A FAM8A1 frameshift variant is associated with REM sleep behavior disorder, urinary retention, and mydriasis in...

REM sleep behavior disorder (RBD) is a disease characterized by the loss of lower motor neuron inhibition responsible for skeletal muscle atonia during REM sleep. It has been reported in humans, dogs and cats, and can be idiopathic or secondary to a neurodegenerative disease. Five young adult Russian Blue cats from two related families were presented for progressively worsening RBD episodes frequently associated with urinary loss. Three of these cats also suffered urinary retention with overflow incontinence between RBD episodes. Neurological examination revealed a large bladder in three cats and a bilateral mydriasis with absent pupillary light reflexes in two cats; further examinations were unremarkable. Treatment attempts were unsatisfactory, with four cats being euthanized. Histopathology of the brain did not reveal any abnormalities. A disease-associated 23-bp deletion in exon 1 of FAM8A1 (NC_058372.1:g.11622168_11622190del), introducing a frameshift at codon 162 and a premature stop codon at codon 276 (XM_019831563.3:c.485_507del p.(Gln162Profs*115)), was identified by whole genome sequencing. The variant segregated in the affected families with a recessive mode of inheritance, showed an allele frequency of 1.5% in West-European Russian Blue cats (N = 68) and was not present in 276 cats belonging to 32 other breeds (including the closely related Nebelung breed). The variant FAM8A1 isoform is predicted to affect the assembly and activity of the endoplasmic reticulum-associated protein degradation pathway, which plays an important role in cell homeostasis. RBD and urinary retention syndrome is a hereditary encephalopathy affecting Russian Blue cats. A genetic test now allows diagnosis and prevention of this debilitating disease.