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
17
Q
Describe the formation of neurofibrillary tau tangles
A
- Normally, tau stabilises microtubules which are used to transport vesicles containing nutrients and other molecules rouond the neuron
- In Alzheimer’s abnormal tau separates from the microtubules causing them to degenerate
- Strands of tau tangle which further destroys the microtubules leading to cell death
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
21
Q
What are the complications of sickle cell disease?
Who is most affected by sickle cell disease?
A
- Compications associated with it include acute chest syndrome, splenic and renal dysfunction, cerebral vascular problems and painful episodes involving soft tissues and bones
- It affects primarily people of African heritage
22
Q
What are the most common causes of mortality with children suffering from sickle cell disease?
A
- Most common causes of mortality in children suffering with sickle cell disease include bacterial infections, splenic dysfunction and acute chest syndrome
23
Q
What are the symoptoms of sickle cell disease?
A
- Yellow appearance of eyes and skin
- pale skin
- Delayed growth
- Bone and joint pain
- Increased risk of infections
- Development of leg ulcers
- eye damage
- Amaemia
- Damage to organs due to restricted blood flow
24
Q
What are the treatment options for sickle cell disease?
A
- No cure for sickle cell disease
- treatments aim to releive symptoms, prevent organ damage and infections
- For patients with acute chest syndrome, oxygenation is improved by treatment with diffusions and bronchodilators
- Drug therapy such as azacytidine and hydroxyurea are used to increase foetal haemoglobin levels which is effective in some patients with sickle cell disease
- Alternatives to long-term therapy include bone marrow and hematopoietic stem cell transplantation
25
What are inherited metabolic disorders and why are they important?
* inherited metabolic disorders are a heterogeneous group of monogenic disorders, which commonly arise from deficient activity in a single pathway of intermediary metabolism
* Although they are individually rare, they are still an important cause of morbidity and mortality in clinical practice
26
How are inherited metabolic diseases classified?
* They are put into three classes
1. Disorders that disrupt the anabolism or catabolism of complex molecules
2. Disorders with symptoms associated with the deficiency of energy production or utilisation
3. Disorders that lead to acute or progressive accumulation of toxic compounds due to a metabolic block
27
Under which class are protein metabolism disorders put under?
Give some examples of protein metabolism disorders
* Protein metabolism disorders are put in the class of disorders that lead to acute or progressive accumulation of toxic compounds due to a metabolic block
* Protein metabolism disorders include phenylketonuria, maple syrup urine disease and tyrosinemia
28
What is phenylketonuria?
* 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
What are the symptoms of phenylketonuria?
* Symptoms of PKU, associated with imbalances in metabolism within the central nervous system, include mental retardation and motor dysfunction
30
When is phenylketonuria diagnosed and how is it treated?
* 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
What is maple syrup urine disease caused by?
* 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
What are the characteristics of maple syrup urine syndrome?
* Characteristics include physical retardation, feeding difficulties and a maple syrup odour of urine
33
What does maple syrup urine disease result in metabolically?
* 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
What are the different subtypes of maple syrup urine syndrome?
* There are five subtypes of maple syrup urine syndrome
1. The "classical" neonatal severe form
2. An "intermediate" form
3. An "intermittent" form
4. A "thiamine-responsive" form
5. An "E3-deficient with lactic acidosis" form
35
How do you get maple syrup urine syndrome ?
How is it treated?
* 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
What is tyrosinemia?
* 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
37
What are the different types of tyrosinemia?
* Type I
* Type II
* Type III
* These are covered separately on different flashcards
38
Outline type I tyrosinemia
What are the characteristics, what happens if left untreated and what is its severity?
* 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
What is type II tyrosinemia?
* 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
What is type III tyrosinemia?
* 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)
