L18- Disorders of Energy Metab 1 (#1) Flashcards
______disorders are a heterogenous group of inherited metabolic disorders resulting from a defective enzyme in the metabolism of glycogen, leading to an abnormal glycogen quality or quantity of glycogen
Glycogen storage disorders
What is glycogen?
A storage form of glucose in animals, mostly found in muscle and liver
Case 1: A 5-year-old female American cocker spaniel has a history of mild anemia since the age of 5 months. Occasionally the owner of the dog noted “stress-related” episodes of dark brown urine and slight depression lasting for one to three days. Severe episodes occurred predictably after extensive exercise, a long car ride or excessive barking. She is presented to the MWU veterinary clinic with anorexia, dark urine, and lethargy after intensive
running while hunting On physical examination she had while hunting. On physical examination, she had pale and icteric pale and icteric mucus membranes, and the body temperature was 40 °C ( o a 38 (normal 38-39 °C). Blood test revealed anemia and abnormally low levels of 2, 3-BPG. _____ deficiency was suspected and confirmed by DNA testing. Family history of this cocker spaniel revealed English Springer spaniel ancestors.
PFK deficiency
PFK is common in what type of dogs?
English spring spaniel, american cocker spaniel
What are the 3 forms of PFK produced?
M-PFK, L-PFK, P-PFK
PFK deficient dogs have a mutation in the ____ gene ?
M-PFK
In PFK deficient dogs, what two things are severely decreased?
- Total RBC
2. Muscle PFK activities
Study Q: What is the role of PFK?
RLS of glycolysis
Study Q: What is the role of 2,3-BPG in RBCs?
Negative allosteric effector of Hb.
It decreases Hb affinity for O2
Study Q: How would you expect the blood 2,3-BPG levels to be in an anemic dog?
High
Since 2,3-BPG decrease Hb affinity for O2, so more O2 can be released from Hb and go to the tissues that are hypoxic as a result of the anemia
Study Q: Blood 2,3-BPG levels are actually lower than normal in this dog- Why?
PFK enzyme is needed to run glycolysis.
One of the intermediates (1,3-BPG) is needed to produce 2,3-BPG in RBCs, but it is not possible to reach the reaction that forms 2,3-BPG without a functional PFK enzyme
PFK deficiency results in a deficiency of ____, which results in tissue hypoxia of affected dogs
2,3-BPG
We know that dogs with PFK deficiency are not ____ because deficiency of 2,3-BPG would stimulate the syntehsis of more RBCs
Anemic
Study Q: Spaniel presented with signs of pale and icteric mucus membranes, in addition to dark urine- what may have caused these signs?
- Hemolytic anemia is observed after exercise and filtered in urine
- Pale and icteris mm are result of increased Hb degradation. Degrad. of heme group in Hb leads to bilirubin prod which gives a yellow coloration
If there is the analyte, ATP in the muscle of the PFK dog, then what happens to the levels compared to normal? Why?
Decrease- metabolic block at the PFK step results in glycolysis inhibition
If there is the Lactate, ATP in the muscle of the PFK dog, then what happens to the levels compared to normal? Why?
Decrease- metabolic block at the PFK step results in glycolysis inhibition
If there is the Sugar phosphates, ATP in the muscle of the PFK dog, then what happens to the levels compared to normal? Why?
Increase- g6P and FGP accumulate as a result of PFK mutation
If there is the glycogen, ATP in the muscle of the PFK dog, then what happens to the levels compared to normal? Why?
Increase- amnts of G6P flows to glycogen syn, due to G6P accumulation and decrease flow to glycolysis
Study Q: Muscles of the PFK deficient dogs have reduced working capacity and may cramp- affected dogs seem to tire more easily. Despite PFK deficiency, signs of myopathy (dmg to muscle cells) are relatively mild. Why are muscle cells less affected than RBCs? What metabolic fuel is muscle tissue using?
- FA can be used by muscle cells to obtain E. However RBCs are not able to do so b/c they lack mitochondria.-There is a high oxid rate of FA in canine skeletal muscle, much higher than in humans
Study Q: What Tx would you recommend for a PFK deficiency dog?
(Need to avoid hemolytic crises- therefore hyperventilation and RBC lysis are prevented)
- Restrict from vigorous exercise
- Restrict from any activity that leads to excessive excitement such as excessive barking or long car rides
Case 2: A 4-year-old male AiQ i f American Quarter horse, had a history of exercise-associated muscle cramping, with the last case 4-5 weeks ago. The owner always considered him a lazy horse reluctant to exercise but things got always considered him a lazy horse, reluctant to exercise, but things got worse that Monday morning after a 30 minute of very light exercise of walking and trotting. His abdomen was tensed up and he developed walking and trotting. His abdomen was tensed up, and he developed tremors in the flank area. When standing, he stretched out as if to urinate.
He was stiff and sweat profusely. The urine had a dark, coffee color, and the veterinarian confirmed muscle damage. The veterinarian suspects of _____________, and takes a blood sample for a genetic test. Results come back positive for the disease.
Polysacchardie storage myopathy (PSSM) type 1
PSSM type 1 is a disease affecting the muscle _______ 1 gene in horses
Glycogen synthase
Study q: What is the RLE in glycogen synthesis? What rxn does it catalyze ? (PSSM)
Glycogen synthase
- In charge of the a(1-4) glycosidic bond in the linear portion of glycogen. The branches formed by a(1-6) glycosidc bonds are formed by the action of the branching enzyme
Some symptoms of PSSM 1 include?
Increasing 2-fold glycogen concentration, Episodes of exertional rhabdomolysis, Pain during exercise, kidney damage
Without a rise in branching activity, the higher glycogen synthase/branching enzyme ratio results in formation of ________ in animal with PSSM
Polyglucosan (structurally abnormal polysaccharides)
____ which normally cleaves a(1-4) gluc-gluc bonds in glycogen is unable to cleave the bonds in these abnormal structures in PSSM
Amylase
Study q: Why does urine have a dark color in this animal with PSSM?
Myoglobinuria- Mb released form dying muscle cells as a result of physical activity
Pain develops becaues of lack of ___________ of PSSM animals- this leads to malfunction of the ______ which increases intracellular Na+ lvls. This overall results in the ____ and rupture of plasma membrane
ATP, Na/K ATPase pump, osmotic swelling
Mb in ____ in the presence of dehydration and the toxicity is related most likely to the iron relaesed in the kidney following degrdation
Nephrotoxic
Free iron catalyzes the formation of reactive ____ species
Oxygen
Exertional rhbdomyolysis of PSSM animal refers to muscle injury and kidney damage- why?
Muscle injury: lack of ATP to keep up with body
Kidney damage: Mb release from damage muscle cells
What enzymes can we use as a marker if the muscle cells of a PSSM animal was damaged?
Increased lvls aminotransferases (eg ALT)
Increased lvls creatine kinase (CK)
What enzymes can we use as a marker if the liver cells were damaged? (not in PSSM animal) - eg?
Increased aminotransferases
EG: poisoning with toxic mushroom cause increase serum ALT lvls
Recommednations for animals with PSSM? (3) and describe
- Avoid prolonged rest- can lead to typing up, rapid breathing, etc
- Exercise- gradual exposure
- Dietary modifications- typically a low starch/sugar and high fat diet is recommended which would lower glucose uptake into muscle cells leading to more FA for use in muscles
Case 3: A 4-week-old male Maltese dog shows a general failure to thrive compared to his siblings. On physical examination, abnormally low weight, muscle wasting, general weakness and massive hepatomegaly were
observed. A sample of blood submitted to the lab for biochemical testing revealed severe fasting hypoglycemia, lactic acidemia, hyperalaninemia, and hypertriacylglyceridemia. Hypoglycemia was persistent, even when fasted for as little as 2 hours Unfortunately he progressed to death at 60 fasted for as little as 2 hours. Unfortunately he progressed to death at 60 days of age. A genetic test on liver and kidney samples revealed _____ deficiency.
g6P deficiency
G6P deficiency is also knowsn as ___________ or type 1 glycogen storage disorder
von Gierke disease
What breed is G6P deficiency more common in?
Maltese
Study q: What is the function of G6Pase? In what tissue do we find G6Pase?
- Catalyzes reaction from G6P to glucose, the last step of glycogenolysis and gluconeogenesis
- This enzyme is found in liver/kidney
Study q: What metabolic pathways maintain normal blood glucose levels during fasting state (G6p)
1) Liver glycogenolysis
2) Liver and kidney glucogenesis
Fasting hypoglycemia was observed in this dog- what is happening with the I/G ratio? Is it releasing glucose? Will glycolysis be active or inactive?
- IG ratio= lower than normal
- Unable to release glucose so that means there will be a G6P accumulation
- Glycolysis will be active
What pathway is activated by high G6P availability?
Hepatic glycogenesis
How does hepatic glycogenesis manifest in terms of liver morphology?
Hepatomegaly (enlarged liver)
Hyperalaninemia was observed in this dog- what is happening with the I/G ratio? what is its muscle lysis activty compared to normal?
- Lower I/G ratio than normal
- Muscle lysis activity will be higher than normal
What H prevents an inc rate of muscle breakdown?
Insulin
How does muscle lysis in hyperalaninemia manifest in terms of physical manifestation?
Muscle wasting, general weakness
Lactic acidemia was observed in this dog- what is happening with lactic levels?
Lactic levels will be increased
In lactic acidemia- why are lactic levels increased?
- Inc muscle lysis: alanine –> pyruvate
- Inc glycolysis, leading to formation of more pyruvate
Where is NADH being produced in lactic acidemia?
Increased rate of glycolysis
