Laryngeal paralysis in dogs is caused by denervation of the intrinsic laryngeal muscles, which prevents normal abduction and adduction of the arytenoid cartilages and vocal folds.1 As affected dogs increase their respiratory effort during hot weather or exercise, the narrow rima glottis increases resistance to effective airflow. This is compounded by swelling caused by turbulent airflow through the glottis. The net result is ineffective airflow, an increase in respiratory work, and, often, life-threatening hypoxemia and hyperthermia.1
Effective surgical treatment for laryngeal paralysis has been described,2–5 but the cause of the condition remains unclear. Although laryngeal paralysis may be a congenital condition in some breeds, including Bouviers des Flandres, Siberian Husky, Dalmatian, and Rottweiller,6–11 it commonly develops in middle-age to older large-breed dogs.1–5 In most of these dogs, no underlying cause for degeneration of the recurrent laryngeal nerves is identified. The possibility of a genetic cause of adult-onset laryngeal paralysis has been raised12 because some breeds (notably Labrador Retriever) appear to be overrepresented in populations of affected dogs.13–15
Dysfunction of the recurrent laryngeal nerve is the only neurologic abnormality clinically apparent in many affected dogs, but laryngeal paralysis has been described as the most obvious sign of an underlying central or peripheral polyneuropathy in some reports.14–19 Electrodiagnostic findings, including decreased amplitude of compound muscle action potentials and decreased nerve conduction velocity, support a die back form of axonal neuropathy,15,17 although this has not been confirmed histopathologically.15 Histologic examination of the muscular branch of the recurrent laryngeal and peroneal nerves in 1 study15 revealed loss of large nerve fibers, axonal degeneration, and endoneurial fibrosis with no evidence of nerve regeneration. Evaluation of biopsy specimens concurrently obtained from the cricoarytenoideus dorsalis and cranial tibial muscles revealed a pattern of neurogenic atrophy.15
A specific, inherited polyneuropathy that manifests initially as laryngeal paralysis has been described in Leonbergers.18 Affected dogs develop clinical signs when they are between 1 and 9 years of age. The first clinical sign reported by owners is often a change in bark. Laryngoscopy of affected dogs is diagnostic for laryngeal paralysis.18 The phenotype in these Leonbergers and other dog breeds with acquired laryngeal paralysis is similar to CMT disease, a group of hereditary motor and sensory neuropathies in humans that has an increasingly apparent genetic basis.20 An ARHGEF10 deletion has recently been described in Leonbergers with polyneuropathy.14 This deletion mutation is highly associated with the juvenile-onset form of the disease but does not explain later-onset cases.21
Although genetic and cellular mechanisms of peripheral nerve degeneration in dogs remain obscure, it is clear that intracellular transport of new proteins to axons and dendrites and retrograde transport of trophic factors and signaling molecules are vital for nerve differentiation and survival.22 Dynein is the major motor for retrograde transport of substances in axons; dynactin is a dynein-activator complex required for most of the cellular functions of cytoplasmic dynein.23 Disruption of the dynactin complex effectively blocks dynein-mediated functions, which appear to be vital to physiologic nerve health and function. Mutations in the p150 Glued component of dynactin inhibit both retrograde and normograde axonal transport in Drosophila spp.24 Targeted disruption of dynein or dynactin in motor neurons causes late-onset, progressive motor neuron disease in mice,25 and transgenic mice developed to have disruption of the dynactin complex also develop late-onset, progressive motor neuron degeneration.26 A human family with an inherited form of motor neuron disease caused by a mutation in dynactin has been described.27–29 Initial clinical signs in that family were related to bilateral laryngeal paralysis with subsequent weakness and atrophy in the hands, face, and distal parts of the pelvic limbs.27 The association between mutations or disruption of dynactin and disruption of axonal transport in Drosophila spp and mice, late-onset motor neuron degeneration, and the human phenotype associated with dynactin mutation suggests dynactin mutations as a potential cause of peripheral nerve degeneration and laryngeal paralysis in dogs. The objectives of the study reported here were to evaluate whether Labrador Retrievers are overrepresented in the population of dogs admitted for treatment of laryngeal paralysis and to assess dynactin mutations in Leonbergers and Labrador Retrievers with laryngeal paralysis.
Supported by an American Kennel Club Canine Health Foundation ACORN grant.
Dynactin subunit 1
Expressed sequence tag
DNASTAR, DNASTAR Inc, Madison Wis.
Platinum Taq DNA polymerase, Invitrogen/Thermo Fisher Scientific Inc, Waltham, Mass.
TaKaRa La Taq DNA polymerase, Clontech Laboratories Inc, Mountain View, Calif.
GC II buffer, Clontech Laboratories Inc, Mountain View, Calif.
QIA Quik, PCR purification or gel extraction kits, QIAgen, Valencia, Calif.
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Primers used in a PCR assay of the DCTN1 gene.
|Reverse primer sequence||Product size (bp)||Annealing temperature (°C)||Sequencing primer name||Sequencing primer sequence|
LA Taq with buffer II; all others were platinum Taq.
— = Not applicable.