Sunday 31 July 2011

Truffle hound helps root out childhood epilepsy gene

The Lagotta Romagnola:fit for function?
The first-ever gene for idiopathic epilepsy in dogs has been found by Professor Hannes Lohi  at the University of Helsinki, heading an international team of scientists.

The mutation - in a gene called LGI2 - appears to be unique to the Lagotta Romagnolo, the appealingly-shaggy Italian breed known for its excellent truffle-hunting skills.  The Lagotta suffers a form of juvenile epilepsy marked by seizures causing tremor, trembling, shaking and wheezing which, typically, set in at around four weeks of age and last for up to two months before stopping completely. The researchers believe the same gene could be responsible for a similar type of epilepsy found in children.

"Remission is so reliable that the epilepsy is considered by many breeders as an unfortunate particularity of the breed and often disregarded" write the authors of a new paper published online in PloS Genetics.

This is indeed the case. Here's what  the Lagotta Romagnolo Club of GB  has to say about the condition (known in the breed as BFJE - Benign Familial Juvenile Epilepsy - although not on the Club website which has had no health updates since, er, 2003. There, they're still referring to it as a "cerebella anomaly").

"So do Members have to worry about their dogs developing this anomaly? ABSOLUTELY NOT," they insist. "It is only when breeding that the Anomaly may be produced.  Furthermore if we followed (and by we I mean everyone in the world breeding Lagotto) the usual advice in eliminating an inherited disease – namely do not breed from a suspected carrier’s descendents, siblings or parents Lagotto would cease to exist as a breed."

A little shocking but probably true. As the researchers report:  "The popularity of the breed fluctuated with the truffle industry and in the early 1970s underwent a strong genetic bottleneck to near extinction, when a group of dog lovers decided to save it."

No surprise, then, that the researchers have found that one in three Lagottos carry the mutation, which is an autosomal recessive. This means that a dog usually has to inherit two copies of it (one from each parent) in order to be affected.  However, the researchers also found that of the 28 affected dogs in the study for which they had DNA samples, two of them (7%) had only one copy of the mutation. This means that carriers can occasionally suffer, too.

In truth, an epilepsy that invariably resolves by the age of four months is not the most serious of problems  - although the researchers still hope that breeders will avail themselves of the new DNA test for Lagottos developed by the Finnish team and offered through Lohi's company Genoscoper Oy (Ltd) for €85.

Sadly, there are other neurological problems in the breed: "The study revealed another form of epilepsy in the breed, unconnected with this mutation and with an age of onset in adulthood. In addition, the breed has a progressive juvenile ataxia (lack of motor coordination) with similar onset and symptoms to juvenile epilepsy except that it does not remit -- ataxic puppies have to be euthanized usually by the first year of life. More samples are needed for both adult-onset epilepsy and ataxia to enable us to investigate their genetics further," says a primary author of the study, Eija Seppälä, PhD.

Epilepsy is the most common neurological disease in children - occuring in 1 in 200 children aged between two and 10 years old. 

It is also the most common neurological disease in dogs - in some breeds 10 times more common than it is in humans.

Meanwhile, two other new canine epilepsy studies report interesting findings - the first that neutered male dogs may be more likely to have epilepsy; the second that giving epileptic dogs essential fatty acids (long recommended by some as an alternative treatment for epilepsy in humans and dogs) made no difference whatsoever.

Characteristics of epileptic episodes in UK dog breeds: an epidimiological approach (A Mount et all, Vet Record, 2011) looked at a cohort of 1260 epileptic dogs from 78 known breeds as well as a group of crossbred dogs.  The researchers found that epilepsy was more common in male than female dogs. This is in line with previous studies but, in a new finding, the researchers found some evidence that neutering may be a risk factor for epilepsy in male dogs. Previously, neutering has been believed to reduce seizure in epileptic dogs.

The authors urge caution re over-interpreting the results as the data come from a laboratory-based recruitment as opposed to a clinical study - but it is nevertheless interesting, especially with the growing awareness that there are health costs as well as benefits to neutering.

The researchers found also that just four pedigree dog breeds - and crossbreeds as a group - accounted for more than half of the cases of epilepsy in their study:

Crossbreeds - 20.5%
Labrador Retriever - 11%
Border Collie - 10.5%
German Shepherd - 6.5%
Staffordshire Bull Terrier - 5.2%

In a separate study (Effects of essential fatty acid supplementation in dogs with idiopathic epilepsy: A clinical trial, Helen Matthews et al, Veterinary Journal, article in-press) researchers found that giving dogs Omega 3 oil - recommended by many as a natural/supplemental treatment for epilepsy - did not help.

"The effects of essential fatty acid supplementation (EFA) on the control of idiopathic epilepsy in dogs were investigated in a blinded, placebo-controlled trial," write the authors. " Fifteen dogs were treated with triple purified Ω-3 oil containing 400 mg eicosapentaenoic acid, 250 mg docosahexaenoic acid and 22 mg vitamin E per 1.5 mL at a dose of 1.5 mL/10 kg once daily for 12 weeks, followed by a 12 week placebo period of supplementation with olive oil. Owners recorded seizure frequency and severity and any adverse events. EFA supplementation did not reduce seizure frequency or severity in dogs with idiopathic epilepsy."

There was one exception though, according to co-author Barbara Skelly from the University of Cambridge Vet School. "Our results showed that in the majority of dogs there was no appreciable difference in the response to both oils but one dog did appear to show a dramatic response and therefore a larger scale investigation is probably merited."

That's probably enough to reassure all the proponents of EFAs....

6 comments:

  1. It is probably true that the "don't breed relatives of affected dogs" advice would doom this breed, but the instance of a heterozygous affected dog is certainly troubling. A working breed ripe for some judicious outcrossing?

    On one level I agree that an issue that reliably self-resolves should not be in the first column of genetic disease concerns. But the seizures themselves alter brain function, and may damage the dog neurologically permanently. Has anyone followed up on the comparative neurological function of puppies who seized v. those that did not?

    Not to mention the simple animal welfare concern for the poor puppies. Seizures are no picnic.

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  2. Having lived with a severely epileptic Dalmatian, Emma I agree with Heather. It is amazing how far down in the sand, breeders heads are over inherited epilepsy. I was the DCA's director of the Epilepsy study groupfor 12+ years until I left because of the unethical behaviour over the regisration of the Low Uric Acid Dalmatians ( we won by the way ) Epilepsy is one of the most devastating diseases especially for the owner.


    Also I was interested in
    "Effects of essential fatty acid supplementation in dogs with idiopathic epilepsy"

    I am not sure if they were trying to accomplish something similar to the ketogenic diet which works for children but not for dogs. In the USA a dog food company ran a study to see if a high fat diet could help the seizures. The research was discontinued after it was found it didn't work The reason is dogs are more resistant to ketosis induced by starvation, compared to people. As carnivores, dogs are adapted to relatively long periods of time between meals. Therefore, diets that induce ketosis in people may not do so in dog.

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  3. Also, I wouldn't make much of the preponderance of epilepsy cases represented by members of only a few breeds. I'm sure it is very nearly true that the proponderance of dogs in Britain are of the very same breeds. Without a sense of what percentage of the dog population is accounted for by, say Labradors, the figures are uninformative.

    In the US, it would not be out of the question that Labradors and "Labradors" are 11% of all dogs.

    There are some rarer breeds in which epilepsy is an acknowledged scourge, but they won't ping the radar looked at this way, as their absolute numbers are so relatively low.

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  4. Interesting about the data on neutering as a possible risk factor for seizures. I am not able to access the research report. Do you know if they looked at the possibility that some of these dogs may have been neutered BECAUSE they were epileptic? Or did the seizures begin after neutering?

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  5. Or the seizures were triggered in a predisposed animal by the anesthesia?

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  6. To Heather Houlahan's question . . . around 3% of Labs were found to be epileptic in Denmark. 70% of the dogs found to be epileptic had partial seizures. . . Reference below. I think they've barely scratched the surface in understanding epilepsy.


    J Vet Intern Med. 2002 May-Jun;16(3):262-8.
    A cross-sectional study of epilepsy in Danish Labrador Retrievers: prevalence and selected risk factors.
    Berendt M, Gredal H, Pedersen LG, Alban L, Alving J.
    Source

    Department of Clinical Sciences, The Royal Veterinary and Agricultural University of Copenhagen, Denmark. meb@kvl.dk
    Abstract

    The purpose of this study was to investigate the prevalence and selected risk factors of epilepsy, the proportion of dogs with epilepsy in remission, and the types of seizures in Danish Labrador Retrievers. A prospective cross-sectional study of epilepsy was conducted in 1999-2000. The study was carried out in 2 phases in a reference population consisting of 29,602 individuals. In phase 1, 550 dogs were selected by random sampling stratified by year of birth. A telephone interview was used to identify dogs with possible epilepsy. In phase 2, dogs judged during phase 1 as possibly suffering from epilepsy were further subjected to physical and neurologic examination, CBC, blood chemistry, and a questionnaire on seizure phenomenology. Seventeen dogs were diagnosed with epilepsy, yielding a prevalence of 3.1% (95% CI 1.6-4.6%) in the Danish population of Labrador Retrievers. A diagnosis of epilepsy was 6 times more probable in dogs >4 years (born before 1995) than in younger dogs (born between 1995 and 1999) (P = .004, relative risk = 6.5). No significant difference in risk between genders was observed, nor could any effect of neutering be proven statistically. The frequencies of primary generalized seizures and partial seizures (with or without secondary generalization) were 24 and 70%, respectively. The type of seizures could not be classified in 6%. In conclusion, the 3.1% prevalence of epilepsy in Danish Labrador Retrievers is higher than the 1% prevalence of epilepsy described in the general canine population, establishing that this breed is at increased risk.

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