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Dr.Giger

he remarks we all seem to have gotten the diagnosis right on the PBL. it 
was a real case and took more than a week to figure it out!

DrG started seeing these cases in 1985 when technology was not as 
advanced.

Keyla and Lance came in with very little clinical problems. problems like 
this often picked up at routine PE during vaccination appointment. they 
have very pale mms. extremely rarely, they will have icteric mms. the HCT 
is constantly low. during crises, eg excercise, infxn, may be VERY low. 
range about 16-25 on the four original cases, and in fact in the dozens 
since then. if you question the client, you find out that the animal may 
be a tad exercise intolerant. but a pet dog doesn't have a lot of demand 
put on it, so may not see it.

he is now going over the lab results seen with the PK deficiency. we 
already know: low HCT, increased MCV, sl low MCHC, increased retics, 
increased #NRBC/100 WBC...

more young RBC put into circulation. increased retic count means bone 
marrow is making RBCs. very regenerative anemia.

best way to assess destruction of RBC is labelling them, and seeing how 
long they survive. not often done. but can show apparent half life - in 
thise dogs is only 6 days where normal is about 19-28 days.

some people were concerned that keyla was not icteric. these dogs are not 
always icteric. but you see bilirubinuria. just not a huge increase in 
plasma bilirubin. it's excreted in the urine. another reason for 
bilirubin increase is liver dz. in this dog there is considerable liver 
dz associated with this.

i really am not going to write down this stuff that is just a repeat of 
the stuff discussed already in the PBL paper.

glycolysis is required for ATP synthesis so without pyruvate kinase...

in vivo, they showed buildup of products proximal to PK and lack of 
distal metaboiltes. they also showed the reduced halflife of RBCs so

Affected dogs have enzyme activity of less than 20% in most dz

in EMUS,they just found today that some storage material in nervous 
tissue..one of the enzymes in MPS is deficient - they have a storage dz ? 
that's what i think he said.

so in this dog, why does PK activity go ABOVE normal range?
this enzyme doesn't act normally. the activation with fructose 
diiphosphate is lower than normal with this form. 

in all species there is a switch from a premature RBC to mature RBC 
switching from M form to R isoform of PK. in normal dog, there is only R 
form PK. in affected, you only have M form. because of enzyme kinetics, 
this enzyme is not functional in the RBC these animals (in humans a small 
group of people have this M type, and some cats. the rest have NEITHER 
form) it's interesting that they have the M type, we're not sure why, and 
not sure why it doesn't compensate for the deficiency.

looking at partial oxygen pressure and O2 sat, at high p, 100% sat, at 
very low p, 0% sat. in middle is curve. normally p50 (50% sat) is at 28 
mmHg. in PK deficiency, it's about 32. in PFK deficiency itis very very 
low. in PK defic, you get build up of DPG which promotes O2 release. with 
PFK defic, you have buildup of fructose6phos and loss of everything else, 
so low DPG in these dogs. this causes a decrease in O2 delivery, and 
increased HbO2 affinity

constant persistent hemolysis results in changes in other organs. 
degenerative hepatopathy: necrosis, proliferation, extramedullary 
hematopoisis, liver failure. could have iron deposition in liver visible 
as dark staining areas on histo: hemosiderosis, degeneration. also the 
other interesting and poorly understood problem right now is that the 
bones are different in these dogs.  this is in all pk defic dogs but not 
cats, not people.trabeculae invade the marrow cavity. lots of fibrosis 
occurs. myelofibrosis and osteosclerosis...also called a "pleotropic 
affect" of this disease, which is poorly understood. because of this, 
this can be used clinically. if someone calls and asks about PK defic in 
a dog, Dr Giger can ask them about xrays...they can look at bone density 
and if it is increased, (usually seen by 1 yr, and is dramatic at 4 or 5 
near death) could be PK defic. once drg was looking at a beagle case and 
wanted to get a look at the bone marrow. owner didn't want them to bother 
the dog. but then this dog was riding around maine on a pickup truck and 
he jumped off. broke a femur! it was an open fracture. so they took a 
biopsy. :) no. he was trying to pin the bone (the surgeon) and finally 
was able to use a very, very fine pin to do the procedure. it was just 
that the BM cavity was full of bone, and didn't allow a pin through the 
nownonexistent canal.

so. what could be done in other breeds? what is up with the DNA testing 
stuff?

remember, keyla is affected, lance is unaffected...pedigree is drawn on 
board...

bunch of irrelevant stuff ignored.

the deletion in the basenji is not found in the other dogs with the 
problem. now, you could go looking at the gene and look for OTHER 
mutations. you could go ahead and clone gene in normal dog, isolate same 
gene from affected dog, and look for mutation. could look at mRNA in the 
reticulocytes. 

one thing to clarify - there are two different PK genes. one makes m1 and 
m2 forms, and one makes R form.

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