Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS): Clinical, Radiological and Epidemiological Aspects

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) (OMIM #270550) was originally found among inhabitants of the Charlevoix-Saguenay region of Quebec (Bouchard et al., 1978). ARSACS patients in Quebec show uniform phenotypes characterized by early-onset spastic ataxia, peripheral neuropathy, retinal hypermyelination, hand or foot deformities, and normal mentality. In 2000, the SACS gene, which is responsible for ARSACS, was identified in Quebec patients (Engert et al., 2000). Since then, ARSACS has been reported worldwide, especially in the Mediterranean area (El Euch-Fayache et al., 2003; Criscuolo et al., 2004; Grieco et al., 2004; Richter et al., 2004) and Japan (Ogawa et al., 2004; Takiyama, 2006). More SACS gene mutations were also identified in other areas (Takiyama, 2007; Ouyang et al., 2008; Vermeer et al., 2008; Gerwig et al., 2010). Meanwhile, ARSACS in non-Quebec patients, especially in Japanese ones, showed marked clinical heterogeneity, i.e., there were patients without spasticity (Shimazaki et al., 2005; Hara et al., 2007; Shimazaki et al., 2007), without retinal hypermyelination (Hara et al., 2007), and with decreased mentality (Shimazaki et al., 2005; Yamamoto et al., 2005; Shimazaki et al., 2007; Hara et al., 2005). The clinical spectrum of the sacsinpathies will expand with the identification of more SACS gene mutations (Gomez, 2004).

We herein review the epidemiology, genetics, clinical phenotypes, radiological and pathological findings in ARSACS cases carrying mutations of the SACS gene.

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ancestors who settled first in the Charlevoix region back in the seventeenth and early eighteenth centuries. ARSACS affects 1/1519 individuals in Charlevoix and 1/1952 in the Saguenay-Lac-St. Jean region, where the carrier frequency was estimated to be 1/22 for the 1941-1985 period (De Braekeleer et al., 1993).

Gene structure and pathological mutations
The SACS gene was originally reported to consist of a single gigantic exon spanning 12,794bp encoding an 11,487bp open reading frame (ORF), which represents the largest exon and the largest ORF within an exon found in any vertebrate (Engert et al., 2000). Recently, eight new exons located upstream of the gigantic one were found (Ouyang et al., 2006). More recently, one more upstream non-coding exon was found (Genbank NG_012342, 13-MAR-2011). The SACS gene comprises ten exons with a 13,737 bp ORF encoding 4579 amino acids ( Figure 2A).
Seventy-four mutations have been reported as pathological ones in the SACS gene (Baets et al., 2010). After publication of that report, we verified the table and found seven additional mutations in exons 6 and 10 of the SACS gene in Japanese patients (Table 1) (Komure et al., 2006;Tsugawa et al., 2009;Haga et al., 2011;Miyatake et al., 2011). As far as we know, at least 81 mutations have been found worldwide to date. Most of the mutations are predicted to generate truncated sacsin proteins, and are located in the largest exon, 10. Seventeen mutations were found in exons 4, 6, 7, 8 and 9. On copy number variation (CNV) analysis, an intragenic SACS deletion of exons 3-5 was identified (Baets et al., 2010). Two types of large deletions of the whole SACS gene and adjacent genes have been reported (Breckpot et al., 2008;Terracciano et al., 2009;McMillan et al., 2009).

Normal sacsin function
Sacsin is highly expressed in neurons, especially in cerebral corticospinal neurons and cerebellar Purkinje cells (Parfitt et al., 2009). The subcellular localization of sacsin in a cultured neuroblastoma-derived cell line was predominantly cytoplasmic and overlapped with that of mitochondrial protein heat shock protein (HSP) 60 (Parfitt et al., 2009). Because sacsin contains a functional J-domain (DnaJ motif), it has been proposed to act as a co-chaperone of the HSP70 chaperone system (Parfitt et al., 2009). The N-terminal segment of sacsin containing the ubiquitin-like (UbL) domain and the first sacsin repeating region (SRR) exhibits molecular chaperone activity and ATP-hydrolyzing activity Barral, 2010, 2011). The UbL domain can interact with the 20 S proteasomal subunit (Parfitt et al., 2009). The HSP70 chaperone machinery is an important component of the cellular response to aggregation prone mutant proteins, and the UbL domain protein is a part of the quality control machinery that regulates protein aggregation. Overall, the main function of sacsin, like other molecular chaperones, is probably to prevent protein misfolding and aggregation. Sacsin prevents polyglutamineexpanded ataxin-1 toxicity (Parfitt et al., 2009). The XPCB domain interacts with ataxin-3, which is involved in spinocerebellar ataxia type 3 ( Kamionka and Feigon, 2004). HEPN may stabilize nucleotide binding in complexes formed with the DnaJ domain (Grynberg, Erlandsen, and Godzik, 2003). Recently, the structure and function of the HEPN domain were determined, it being shown that it dimerizes and has a high affinity binding site for GTP, but it does not have GTPase activity (Kozlov et al., 2011).

Pathogenesis of ARSACS
Although the molecular mechanism underlying ARSACS remains unclear, the autosomal recessive transmission and truncating nature of most SACS mutations suggest the loss of sacsin function might cause development of this disease. Several functional alterations of sacsin proteins have been reported. An aspartate to tyrosine mutation (D168Y), located in the first SSR domain, abrogates its ATP-hydrolyzing activity (Anderson, Siller, and Barral, 2010). An asparagine to aspartate mutation (N4549D) in the HEPN domain of the sacsin protein disrupts dimerization and correct protein folding (Kozlov et al., 2011). Premature termination of other mutations and loss of the HEPN domain might lead to ARSACS disease.

Clinical phenotypes 4.1 Original Quebec phenotype
ARSACS is clinically characterized by early-onset spastic ataxia, axonal and demyelinating neuropathy, and hypermyelination of retinal nerve fibers (Bouchard et al., 1978;Bouchard, 1991). Unsteadiness of gait is usually the initial symptom. None of the patients ever walk normally, but walking is not delayed in most cases (rarely beyond 18 months of age) (Bouchard et al., 1978;Bouchard, 1991). The disease progression becomes most obvious in the late teens or early twenties, and the mean age for patients becoming wheelchair-bound is 41 years in Quebec patients (Bouchard, 1991). Concerning Quebec patients, ataxia, dysarthria, nystagmus, Babinski sign, hyperreflexia, spasticity, and retinal striations are noted in all of them. Distal amyotrophy of the feet is present in all patients after 20 years old (Bouchard, 1991), and pes cavus is noted in most Quebec patients. With these clinical features, ARSACS is clinically homogeneous in Quebec patients. Bouchard described progressive signs and early non-progressive ones of ARSACS in a review of this disease (Bouchard, 1991). The progressive signs are mostly spastic ataxia of the four limbs, slurred and dysrhythmic speech, discrete to severe distal amyotrophy, and absent ankle jerks after 25 years of age. The early non-progressive signs are increased deep tendon reflexes, a bilateral abnormal plantar response, marked saccadic alteration of smooth pursuit, and prominent myelinated fibers radiating from the disc on the retina.

Non-Quebec atypical phenotypes
The mean ages at onset are 5.4 and 4.5 years old in Japanese and Tunisian patients, respectively (Takiyama, 2007), while the ages at onset range from one to 1.5 years old in Quebec ones (Bouchard, 1991). Thus, the age at onset in these non-Quebec patients seems to be later than that in Quebec patients. According to a recent report from Belgium, the disease onset was over 20 years in five patients and as late as 40 years in one patient (Baets et al., 2010).
Although ataxia is noted in all non-Quebec ARSACS patients, one report stated that the cerebellar features were very mild in two patients (Baets et al., 2010). Other core clinical features of ARSACS, i.e., dysarthria, nystagmus, distal amyotrophy, Babinski sign, hyperreflexia, and pes cavus, are noted in most non-Quebec patients, which are similar to in Quebec patients.
Non-Quebec patients, however, show some atypical features in comparison with Quebec ones. First, although spasticity is a core clinical feature of ARSACS, we found that two patients in a Japanese family with ARSACS lacked spasticity in the legs and showed areflexia or hyporeflexia . In Quebec and Tunisian patients, spasticity becomes progressively worse during the disease course and is prevalent in older patients, and tendon reflexes remain preserved throughout the disease, except for ankle jerks (Bouchard et al., 1978;El Euch-Fayache et al., 2003). Since we did not observe the two above patients in their childhood, we were not able to determine whether or not their spasticity had decreased during the disease course or had been absent from the onset . The cases without spasticity, this depended on the fact that the neuromuscular manifestations were severe enough to diminish muscle tone and masked spasticity, and the planter responses were extensor, demonstrating that pyramidal tract sign was present.
Recently, however, we observed another ARSACS patient whose spasticity had disappeared, probably due to the progressive peripheral nerve degeneration in the disease course of 29 years (Shimazaki et al., 2007). Thus, we should recognize that there is a rare ARSACS phenotype without spasticity, and the SACS gene should be analyzed even in cases of early-onset cerebellar ataxia without spasticity. After that, several reports on spasticity-lacking ARSACS patients were published Baets et al., 2010;Miyatake et al., 2011).
Second, intellectual impairment is sometimes found in non-Quebec patients. The verbal IQ was 58, 88, 100, and 66 (mean: 78.00) in the four Japanese patients we examined (Takiyama, 2006). Similarly, mental retardation and dementia have been found in Italy (Criscuolo et al., 2004), Japan (Hara et al., 2005), and Turkey (Richter et al., 2004). Meanwhile, the verbal IQ (mean: 92.67) of Quebec patients is considered to be within normal limits, and a number of ARSACS patients have completed the secondary and university levels of education (Bouchard, 1991). Thus, intellectual impairment seems to be variable in ARSACS. Since the mode of inheritance of ARSACS is autosomal recessive, genes other than SACS might influence the intellectual impairment.
Defects in conjugate pursuit ocular movements, decreased or absent vibration sense in the toes, hand deformities, and urinary or fecal incontinence are rather frequently noted in Quebec (Bouchard, 1991) and non-Quebec patients (El Euch-Fayache et al., 2003;Takiyama, 2006). Cardiovascular evaluation revealed mitral valve prolapse in a majority of Quebec patients examined (Bouchard, 1991).
Very recently, the disease initially presented with symptoms mainly orienting toward peripheral neuropathy in several patients, and there was one patient who did not exhibit any clinical or electrophysiologic signs of peripheral neuropathy (Baets et al., 2010).
Recently, Desserre et al. have reported that the retinal nerve fiber layer was thickened, as shown using optical coherence tomography (OCT), and that the retina did not show hypermyelinated areas on funduscopy (Desserre et al., 2011). Likewise, Vingolo et al. reported that four patients with ARSACS showed myelinated fibers on funduscopy, and also increased thickness of the retina on OCT, which is a finding not characteristic of persistent myelination of the retina (Vingolo et al., 2011). It is possible that persistent myelination of the retina, a general common finding, was present in those patients without bearing relation to the disease.

Brain MRI findings
Some reports have mentioned that characteristic MRI findings in ARSACS are superior cerebellar vermian atrophy and cervical spinal cord atrophy (Bouchard et al., 1998;Takiyama, 2007). Recently, MRI of five patients in Quebec revealed linear hypointensity in T2-and Fluid-Attenuated Inversion Recovery (FLAIR) images of the pons (Martin et al., 2007). Thereafter, the same findings have been reported in only one patient in each of the Netherlands (Van Damme et al., 2009), France (Anheim et al., 2010), and Italy (Terracciano et al., 2010).
We recruited six ARSACS patients with SACS mutations in four Japanese families. Brain MRI was performed in all six patients. Brain MRI in the six patients showed superior cerebellar vermian atrophy. In addition, not only pontine linear hypointensity but also middle cerebellar peduncle hypointensity was observed in T2-weighted and FLAIR images (Shimazaki et al., in press) ( Table 2). These areas showed isointensity in T1-weighted images. Figure 3 shows representative brain MRI findings in patients 3 (A) and 2 (B). In patient 3, T2*-weighted images were obtained showing no abnormal findings in the pons and middle cerebellar peduncles (Figure 3, A-1).
We found the characteristic MRI findings in the six Japanese ARSACS patients, who all exhibited linear hypointensity in the pons, and a hypointense area in the middle cerebellar peduncles in T2-weighted and FLAIR images (Shimazaki et al., in press). A middle cerebellar peduncle hypointense area has not previously been reported in ARSACS patients, although pontine linear hypointensity was originally reported in five Quebec patients (Martin et al., 2007). Furthermore, as far as we know, hypointensity in these portions has not been described as a MRI finding in spinocerebellar ataxias and hereditary spastic paraplegias.
We thought these hypointense areas were close to the location of the pontocerebellar fibers. We could find low intensity in the middle cerebellar peduncle (MCP) because the pontocerebellar fiber runs from the middle pons to the cerebellum through the MCP. We can detect low MCP intensity in an Italian case (Terracciano et al., 2010). We think an abnormal MCP signal is not specific for Japanese patients.
The hypointensity in the pons and middle cerebellar peduncle might be specific findings for ARSACS cases even in non-Quebec ones with clinical heterogeneity . Thus, pontine and middle cerebellar peduncle T2 hypointensity detectable on MRI should prompt us to perform SACS gene analysis even in such atypical early-onset cerebellar ataxia cases.

Spinal MRI findings
In Quebec cases, the cervical cord is small and flat (Bouchard, 1991). In our cases, upper cervical cord and medulla oblongata atrophy was not observed in three of the six patients for whom cervical MRI was performed . Upper cervical atrophy is not a constant feature of ARSACS. In thirteen Belgium cases, cervical spinal cord atrophy was observed on MRI in only one case (Baets et al., 2010).

SPECT findings
Single photon emission computed tomography (SPECT) of the brain with three-dimensional stereotactic surface projection (3D-SSP) analysis for five cases showed decreased blood flow in the upper cerebellar vermis in three cases (Shimazaki et al., 2007;Shimazaki, Nakano, and Takiyama, 2008) (Figure 4). Meanwhile, early onset cerebellar ataxia with retained tendon reflexes (EOCA) and Friedreich's ataxia often show a reduction in the parietotemporal cortex blood flow as well as cerebellar hypoperfusion (De Michele et al., 1998), this being a different feature from in ARSACS. The results showed decreased blood flow in the superior cerebellar vermis and cerebellar hemisphere.

Postmortem autopsy and comparison with the characteristic brain MRI findings
The pathological findings in ARSACS patients have only been reported in a 21-year-old man (Bouchard, 1991) and a 59-year-old man (Richter et al., 1996). The former report of a young man described no findings regarding pontocerebellar fibers, but mentioned a small corticospinal tract and normal pontine nuclei in the pons (Bouchard, 1991). A T2* image of patient 3 disclosed no remarkable low intensity in the pontine tegmentum or cerebellar peduncles. These findings suggest that T2 hypointensity in the pons and cerebellar peduncles is not reflected by iron deposition in these portions. However, a second autopsy on the 59-year-old man revealed the presence of swollen thalamic and cerebellar cortical neurons (Bouchard et al., 1998). Most of these neurons had dense, lipofuscin-like granules within their lysosomes, and the authors suggested that ARSACS may be a lysosomal storage disease (Richter et al., 1996). In neuronal ceroid lipofuscinosis, MRI can often reveal hypointensity of the thalamus and putamen in T2-weighted images, which may reflect the storage of lipofuscin and the increase in the viscosity in these neurons (Autti, Joensuu, and Aberg, 2007). Therefore, the linear hypointensity of the pons that was found among ARSACS patients can also be explained by possible storage of lipofuscin-like materials. Further pathological study is needed to disclose the origin of the T2 hypointensity.

Nerve and muscle biopsy
Sural nerve biopsy revealed severe axonal degeneration and loss of large myelinated fibers (Peyronnard, Charron, and Barbeau, 1979;Bouchard, 1991;El Euch-Fayache et al., 2003;Takiyama, 2006). These findings in Quebec and non-Quebec patients are consistent with an axonal neuropathy associated with demyelinating features.

Peripheral nerve conduction studies
The peripheral nerve conduction study in Quebec patients revealed an axonal neuropathy with absent sensory action potentials and low motor conduction velocity (Peyronnard, Charron, and Barbeau, 1979;Bouchard, 1991). We have presented the peripheral nerve conduction data for cases 4 and 5 . In each patient, the motor nerve conduction velocity was mildly reduced in the ulnar and median nerves, and moderately in the posterior tibial nerves. Each compound muscle action potential (CMAP) was markedly decreased. In case 5 (patient 1 of ), a CMAP was not evoked in the common peroneal nerves. No sensory nerve action potential was evoked in any of the extremities. These data indicate not only a severe to moderate axonal neuropathy but dysmyelinating neuropathy complicated by secondary axonal degeneration as in Quebec and Tunisian patients (Peyronnard, Charron, and Barbeau, 1979;El Euch-Fayache et al., 2003).

Motor and sensory evoked potentials
Central pathway conduction studies including ones on somatosensory evoked potentials, brainstem auditory evoked potentials, and pattern reversal visual evoked potentials were performed in 67 Quebec patients (De Lean, Mathieu, and Bouchard, 1989). The findings that showed marked delays revealed widespread processes of demyelination in the primary sensory neurons as well as in the central nervous system (Bouchard, 1991). The central sensory and motor pathways were markedly impaired that could be attributed to myelinopathies, and there were high incidences of asymptomatic auditory and visual pathway involvement (Bouchard, 1991).
Electronystagmography showed horizontal gaze nystagmus in all Quebec patients with marked impairment of smooth ocular pursuit and optokinetic nystagmus, and defective fixation suppression of caloric nystagmus (Dionne et al., 1979). Recently, both the masseter and blink reflexes were found to be abnormal in two ARSACS patients (Garcia et al., 2008), whereas the masseter reflex was preserved but a bilateral delay of the late response of the blink reflex was observed in Friedreich' ataxia patients.

Therapy and management
Spasticity, the main feature of ARSACS during childhood, is rather mild in most patients. In the teens, however, the spasticity increases in the lower limbs and patients often present a www.intechopen.com Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS): Clinical, Radiological and Epidemiological Aspects 167 spastic gait with evolving pes cavus . Physical therapy and use of oral medications such as baclofen to control spasticity in the early phase of the disease may prevent tendon shortening and joint contractures. When spasticity becomes significant, intrathecal baclofen may be considered. The most effective surgical procedures were triple arthrodesis with percutaneous lengthening of the Achilles tendon, and adductor and psoas tenotomies combined with neurectomy of the obturator nerve for perineal hygiene in a retrospective study of 26 patients who received surgical orthopaedic treatment (Bouchard and Langlois, 1999).