Canine Lafora Disease: An Unstable Repeat Expansion Disorder.

Thilo Von Klopmann,Peixiang Wang,Berge Arakel Minassian,Helene Vandenberghe,Jeremy Rose,Saija Ahonen,Clare Rusbridge,Daniel Sanchez-Masian,Irene Espadas-Santiuste,Kaspar Matiasek,Travis Wang,Stefan Rupp

doi:10.3390/life11070689

Abstract

Canine Lafora disease is a recessively inherited, rapidly progressing neurodegenerative disease caused by the accumulation of abnormally constructed insoluble glycogen Lafora bodies in the brain and other tissues due to the loss of NHL repeat containing E3 ubiquitin protein ligase 1 (NHLRC1). Dogs have a dodecamer repeat sequence within the NHLRC1 gene, which is prone to unstable (dynamic) expansion and loss of function. Progressive signs of Lafora disease include hypnic jerks, reflex and spontaneous myoclonus, seizures, vision loss, ataxia and decreased cognitive function. We studied five dogs (one Chihuahua, two French Bulldogs, one Griffon Bruxellois, one mixed breed) with clinical signs associated with canine Lafora disease. Identification of polyglucosan bodies (Lafora bodies) in myocytes supported diagnosis in the French Bulldogs; muscle areas close to the myotendinous junction and the myofascial union segment had the highest yield of inclusions. Postmortem examination of one of the French Bulldogs revealed brain Lafora bodies. Genetic testing for the known canine NHLRC1 mutation confirmed the presence of a homozygous mutation associated with canine Lafora disease. Our results show that Lafora disease extends beyond previous known breeds to the French Bulldog, Griffon Bruxellois and even mixed-breed dogs, emphasizing the likely species-wide nature of this genetic problem. It also establishes these breeds as animal models for the devastating human disease. Genetic testing should be used when designing breeding strategies to determine the frequency of the NHLRC1 mutation in affected breeds. Lafora diseases should be suspected in any older dog presenting with myoclonus, hypnic jerks or photoconvulsions.

Highlights

Lafora disease is one of the severest forms of myoclonic epilepsies that is observed in several species but in humans and dogs
Magnetic resonance imaging of the brain revealed the presence of Chiari-like malformation and a partially empty sella/pituitary cyst
We describe here three dog breeds and a mixed-breed dog affected with Lafora disease

Summary

Introduction

Lafora disease is one of the severest forms of myoclonic epilepsies that is observed in several species but in humans and dogs. It is a recessively inherited disease caused by several different mutations in genes coding for laforin glucan phosphatase (EPM2A) or NHL repeat containing E3 ubiquitin protein ligase 1 (NHLRC1, known as EPM2B) [1,2,3]. Primary clinical signs include myoclonus (photomyoclonic response), tonic–clonic seizures, visual hallucinations and blindness [4,5]. Rapid progression of the disease leads to more severe and frequent seizures with increased refractoriness, ataxia, dementia and, eventually, in humans, a vegetative state. Dogs are typically euthanized when quality of life is significantly impacted by the disease [5]

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