Genetic basis of ARSACS in Great Pyrenees - is caused by a 4 base pair (bp) deletion mutation in the SACS gene. This deletion causes a frameshift leading to truncation of the sacsin protein by 343 amino acids at the C-terminus (p.Val4244AlafsTer32). The SACS gene encodes sacsin, a large protein critical for neuronal health and function, especially in the cerebellum and peripheral nerves. The condition is inherited in an autosomal recessive manner: affected dogs have two copies of the mutated gene, while carriers have one copy and are asymptomatic. This mutation appears to be private (unique) to Great Pyrenees dogs.
Pathophysiology - The mutation results in widespread degeneration of neurons in the central and peripheral nervous systems. Remarkable features include degeneration of cerebellar Purkinje cells, neuronal loss in brainstem nuclei, spinal cord white matter degeneration, and peripheral nerve demyelination. Clinical signs appear early, as young as 4 months old, and progress slowly over years. The disease manifests as progressive cerebellar ataxia (loss of motor coordination and balance), spasticity (muscle stiffness), and peripheral neuropathy with muscle weakness and wasting.
Complications - Signs include poor coordination, unsteady gait, progressive weakness, and muscle wasting. Dogs develop spasticity and difficulties with voluntary movements. The condition progressively worsens but tends to have a slow course over several years. Histopathology reveals extensive neural damage, including demyelination in peripheral nerves. There is no known cure; management focuses on supportive care.
Why This Matters to Breeders and Vets - Early identification through clinical signs and genetic testing is vital for diagnosis and to prevent producing affected puppies. Understanding this condition helps differentiate it from other ataxias or neurological disorders in Great Pyrenees. Genetic testing enables breeders to identify carriers and make informed breeding decisions to reduce disease incidence. Veterinarians can provide appropriate counseling to owners regarding prognosis and management.
Summary - ARSACS (Great Pyrenees Type) is an autosomal recessive neurodegenerative disorder caused by a unique 4 bp deletion in the SACS gene, leading to truncated sacsin protein and widespread neuronal degeneration. Clinically, affected puppies show early-onset progressive cerebellar ataxia, spasticity, and peripheral neuropathy. Genetic testing is essential for diagnosis and prevention. Responsible breeding strategies that avoid carrier matings are critical to reduce disease frequency in the breed.