Canine Lafora Disease: An Unstable Repeat Expansion Disorder

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.

Lafora Disease and Alpha-Synucleinopathy in Two Adult Free-Ranging Moose (Alces alces) Presenting with Signs of Blindness and Circling

“…The exact mechanism of regulation of glycogen metabolism by the laforin-malin system in the generation of PGBs remains unknown. The transformation of spherical and soluble glycogens to insoluble misstructured polyglucosans in the neurons and astrocytes due to mutations in the EPM2A or EPM2B genes is thought to be the pathogenesis underlying LD in humans and animals [26,28,34,51,52]. However, it was suggested that glycogen synthase is the only enzyme that catalyzes formation of α1 ± 4 interglucosidic linkages that generate glycogen (or polyglucosan) strands [53].…”

“…Among non-human species, LD has been reported in cats, cows, dogs, gray-headed flying foxes, raccoons, fennec foxes, and parakeets [21][22][23][24][25]. However, genetic abnormalities with inheritance have been demonstrated only in certain breeds of dogs [26][27][28][29][30][31][32][33][34][35]. The key factor involved in neurodegeneration in Parkinson's disease (PD) in humans is the accumulation of α-synuclein caused by mutations in the SNCA gene, which encodes α-synucleins.…”

Dogs as a Natural Animal Model of Epilepsy

“…In addition to idiopathic epilepsy in Beagle dogs, Hegreberg and Padgett ( 263 ) described a form of familial epilepsy and its relationship to a similar condition in man, i.e., PME (or Lafora disease), a rare late-onset neurological storage disease characterized by deposits of polyglucosans (Lafora bodies) in the brain and caused by an autosomal recessive genetic defect resulting in myoclonus as well as focal and generalized seizures ( 264 ). In addition to Beagles, PME has been described in several other breeds including the Basset hound, Chihuahua, French Bulldog, Pointer, Miniature Poodle, Miniature Dachshund, and Welsh Corgi ( 49 , 265 ). More recently, PME in Beagle dogs has been characterized in more detail ( 266 ).…”

Advancing genomic technologies and clinical awareness accelerates discovery of disease-associated tandem repeat sequences

“…Prominent examples include various canine diseases associated with repeat expansions, such as (1) the dodecamer GCCGCCCCCCGC pathogenic repeat associated with a epilepsy (canine Lafora disease) in many species of dogs ( Lohi et al 2005 ; Webb et al 2009 ; Barrientos et al 2019 ; Kehl et al 2019 ; for review, see von Klopmann et al 2021 ), (2) a 38-bp VNTR in the dopamine transporter gene, DAT / SLC6A3 , associated with seizures and behavioral issues in Belgian Malinois dogs ( Lit et al 2013 ), and (3) the GAA repeat expansion associated with spinocerebellar ataxia in Italian Spinone dogs ( Forman et al 2015 ). Oddly, nonrepeat mutations in the human homologs of some of these genes, like NHLRC1 and ITPR1 , cause similar disease in humans, but the human gene does not contain the unstable repeat present in the canine gene as outlined in Table 3 ( Chan et al 2003 ; Das et al 2017 ; Zambonin et al 2017 ; for review, see von Klopmann et al 2021 ). While it remains puzzling that the highly unstable, pathogenic “dynamic” repeat mutations seem to be mostly confined to humans, in these particular cases, it seems that the canine disease, but not the human, is linked to repeat expansions.…”