Inherited neuroaxonal dystrophy in dogs causing lethal, fetal‐onset motor system dysfunction and cerebellar hypoplasia

Abstract

Neuroaxonal dystrophy in brainstem, spinal cord tracts, and spinal nerves accompanied by cerebellar hypoplasia was observed in a colony of laboratory dogs. Fetal akinesia was documented by ultrasonographic examination. At birth, affected puppies exhibited stereotypical positioning of limbs, scoliosis, arthrogryposis, pulmonary hypoplasia, and respiratory failure. Regional hypoplasia in the central nervous system was apparent grossly, most strikingly as underdeveloped cerebellum and spinal cord. Histopathologic abnormalities included swollen axons and spheroids in brainstem and spinal cord tracts; reduced cerebellar foliation, patchy loss of Purkinje cells, multifocal thinning of the external granular cell layer, and loss of neurons in the deep cerebellar nuclei; spheroids and loss of myelinated axons in spinal roots and peripheral nerves; increased myocyte apoptosis in skeletal muscle; and fibrofatty connective tissue proliferation around joints. Breeding studies demonstrated that the canine disorder is a fully penetrant, simple autosomal recessive trait. The disorder demonstrated a type and distribution of lesions homologous to that of human infantile neuroaxonal dystrophy (INAD), most commonly caused by mutations of PLA2G6, but alleles of informative markers flanking the canine PLA2G6 locus did not associate with the canine disorder. Thus, fetal-onset neuroaxonal dystrophy in dogs, a species with welldeveloped genome mapping resources, provides a unique opportunity for additional disease gene discovery and understanding of this pathology.

Identification of the PLA2G6 c.1579G>A Missense Mutation in Papillon Dog Neuroaxonal Dystrophy Using Whole Exome Sequencing Analysis

“…In dogs, NAD has previously been reported in several breeds, such as Rottweilers [9–11], Collie sheepdogs [12], Papillons [13–16], Giant Schnauzer-Beagle crossbreeds [18], Jack Russell terriers [19], Spanish Water dogs [20], and a Dachshund-cross dog [21]. Among these, genetic studies have been extensively performed for a few breeds, and only two forms of canine NAD have been characterized at the molecular level: a mitofusin 2 (MFN2) missense mutation with foetal onset NAD in laboratory dogs [18] (Giant Schnauzer-Beagle crossbreed) and a TECPR2 missense mutation in Spanish Water dogs [20].…”

“…Among these, genetic studies have been extensively performed for a few breeds, and only two forms of canine NAD have been characterized at the molecular level: a mitofusin 2 (MFN2) missense mutation with foetal onset NAD in laboratory dogs [18] (Giant Schnauzer-Beagle crossbreed) and a TECPR2 missense mutation in Spanish Water dogs [20]. However, the causal mutations of the other forms of canine NAD remain unclear.…”

A novel mitofusin 2 mutation causes canine fetal-onset neuroaxonal dystrophy

“…Using a genetic linkage-based approach and gene expression analysis, we demonstrated that a novel homozygous mutation of the MFN2 gene causes lethal, autosomal recessive FNAD in dogs [10]. Familial NAD has been described in dogs previously [29–35], but none have been of obviously fetal-onset, nor has a canine NAD-causing mutation been determined before.…”

“…Axonal swellings of affected pups were filled with membrane bound fragments of variably degenerated mitochondria and other tubulomembranous material embedded in disorganized whorls of neurofilaments [10]. This pathology is similar to that in human patients exhibiting INAD caused by PLA2G6 mutations or neurodegeneration with brain iron accumulation (NBIA1; a.k.a.…”

“…Recently we described autosomal recessive, fetal-onset neuroaxonal dystrophy (FNAD) causing late-gestational fetal akinesia, multiple joint fixation, and pulmonary hypoplasia in a large family of dogs [10] that mimics the connatal human phenotype. Affected fetuses exhibited swollen axons/spheroids throughout the extrapyramidal motor system of brainstem, spinal cord, and peripheral nerves and died at birth due to respiratory failure.…”