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.

Suggestive Findings

ARSACS should be suspected in individuals with the following cluster of symptoms:

• Slowly progressive cerebellar ataxia with difficulty walking and gait unsteadiness noted as early as age 12 to 18 months, or appearing later
• Spasticity of the lower limbs
• Peripheral neuropathy with distal wasting and weakness
• Brain MRI findings of vermis atrophy with upper predominance and/or atrophy of the cerebellar hemispheres and hypointense bilateral stripes in the paramedian pons
• Thickened retinal hypermyelinated fibers identified as:
  • Yellow streaks radiating from the edges of the optic disc on ophthalmic exam;
  • A thicker-than-119-µm average peripapillary retinal nerve fiber layer on optical coherence tomography.

Establishing the Diagnosis

The diagnosis of ARSACS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in SACS identified on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, mulitgene panel), and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of ARSACS is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with ataxia and/or spasticity are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) defines a spastic ataxia first described in 1978 among a cohort of about 325 French-Canadian individuals from 200 families born in the Saguenay-Lac-St-Jean area of northeastern Quebec [Bouchard et al 1978]. The disorder has since been identified in other areas of the world (see Prevalence). Most individuals display a slowly progressive course of unsteadiness, often with onset before age ten years (usually of late-infantile onset) and associated with spasticity during childhood and neuropathy during teenage years.

In addition to the classic triad of symptoms of progressive cerebellar ataxia, peripheral neuropathy, and lower-limb spasticity, some individuals with ARSACS have features such as hearing loss, intellectual disability, and myoclonic epilepsy [Breckpot et al 2008, McMillan et al 2009, Terracciano et al 2009, Ali et al 2016, Nascimento et al 2016, Briand et al 2019]. Furthermore, absence of one of the three defining clinical features has been described in several individuals [Shimazaki et al 2005, Shimazaki et al 2007, Baets et al 2010, Synofzik et al 2013, Vill et al 2018, Rezende Filho et al 2019].

Both intra- and interfamilial phenotypic variability has been observed in ARSACS.

To date, more than 190 individuals have been identified with biallelic pathogenic variants in SACS [Vermeer at al 2008, Baets et al 2010, Synofzik et al 2013, Pilliod et al 2015, Vill et al 2018, Rezende Filho et al 2019] (LOVD3 Database). The following table of the phenotypic features associated with this condition is based on the table in the publication of Pilliod et al [2015]. Note: Not all features were measured in the different groups of affected individuals; some relative frequencies are less representative due to a lower total number of individuals measured.

Onset and progression. The mean age at onset is approximately six years (range: 0-40 years) [Vermeer et al 2008, Baets et al 2010, Duquette et al 2013, Prodi et al 2013, Synofzik et al 2013, Pilliod et al 2015].

Most individuals show the highly characteristic triad of cerebellar ataxia, peripheral neuropathy, and pyramidal tract signs [Ogawa et al 2004, Vermeer et al 2008, Baets et al 2010, Duquette et al 2013, Prodi et al 2013, Synofzik et al 2013, Pilliod et al 2015]. The first signs of the disease are a slowly progressive cerebellar ataxia (which can lead to delayed walking because of gait unsteadiness in very young infants [Bouchard et al 1978]) usually with subsequent lower-limb spasticity, followed by features of peripheral neuropathy. However, pronounced peripheral neuropathy as a first sign of ARSACS, followed by pyramidal and cerebellar signs, has also been observed [Synofzik et al 2013]. Often, this leads to significant and severe lower-limb and gait impairment.

Neurologic findings. A childhood-onset mixed sensorimotor peripheral neuropathy with both axonal and demyelinating features is observed in most affected individuals. This leads to distal muscle atrophy and weakness, foot deformities, impaired tactile and vibration sense, and (eventually) a decrease in or loss of tendon reflexes in the legs [Vermeer et al 2008].

• Electrophysiology often confirms a mixed demyelinating and axonal neuropathy [Bouchard et al 1978, García et al 2008, Baets et al 2010].
• Distal amyotrophy, which leads to loss of ankle reflexes and sometimes bilateral foot drop, is found in most individuals after age 21 years. Other deep tendon reflexes may remain brisk or disappear with time.
• Oculomotor disturbances (nystagmus), dysarthria, and upper-limb ataxia usually progress much slower than gait ataxia, spasticity, and neuropathy.

Dysarthria, one of the features associated with cerebellar dysfunction, usually appears in late childhood and is slowly progressive.

Brain imaging. Findings include atrophy of the superior vermis and the cerebellar hemisphere, linear hypointense stripes in the paramedian pons, a hyperintense lateral pons where merging into the cerebellar peduncles, thickened middle cerebellar peduncles [Synofzik et al 2013], and hyperintense rim around the thalami [Oguz et al 2013, Kuchay et al 2019]. However, some individuals with ARSACS are reported to display no abnormalities on brain MRI. This notion has to be interpreted with caution, however, as even some of the published cases with allegedly none of these MRI signs show hyperintense stripes in the pons on closer inspection [Vill et al 2018].

Cognitive skills. Difficulties in school performance are reported, in some cases due to mild intellectual disability. ARSACS is not associated with severe intellectual disability.

• Detailed neuropsychiatric and neurophysiologic assessments were reported in two individuals with ARSACS. Apart from motor symptoms, motivational deficits along with cognitive and behavioral dysfunction were present [Verhoeven et al 2012].
• Cognitive abilities tend to be preserved into late adult life, although in the oldest affected individuals cognitive decline has been documented.

The extent to which cognitive impairment is a feature of ARSACS is still unclear and is being studied.

Hearing loss has been described in a minority of affected individuals; it is not known whether this is a true feature of ARSACS . The type of hearing loss in most cases has not been described; Breckpot et al [2008] described bilateral sensorineural hearing loss in a person age 26 years with ARSACS involving a large deletion on chromosome 13q12.12. Of note in this individual, the brain auditory evoked potentials on the left were abnormal whereas those on the right side were normal.

Urinary dysfunction. Urinary urgency and incontinence, mainly due to pyramidal tract dysfunction, can be present.

Atypical neurologic phenotype. Three individuals with biallelic pathogenic variants in SACS and an unusual phenotype (lacking either spasticity or peripheral neuropathy) have been described [Shimazaki et al 2005, Baets et al 2010]. However, the two affected individuals described by Shimazaki et al with absence of lower-limb spasticity both displayed bilateral Babinski signs indicating pyramidal involvement; here, the spasticity was likely masked by the severe neuropathy. In the third individual, from a Belgian cohort, clinical or electrophysiologic signs of peripheral neuropathy were lacking. Disease onset in this individual was unusually late (age 40 yrs); it may be that peripheral neuropathy had not yet developed. Unfortunately, this individual was lost to further follow up.

Vill et al [2018] described nine individuals who were clinically diagnosed with hereditary motor and sensory neuropathy (HMSN) and harbored biallelic pathogenic variants in SACS. None of these individuals displayed spasticity or pyramidal signs and only three displayed ataxia, which was considered to be a sensory ataxia [Vill et al 2018]. However, on closer inspection, eight of the nine individuals were found to have either cerebellar oculomotor disturbances and/or cerebellar atrophy (specifically of the vermis).

Ophthalmologic findings. A characteristic retinal finding is the presence of yellow streaks of hypermyelinated fibers radiating from the edges of the optic disc.

Retinal nerve fiber hypertrophy as demonstrated on ocular coherence tomography has been reported in several individuals with ARSACS [Pablo et al 2011, Kuchay et al 2019], but is not present in all affected individuals.

A thicker-than-119-µm average peripapillary retinal nerve fibre layer provides a sensitivity of 100% and specificity of 99.4% in individuals with ARSACS [Parkinson et al 2018].

These ocular findings do not have an impact on vision in most affected individuals, though the oldest individuals with ARSACS may have visual impairment.

Cardiac findings. Mitral valve prolapse was described as a frequent feature among individuals with ARSACS from Quebec [Bouchard et al 1978]. To date it has been reported in only one affected individual not of Quebec origin [Baets et al 2010]. One affected individual developed severe enlarged cardiomyopathy [Synofzik, unpublished observation], but whether the cardiomyopathy is related to the presence of pathogenic variants in SACS has not been determined. At this stage, as cardiac abnormalities are apparently not a frequent part of the phenotype of ARSACS overall, a special workup on a routine basis does not appear to be required.

Life span. The only study to date that reported on life expectancy in those with ARSACS concluded that it was shortened on average to 51 years [Dupré et al 2006].

Genotype-Phenotype Correlations

No clear genotype-phenotype correlations for SACS have been identified.

Nomenclature

Guided by the classification system developed by the International Parkinson and Movement Disorder Society Task Force on Classification and Nomenclature of Genetic Movement Disorders, Rossi et al [2018] proposed a nomenclature system for recessive cerebellar ataxia that combines phenotypic and genetic information. In this classification system, the new designation for ARSACS is ATX/HSP-SACS.

Prevalence

The exact prevalence of ARSACS is unknown in most countries. More than 300 individuals with ARSACS live in Quebec:

• The estimated carrier frequency of SACS pathogenic variants in the Saguenay-Lac-St-Jean (SLSJ) region of Quebec, northeast of Quebec City, Canada is 1:21, based on data gathered between 1941 and 1985 [Dupré et al 2006].
• The birth incidence of ARSACS was 1:1,932, but is now declining because of voluntary carrier screening. A founder effect for 6594delT, the most common pathogenic variant, explains the high regional prevalence.

Although thought to be largely confined to Quebec, genetically confirmed ARSACS has now been reported in individuals all over Europe, Tunisia, Japan, and Turkey (LOVD3 Database) as well as India [Kuchay et al 2019] and Australia [Vogel et al 2018]. In a Belgian cohort of individuals with cerebellar ataxia suggestive of ARSACS, a relative prevalence of 13% was identified [Baets et al 2010]. In another cohort of 232 (index) individuals with cerebellar ataxia, a comparable prevalence of 12% was found [Vermeer et al, unpublished data]. ARSACS is now considered one of the more common recessive ataxias worldwide.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ARSACS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Curative therapy is not available; all treatments are symptomatic and tailored to the needs of the individual patient.

Surveillance

Agents/Circumstances to Avoid

There is no absolute contraindication to specific drugs in ARSACS. As in all conditions with neuropathic components, known neurotoxic drugs (e.g., some chemotherapies) should be given with caution.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Pregnancy Management

Women with ARSACS have experienced normal pregnancy and delivery. Some will have a functional decline during pregnancy that is reversible when they recover their prepregnancy weight and level of activity.

See MotherToBaby for further information on medication use during pregnancy.

Mode of Inheritance

ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one SACS pathogenic variant).
• A report of uniparental isodisomy of the paternal chromosome 13 resulting in a homozygous p.Arg4378Ter pathogenic variant in an affected individual suggests that not all parents are heterozygous [Anesi et al 2011].
  Note: The finding of a single SACS pathogenic variant in an affected individual may reflect homozygosity for the SACS pathogenic variant but could also be explained by compound heterozygosity for a pathogenic variant on one allele and a large deletion on the other allele.
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a SACS pathogenic variant and allow reliable recurrence risk assessment.
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• 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.
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual’s reproductive partner also has ARSACS or is a carrier (see Related Genetic Counseling Issues, Population screening), offspring will be obligate heterozygotes (carriers) for a pathogenic variant in SACS.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a SACS pathogenic variant.

Carrier Detection

Carrier detection for at-risk relatives requires prior identification of the SACS pathogenic variants in an affected family member.

See Related Genetic Counseling Issues, Population screening for information about carrier testing in individuals who do not have a family history of ARSACS.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Population screening. In Quebec, individuals with a genealogic link to regions of high ARSACS prevalence may choose to have carrier testing for the most common SACS pathogenic variants.

Prenatal Testing and Preimplantation Genetic Testing

Once the SACS pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for ARSACS are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SACS encodes sacsin, a 11.7-kb protein of yet-unknown function [Engert et al 2000]. Normal sacsin is expressed throughout the CNS, in skeletal muscles, and in skin fibroblasts. Sacsin is a multi-domain protein [Parfitt et al 2009, Anderson et al 2010, Kozlov et al 2011] containing:

• An N-terminal ubiquitin-like domain shown to bind to the proteasome;
• A C-terminal DnaJ domain followed by a higher eukaryote and prokaryote nucleotide-binding (HEPN) domain.

Sacsin localizes in close proximity to mitochondria in non-neuronal cells and primary neurons. In addition, it interacts with dynamin-related protein 1, which participates in mitochondrial fission [Girard et al 2012, Larivière et al 2015, Duncan et al 2017]. It is likely that sacsin plays a role in the regulation of mitochondrial dynamics in part through a co-chaperone role in ensuring the normal organization of the intermediate filament cytoskeleton key for cargo transport along axons and dendrites [Gentil et al 2019].

Consistent with these observations, an altered mitochondrial network (displaying fused mitochondria and altered mitochondrial morphology with reduced mitochondrial oxygen consumption in primary culture fibroblasts) and vimentin intermediate filament bundling appear to be hallmarks of ARSACS [Pilliod et al 2015, Duncan et al 2017].

Mechanism of disease causation. Most reported disease-associated SACS variants are predicted to be loss-of-function variants. The knockout Sacs mouse model recapitulates ARSACS ataxic behavior, the major mitochondrial and neurofilament bundling pathologic findings, and abnormal Purkinje cell electrophysiologic firing [Larivière et al 2015, Ady et al 2018]. Furthermore, the Sacs^R272C knock-in mouse model supports a partial loss-of-function mechanism for missense variants [Larivière et al 2019]. Other missense variants may lead to partial loss of function.

Quantifying sacsin levels by western blot in human circulating blood lymphoblasts and fibroblasts has been used to evaluate disease-associated variants [Duncan et al 2017, Larivière et al 2019]. Furthermore, a mild decrease in fibroblast respiratory function, abnormal mitochondrial network architecture, and excessive vimentin bundling have been observed in diagnosed individuals [Pilliod et al 2015, Duncan et al 2017].

Author History

Jean-Pierre Bouchard, MD; Laval University (2003-2012)
Bernard Brais, MD, PhD (2020-present)
Erik-Jan Kamsteeg, PhD (2012-present)
Jean Mathieu, MD, FRCPC; Complexe Hospitalier de la Sagamie (2003-2012)
Andrea Richter, PhD; University of Montreal (2003-2012)
Yves Robitaille, MD, FCAP; University of Montreal (2003-2012)
Matthis Synofzik, MD (2020-present)
Bart P van de Warrenburg, MD, PhD (2012-present)
Sascha Vermeer, MD, PhD (2012-present)

Acknowledgments

This project was supported, in part, via the European Union's Horizon 2020 research and innovation program by the BMBF under the frame of the E-Rare-3 network PREPARE (01GM1607 to MS, BvW, and BB) and grant 779257 "Solve-RD" (to MS and BvW).

Revision History

• 2 January 2020 (ha) Comprehensive update posted live
• 11 October 2012 (me) Comprehensive update posted live
• 11 April 2007 (me) Comprehensive update posted live
• 3 January 2005 (me) Comprehensive update posted live
• 9 December 2003 (me) Review posted live
• 2 July 2003 (yr) Original submission

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