LAFORA DISEASE

RESEARCH

 

 

Overview

Lafora disease is an inherited late onset progressive myoclonic epilepsy. Myoclonus (jerking) is a feature of the disease which characteristically 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.

Signalment

Lafora disease can occur spontaneously in any breed however the Miniature Wire Haired Dachshund, Bassett Hound and Beagle are predisposed. Age of onset is after 5 years and both sexes can be affected. The Beagle has a more severe version of the disease and the associated epilepsy can be drug resistant.

Signs

A characteristic of the disease is myoclonus, 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. 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.

Causes and risk factors

Lafora’s disease is caused by a mutation in the EPM2B (NHLRC1) a gene which 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.

Diagnosis

In the miniature wire-haired Dachshund and Basset Hound the disease causing genetic mutation has been identified however at the present time no commercial DNA blood test exists. The disease may be diagnosed by identification of the Lafora bodies in a liver, muscle or nerve biopsy).

Differential diagnosis

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

Hematology / biochemistry / Urinalysis

Normal

Other Laboratory tests

Lafora bodies may be identified in a liver, muscle or nerve. The liver is the most reliable biopsy site

Magnetic resonance imaging

Normal

Treatment

Anecdotally Miniature Wirehaired Dachshunds with early Lafora’s disease respond to a proprietary antioxidant rich diet (Hills b/d ™). Hills b/d ™ has been shown to protect nerve cells against oxidative damage however this may not be the mechanism by which it is effective for Lafora disease as the same beneficial effect is not seen if the dog is maintained on the existing diet and supplemented with  anti-oxidants. It is possible that Hills b/d ™ is effective because it has a low glycaemic index. Starchy/sugary treats may aggravate the condition and should be avoided. Other diets with a low glycaemic index may be effective.

 

Epilepsy should be treated symptomatically. In some cases this can be difficult as some dogs do not respond to traditional drugs like phenobarbital. 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 (it takes 4 months to achieve steady state so ideally 16 weeks)  aiming for a concentration of ~ 1000mg/l / 15 mmol/l - 2000mg/l / 25mmol/l. Higher serum concentrations are acceptable if there are no adverse effects e.g. sedation and ataxia.

 

If this concentration has been achieved and the number of seizures is still unacceptable then phenobarbital at 3mg/kg every 12 hours should be added. Phenobarbitone 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 phenobarbital serum concentration is ≥25mg/l (120μmol/l) then switching to an unlicensed anti-epileptic drug should be considered. The author typically chooses Levetiracetam (Keppra) at a dose of 10-20mg/kg twice to three times daily. Coincidently with starting the levetiracetam the phenobarbital is slowly withdrawn (as long as the seizure frequency does not increase). Anecdotally levetiracetam is more effective than phenobarbital or bromide for controlling the myoclonus (jerking) and one should consider using this drug as first line therapy if the myoclonus is disabling.

 

Some dogs have a problem walking in sunlight and some owners have found that the jerking significantly improves if the dog wears sunglasses (DOGGLES).

Follow up

The 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 euthanasia. The Beagle has a different genetic mutation and a more severe 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 beyond their second decade.

 

Clare Rusbridge BVMS PhD DECVN MRCVS RCVS and European Specialist in Neurology

References

Sainsbury R (2011) DNA screening for Lafora's disease in miniature wire-haired dachshunds. Vet Rec. 169(11):292. - PubMed -.

 

Thomas WB (2010) Idiopathic epilepsy in dogs and cats. Vet Clin North Am Small Anim Pract. 40(1):161-79. Review. - PubMed -

 

Webb AA, McMillan C, Cullen CL, Boston SE, Turnbull J, Minassian BA (2009) Lafora disease as a cause of visually exacerbated myoclonic attacks in a dog. Can Vet J. 50(9):963-7.- PubMed -

 

 

Share this with your friends

Click here for the legal bits