

length of Okazaki fragment and absence of AGG
interruptions

Molecular Mechanism

FMRP
o highest concentration in the brain and testes
o responsible for selectively binding mRNAs in the
mammalian brain
o part of neuronal polyribosomes

Hu ti gto s Disease HD

a progressive degenerative brain disorder

Pattern of Inheritance: Autosomal Dominant
onset: typically between 25 and 45 years of age
o onset under the age 20: called juvenile, akinetic-rigid or
Westphal-variant HD
Biochemical Basis

increase in the number of glutamine (CAG) repeats (>36)

coding for the cytoplasmic protein Huntingtin (HTT)
o HTT gene located on chromosome 4p
o CAG repeats produces a chain of glutamine (polyQ
tract)

polyQ region repeated part of the gene

NOTE: pag repeated a i o a ids, TACT. pag repeated
nucleotides, REGION.
o mutant Huntingtin (mHTT) protein increases the
decay rate of certain types of neurons

goes into the nucleus and interferes with

transcriptional regulatory proteins
HTT - widely distributed in the CNS but function is not fully
known

Table X. Classification of the trinucleotide repeats and resulting disease

status.
Repeat
count
<26
2735
3639

FMRP selectively binds mRNA

40+

Classification

Disease status

Normal
Intermediate
Reduced
Penetrance
Full Penetrance

Will not be affected

Will not be affected
May or may not be
affected
Will be affected

translocation of the mRNA from the nucleus to the

synapses of neurons
mRNA translated to its protein
formation of synaptosomes
synaptic development and brain plasticity

patients with FXS

o abnormal dendritic spines impaired neuroplasticity
mental retardation

Transcribers: Partners in Crime Biochem Trans Team + Sentais Angels and Demons

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Parki so s Disease PD

Neuropathology
cleavage of mHTT protein

shorter fragments of polyQ tract

mHTT protein form H-bonds with one another

protein misfolds and aggregates

formation of inclusion bodies within neuronal cells

transmission of neurotransmitters stop

Biochemical Basis
most commonly affected: NEOSTRIATUM of the basal
ganglia
o basal ganglia plays a key role in control of movement
and behavior

accumulating damage: characteristic erratic

movements associated with HD
o neostriatum = caudate nucleus + putamen
middle and late stages of the disease: atrophy of the caudate
nuclei
diffused cortical atrophy associated with decreased
concentrations of GABA and its synthesizing enzyme glutamic
acid decarboxylase
Signs and Symptoms

also known as shake/shaking palsy and paralysis agitans

a progressive neurodegenerative disorder, idiopathic in
nature, affecting neurophysiologic functions and movement
abilities
average age of PD onset: 50 to 60 years; males more affected
than females
primarily affects dopamine-producing neurons in
the nigrostriatal pathway of the basal ganglia, specifically in
the substantia nigra
o basal ganglia - responsible in motor planning and
modulating motor programs
o nigrostriatal pathway - efferent connection between
the susbtantia nigra and corpus striatum

dual effect of exciting the direct pathway while

simultaneously inhibiting the indirect pathway
dopamine - major neurotransmitter of nigrostriatal pathway
o excitatory effect on the direct pathway
o inhibitory effect on the indirect pathway

Hereditary PD
o associated genes: PARK3, 10, 11, 12
o proteins involved:

kinases PINK1, LRRK2

regulates protein folding and disposal Parkin,

ATP13A2, HtrA2, DJ-1

anti-oxidants DJ-1

-synuclein
NOTE: Familiarize lang tayo rito, mga bakla.
Sporadic PD
o problems with mitochondrial dynamics

oxidative stress
2+

Ca influx

protein folding, transport and degradation

progressive motor, behavioral, and cognitive dysfunction rapid, nonpatterned, choreiform (abnormal gait) movements
dysarthria (unclear speech), gait disturbance, and
oculomotor abnormalities with psychiatric disturbances such
as depression or mania
psychosis
Treatment and Management
no treatment or cure management of symptoms only
medical, neuropsychiatric, social, and genetic counseling for
the patient and the family
no adequate treatment for the cognitive or motor decline of
HD
st
o tetrabenazine 1 drug approved in the US to treat
Hu ti gto s ho ea
o other drugs: dopamine-blocking agents
antidepressant, antianxiety and antipsychotic drugs for those
with psychiatric disturbances
o atypical neuroleptics: clozaptine, quetiapine, and
risperidone
antiglutamate agents due to increased CAG repeats

Transcribers: Partners in Crime Biochem Trans Team + Sentais Angels and Demons

Figure X. Etiology of Parkinson's disease.

(GSH: Glutathione; ROS: Reactive oxygen species; SOD: Superoxide
dismutase; UPS: Ubiquitinproteasome system)

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central to the onset of PD:
o levels of UPS (Ubiquitin Proteasome System)
o altered mitochondrial dynamics
o output of RO

1.
2.

Signs and Symptoms

altered mitochondrial dynamics

output of ROS

protein damage
formation of Inclusion/Lewy Bodies

Conversion of L-tyrosine to L-DOPA via tyrosine hydroxylase

L-DOPA converted to dopamine by the aromatic DOPA
decarboxylase
Coenzyme: pyridoxal phosphate

Hallmarks of PD: tremor of the extremities, jaw, and face

(resting), bradykinesia (slowness of movement) or akinesia
(absence of planned motor image prior to movement),
rigidity or stiffness of the limb and trunk, and postural
instability
Note: 2 out 4 Hallmarks check na for PD
other symptoms: poor balance, masked face, festinating gait,
speech and respiratory impairments, cognitive deficitswith
higher risk of having dementia, and autonomic symptoms.

Cell death

Treatment and Management

cell ATTEMPTS to remove aggregating proteins and defective
cellular constituents through autophagy and UPS
o defective, depolarized mitochondria removed from cells
via mitophagy promoted by Parkin and DJ-1
o stress response may activate kinases (PINK1, LRRK2)
NOTE: Kaso nga lang, hindi sila natatangal kasi nga
decreased ang activity of UPS. Huehue.

Dopamine Interaction and Synthesis

Dopamine - has five receptors

o stimulatory D1, D5
o inhibitory D2, D3, D4
o must be stimulated for G-proteins to be activated

-subunits of these G-proteins aggravate or relieve the

symptoms of PD

effect of dopamine LESS than that of Ach

Table X. Different types of G-proteins and their corresponding effects
on PD.
Types of alpha
G proteins that aggravate PD
Gs 1 alpha
G proteins that relieve PD
Gi 1a, Gi 2a, Gi 3a
G proteins that have little effect
Go alpha
on PD

pharmaceutical management - main management for PD

o relieve symptoms of the patient
o replacing deficient dopamine with dopamine agonists:
monoamine oxidase-B inhibitors (MAO-B) or levodopa
(L-dopa)
L-dopa most commonly used anti-PD drug
o metabolic precursor of dopamine
o has known side-effects (i.e., nausea, vomiting,
hypotension, etc.)
Carbidopa DOPA analog
o minimizes side-effects of L-dopa
other management:
o surgical management (deep brain stimulation,
neuroablative lesion surgeries etc.)
o physiotherapy and other rehabilitation facilities
o diet monitoring

Schizophrenia

characterized by:
o positive symptoms - delusions and hallucinations
o negative symptoms impaired cognition, volition and
emotion
o substantial functional deterioration work,
interpersonal relationships, or self-care
causes can include:
o genetic predisposition
o upbringing and developmental factors
o changes in brain chemistry
theories (most) relevant to the etiology of schizophrenia:
DOPAMINE and SEROTONIN theory
Dopamine Theory

Figure X. Biosynthesis of Dopamine.

Transcribers: Partners in Crime Biochem Trans Team + Sentais Angels and Demons

Dopamine Pathways - responsible for functions that regulate

motivation and reward, pleasure, fine-tuning of motor
function, compulsion and perseveration
postulates that there is an increase in (stimulatory)
dopamine transmission to the D2 receptors in the
mesolimbic dopaminergic system and other associated
structures that are responsible for behavior

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o explains the positive symptoms experienced
mechanism includes a mutation in dopamine hydroxylase
blocks the conversion of dopamine to NE accumulation of
dopamine
Tx: Typical antipsychotics eg, chlorpromazine & haloperidol
o cause blockage of the D2 receptors in the CNS
o Extrapyramidal symptoms most common side effect
of antipsychotics blockage of the inhibitory effect of
dopamine muscle twitching and uncontrolled body
movements
Serotonin (5-HT) Theory

Alzhei ers Disease AD

Hallmark: presence of amyloid plaques or neurofibrillary

tangles (NFT)
o can be accompanied by neuronal/synaptic loss or brain
atrophy
incurable - leads to death within an average of 8 years after
diagnosis
notable signs and symptoms: memory loss, dramatic
personality changes, disorientation and declining physical
coordination

Types of Alzhei ers Disease

A. Familial AD (FAD)

less common

early onset (mostly between 30 60 y/o)

cause: amyloid cascade

o does not include NFT formations, inflammation and
oxidative stress
B. Sporadic AD (SAD)

more common

typically occurs after 65 y/o

no inheritance pattern

risk factor: mutation on chromosome 19, APOE4 allele

Biochemical Basis

Fig X. Biosynthesis of serotonin.

Serotonin - involved in pathways affecting mood, memory

processing, sleep and cognition
postulates that stimulation of the 5-HT2A receptors induces
hallucinations similar to that of schizophrenia
In schizophrenia, an increase in 5-HT transmission in the
presynaptic neurons affects the modulating property of 5-HT
to post-synaptic dopamine (excitatory), glutamate
(excitatory) and GABA (inhibitory) neurons
o results to altered brain functioning
Tx: Atypical antipsychotics eg, clozapine & risperidone
o cause blockage of the 5-HT2A receptors in the CNS
o Extrapyramidal symptoms - less apparent; dopamine
receptor inhibition is minimal
Other Theories

Glutamate - loss of responsiveness of neurons excited by

glutamate (ie, NMDA receptor) cause of deficits observed
in schizophrenic patients
GABA
Acetylcholine
Norepinephrine

Transcribers: Partners in Crime Biochem Trans Team + Sentais Angels and Demons

Amyloid Cascade

Amyloid Precursor Protein (APP)

o a neuron membrane protein thought to be a natural
neuroprotective agent upregulated during neuronal
stress or injury
o the precursor protein of A-42 a yloid protei

A- 42 a yloid protei
o clamps together to form insoluble amyloid plaques
(hydrophobic) causes inflammatory response and
oxidative damage which further aggravates the situation

inflammatory response: activation of astrocytes

i PG/a a hido i a id

o idati e espo se: i i oglial ells i

superoxides

inflammatory + oxidative response = accounts for

the neuronal death
*highly ironic, eh? Kung sino pa tumutulong sayo,
in the end, sila pa nakakasakit sayo.
o synthesis involves:

APP cleaved by -secretase to form A- a yloid

protein

A- lea ed -secretase to form A- 42 a yloid

protein

formed intracellularly, but when transported

outside the cell, these plaques have damaging
effects
o MOST TOXIC FORM: soluble oligomer

forms a halo around amyloid plaques

associated with excitatory synapse loss

deterioration of the synapse
o another effect: positive feedback loop caused by
accumulation of A- a loidplaques

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positive feedback loop
fu the of-

accumulation of amyloid plaques

loidpla ues

influx of Ca2+

amyloid plaques accumulate on blood vessels

activation of calcium-activated kinases

ischemia
excessive phosphorylation of tau protein
release of Ca2+
tau protein loses its capacity to bind microtubulues
disturbance of ER PS1 protein
fu the i p odu tio ofA-42 amyloid plaques

tau proteins bind with each other, tying themselves,

forming NFTs
o

NOTE: Remember the mechanism in stroke induced by increased Ca2+?

Ganun din mangyayari kaya madidisturb si PS1 protein. Different
e ha is s, o e result: A-42 amyloid plaques.
o

first appear in the association areas of the cerebral

cortex

Genetics

PS1 (Pre-Senilin 1) gene

o Chromosome 14
o codes for -secretase
o mutant PS1 - p odu tio of- a

APOE gene
o Chromosome 19
o Mutant APOE risk factor for SAD

APP gene
o Chromosome 21
o abnormal APP protein

loidpla ues

Neurofibrillary Tangles (NFT)

abnormally phosphorylated tau protein

Tau protein
o microtubule associated protein that functions to
assemble and stabilize the microtubules that convey
cell organelles, glycoproteins and other important
materials throughout the neuron

serotogenic neurons in the raphe nuclei of brainstem

preferential site of NFT formation and neuronal loss in
AD
absence of NFT neuronal death due to Lewy bodies

Lipoprotein / Cholesterol

APOE synthesized independently in brain astrocytes and

oligodendrocytes
o has the following functions:

mobilization of cholesterol for synapse plasticity

and repair of damaged neurons (binding site for
LDL receptors)

lipid transport in CSF and between cells in the

brain tissue
o has 3 forms: APOE2, APOE3, APOE4
o APOE2

relatively rare

provides protection against AD

people with this allele develop AD later in life

o APOE3

most common allele

neutral role in the disease neither decreasing nor

increasing risk
o APOE4

present in about 40% of AD cases

promotes A- sheetfo atio

stabilizes A- oligo e i to i fo

increased AD risk
Glycation, Immune and Inflammatory response

A- a ti atesRGE Re epto fo d a edGl atio E dProducts)

o activates microglia production of IL-
aggregation of acidic A-fo atio

IL- promotes APP synthesis and phosphorylation of tau

proteins
Metal Toxicity and Free Radicals

Zinc, Copper and Iron promotes formation of A-pla ues

3+
2+
3+
2+

A-pla ues converts Fe to Fe , Cu to Cu , generating

H2O2 in the process (oxidative damage)
o causes inflammation cascade enhances A- sheet
formation, mediated by APOE4

Transcribers: Partners in Crime Biochem Trans Team + Sentais Angels and Demons

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Bipolar Disorder (BD)

Signs and Symptoms

tend to follow a characteristic pattern, starting with memory

impairment and spreading to language and visuospatial
deficits

Early Stage AD

Memory loss may go unrecognized or be ascribed to benign

forgetfulness
o e.g. fo getful essa outo eso pe so alhisto

trouble understanding visual images and spatial relationships

Mid-stage AD

confused on where they are and what day it is

major personality and behavioral changes

unable to work
o Aphasia difficulty in speaking
o Apraxia trouble with performing sequential motor
tasks
Late Stage AD

major changes in sleep pattern

tend to wander and become lost

lose the ability to respond to their environment, carry on

conversations, or control movements

loss of judgment, reason and cognitive abilities

End-stage AD

becomes rigid, mute, incontinent, bedridden

generalized seizures may occur

also known as manic-depressive illness

a brain disorder that causes unusual shifts in mood, energy,
activity levels, and the ability to carry out day-to-day tasks
Types of Bipolar Disorder

Bipolar I

manic or mixed episodes that last at least seven days OR

manic symptoms so severe that the person needs immediate
hospital care
Bipolar II

pattern of depressive and hypomanic episodes

no full-blown manic or mixed episodes

Bipolar Disorder Not Otherwise Specified (BP-NOS)

symptoms of the illness exist but do not meet the diagnostic

criteria for either bipolar I or II
Cyclothymia / Cyclothymic Disorder

mild form of bipolar disorder

patients have episodes of hypomania as well as mild

depression for at least 2 years

symptoms do not meet the diagnostic requirements for any

other type of bipolar disorder
Rapid-cycling Bipolar Disorder

severe form of bipolar disorder

patient with four or more episodes of major depression,

mania, hypomania or mixed states all WITHIN A YEAR

affects more women than men

Biochemical Basis

Treatment and Management

Pharmacological

Cholinesterase inhibitors
o prevents breakdown of Ach supports communication
amonf nerve cells
o Donepezil, Rivastigmine

Memantine regulates the activity of glutamate

o improves memory, reason, language, and ability to
perform simple tasks

problem with the balance of neurotransmitters involved in

both brain and bodily functions
o main NT involved: serotonin and dopamine

Hypothesis
*kadalasan, puro effects. Hindi pa rin kasi fully explained mga
mechanisms kung bakit nagkakaroon ng Bipolar Disorder kaya puro
haka-haka muna ang meron.
Catecholamine Hypothesis

INCREASE in EPI and NOREPI mania

DECREASE in EPI and NOREPI depression

Monoamine Hypothesis

DEPLETED levels of monoamines - depression

Noradrenaline

BD - low plasma concentration of noradrenalin

increased levels - hypomania

Serotonin (5-HT)

depression se oto i e epto s; se oto i

receptors
Dopamine

reward/incentive circuit of the brain

dopa i e mania

dopa i e depression

Transcribers: Partners in Crime Biochem Trans Team + Sentais Angels and Demons

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Homovanillic acid (HVA) most important metabolite that
affects mood swings

Substance P

important neuromodulator
o regulates the release of ACTH

su sta eP depression
o tricyclic antidepressants downregulation of SP
o a tago istofPs e epto NK-1) antidepressant and
anxiolytic activity

su sta eP mania
Signaling System Dysfunction

dysfunction in second messenger mechanisms

cAMP and PKA

o patients with BD

altered post-receptor sensitivity to cAMP

toplas i PK
o normal pathway:
MP CREB MP Respo se Ele e t Bi di g
Protein) ai -derived neurotrophic factors in
neurons survival and efficacy of neurons

phosphoinositol and PKC

o phosphoi ositoland PKC manic state
o patie ts ithBD:Gp otei s
Genetic Basis

Non-Mendelian
*does not follow the Law of Independent Segregation and
Assortment of Chromosomes

associated with major affective disorder (MAFD) loci

o 8 loci: MAFD(1-8)
Environmental Basis

traumatic/abusive experiences associated with early onset

of BD
Signs and Symptoms
MANIA
a long period of feeling
"high," or an overly
happy or outgoing mood
extreme irritability

DEPRESSION
o an overly long period of
feeling sad or hopeless
o loss of interest in
activities once enjoyed,
including sex
Behavioral Changes
o feeling tired or "slowed
talking very fast with
down"
racing thoughts
o having
problems
being easily distracted
concentrating,
increasing activities
remembering,
and
overly restless
making decisions
sleeping little or not
o being
restless
or
being tired
irritable
having an unrealistic
o changing
eating,
belief in one's abilities
sleeping, or other habits
behaving impulsively and
o thinking of death or
engaging in pleasurable,
suicide, or attempting
high-risk behaviors
suicide.
*O, baka meron na sa inyo dyan na may BD, a? Patingin na sa doctor!

Transcribers: Partners in Crime Biochem Trans Team + Sentais Angels and Demons

Treatment and Management

Mood stabilizers

first choice to treat bipolar disorder

Lithium Carbonate mainly for manic episodes

*pero pwede rin for depressive
Anti-convulsants

Valproic acid/Divalproex sodium

Atypical Antipsychotics

Olanzapine mania and psychosis

Aripiprazole mania or mixed

Antidepressants

Fluoxetine, Paroxetine
Psychotherapy

Cognitive behavioral therapy (CBT)

Family-focused therapy

Interpersonal and social rhythm therapy

Autism

a neurodevelopmental disorder that manifests in early

childhood
characterized by qualitative abnormalities in social
interactions, markedly aberrant communication skills, and
restricted repetitive and stereotyped behaviors
one of the three recognized disorders in the autism spectrum
disorder (ASD)
o ASD includes:
1. Asperger Syndrome: lack or delays in cognitive
development and language
2. Pervasive Developmental Disorder (PDD-NOS):
diagnosed when the full set of criteria for Autism or
Asperger Syndrome are not met
Biochemical Basis

Genetic Basis

Polygenic, Epistatic model Autism caused by two or more

genes interacting in a complex manner

epigenetic mechanisms may increase the risk of autism

o regulates gene expression without changing the DNA
sequence
o DNA cytosine methylation and post-translational
modifications to histones

DLX5, DLX2
o directly regulate expression of glutamic acid
decarboxylase

produces the NT GABA

o located on Chromosome 7
Neuropathology

10% of cases: due to breakdown of mitochondrial function

o presence of genetic mutations

most cases: reduced cerebellar Purkinje neuron density

o Purkinje neurons glutamate receiving (excitatory) and
GABA transmitting

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BIOCHEMISTRY
Group 2 | Seminar Report: Neuropsychiatric Disorders
Patients with ASD have activated microglia which export
copious amounts of glutamate
o glutamate when present in excessive amounts are toxic
to the mitochondria and neurons
EAAT4 principal glutamate uptake transporter expressed by
Purkinje neurons, along with EAAT3

Effect of Glutamate on Glutathione Metabolism (Astrocytes)

glutamate toxicity resulting from activated
microglia
increases astrocytic GSH synthesis and oxidation

nd

2 -gen antipsychotic agents (Risperidone, Aripiprazole,

Ziprasidone)
o Risperidone mixed serotonin-dopamine antagonist

binds to 5-HT2 with very high affinity

binds to dopamine D2 receptor with less affinity

o Aripiprazole partial dopamine (D2) and serotonin (5HT1A) agonist

antagonist of serotonin (5-HT2A)

o Ziprasidone control aggression, irritability, and
agitation

a tago ist of dopa i e D , D , se oto i , adrenergic neurons and histamine

inhibits reuptake of serotonin and norepinephrine

Methylphenidate blocks reuptake of norepinephrine and
dopamine into the presynaptic neuron

decreases levels of GSH precursors and GSH

neurons utilize EAAT2 and EAAT3 to import
cysteine for the synthesis of GSH

ADHD

import process competitively inhibited by

glutamate

effect: depletion of cysteine in favor of ensuring

adequate astrocytic levels of GSH

Signs and Symptoms

A. Behavioral/Cognitive Manifestations

difficulty in social interactions attachment to objects

high pain threshold

language delays

Odd Play: highly predictive of a later diagnosis of autism

Self-injurious behaviours:
o Picking at the skin
o Self-biting
o Head punching and slapping
o Head-to-object and body-to-object banging
* u g ahihilig ag head a g d a . Be are. Huehue.

Attention Deficit Hyperactivity Disorder

a developmental condition of inattention and distractibility,
with or without accompanying hyperactivity
3 basic forms as described by the American Psychiatric
Association:
inattentive,
hyperactive-impulsive,
and
combined
specified by the severity based on social or occupational
functional impairment:
o mild minor impairment
o moderate impairment between mild and severe
o severe symptoms in excess of those required to meet
diagnosis; marked impairment
Biochemical Basis

involved genes or chromosomes not definitively known

moderately associated with ADHD genes coding for
dopamine and serotonin receptors
o DRD4, DRD5, DAT, 5-HTT, 5-HTR1B

B. Physical Findings

Body movement: clumsiness, awkward walk, and abnormal

motor movements
o most common abnormal motor movements: hand
flapping

Head and hand features: aberrant palmar creases and other

dermatoglyphic anomalies
o head i u fe e e more common in boys;
associated with poor adaptive behaviour
Treatment and Management
A. Non-Pharmacologic

Special Education central to the treatment of autism

B. Pharmacologic Treatment

no pharmacologic agent is effective in the treatment of the

core behavioral manifestations
o may be effective in treating associated behavioral
problems and comorbid disorders

Transcribers: Partners in Crime Biochem Trans Team + Sentais Angels and Demons

Figure X. Dopamine as a neurotransmitter.

Dopamine and Norepinephrine

main neurotransmitters involved in ADHD

affects regions of brain that control executive functioning,

motivation, and impulsiveness

patients with ADHD

o diminished overall stimulation of the post-synaptic
terminal
o limited probability that the signal will continue to the
next neuron
o dopa i e inattention

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BIOCHEMISTRY
Group 2 | Seminar Report: Neuropsychiatric Disorders
Signs and Symptoms

Appearance: hyperactivity and distractibility - fidgety,

impulsive, unable to sit still, etc.
Speech/thought processes: normal rate but may be louder
due to impulsivity; may reflect difficulties staying on a topic
or task
Cognition: difficulty with calculation tasks and recent
memory tasks
Treatment and Management

A. Pharmacological
1. Stimulants

methylphenidate, dextroamphetamine

best first-line therapeutic option

targeted symptoms: impulsivity, distractibility, poor task

adherence, hyperactivity, and lack of attention
o side effects: appetite suppression, weight loss, and
headaches
2. Non-stimulants

atomoxetine

second-line
B. Non-pharmacological

behavioral psychotherapy

cognitive therapy for adults with ADHD

psychosocial interventions
o behavioral parent training (BPT)
o behavioral classroom management (BCM)

-----END OF SEMINAR REPORT-----

Figure X. 1A with the witty and ever weird Dr. Menorcs.

,letsgofo

%p o otio !Wala gsusuko!Kapitla g.

Transcribers: Partners in Crime Biochem Trans Team + Sentais Angels and Demons

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