Leonberger Polyneuropathy (LPN)

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Acronyms: LPN
Gene: ARHGEF10
Mutation: Deletion
Mode of inheritance: Autosomal recessive
Breeds: Leonberger, St. Bernard

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Product Description

Leonberger Polyneuropathy (LPN)

Leonberger Polyneuropathy (LPN) is a collective name for neuromuscular diseases affecting the Leonberger dogs. Polyneuropathy is a term used for simultaneous malfunction of many peripheral nerves throughout body and in literally translation it means “many abnormalities of the nervous system”. Polyneuropathy observed in Leonbergers shows similar clinical symptoms to Charcot-Marie-Tooth (CMT) in humans. Charcot-Marie-Tooth (CMT) is a genetically heterogeneous group of neuropathies that cause damage of peripheral nerves. CMT is the most common inherited disorder of peripheral nerves in humans.

Characteristics and Symptoms

LPN has been characterized clinically, electrophysiologically, histologically and morphometrically. Two main symptoms of Leonberger Polyneuropathy (LPN) are laryngeal paralysis and rear weakness characterized also by lack of coordination. These two symptoms usually do not develop simultaneously. Laryngeal paralysis can be recognized by specific coughing after eating or drinking, or in a change of the dog’s bark which will appear like hoarse. Dog will have also problems with breathing which will seem louder and heavier than usual even after a light exercise. Affected dog will tend to easily get tired after exercising and will require a long rest. In the end stages of Leonberger Polyneuropathy (LPN) stridor develops. Stridor is a high-pitched sound made during dog’s breathing as a result of turbulent air flow in the larynx. This high-pitched breathing sound is always an indicator of a serious problem.

Neurological examinations reveal atrophy of the distal limb muscles, depressed spinal and cranial nerve reflexed, and weak or missing movements of laryngeal muscles. Electrophysiological examination reveals lack of muscle action potentials and slowed motor nerve conduction velocity. Biopsy shows muscle atrophy. Axonal degeneration in LPN affected dogs causes decreased myelinated fibre density. This examination results can be recognized by following symptoms: high-stepping pelvic limb gait, decreased or absent tendon reflexes, and changes associated with degeneration of the recurrent laryngeal nerve, including inspiratory stridor resulting from laryngeal paralysis.

The age on LPN onset is variable, from less than 1 year of age to 11 years of age. Dogs affected with an early onset of the disorder usually develop more severe symptoms and stages of the disorder.

Since Leonberger Polyneuropathy (LPN) is a progressive disorder, owners in its beginning stages may not even notice the first symptoms, such as unbalanced walk. It is common that veterinarians are not able to recognize the disorder before the already progressed stages.

Genetics

Leonberger Polyneuropathy (LPN) is caused by a mutation in the AHGEF10 gene. This is the first documented severe polyneuropathy associated with a mutation in ARHGEF10 in any species. The mutation comprises a 10 base deletion that affects the coding sequence.

AHGEF10 is known as one of the Rho guanine nucleotide exchange factors (GEFs). GEFs have a role as activators of Rho-GTPases that participate in the regulation of various signal transduction pathways. Some of these pathways are essential for neuron morphology, including axon, dendrite and spine growth as well as axon guidance. Rho-GTPases have a role also in directing the movement of Schwann cell precursors along outgrowing axons. AHGEF10 is expressed in multiple tissues, and higher expression has been identified in the spinal cord and dorsal root ganglion. This explains loss of proper signalling for axon and myelination in LPN.

Leonberger Polyneuropathy (LPN) is inherited as an autosomal recessive disorder. Healthy parents of an affected puppy are obligate heterozygotes, and therefore carry one mutant allele. Heterozygotes have no symptoms. Dogs homozygous for the mutation will display the symptoms of the LPN. At conception, when mating two carrier dogs, each cub has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

References:

Ekenstedt KJ, Becker D, Minor KM, Shelton GD, Patterson EE, et al. (2014) An ARHGEF10 Deletion Is Highly Associated with a Juvenile-Onset Inherited Polyneuropathy in Leonberger and Saint Bernard Dogs. PLoS Genet 10(10): e1004635. doi:10.1371/journal.pgen.1004635

Shelton, G. D. et al. (2003.): Inherited polyneuropathy in Leonberger dogs: A mixed or intermediate form of Charcot‐Marie‐Tooth disease? Muscle & Nerve 27(4):471 – 477 April 2003.