ARSACS

Excerpt

Clinical characteristics: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is clinically characterized by a progressive cerebellar ataxia, peripheral neuropathy, and spasticity. Disease onset of classic ARSACS is often in early childhood, leading to delayed walking because of gait unsteadiness in very young toddlers, while an increasing number of individuals with disease onset in teenage or early-adult years are now being described. Typically the ataxia is followed by lower-limb spasticity and later by peripheral neuropathy – although pronounced peripheral neuropathy has been observed as a first sign of ARSACS. Oculomotor disturbances, dysarthria, and upper-limb ataxia develop with slower progression than the other findings. Brain imaging demonstrates atrophy of the superior vermis and the cerebellar hemisphere with additional findings on MRI, such as linear hypointensities in the pons and hyperintense rims around the thalami. Many affected individuals (though not all) have yellow streaks of hypermyelinated fibers radiating from the edges of the optic disc noted on ophthalmologic exam, and thickened retinal fibers can be demonstrated by optical coherence tomography. Mild intellectual disability, hearing loss, and urinary urgency and incontinence have been reported in some individuals.

Diagnosis/testing: The diagnosis of ARSACS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in SACS identified on molecular genetic testing.

Management: Treatment of manifestations: Physiotherapy and exergames tailored to ataxia; physical therapy and oral medications such as baclofen to control spasticity in the early phase of the disease may prevent tendon shortening and joint contractures and, hence, may help to postpone major functional disabilities until severe muscle weakness or cerebellar ataxia occur. As needed, services for mild intellectual disability and dysarthria and use of hearing aids. Urinary urgency and incontinence may be controlled with low doses of amitriptyline, oxybutynin.

Surveillance: Annual neurologic examination.

Genetic counseling: ARSACS is inherited in an autosomal recessive manner. If each parent is known to be heterozygous for a SACS pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if both pathogenic variants have been identified in an affected family member. Population screening for the most common SACS pathogenic variants is an option for individuals with a genealogic link to regions of high ARSACS prevalence.