Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ORPHA:98)
A rare neurodegenerative disorder characterized by early-onset cerebellar ataxia, a pyramidal syndrome and peripheral neuropathy.
Epidemiology
It was initially described in the Charlevoix-Saguenay region of Quebec where incidence of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) at birth has been estimated at 1 in 1,932. The incidence and prevalence worldwide remain unknown but ARSACS is now considered one of the more common recessive ataxias worldwide with cases described in several countries including Turkey, Japan, the Netherlands, Italy, Belgium, France, Spain and more than 20 other countries.
Clinical description
ARSACS is a slowly progressive disease with variable clinical presentation. The age of onset in non-Quebec patients is variable (ranging from late infantile, juvenile to early-adult onset) but in individuals from Quebec, onset occurs between 12 and 18 months of age with gait disturbance and walking difficulties. Other early signs of cerebellar ataxia include upper limbs incoordination, dysarthria and nystagmus. The pyramidal syndrome is characterized by lower limbs spasticity, brisk patellar tendon reflexes and the Babinski sign. Onset of the peripheral neuropathy generally occurs later and leads to absence of the Achilles tendon reflex, distal amyotrophy, pes cavus and deep sensory disturbances (impaired vibration sense). Retinal hypermyelination (without vision loss) is a constant feature in ARSACS patients from Quebec but may be absent in patients from other countries. Cognitive impairments related to cerebellar involvement have been documented. Other manifestations may include spasms, lower limb neuropathic pain and bladder dysfunction.
Etiology
ARSACS is caused by autosomal recessive mutations in the SACS gene (13q11), which encodes a large protein of partially known function named sacsin.
Diagnostic methods
The diagnosis of ARSACS is established by molecular genetic testing. Clinical diagnosis relies on the results of neurophysiological data (signs of both axonal and demyelinating neuropathy, with nerve conduction studies revealing loss of sensory nerve conduction and reduced motor conduction velocities). MRI brain revealed superior cerebellar vermian atrophy and T2 linear ''striped'' hypointensities in pons. Retinal examination may also be useful for diagnosis.
Differential diagnosis
Differential diagnoses include other autosomal recessive ataxias, such as Friedreich ataxia, ataxia with vitamin E deficiency (AVED), Abetalipoproteinemia and hereditary forms of spastic paraplegia, in particular spastic paraplegia type 7, spastic paraplegia type 30 and spastic paraplegia type 20 (SPG20-Troyer syndrome).
Antenatal diagnosis
Antenatal diagnosis is possible for at-risk couples (both individuals are carriers of a disease-causing mutation) by genetic testing.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment is symptomatic aiming towards improving motor control, decreasing spasticity and should include a rehabilitation team approach that includes physiotherapy, occupational therapy and pharmacotherapy.
Prognosis
Most patients become wheelchair-dependent by the fifth decade of life. Death generally occurs during the sixth decade but survival into the seventies has been reported.

                            Last update: 
                            April 2024


                            - Expert reviewer(s): 
                            Pr Bernard BRAIS  - Pr Cynthia GAGNON  - Dr Jean MATHIEU