Biochemistry 4.03Neuropsychiatric Disorders.- Neuropsychiatric Disorders

4.03

BIOCHEMISTRY SEMINAR REPORT

TOPIC OUTLINE

disease: 1. Memory loss

Outline I.

Alzheimer’s Disease



Occurs at an early stage of the disease



Difficulty in remembering both recent and past information

II. Parkinson’s Disease III. Huntington’s Disease



in simple problems

IV. Myasthenia Gravis V. Schizophrenia

2. Difficulty in performing familiar tasks

VI. Fragile X Syndrome 

3. Problems with language

Overview Most common form of dementia which describes the loss or decline of mental functions such as memory and reasoning 

Symptoms include short and long term memory loss, language problems, confusion, irritability,

 

words in the middle of conversations 

effectively anymore and can only convey very



Beta-amyloid proteins, which are proteolytic byproducts of amyloid precursor proteins (AAP's) neurons,

undergo Beta



5. Poor judgment

then



•

Accumulations of these fibrils in the gray matter



•

Senile plaques are neurotoxic

proteins

are

then

formed

which

will

aggregate to form amyloid fibrils

neuronal degradation •

These

plaques

can also

displace



functions

for

stability

of

microtubules in these cells •

assess

situation

Decision making is highly compromised

Rationalization and critical thinking skills are

Patients often lose things and may accuse people

8. Changes in mood behavior 

These tangles are neurotoxic and degrade the

10 Classical Signs and Symptoms of Alzheimer's

signs

of

behavioral

change

are

aggression 

Moods change very often and are difficult to predict

cytoskeleton of neurons Manifestations

Common

depression, irritability, confusion, anxiety, and

Tau proteins when hyperphosphorylated can cause the formation of neurofibrillary tangles

•

to

of stealing

Tau proteins found in the neurons of the central system

able

7. Misplacing objects

Formation of neurofibrillary tangles nervous

not

highly affected

neuronal connections, and other tissues in the

•

are

6. Problems with abstract thinking 

synapses,

brain

Patients effectively

of the brain are called senile plaques

and promote

Forget how they get to places and difficulty in recognizing landmarks

conformational sheet-rich

Do not recognize dates and often lose track of time

change •

In advanced cases, patients cannot communicate

4. Disorientation to time and place

Protein misfolding

in

Difficulty in learning new words and may forget

simple ideas

Causes

found

Difficulty in expressing complex ideas due to their diminishing vocabulary and fluency

aggression, and mood swings

•

Hard time in doing daily activities such as eating using utensils or writing

ALZHEIMER’S DISEASE



Difficulty in learning new tasks and concentrating

9. Changes in personality 

Examples include patients who are previously timid and shy may exhibit aggressiveness and

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BIOCHEMISTRY

NEUROPSYCHIATRIC DISORDERS

irritability

•

Etiology is still unclear; however, there are hypotheses relating it to be a combination of

10. Loss of initiative 

genetic and environmental factors

Withdrawal from social activities, hobbies, and

•

activities they used to enjoy before

Associated with neuronal degradation in the substantia nigra and to lesser extent globus

In advanced cases, patients may be immunocompromised, giving way to pathogenic agents

pallidus, putamen, and caudate nucleus •

Degradation of the neurons of the substantia nigra that send their axons to the corpus striatum results in a reduction in the release of the neurotransmitter dopamine within the corpus

Alzheimer's disease is diagnosed when:

striatum

1. Sufficient cognitive decline to meet criteria

•

for dementia

This

leads

dopamine

2. Clinical course consistent with that of

to

the

hypersensitivity

receptors

in

the

neurons

of

the

in

the

striatum

Alzheimer's disease 3. No other brain diseases

Causes I.

3 Clinical Evaluation of Dementia

Genes

1. General medical workup 2. Neurological

examination

including

testing

of

memory and other functions of thinking 3. Psychiatric evaluation to assess mood, anxiety, and clarity of thought Other methods to assess Alzheimer's disease include:

with

Autosomal

Dominant

1. SCNA (alpha-synuclein) •

Expressed throughout the mammalian brain and enriched in presynaptic nerve terminals

•

Protein

can

adopt

to

partially

folded

structures but in its native form is unfolded and can assume both monomeric and oligomeric

2. CT scan

alpha helix and beta sheet conformations •

Management the

moment,

As

•

One such symptom being treated is memory loss

Alzheimer's disease

These

proteins

can

also

assume

morphologically diverse aggregates ranging from

•



Associated

Parkinson Disease

1. MRI

of

Genetic Cause

there's

no

cure

for

•

amorphous and amyloid-like fibrils

Fibrillar moieties are a component of lewy

bodies in both familial and idiopathic Parkinson

Cholinesterase inhibitors such as Donepezil

disease

are used to prevent the breakdown of acetylcholine by acetylcholinesterase since

2. LRRK2

patients are observed to have decreased

•

synthesis of acetylcholine 

Repeat Rich Kinase 2

Memantine is used to regulate the levels of

•

glutamate •

such

as

behavioral

and

•

personality

changes 

LRRK2 functions as a tyrosine-like kinase protein

Other symptoms being treated are psychiatric in nature,

Gene for LRRK2 was identified as Leucine

Mutations appear to exert increased kinase activity

•

Medications include antidepressants, anti-

Interacts

with

other

familial

Parkinson

Autosomal

Recessive

disease protein

anxiety medicines, sleep medicines, and antipsychotics 

Non-medication

Genes include

recreational

activities and cognitive rehabilitation

1. Parkin

Second most common neurodegenerative disease

465-amino acid protein that belongs to the "ring between ring fingers" (RBR)

PARKINSON’S DISEASE

•

with

Parkinson Disease •

Overview

Associated

family of E3 ubiquitin ligases •

Dystonia is frequently present and patients are levadopa responsive

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BIOCHEMISTRY •

Substantia

NEUROPSYCHIATRIC DISORDERS nigra

undergoes

and tremor which progressed over several weeks

severe neuronal loss and gliosis •

and

Locus coeruleus is much less

improved

with

dopamine

replacement

therapy

severely involved •

Usually of lewy bodies

Manifestations Cardinal Features of Parkinson Disease:

2. DJ1

1. Rest tremor

•

Encodes a protein consisting of 189 amino acids

•

Homodimer that belongs to the peptidase C56



family of proteins •

and antagonists 

A cytoplasmic protein but can also translocate

•

DJ1 might act as either a redox-sensor protein that can prevent the aggregation of alpha-

2. Rigidity 

Caused by lesions of the upper motor neurons



if tremor is absent, the rigidity is felt as

synuclein or an antioxidant •

resistance to passive movement and referred to

It might also act as a reactive oxygen species scavenger

through

auto-oxidation.

This

is

as plastic rigidity 

important in nigral dopamine neurons that are

rigidity

stress • •

3. Bradykinesia

Encodes a protein with 581 amino acids Has

a

serine/threonine

protein



kinase

domain •





Lysosomal

membrane

protein

with

an

ATPase domain Member of the P5 subfamily of ATPases which transports inorganic cations and other substrates

Expressed in the brain with the highest

levels reported in the ventral midbrain

Swinging of the arm during walking is lost

Patient stands with a stoop, and his or her arms are flexed

Additional clinical manifestations include freezing of gait, postural instability, speech difficulty, autonomic disturbances, sensory alterations, mood disorders, sleep

dysfunction,

impairment,

and

No proven neuroprotective and disease-modifying therapy

3. Consumption of well water

I. Pharmacologic Treatment:

4. Exposure to herbicides

1. Levadopa coupled with carbidopa

5. Proximity to industrial plants and quarries

• Carbidopa

were

identified

inhibits

the

decarboxylation

of

levadopa to dopamine in the systemic circulation,

MPTP interference with mitochondrial function individuals

cognitive

Management

2. Living in rural environment

who

developed parkinsonism after self-injection of 1methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) •

performing

dementia

1. Pesticides

Several

and

Movements are slow, the face is emotionless,

II. Environmental Cause

•

initiating

4. Gait impairment

4. ATP13A2

•

in

and the voice is slurred and unmodulated 

and systemic organs

•

Difficulty movements

Mitochondrial protein located in the matrix and the intermembrane space that is in the brain

•

If tremor is present, the muscle resistance is overcome as a series of jerks, called cogwheel

exposed to particularly high levels of oxidative 3. PINK1

Tremor is slow and most obviously when the limbs are at rest and disappears during sleep

into the mitochondria and appears to act as an antioxidant

Results from alternating contraction of agonist

These patients developed bradykinesia, rigidity,

allowing greater levadopa distribution

• Levadopa

provides

the

greatest

antiparkinsonianbenefit for motor and signs and symptoms 2. Monoamine oxidase (MAO)-B inhibitor

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BIOCHEMISTRY •

NEUROPSYCHIATRIC DISORDERS

Initial treatment for the disease

nucleotides

are

introduced

during

DNA

repair processes and may result from hairpin 3. Dopamine agonists (ropinirole, pramipexole)

formation

•

region.

Provide

moderate

symptomatic

within

the

These

trinuleotide

intrastrand

repeat

base-paired

benefit and delay the development of dyskinesia

structures may lead to misalignment of DNA

compared to levodopa

strands and polymerization of additional nucleotides to fill the gaps.

II. Deep Brain Stimulation

•

Huntingtin, a polymorphic protein of unknown

Surgical procedure of choice for Parkinson disease

function,

for the following reasons:

consecutive Glutamine (Gln) residues beginning



It does not involve destruction of brain tissue It is reversible



it can be adjusted as the disease progresses Bilateral

stretch

of

11

to

34

In

Huntington

disease,

this

poly(Gln)

has

expanded to 37 and 86 repeats •

or adverse events occur 

a

17 residues from its N-terminus •



contains

procedures

Defect in Huntington disease was localized to the

can

be

performed

terminal

region

of

the

short

arm

of

chromosome 4

without a significant increase in adverse events

Manifestations

Thalamotomy •

Involves destruction of part of the thalamus, generally the ventralis intermedius to relive tremor

•

Choreic (jerky and disordered) movements

•

Cognitive decline

•

Emotional disturbances

Pallidotomy

Management

•

Involves the destruction of globus pallidus

•

Demonstrated significant improvements in each of the cardinal symptoms of Parkinson disease (tremor, rigidity, bradykinesia) as well as a significant reduction in dyskinesia

areas

of

neuroleptics

risperidone

can

such

as

clozapine,

be

used

to

treat

psychosis

the

difficulties,

which control the chorea

quetiapine,

Inherited neurodegenerative disorder, damages movement

1. Dopamine-blocking agents such as tetrabenazine

3. Atypical

Overview specific

I. Pharmacologic Treatment

2. Antidepressant and anti-anxiety drugs

HUNTINGTON DISEASE

•

No adequate treatment for cognitive or motor decline

brain,

resulting

cognitive,

II. Non-pharmacologic Treatment

in

•

behavioral

Important for people with HD to maintain

physical fitness, as individuals who exercise and

changes

keep active tend to do better than those who do not Causes

•

MYASTHENIA GRAVIS

Trinucleotide repeat disease results from the moderate expansion of a CAG triplet (which

codes for glutamine) in the protein coding region of the gene •

Overview 

Expansion of trinucleotide repeats occurs by an unknown mechanism 

of neuromuscular transmission 

One theory, that additional nucleotides are introduced polymerases

by

the

slippage

during

of

replication,

DNA



Another

possibility

Transcribers: Maja

and Krizelle



that

the

additional

The hallmark of the disorder is a fluctuating degree and variable combination of weakness in

inconsistent with the gradual accumulation such as neurons that normally do not divide

It is now one of the best characterized and understood autoimmune disorders

is

of trinucleotide repeats overtime in cells

Myasthenia gravis is the most common disorder

ocular, bulbar, limb, and respiratory muscles. 

Weakness is the result of an antibody-mediated, T-cell dependent immunological attack directed

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BIOCHEMISTRY at proteins in the postsynaptic membrane of the

NEUROPSYCHIATRIC DISORDERS •

neuromuscular junction

Bulbar muscles — Muscles of jaw closure are often involved and produce weakness with prolonged chewing (fatigable chewing). Oropharyngeal muscle weakness produces

Causes 

dysarthria and dysphagia.

Reduction in the number of AChRs (acetylcholine receptors) available at the muscle endplate and flattening of the postsynaptic folds 

•

involved and make the patient appear

anti-AChR antibodies are produced and block

expressionless.

the target receptors, cause an increase in turnover of the receptors, and damage the postsynaptic membrane 

•

weight of the head may overcome the extensors, particularly late in the day, producing a "dropped

and they may fall below the threshold value

head syndrome." Posterior neck muscles may

for generation of an action potential. The end

ache due to the added effort in keeping the head

result of this process is inefficient

up with the weakened muscles.

neuromuscular transmission The cholinergic receptors of smooth and cardiac muscle have a different antigenicity than skeletal muscle and usually are not affected by the



Neck and limb muscles — Neck extensor and flexor muscles are commonly affected. The

Even if a normal amount of ACh is released, fewer endplate potentials will be produced,



Facial muscles — Facial muscles are frequently

•

Respiratory muscles — Involvement of the muscles of respiration produces the most serious symptoms in myasthenia gravis. Respiratory

disease

muscle weakness that leads to respiratory

Thymic abnormalities are clearly associated with

life-threatening situation called "myasthenic

insufficiency and pending respiratory failure is a

myasthenia gravis but the nature of the

crisis."

association is uncertain 

Management

thymic abnormalities cause the breakdown in

tolerance that causes an immune-mediated

Anticholinesterase (AChE) inhibitors

attack on AChR in myasthenia gravis







Pyridostigmine, Neostigmine

for the pathogenesis of myasthenia gravis: myoid



Corticosteroid provides a short-term benefit

cells that express the AChR antigen, antigen



Azathioprine, Cyclosporine A

Thymus contains all the necessary elements

Initial treatment for mild MG

presenting cells, and immunocompetent T-cells IVIg (Intravenous Immunoglobulin) Manifestations Two clinical forms of myasthenia gravis: ocular and generalized •

In ocular myasthenia, the weakness is limited to the eyelids and extraocular muscles.

•

In generalized disease, the weakness commonly



(no value in mild disease) 

Elderly patients



Patients with complex comorbid diseases (eg, acute respiratory failure)



respiratory muscles. •

Ocular muscles — Weakness of the eyelid muscles can lead to ptosis, the degree of which can be quite variable throughout the day. At times, it may be so severe as to occlude vision.

Patients

with

severe

weakness

poorly

controlled with other agents

affects ocular muscles, but it also involves a variable combination of bulbar, limb, and

Moderate or severe MG worsening into crisis

Plasmapheresis 

Generally reserved for myasthenic crisis and refractory cases



Also effective in preparation for surgery



Can be used long-term or if other treatments cannot control the disease

Thymectomy

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NEUROPSYCHIATRIC DISORDERS

Proposed as a first-line therapy in most patients with generalized myasthenia gravis

3. Neurodevelopmental Hypothesis of Schizophrenia

Not recommended in patients with antibodies



to muscle-specific kinase (MuSK)

Developmental insults as early as late first or early second trimester lead to the activation of pathologic neural circuits during adolescence or

Diagnostic approach • •

young adulthood

Uses bedside tests (the Tensilon test and the ice



schizophrenia requires not only

pack test) that are easy to perform and sensitive

genetically induced neurological deficits,

Serologic tests for autoantibodies and

but unique psychological stressors as well

electrophysiological studies (repetitive nerve



"self-induced" to some extent

stimulation studies and single-fiber EMG)



it results from an otherwise normal process for plasticity that advances to form a "parallel", isolated circuit

SCHIZOPHRENIA

4. Abnormal Immune System Development

Overview 

Schizophrenia is a mental disorder characterized by breakdown of thought processes and impaired

Hypothesis 

hazards, post-pubertal onset, stress, genes,

emotional response. It is a chronic, severe, and

climate, infections, and brain dysfunction in the

debilitating condition that warrants life-long management

onset of schizophrenia 

The immune hypothesis is supported by findings of high levels of immune markers in the blood of

Causes

schizophrenia patients. High levels of immune

1. Dopamine Hypothesis 

This hypothesis explains the role of prenatal

Malfunction involving dopamine pathways systems in the mesolimbic pathway may

markers have also been associated with having more severe psychotic symptoms

contribute to the 'positive symptoms' of schizophrenia whereas problems with dopamine function in the mesocortical pathway may be responsible for the 'negative symptoms', such



Manifestations 1. Delusions - fixed beliefs that are not amenable to change in light of conflicting evidence

as avolition and alogia

2. Hallucinations - perception-like experiences that

2. Glutaminergic Abnormalities

3. Disorganized thinking and speech - typically

occur without an external stimulus

Of specific interest in this disorder are the presynaptic metabotropic receptors, which act as autoreceptors, regulating glycine and glutamate receptors, also known as NMDA receptors 

NMDA receptors are voltage dependent, that is, at 0 or near 0 membrane potential; they are blocked by Mg

2+

ions. Only when

there is a depolarization do these

inferred from the individual's speech. The individual may switch from one topic to another 4. Grossly disorganized motor behavior - childlike "silliness" to unpredictable agitation

Catatonic behavior is a marked decrease in reactivity

to the environment.   

receptors 

Glutamate blocking drugs can mimic the symptoms and cognitive problems associated with the condition, while the dopaminergic part of this illness is suggested by the D2 antagonisms that is a common mechanism of action by all

complete lack of verbal and motor responses

(mutism and stupor)

The NMDA component has largely been suggested by abnormally low levels of glutamate

maintaining a rigid, inappropriate or bizarre posture

Ca2+ channels open 

resistance to instructions (negativism)



Purposeless and excessive motor activity

without obvious cause (catatonic excitement)

5. Negative symptoms 

Diminished emotional expression includes

reductions in the expression of emotions in the face, eye contact, intonation of speech (prosody), and movements of the hand, head,

antipsychotic drugs

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and face that normally give an emotional



emphasis to speech 

Fragile X tremor ataxia syndrome is classified as a ‘pre-mutation’ of the full blown Fragile X

Avolition is a decrease in motivated self-

syndrome

initiated purposeful activities



Physical manifestations include tremors, ataxia, mild cognitive impairment, and ovarian insufficiency

Management Treatment of schizophrenia thus has two main 

phases 

200 CGG repeats can be observed causing the

Acute phase - when higher doses might be

methylation of the promoter region resulting to

necessary in order to treat psychotic symptoms 

the non-expression of FMRP-1

Maintenance phase - dosage is often gradually reduced to the minimum required to prevent





This would eventually result in cognitive impairment and behavioral abnormalities

further episodes and control inter-episode symptoms

In individuals with a ‘full’ mutation, more than

Genetic anticipation - mutation is passed from one

Neuroleptics- Thorazine, Haldol, Prolixin, Navane, Stelazine, Trilafon, and Mellaril

Although effective in treating positive symptoms (acute symptoms such as hallucinations, delusions,

generation to another, there is an increase in the size of the CGG repeat. 

The absence of FMRP is elucidated as the primary cause of the Fragile X syndrome

thought disorder, loose associations, ambivalence, or emotional lability), they can cause cognitive dulling

Manifestations

and involuntary movements, among other side effects. These older medications also are not so

Symptoms associated with Fragile X syndrome

effective against so-called negative symptoms such

overlaps with that of autism.

as apathy, decreased motivation, and lack of



emotional expressiveness

Echolalia, repetitive speech, poor conversation, poor eye contact, lack of peer relationship, hand flapping, obsessive compulsive behavior, and



Atypical antipsychotics

Fewer manifestations of the neurological side effects,

intense interests

which often include such symptoms as muscular

The key symptoms associated with Fragile X

rigidity, painful spasms, restlessness, or tremors, are

syndrome

seen



Developmental delay, mental retardation, prominent forehead, long narrow face, prominent



Clozaril is the only drug that has been shown to

jaw, protruding ears, large testes and social

be effective where other antipsychotics have

anxiety, strabismus, cleft palate, dental

failed

malocclusion, scoliosis and clubfoot, gastroesophageal disease, and otitis media FRAGILE X SYNDROME Overview



The Fragile X syndrome is considered as one of the most common cause of intellectual disability,

A subgroup of patients with full blown mutation exhibit symptoms which are characteristic of PraderWilli syndrome. This includes obesity, short stature, chubby hands, and diffuse hyperpigmentation.

occurring in 1 in 4,000 males and 1 in 8,000

Management

females Causes 

Mutation in Fragile X Mental Retardation Factor-1 (FMR1) gene which encodes for the protein FMRP (for normal brain development)

Pharmacological 

α-2-adrenergic agonists such as clonidine in order to treat hyperactivity, impulsivity, and aggressiveness

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BIOCHEMISTRY 

Serotonin reuptake inhibitors may also be used to

NEUROPSYCHIATRIC DISORDERS c. Plasmapharesis is the primary treatment for

treat anxiety, obsessive compulsive disorders, and tantrums 

patients with generalized MG d. Presence of anti-AChR antibodies cannot

Atypical antipsychotics may also be used to stabilize the mood of the patient

hinder production of end plate potentials e. All of the above f.

NOTA

Non-pharmacological 

Speech therapy, behavioral therapy, and occupational therapy

5. Which of the following is correct? a. NMDA receptors are blocked by Ca ions far from membrane potential b. Glutamine blocking drugs can mimic

REVIEW QUESTIONS 1. Which of the following statements is correct? a. In MG, ocular muscles are affected only in ocular MG but not in generalized MG b. Problems with dopamine function in the mesocortical pathway may be responsible for both positive and negative symptoms c. Some of the symptoms of Fragile X Syndrome that do not overlap with autism are prominent jaw, protruding ears, large testes and social anxiety d. ACE inhibitors are used as treatment for Schizophrenia e. All of the above f.

NOTA

symptoms of Schizophrenia c. Glutamic acid blocking drugs can mimic symptoms of Schizophrenia d. Glutamate blocking drugs can mimic symptoms of Schizophrenia e. All of the above f.

NOTA

6. Alzheimer's disease can be caused by a. Protein misfolding b. Hyperphosphorylation of tau proteins c. Formation of neurofibrillary tangles d. All of the above 7. Disease associated with the neuronal degradation of substantia nigra, and to lesser extent, globus pallidus, putamen and caudate nucleus

2. Which of the following is correctly paired?

a. Avolition: self-initiated purposeful activities b. Hallucinations: occur without an external

a. Alzheimer's disease b. Parkinson's disease c. Huntington's disease

stimulus

d. Fragile X Syndrome

activity with obvious cause

8. Symptoms associated with this disease include

c. Catatonic excitement: excessive motor d. Delusions: fixed beliefs that can be changed e. All of the above f. NOTA

short and long term memory loss, language

3. Which of the following is correctly paired?

b. Alzheimer's disease

a. Fragile X Syndrome: CCG repeats b. Fragile X Syndrome: CGC repeats c. FMR1 gene: FRMP protein d. FRM1 gene: FRMP protein e. All of the above f.

NOTA

problems, confusion, aggression, irritability, and mood swings a. Parkinson's disease c. Huntington's disease d. Fragile X Syndrome

9. Genes associated with autosomal dominant Parkinson disease a. SCNA b. Parkin

4. Which of the following statements is correct? a. Thymic problems can cause an immune-

c. LRRK2 d. Both A and C

mediated attack on ACh receptors b. Acetylcholinesterase is the enzyme needed to increase the concentration of ACh

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10. Patients with this disease suffer progressively with choreic (jerky and disordered) movements, cognitive decline, and emotional disturbances a. Alzheimer's disease b. Parkinson's disease c. Huntington's disease d. Schizophrenia Answers

1.C

2.B

3.F

4.A

5.D

6.D

7.B

8.B

9.D

10.C

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