Friday, September 29, 2017

How clinical research can help human and animal patients: Lafora disease

anti epileptic drugs, anti seizure drugs, dog seizurs, Lafora
Some of the medications used to control seizures. These may control symptoms in dogs with early stage Lafora disease, but there is currently no cure.

When we think about animal-based research to benefit humans, we tend to think about animals in laboratories. But clinical-based research can incredibly helpful, and may benefit both species.

For example, collaboration between pet owners, vets and researchers at the University ofSurrey’s School of Veterinary Medicine and Fitzpatrick Referrals in Surrey is helping dogs and children with a rare, severe form of epilepsy.

The condition, Lafora disease, is very rare in dogs – although more prevalent in miniature wirehaired dachshunds, and has been seen in beagles and Basset hounds. Potentially, the genetic mutation that causes the disease could occur in any breed of dog spontaneously but it is autosomal recessive, so they need two copies of the disease gene to have disease i.e. both parents must be carriers or affected. The disease occurs due to a mutation in the Epm2b gene which leads to accumulation of glycogen in cells (Lafora bodies).

The disease affects around 50 children worldwide. Laforadisease is a fatal form of epilepsy caused by a genetic mutation, leading to abnormal levels of glycogen in the body. These abnormal levels of glycogen cause children and dogs to suffer progressive seizures, dementia and loss of mobility. In dogs, anti-epileptic drugs control seizures in the early stages of the disease, but there is no curative or long-term treatment available currently.

Understanding the signs and progression of the disease may help develop an effective treatment which could be used to treat affected children and dogs.

Veterinary researchers surveyed the owners of 27 miniature wirehaired dachshunds over the course of 12 months to study the clinical signs and physical advancement of the disease. The good news is that this involved patients with naturally occurring disease.

They discovered that the average age of onset of clinical signs in dogs was around 7 years. The most common clinical sign of Lafora are reflex and spontaneous muscle contractions, uncontrollable jerks and generalised seizures. Other common signs include focal seizures, jaw smacking, fly (of the non-existent kind) catching, panic attacks and aggression. Reflex and spontaneous muscle contractions was a clinical sign in 77.8 per cent of affected dogs. 51.9 per cent of affected dogs experienced uncontrollable jerks and 40.7 per cent experienced generalised (sometimes referred to as grand mal) seizures.

Signs that developed later in the disease include dementia (51.9%), blindness (48.1%), aggression to people (25.9%), aggression to dogs (33.3%), deafness (29.6%) and faecal (29.6%) and urinary (37.0%) incontinence as a result of loss of house training (disinhibited type behaviour). Read more here.

It sounds simple, but characterising rare diseases like this is incredibly challenging yet vitally important. How does a veterinarian know that a dog or puppy has Lafora disease, and not another seizure disorder?

For veterinarians, differentiating Lafora from other seizure disorders can be difficult, but is done on the basis of a) the presence of characteristic myoclonic (jerking) type seizure in response to flashing lights, sounds, movement; b) genetic testing and c) MRI changes (cortical atrophy), although these changes are not specific to Lafora.

Genetic testing is performed on blood submitted to the University of Toronto or via the Dachshund Breed health Council testing scheme

Dr Clare Rusbridge, Reader in Veterinary Neurology at the University of Surrey and Chief Neurologist at Fitzpatrick Referrals, said: “Lafora disease is a fatal disease that causes unbearable suffering for dogs and in rare cases young children.”

“Due to its rarity, little is known about the onset of this illness but what we have discovered, with the help of dog owners, is the clinical sign of Lafora helping to lead to quicker diagnosis. The more we learn about Lafora, the better chance we have of treating it effectively.”

The longstanding relationship between Dr Rusbridge and the Hospital for Sick Children in Toronto has led to the ground-breaking collaboration between human and veterinary medicine, which led to the discovery of the canine Lafora genetic mutation in 2005.

This research has already helped reduce the incidence of Lafora in dogs and thereby reduced suffering. Campaigning by the Wirehaired Dachshund Club and Dachshund Breed Council has led to an increased awareness and testing for the disease in breeding dogs. In 5 years, the proportion of litters bred with a risk of Lafora-affected puppies has been reduced from 55% to under 5%.

This represents huge progress, but there’s still a need to develop an effective treatment. Its another important example of how study of naturally occurring, rather than experimentally induced disease, can benefit humans and animals.