TY - JOUR
T1 - Canine lafora disease
T2 - An unstable repeat expansion disorder
AU - von Klopmann, Thilo
AU - Ahonen, Saija
AU - Espadas-Santiuste, Irene
AU - Matiasek, Kaspar
AU - Sanchez-Masian, Daniel
AU - Rupp, Stefan
AU - Vandenberghe, Helene
AU - Rose, Jeremy
AU - Wang, Travis
AU - Wang, Peixiang
AU - Minassian, Berge Arakel
AU - Rusbridge, Clare
N1 - Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
KW - Canine
KW - Chihuahua
KW - Dodecamer repeat mutation
KW - EPM2A
KW - French Bulldog
KW - Griffon Bruxellois
KW - Hypnic jerk
KW - Muscle biopsy
KW - NHLRC1
KW - Photoconvulsions
KW - Progressive myoclonic epilepsy
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U2 - 10.3390/life11070689
DO - 10.3390/life11070689
M3 - Article
C2 - 34357061
AN - SCOPUS:85111253289
SN - 0024-3019
VL - 11
JO - Life
JF - Life
IS - 7
M1 - 689
ER -