Narcolepsy (HCRTR2 gene, Doberman Pinscher)

Narcolepsy is a neurological disorder that affects sleep and is characterized by excessive sleepiness and cataplexy or muscle weakness. The onset of the disease has been linked to mutations in the HCRTR2 gene, an essential element in the regulation of sleep and wakefulness.

Symptoms

Symptoms of narcolepsy usually manifest between the fourth week and the sixth month of life. Clinical signs include drowsiness, rapid eye movements and twitching. In response to positive stimuli such as food or play, dogs may experience episodes of cataplexy. These episodes begin with flexion of the hind limbs and drooping of the neck, followed by the dog falling over and remaining motionless for a few seconds or minutes. Fortunately, narcolepsy is neither progressive nor life-threatening.

Disease Management

There is no definitive cure for narcolepsy. Mild symptoms do not require any treatment, while severe symptoms that hinder the dog's normal life can be treated with anti-narcolepsy drugs. Physostigmine helps to reduce the frequency of seizures, while imipramine can reduce the severity of symptoms.

Genetic basis

This disease follows an autosomal recessive mode of inheritance. Autosomal recessive inheritance means that the dog, regardless of sex, must receive two copies of the mutation or pathogenic variant to be at risk of developing the disease. Both parents of an affected dog must carry at least one copy of the mutation. Animals with only one copy of the mutation are not at increased risk of developing the disease, but may pass the mutation on to future generations. Breeding between dogs carrying genetic variants that can cause disease, even if they do not show symptoms, is not recommended.

Technical report

Narcolepsy is a disabling sleep disorder characterized by the presence of excessive sleepiness and cataplexy. The occurrence of this condition has been found to be related to mutations in the HCRTR2 gene, suggesting that hypocretins and hypocretin receptor 2 play a crucial role as neuromodulators of sleep, along with the aminergic and cholinergic systems. In a study by Lin et al. (1999), a SINE insertion (c.647-36_647_647-35insN[226]) in the HCRTR2 gene was found to be responsible for narcolepsy in Doberman dogs. This insertion leads to the deletion of 38 amino acids in the fifth transmembrane domain of the protein, suggesting that these changes could cause a loss of function or mislocalization of this highly conserved protein. This specific mutation cannot explain the occurrence of narcolepsy in all breeds of dogs, however, other mutations have been described in different breeds, some of which are included in our test.

Most affected breeds

Doberman Pinscher

Bibliography

Lin L, Faraco J, Li R,et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999 Aug 6;98(3):365-76.