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Lafora's disease

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Introduction

Lafora's disease is an inherited, late onset, progressive myoclonic epilepsy. Myoclonus (jerking) is a feature of the disease and characteristically this can be induced by flashing lights, sudden sounds and movement (especially that close to the dog’s head). Generalised or complex partial seizures may be seen in some dogs. The disease progresses slowly over many years and gradually other neurological deficits such as ataxia, blindness and dementia occur.
Lafora's disease can occur spontaneously in any breed however the miniature wire-haired dachshund, Bassett hound and beagle are predisposed. Typically the first signs occur in animals over 5 years (usually over 7 years) age and both sexes can be affected. The beagle has a more severe version of the disease and the associated epilepsy can be drug resistant.

A characteristic of this disease is myoclonus (clinical sign of a sudden contraction of a group of muscle), typified by rapid shuddering/jerking the head backwards. The myoclonus occurs spontaneously and in response to noise, flickering light (including television), and sudden movement in the visual field.




Video of MWDC with myoclonus links
1- click here for movie (mpg, takes longer to load)
2- Lafora dog wakes here (Youtube)

Hypnic (sleep related) myoclonus may also occur.Some dogs also develop epilepsy (generalised tonic clonic seizures and complex partial seizures). The complex seizures are often characterised by high pitched vocalisations and behaviour as if the dog is panicking.

The main differential diagnoses of this disease are other causes of epileptic seizures and idiopathic epilepsy. Haematological and biochemical screens should be performed to rule out reactive causes of epileptic seizures, but will be normal in Lafora disease. Magnetic resonance imaging is useful to identify structural brain disease which may cause acquired epilepsy. Idiopathic epilepsy typically occurs in younger dogs (6 months to 6 years) and in most breeds myoclonus is not a feature.

The genetic mutation in the Dachshund and Bassett Hound was identified at The Hospital for Sick Children, Toronto. Click here to read about the discovery of the gene. 
The Hospital offers a test for affected dogs in return for a $350 (Canadian dollars) donation to the hospital (credit cards are accepted).
10mls of EDTA blood should be submitted to:
Dr. Berge Minassian Room 6536B The Hospital for Sick Children 555 University Ave. Toronto, ON M5G 1X8 Canada Tel: 416-813-7721 berge.minassian@sickkids.ca

In the UK, the Wirehaired Dachshund Club run a national Lafora screening programme, which means that testing is available from the team at the Toronto Hospital for Sick Children at a significantly subsidized rate and can contribute to research and responsible breeding, with an eventual aim of eliminating the condition from the breed. For more information on how to get involved, contact:
Nora Price: E-mail laforatesting@mypostoffice.co.uk tel: 01543 276797

The disease may also be confirmed by identification of the Lafora bodies in a liver, muscle or nerve biopsy).
Lafora’s disease is caused by a mutation in the EPM2B (NHLRC1) a gene that encodes malin E3 ubiquitin ligase, a protein involved with carbohydrate metabolism. Early data suggests that these proteins safeguard neurons against accumulating too many carbohydrates. A characteristic feature of the disease is accumulation of toxic starch-like material (polyglucosan) within cells, particularly nervous, hepatic and muscle tissue. Lafora disease has an autosomal recessive inheritance i.e. both the sire and the dam will either carry (i.e. have no signs of the disease and have one copy of the abnormal gene) or have the disease.

Medication
Not all dogs with Lafora’s disease require medication however if they have frequent seizures (for more information on epilepsy click here) or if the myoclonic jerking is disabling then therapy is advised. In some cases this can be difficult since some dogs do not respond to traditional anti-epileptic drugs like phenobarbital.

If the main problem is seizures then the author typically starts with potassium bromide at 30-40mg/kg once daily. A serum bromide concentration should be assessed 8-16 weeks after initiating the drug (since it takes 4 months to achieve steady state levels of bromide so ideally blood samples should be taken at 16 weeks) aiming for a concentration of ~ 1000mg/l (or 15 mmol/) - 2000mg/l / (or 25mmol/l). Higher serum concentrations are acceptable if there are no adverse effects such as sedation, ataxia.

If this serum concentration of bromide has been achieved and the number of seizures is still unacceptable then phenobarbital at 3mg/kg every 12 hours should be added to the regime. Phenobarbital should also be considered if there are clusters of seizures. A serum phenobarbital concentration should be assessed 2 weeks after initiating the drug. If the seizures are still not adequately controlled when the phenobarbitone serum concentration is ≥25mg/l (120μmol/l) then switching from phenobarbital to unlicensed (i.e. human) anti-epileptic drug should be considered (for example Levetiracetam or Zonisamide) It is worth considering referral to a veterinary neurologist at this stage as they are likely to be more experienced in prescribing these drugs (for details on how to arrange a referral to the Stone Lion Veterinary Centre click here).
doglasses
Lafora’s disease is due to excess storage of a starch-like compound, polyglucosan in the nerve cells. Latest research suggests that in Lafora’s disease there is a problem with the control of the manufacture of glycogen and/or regulation of insulin sensitivity. Glycogen is a polysaccharide (complex carbohydrate) of glucose which is stored in the animal cell providing the most important source of short term energy.

Anecdotally there is some evidence to suggest that dogs with Lafora’s disease are improved on a low GI diet - in other words a diet which is low in simple carbohydrates. Simple carbohydrates e.g. glucouse and starch are easily and quickly digested and release glucose rapidly into the bloodstream. There are many proprietary dog food diets that that have a low GI-index and/or are low in carbohydrates (look for a low grain content) and some owners use homemade diets however, remember that before changing your dog’s diet you should seek the advice of your veterinary surgeon. Starchy/sugary treats may aggravate Lafora’s disease and should be avoided.
Some dogs have a problem walking in sunlight and some owners have found that the jerking significantly improves if the dog wears sunglasses (DOGGLES).
Signs of Lafora’s disease can be aggravated by stress and anxiety and dogs with Lafora’s disease can be more likely to become anxious. Contact your veterinary surgeon for advice. Simple aids include Dog Appeasing Pheromone (DAP) which is available as a spray, a diffuser or a collar. DAP is the synthetic equivalent of the pheromone secreted by bitches to reassure their pups.


Lafora's disease is not generally fatal in the dog however the myoclonus and seizures may worsen with time and older dogs may become blind and ataxic compelling the owner to request euthanasia. The beagle has a different genetic mutation and a more servere form of the disease. In particular the epilepsy may be drug resistant in this breed. The human form of the disease is also more serious with affected children developing dementia and status epilepticus; most do not survive beyound their second decade.

Lafora’s disease is inherited as an autosomal recessive condition. To have the disease the affected dog will have inherited one copy of the disease gene from each of the parents – this means that…

Both the SIRE and the DAM of a dog with Lafora’s disease will be either a CARRIER (one copy of the gene and unaffected) or AFFECTED (two copies of the gene)

ALL of the puppies of a dog with Laforas disease will be either a CARRIER (one copy of the gene and unaffected) or AFFECTED (two copies of the gene). They will only be affected if the mate of the Lafora’s affected dog was also either a carrier or affected.

Ian Seath, Chair of the Dachshund Breed Council, has created a diagram which illustrates how important how important it is to know the affected/carrier/clear status of a dog.
Genetics chart (see attached)

Lafora dogs http://laforadogs.org/ This website aims to provide central hub for information for people who have dogs that they think might be suffering from Lafora’s disease, has just been diagnosed with it or are concerned that they might develop it in the future. There is also information on management based on other owners’ personal experience and what is currently being done to try to reduce the number of affected dogs in the future.