Neuroaxonal Dystrophy and Cavitating Leukoencephalopathy of Chihuahua Dogs

Abstract

A novel form of neuroaxonal dystrophy is described in 3 Chihuahua pups, 2 of which were from the same litter. It was characterized not only by accumulation of numerous and widely distributed axonal swellings (spheroids) but also by a severe cavitating leukoencephalopathy. The dogs presented with progressive neurological signs, including gait abnormalities and postural reaction deficits. Magnetic resonance images and gross examination at necropsy revealed dilation of lateral ventricles and cerebral atrophy, accompanied by cavitation of the subcortical white matter. Histopathologically, severe axonal degeneration with formation of large spheroids was found in the cerebral and cerebellar white matter, thalamus, and brainstem nuclei. Small-caliber spheroids were observed in the cerebral and cerebellar gray matter. The telencephalic white matter had severe myelin loss and cavitation with relative sparing of the U-fibers. Different from previously reported cases of canine neuroaxonal dystrophy, in these Chihuahuas the spheroid distribution predominantly involved the white matter with secondary severe leukoencephalopathy.

Ultrastructural features of canine neuroaxonal dystrophy in a Papillon dog

“…Canine neuroaxonal dystrophy (NAD), an inherited neurodegenerative disease characterized by severe axonal swelling (spheroids) throughout the nervous system, has been reported in several breeds including Papillons, Rottweilers, Chihuahuas, Collie sheepdogs, Jack Russell Terriers, Spanish water dogs, crossbreed laboratory dogs and Dachshund-cross dogs [ 2 , 4 , 5 , 6 , 9 , 13 , 14 , 15 , 18 , 21 ]. Recently, a missense mutation in PLA2G6 gene, encoding a calcium-independent group VI phospholipase A2 beta (iPLA2β), has been identified in the Papillon dog NAD [ 20 ].…”

“…Canine NAD has previously been reported in several breeds [ 2 , 4 , 5 , 6 , 9 , 13 , 14 , 15 , 18 , 21 ], but both ultrastructural and genetic/molecular analyses have been performed for a few cases. For example, spheroids consisted of the accumulation of autophagosomes in Spanish water dogs with a tectonin beta-propeller repeat-containing protein 2 ( TECPR2 ) mutation [ 9 ].…”

A Missense Mutation in the Vacuolar Protein Sorting 11 (VPS11) Gene Is Associated with Neuroaxonal Dystrophy in Rottweiler Dogs

“…Neuroaxonal dystrophy in humans without iron accumulation is seen in Wilson’s disease and Nasu-Hakola disease involving the ATP7B and DAP12/TREM2 genes respectively, and in “neuroaxonal leukoencephalopathy with axonal spheroids” which has no defined genetic cause to date ( Revesz et al 2015 ). Primary NAD has been reported in most domesticated species including dogs ( Clark et al 1982 ; Chrisman et al 1984 ; Blakemore and Palmer 1985 ; Evans et al 1988 ; Sacre et al 1993 ; Franklin et al 1995 ; Bennett and Clarke 1997 ; Siso et al 2001 ; Nibe et al 2007 ; Fyfe et al 2010 ; Fyfe et al 2011 ; Hahn et al 2015 ; Pintus et al 2016 ; Degl’Innocenti et al 2017 ; Tsuboi et al 2017 ), cats ( Woodard et al 1974 ; Carmichael et al 1993 ; Rodriguez et al 1996 ; Résibois and Poncelet 2004 ), cattle ( Hanshaw et al 2015 ), sheep ( Cordy et al 1967 ; Nuttall 1988 ; Harper and Morton 1991 ; Kessell et al 2012 ; Finnie et al 2014 ), pigeons ( Barrows et al 2017 ), mice ( Bouley et al 2006 ), and horses ( Beech 1984 ; Blythe et al 1991 ; Aleman et al 2011 ; Finno et al 2013 ; Finno et al 2016 ), where an association with vitamin E deficiency, along with a genetic susceptibility, has been reported.…”

“…In dogs, breed related NAD has been reported as fetal onset in Giant Schnauzer-Beagle mix breed dogs ( Fyfe et al 2010 ; Fyfe et al 2011 ), juvenile onset in Dachshund mix breed dogs ( Pintus et al 2016 ), Border collies ( Clark et al 1982 ), Chihuahuas ( Blakemore and Palmer 1985 ; Degl’Innocenti et al 2017 ), Jack Russell Terriers ( Sacre et al 1993 ), Papillons ( Franklin et al 1995 ; Nibe et al 2007 ; Tsuboi et al 2017 ), Spanish Water Dogs ( Hahn et al 2015 ), and young adult or adult onset in Rottweilers ( Cork et al 1983 ; Chrisman et al 1984 ; Evans et al 1988 ; Bennett and Clarke 1997 ; Siso et al 2001 ) and English Cocker Spaniels ( McLellan et al 2003 ). NAD in Cocker Spaniels is accompanied by retinal degeneration and is associated with vitamin E deficiency ( McLellan et al 2003 ).…”

Spontaneous Axonal Dystrophy in the Brain and Spinal Cord in Naïve Beagle Dogs

“…Axonal dystrophy is a known age-related spontaneous finding in the nervous system, especially brain, and has been reported in many animal species and humans. [1][2][3][4][13][14][15][16][17][18][19][20] Increased AD numbers have been seen in several breeds of dogs due to autosomal mutations leading to progressive degeneration of central and/or peripheral neurons [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] ; vitamin E deficiency, 4,38,39 presumably leading to increased oxidative stress 39 ; or exposure to toxicants that cause cytoskeletal cross-linking among other mechanisms of toxicity. [40][41][42][43][44][45][46][47][48][49] Axonal dystrophy also has been described in dogs with chronic wasting diseases (eg, filariasis, tumor-related cachexia).…”