SACS – Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS)

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder characterized by early-onset cerebellar ataxia, lower limb spasticity, and a sensorimotor peripheral neuropathy. The SACS gene (HGNC:10519) encodes sacsin, a large multimodular chaperone protein. Biallelic SACS variants were first linked to ARSACS based on a homozygous missense p.Trp3248Arg in Japanese families (PMID:14718708).

ARSACS follows autosomal recessive inheritance, with confirmed segregation of SACS variants in multiple consanguineous and outbred families. A founder g.6594delT (ΔT) allele accounts for 96% of Quebec cases and is reliably detected by ASO hybridization (PMID:11788093). In a Dutch cohort of 43 index patients, 16 index cases (23 affected) harbored homozygous or compound heterozygous SACS mutations (PMID:18465152).

Over 200 distinct SACS mutations have been reported, spanning missense, nonsense, frameshift, splice, large deletions, and duplications. Common recurrent LoF alleles include c.5151dup (p.Ser1718fs) and c.8793dup (p.Arg2932fs) (PMID:21745802; PMID:11788093). A representative variant is c.3161T>C (p.Phe1054Ser) identified in Japanese siblings with atypical ARSACS lacking spasticity (PMID:15985586).

Clinical presentations vary: some patients exhibit atypical features such as dementia and ophthalmoplegia without retinal myelinated fibers (PMID:15486997), while others present with pure demyelinating neuropathy without spasticity or ataxia (PMID:30460542).

Functional studies demonstrate sacsin loss-of-function as the pathogenic mechanism. The HEPN domain mutant p.Asn4549Asp disrupts domain dimerization and nucleotide binding (PMID:21507954). Sacsin knockout and R272C missense mice express reduced sacsin levels and recapitulate Purkinje cell loss and ataxia (PMID:30866998. Mitochondrial network fragmentation in patient fibroblasts further supports a chaperone defect (PMID:26288984).

Integration of genetic and functional data establishes a definitive gene–disease relationship between SACS and ARSACS. Molecular diagnosis via sequencing and CNV analysis is recommended for patients with early-onset ataxia, spasticity, and neuropathy. Key biomarkers include thickened peripapillary retinal nerve fiber layer on OCT and linear pontine hypointensities on MRI. Prompt genetic confirmation informs prognosis, family planning, and emerging therapeutic strategies.

References

• Neurology • 2004 • Identification of a SACS gene missense mutation in ARSACS PMID:14718708
• Genetic Testing • 2001 • Rapid detection of the sacsin mutations causing autosomal recessive spastic ataxia of Charlevoix-Saguenay PMID:11788093
• Neurogenetics • 2008 • ARSACS in the Dutch population: a frequent cause of early-onset cerebellar ataxia PMID:18465152
• Archives of Neurology • 2003 • Phenotypic features and genetic findings in sacsin-related autosomal recessive ataxia in Tunisia PMID:12873855
• Neurology • 2005 • A phenotype without spasticity in sacsin-related ataxia PMID:15985586
• Movement Disorders • 2005 • Sacsin-related autosomal recessive ataxia without prominent retinal myelinated fibers in Japan PMID:15486997
• Journal of Child Neurology • 2011 • Autosomal recessive spastic ataxia of Charlevoix-Saguenay: compound heterozygotes for nonsense mutations of the SACS gene PMID:21745802
• J Biol Chem • 2011 • Structural basis of defects in the sacsin HEPN domain responsible for ARSACS PMID:21507954
• Mol Brain • 2019 • Sacs R272C missense homozygous mice develop an ataxia phenotype PMID:30866998
• Annals of Neurology • 2015 • New practical definitions for the diagnosis of ARSACS PMID:26288984

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