Glycogenosis Type IV - GSD IV

 

Information about GSD IV

 


Glycogen Storage Disease IV (GSD IV) of the Norwegian Forest Cat in Europe

History
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This hereditary disease has been described for the first time in United States 15 years ago and was characterized by strange deaths after neuromuscular troubles concerning only related young cats. At this time Professor John Fyfe succeeded in proving that there was a genetic cause because of the narrow inbreeding for starting American NFC lines.
The mutation has been sequenced by J. Fyfe, a genetic test has been developed and is available since 1996.

Though the first cases have only been reported two years ago in Germany, the disease is likely to be more frequent that we could believe because ancestors of American NFC stayed in Europe. They unfortunately contribute to widespread the mutation in the NFC European population. As nobody (breeders and veterinarians) really knew about this problem and that almost all cases are just represented by neonatal death, the situation was unknown in Europe.
In France GSD IV testing enables us to keep veterinarians informed of this disease and we have already gathered three young NFC which were likely to be affected by GSD IV according to their veterinarian's memory.

A smattering of genetics


Like for each Mammal, cats have several pairs of chromosomes, support of their genetically information. Each chromosome is composed by several genes and all genes present different possible forms which are called alleles.
Each animal inherits a chromosome from his father and the other from his mother that is to say a paternal and a maternal allele.
This allele is called recessive whether it expresses itself only when it's present twice in the same animal. Otherwise it's a dominant allele (or co-dominant whether both alleles express themselves at the same time). GSD IV mutation is recessive to wild (or normal) allele.

Well three different possibilities can be found:

(1) Both parents are healthy (they are homozygote for the normal allele), so their children will be healthy.
(2) If one is carrier (heterozygote), we will get around 50% of carriers and 50% of healthy cats among their children. Unfortunately when an unknown carrier is always married with healthy cats, he doesn't show he carries the mutation and it's disastrous when such a cat has plenty of descendants.
(3) When two carriers are married together we get 25% of ill cats, 50% of carriers and 25% of healthy cats.

Inherited alleles (mother / father)

M

N

M

Mm (= ill)

Nm (= carrier)

N

Nm (= carrier)

NN (= healthy)


Should I feel concerned by this story?
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At least two different lines seem to be concerned by this problem. Unfortunately it could be three or four … We have no backward with this disease and we do not have enough data for assuring that only two novices were carriers.
However mutations are scarce events that is why we are currently searching for a relation between these lines, maybe a geographical or professional relation but researches are difficult because of novices.

What are clinical signs of affected cats?


GSD IV pathogenic corresponds to a deficiency in glycogen stocking. Clinical signs are due to a chronic hypoglycaemia getting gradually worse. Consequently GSD IV is especially dominated by neuromuscular signs.

· Most of affected kitten are still-born or die quickly after birth (in the first hours or days).
· There is another clinical form; this form is scarcer but more specific too. Some homozygote affected kittens grow normally until age of 5-7 months. But suddenly they stop their development and become weaker and weaker with the following clinical signs:

> High hyperthermia (over 40 degree Celsius). Corticosteroids are completely ineffective against this fever.
> ntermittent generalized body tremors getting permanent
> Intermittent listlessness and "bunny hopping".
> Muscle weakness then muscle atrophy, fibrotic contractures of selected joints leading to difficulties for moving itself, eating … involving a lot of nursing for the owner.
> Tetraplegia
> The disease is inevitably lethal, often around age of 10 to 14 months. Such young adult die of hearth attack sometimes after coma. Nevertheless the owner often decides to euthanatize his pet because this seems to suffer a lot in the last months of life.

GSD IV diagnosis?
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Different analyses can be led: creatinine kinase (CK) activity increases (proving muscular lesions) and sometimes hepatic parameter ALT too.
Needle electromyography is informative but the only sure diagnosis needs genetic test. Two labs propose currently this test in Europe: Antagène in France, Lakoblin in Switzerland.
In the past they used histopathology or measured GBE activity (GBE is the deficient enzyme in GSD IV).

What should we do?
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Now genetic test enables us to detect not only affected cats but carriers which are the real problem and THE danger for the breed.
Nobody can assure that his lines are healthy. Indeed still-born babies are quite usual in breeding whereas the neuromuscular form still was completely unknown from most of European breeders and veterinarians until the beginning of this year.

Of course we are unlikely to find GSD IV allele in a cattery never having any problems in his lines despite lots of inbreed. However it cannot be excluded, GDS IV problems take sometimes until ten years before being obvious. For example we find GDS IV in unexpected lines in France and Germany

By disregarding this problem, the carrier frequency is going to increase as soon as the mutation will meet a well-known line.
We currently know that well-known North-European catteries already had (or always have?) carriers because some exported kittens have been tested positive.
Besides I must add that we have a doubt too for a World Winner who bred at least two suspected cats in two different litters.

Nevertheless this disease is sublethal: all affected cats die before having the opportunity to have descendants and to widespread the mutation. Consequently the disease frequency should remain constant what explains why we "just" have 6% of carriers in France.

Well you are likely to wonder why we advise you to test your cats if the frequency doesn't increase. For answering I invite you to imagine owner's ordeal when he bought an affected babies developing the first signs only two months after. Today we know the disease and we have ways for battling against.
Moreover each breeder has liabilities towards the breed and its followers but other towards other breeders too. History is an eternal beginning and the American situation in the nineties could be lived again elsewhere on earth, if a carrier was exported in a country where NFC pool is limited. Now we know so we will be in charge of such problems.

Of course every breeders still had still-born kittens … I don't want you to worry uselessly but just to ask you the good questions before saying that you are not concerned.
Test a cat today corresponds to several cats that we won't need to test in years to come.

I was the first to think that we could neglect this story. However we found around 6% of carriers in France and 8% in France with Germany. It's quite important for a disease that was not known at the beginning of the year.

What should I do if one of my cats is a carrier?
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· This cat should be neutered and all his breeding descendants have to be tested.
· However if the concerned cat is very important for your breeding plans and is nearly perfect he can be married with healthy cats. All breeding kittens have to be tested and carriers reserved as pets. Before being sold such kittens should be neutered and get a chip.
· If you don't have any carriers and if you want to buy a new cat require the breeder to sell you a healthy cat. Do the same when you accept to do strange covering.

Amber and Glycogen Storage Disease?
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The two first European affected cats were amber and enabled us to unearth a problem we have already heard about without feeling really concerned.
However GDS IV does not concern only amber cats! Unfortunately some amber ancestors met GSD IV carriers and the inbreeding for fixing the colour selected in the same time GSD IV. Indeed GSD IV has been described for the first time in the United States but amber colour never appeared over there despite inbreeding.

Today GSD IV testing has been led in several amber German catteries.
If the first results seemed to be frightening the definitive results are rather good and there are only some carriers.
An appropriate selection will enable to forget GSD IV in several years. For avoiding the same problem in the future all introduced cats in these breeding plans have to be tested.

If you want to know more …
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Articles

FYFE et al. (2007)
A complex rearrangement in GBE1 causes both perinatal hypoglycaemic collapse and late-juvenile-onset neuromuscular degeneration in glycogen storage disease type IV of Norwegian forest cats, Mol Genet Metab. 90, 4, 383-92.

FYFE et al. (1992)
Glycogen storage disease type IV: inherited deficiency of branching enzyme activity in cats., Pediatr Res. 32, 6, 719-25.

FYFE (1995)
Glycogen storage disease in cats, J Am Vet Med Assoc. 206, 3, 286.

GASCHEN et al.
In Congenital feline myopathies, Glycogen Storage disease type IV, 360-361

Web

http://ourworld.compuserve.com/homepages/L_P_SWEPSTON/GSD.htm

http://www.antagene.com/index.php?page_id=214&rubrique_id=126&coderub1=3&coderub2=0&coderub3=7&langue=L1&menu= (pour le dépistage)

http://www.winterfyre.com/testing/

http://w3.vet.upenn.edu/research/centers/penngen/services/deublerlab/gsd4.html

http://gsd4.de.vu/ (german)

© Marc PETERSCHMITT, veterinarian

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Olympias clinical course

Anamnesis

D*Olympia Edle von Rada, NFO is born in April 2006. The first clinical signs appeared when she was 4-5 months old. Firstly there were just hyperthermia (over 40°Celsius), some tremors and apathy.

From August of this year her growth stopped, tremors and ataxia in all limbs (but especially hind limbs) got gradually worse. Until the age of 7 months her appetite was normal. Her owner reported nervous fits everyday, these lasted around 2-10 minutes: she tumbled; she licked furiously her back and bit furiously all objects she found.

Olympia was seen by different veterinarians and finally followed by the National Veterinary School in Nantes (ENVN) when she was 7 months old.

Between August and October, different analyses were done: her hemogram was normal, usual biochemical analyses were twice normal (urea, creatinine, ALT, PAL, inorganic phosphate, calcemia); just her glycaemia was a little too low. On the contrary creatinine kinase activity was high (1048U/L)

In ENVN the only clinical signs were high hyperthermia, deficient development, and muscle atrophy. The neurological examination revealed just intermittent generalized body tremors:

At this stage five hypotheses were firstly viewed:

Diagnostics

Results

Usual values

Urea (g/l)

0.38

0.2-0.6

Créatinine (mg/l)

14.1

< 16

Phosphatases alcalines (PAL) (U/l)

37

< 200

Alanine aminotransférase (ALT) (U/l)

107

< 80

Protein (g/l)

80

65-75

Glycemia (g/l)

0.72

0.6-1.1

Calcemia (mg/l)

108

90-115

Sodium (mEq/l)

150

147-156

Potassium (mEq/l)

4.5

3.5-4.5

After these results a metabolic cause was privileged and Olympia has been tested for GDS IV in USA thanks to French breeders who heard about a similar case in Germany two years ago and reminded of an article. Olympia was homozygote positive.

Evolution

Olympia got corticosteroid (anti-inflammatory dose) but there was no amelioration. Olympias state got gradually worse. She had difficulty in prehending and swallowing food. Her nervous fits were more frequent and because of ataxia she wasn’t able anymore to move herself after December; generalized body tremors became permanent excepting when she slept. Her owner decided to euthanatize Olympia in the end of January, because she seemed to suffer a lot.

© Delphine Hecquet, veterinarian

Translated by Marc Peterschmitt, veterinarian

This side ready posed of: Cattery von Rada

 

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