Week 7 - metabolic disorders Flashcards
1
Q
Give six examples of metabolic diseases
A
- Amyloidosis
- Alzheimer’s disease
- Sickle cell disease
- Phenylketonuria
- Maple syrup urine disease
- Tyrosinemia
2
Q
What is protein folding and what is the likelihood of protein misfolding
A
- Protein folding occurs when newly synthesized protein molecules fold into their three-dimensional structure
- Protein misfolding is a common occurence for proteins
3
Q
What is protein misfolding and what is it dependant on?
A
- Protein misfolding is dependent upon the amino acid composition and environmental factors such as increases in temperature, pH changes, increasing in glucose and oxidative agents
- When proteins are exposed to these factors their native conformation is disrupted (denaturation) which commonly results in the unfolding of proteins
- Denatured proteins are nonfunctional
4
Q
What does the term “protein misfolding diseases” refer to?
Give some examples of these diseases
A
- Protein misfolding diseases refer to a group of diseases that have protein aggregation and plaque formation in common
- Some diseases include:
- Amyloidosis
- Alzheimer’s disease
- Sickle cell anaemia
5
Q
What is amyloidosis?
How can you get amyloidosis?
A
- Amyloidosis refers to a group of protein misfolding diseases which involves the accumulation of protein aggregates either systemically or locally in organs and tissues
- Amyloidosis can be either hereditary or acquired
6
Q
How does herediary and acquired amyloidosis arise?
A
- Hereditary amyloidosis arises from mutations in the genes of plasma proteins
- Conditions that cause acquired amyloidosis are still unknown
7
Q
What are the symptoms of amyloidosis?
A
- The symptoms associated with amyloidosis vary amongst patients, depending on which protein is disrupted and where the aggregation occurs
- The affected organs are typically enlarged
- Most patients with amyloidosis have kidney failure, heart problems and gastrointestinal abnormalities
8
Q
What is the most common form of amyloidosis?
A
- Most common form is primary systemic amyloidosis which involves the production of immunoglobulin light chains from plasma cell clones
9
Q
What treatments are available for amyloidosis?
A
- In most form of amyloidosis corrective therapy is not available
- Objective of current treatment methods is to minimise the supply of immunoglobulin light chain by suppressing the underlying plasma clone
10
Q
What is Alzheimer’s disease and what is it characterised by?
A
- One of the most studied protein conformational diseases
- Neurodegenerative disorder and is the most common form of pregressive dementia in the elderly
- Characterised by the accumulation of the amyloid-β peptide aggregates and intracellular neurofibrillary tangles of tau proteins which forms a senile plaque in the brain
11
Q
How is amyloid-β formed?
A
- Amyloid-β is cleaved from the amyloid precursor protein (APP)
12
Q
What are the changes associated with Alzeimer’s disease?
A
- Emotional, cognitive and behavioural changes associated with Alzheimer’s varies for each person
- A stage model describes the broad characteristics for most patients and is divided into three phases (see #12)
13
Q
What is the stage model of Alzheimer’s disease?
A
- Describes broad characteristics amongst most patients
-
First stage - commonly referred to as the “forgetfulness phase”, in which patients have difficulties in recalling recent events, with the tendancy to forget where objects have been placed
- Emotional changes associated with this stage include anxiety, irritability and denial
-
Second stage - commonly referred to as the “confusion phase”
- Associated with decline in congitive performance, deteriorating memory, poor attention span & disorientation
- Third stage - this is the “dementia phase” which is characterised by bizarre and disjointed behaviour
14
Q
How can patients get Alzheimer’s disease?
A
-
Acquired - environmental factors may have a role in triggering Alzheimer’s disease in succeptible individuals
- Research has shown as possible link between aluminium and Alzheimer’s
- Hereditary - gene mutations and polymorphisms that either cause Alzheimer’s or increase the risk of developing it have become increasingly credible
15
Q
What are the current treatments available for Alzheimer’s?
A
- Currently no cure for Alzheimer’s disease
- Acetylcholinesterase inhibitors are used for the treatment of early onset of Alzheimer’s disease with variable effectiveness
16
Q
Describe the formation of amyloid-β plaques
A
- In healthy neurons the enzyme α-secretase cleaves amyloid precursor protein (APP) on the plasma membrane and then γ-secretase cleaves APP at another site to release two fragments
- Both benefit the health of neurons
- In Alzheimers, the first cleavage is made by another enzyme, β-secretase, fragments combines with that produced by γ-secretase to release amyloid-β
- amyloid-β clumps together to form insoluble oligomers leaving to amyloid-β plaques
18
Q
What is sickle cell disease and how is it caused?
A
- Defined as a group of genetic disorders characterised by the inheritance of sickle haemoglobin (Hb S) from both parents
- Alternatively, it can arise from inheritance of Hb S from one parent and a gene from an abnormal haemoglobin or β-thalassemia from the other parent
19
Q
What effect does Hb S have on erythrocytes?
What are the long-term implications of this?
A
- Presence of Hb S cause the shape of erythrocytes to change from their biconcave disk shape to a sickle shape during deoxygenation
- Upon reoxygenation, erythrocytes resume their biconcave shape
- Repeated cycles of “normal and abnormal” configurations cause the erythrocytes to become permanently damaged and haemolyzed
20
Q
What does haemolysis, resulting from sickle cell disease, cause?
What does the difference in shape result in?
A
- Haemolysis of erythrocytes is responsible for anaemia which is the hallmark of sickle cell disease
- Abnormally, sickle, shape erythrocytes can cause the obstruction of blood flow which can lead to acute and chronic tissue injury
28
Q
What is phenylketonuria?
A
- Phenylketonuria (PKU) is the most common autosomal recessive disorder of amino acid metabolism which targets PAH gene
- PAH gene encode phenylalanine hydroxylase
- Defects in PAH result in hyperphenylalanemia which arises because the hydroxylation of phenylalanine to tyrosine is blocked
29
Q
What are the symptoms of phenylketonuria?
A
- Symptoms of PKU, associated with imbalances in metabolism within the central nervous system, include mental retardation and motor dysfunction
30
Q
When is phenylketonuria diagnosed and how is it treated?
A
- Commonly diagnosed at birth through elevated phenylalanine blood plasma levels
- The current method of PKU treatment is enforcing a dietary restriction on the intake of phenylalanine
- Ongoing research in gene therapy is promising
31
Q
What is maple syrup urine disease caused by?
A
- Caused by mutations in at least three genes:
- branched-chain keto acid dehydrogenase E1 (BCKDHA)
- branched-chain keto acid dehydrogenase E1 (BCKDHB)
- Dihydrolipoamide branch-chain transacylase (DBT)
- These genes encode 2 of the catalytic components of the branched-chain alpha-keto acid dehydrogenase complex (BCKDHD) which functions to catalyse the catabolism of branch-chain amino acids
32
Q
What are the characteristics of maple syrup urine syndrome?
A
- Characteristics include physical retardation, feeding difficulties and a maple syrup odour of urine
33
Q
What does maple syrup urine disease result in metabolically?
A
- Condition results in a block of oxidative decarboxylation which results in the presence of keto acids of the branched-chain amino acids in the urine
34
Q
What are the different subtypes of maple syrup urine syndrome?
A
- There are five subtypes of maple syrup urine syndrome
- The “classical” neonatal severe form
- An “intermediate” form
- An “intermittent” form
- A “thiamine-responsive” form
- An “E3-deficient with lactic acidosis” form
35
Q
How do you get maple syrup urine syndrome ?
How is it treated?
A
- Maple syrup urine syndrome is inherited in an autosomal recessive manner which affects girls and boys equally
- Treatment includes a strict diet to control the intake of branched chain amino acids which is continued throughout life
- Most forms of the disease, if left untreated, can result in life threatening neurological damage or death
36
Q
What is tyrosinemia?
A
- It is a genetic disorder characterised by elevated levels of tyrosine
- In this condition tyrosine is not catabolised correctly which leads to accumulation of the amino acid and its metabolites in tissues and organs
38
Q
Outline type I tyrosinemia
What are the characteristics, what happens if left untreated and what is its severity?
A
- Type I tyrosinemia is an autosomal recessive disorder caused by deficiency of fumarylacetoacetase which is the last enzyme of tyrosine degratation
- Characteristics include progressive liver disease and secondary renal tube dysfunction which leads to hypophosphatemic rickets
- Left untreated, patients typcially die at a young age from cirrhosis or liver cancer
- Type I tyrosinemia is the most severe form
39
Q
What is type II tyrosinemia?
A
- It is an autosomal recessive disorder caused by a mutation in the tyrosine aminotransferase gene
- Characterised by mental retardation, elevated serum levels of tyrosine, keratitis and photophobia (abnormal sensitivity to light)
- Caused by a deficiency of hepatic tyrosine aminotransferase
40
Q
What is type III tyrosinemia?
A
- It is a rare autosomal disorder caused by the deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase
- Characterised by elevated levels of blood tyrosine and excessive excretion of its derivatives into the urine
- Patients with type III tyrosinemia have mild mental retardation, seizures and intermittent ataxia (periodic loss of balance and coordination)
