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Leonberger polyneuropathy type 1 (LPN1)

Neurological · Dog

Hereditary polyneuropathy of the Leonberger type 1 (LPN1), a mixed peripheral neuropathy of juvenile onset, chronic and progressive, presenting with generalised weakness, hypotonia and muscle atrophy (especially of the pelvic limbs), decreased or absent reflexes and laryngeal paralysis with inspiratory stridor. It is associated with a deletion in ARHGEF10 and is inherited in an autosomal recessive manner.

Inheritance pattern	Autosomal recessive (OMIA classifies it as probably autosomal recessive). Homozygosity of the deletion is associated with the severe juvenile-onset phenotype; the effect of heterozygosity is not fully clarified.
Gene / Mutation	ARHGEF10 10 bp deletion: c.1955_1958+6delCACGGTGAGC (CanFam3.1 g.54349199_54349208del); OMIA001917-9615. It eliminates 4 nucleotides from the 3' end of exon 17 and 6 from the 5' end of intron 17, suppresses the splice junction, induces an alternative site and causes a frameshift with truncation of ~50% of the protein. OMIA classifies it as LP/P.
Penetrance	High in homozygotes for the severe juvenile-onset phenotype; heterozygotes are generally asymptomatic, although the effect of heterozygosity and of sex is not completely defined. Age of onset and progression may vary, probably due to the coexistence of other forms of polyneuropathy.
Code	xcpg
Turnaround time	15 days
Price	52,60 €

Incidence

Main breed: Leonberger (also described in St. Bernard). Carrier frequency has been described as moderate in Nordic and North American breeding populations; there are no reliable figures for the Spanish population (limited data).

Breeder management

- Genotype breeding animals before mating.\n- Do not cross two carriers (25% of affected homozygotes).\n- Cross carriers with clear homozygotes: 0% affected and 50% carriers.\n- Do not breed affected animals.\n- After a confirmed clinical case, do not repeat the parental cross and communicate the status to buyers.

Specialist notes

Differential diagnosis within the breed with LPN2 (GJA9, OMIA002119-9615, autosomal dominant inheritance with incomplete penetrance) and LPPN3 (CNTNAP1, OMIA002301-9615, autosomal recessive, laryngeal paralysis and later-onset polyneuropathy). Electromyography and nerve conduction studies guide the diagnosis; rule out acquired causes (toxic, endocrine). Laryngeal paralysis may require arytenoidopexy, but the underlying polyneuropathy determines the prognosis.

References

1. Ekenstedt KJ et al. 2014. An ARHGEF10 deletion is highly associated with a juvenile-onset inherited polyneuropathy in Leonberger and Saint Bernard dogs. PLOS Genetics. PMID: 25275565
2. Becker D et al. 2017. A GJA9 frameshift variant is associated with polyneuropathy in Leonberger dogs. BMC Genomics. PMID: 28841859
3. Letko A et al. 2020. A CNTNAP1 Missense Variant Is Associated with Canine Laryngeal Paralysis and Polyneuropathy. Genes. PMID: 33261176
4. Cocostîrc V et al. 2023. An Overview of Canine Inherited Neurological Disorders with Known Causal Variants. Animals. PMID: 38003185
5. OMIA:001917-9615. Polyneuropathy, ARHGEF10-related in Canis lupus familiaris. Online Mendelian Inheritance in Animals.

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