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

Haruo Shimazaki1 and Yoshihisa Takiyama2

*1Division of Neurology, Department of Internal Medicine, Jichi Medical University, Tochigi 2Department of Neurology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo-City, Yamanashi, Japan* 

#### **1. Introduction**

154 Spinocerebellar Ataxia

Worth PF & Wood NW. (2001). Spinocerebellar ataxia type 12 is rare in the United

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Kingdom. *Neurology*. Vol. 56, No. 3, (Feb 13 2001),pp.419-420, ISSN 0028-

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.

#### **2. Epidemiology**

#### **2.1 Quebec**

ARSACS is the most common of all inherited spastic ataxias, 320 affected patients having been identified in Quebec (Bouchard et al., 1998). In Quebec, most of the patients' families originate from the Charlevoix and Saguenay-Lac-St. Jean (SLSJ) regions. These regions have a population of about 300,000 inhabitants today that share a limited number of French

Autosomal Recessive Spastic Ataxia of Charlevoix-

numbers of families identified in the regions.

G1734fsX1736 10

V1231del 10

P3559L 10

C395fsX407 8

N161fsX175 7

G1257X 10

Y138X 6

**3.1 Gene structure and pathological mutations** 

**3. Genetics** 

Saguenay (ARSACS): Clinical, Radiological and Epidemiological Aspects 157

ARSACS families show a nationwide distribution in Japan. The numbers in circles are the

W3248R 10 2 Ogawa, 2004, Takiyama, 2006

1 Komure, 2006

Amino acid substitutions Exon family references

K2931fsX2952 10 1 Hara, 2005

F1054S 10 1 Shimazaki, 2005

1 Yamamoto, 2005 S2058fsX2076 10

Q1345X 10 1 Okawa, 2006 R4325X 10 1 Yamamoto, 2006

1 Ouyang, 2006 D687fsX713 8

1 Kamada, 2008 L802P 10

1 Tsugawa, 2009 R3788fsX3820 10

1 Haga, 2011 K1755fsX1775 10

R3636X 10 1 (unpublished) S4007F 10 1 Miyatake, 2011

Table 1. Previously identified *SACS* gene mutations in Japanese patients.

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-

R2119X 10 1 Hara, 2007 L308F 8 1 Takado, 2007 D1996fsX1999 10 1 Shimazaki, 2007

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).

#### **2.2 Non-Quebec**

*SACS* gene identification has enabled us to find ARSACS patients worldwide outside Quebec: Tunisia (El Euch-Fayache et al., 2003) in 2003, Italy (Criscuolo et al., 2004; Grieco et al., 2004)in 2004, Japan (Ogawa et al., 2004) in 2004, and Turkey (Richter et al., 2004) in 2004. More cases were then reported in Spain (Criscuolo et al., 2005), France (Anheim et al., 2008), Belgium (Ouyang et al., 2008), the Netherlands (Vermeer et al., 2008), Germany (Gerwig et al., 2010), Maritime Canada (Guernsey et al., 2010), and Morocco and eastern Europe (Baets et al., 2010). In eastern France, ARSACS was identified in two index patients among 102 autosomal recessive cerebellar ataxia (ARCA) ones (Anheim et al., 2008), meanwhile among 43 Dutch ARCA patients, 16 with mutations in the *SACS* gene were identified (Vermeer et al., 2008). In Japan, 17 Japanese ARSACS families have been discovered on SACS gene analysis so far (Ogawa et al., 2004; Hara et al., 2005; Shimazaki et al., 2005; Yamamoto et al., 2005; Ouyang et al., 2006; Yamamoto et al., 2006; Okawa et al., 2006; Hara et al., 2007; Takado et al., 2007; Shimazaki et al., 2007; Kamada et al., 2008; Tsugawa et al., 2009; Haga et al., 2011; Miyatake et al., 2011; Komure et al., 2006). ARSACS might be the second most frequent ARCA next to ataxia with oculomotor apraxia 1 (AOA1) in Japan. Figure 1 shows the geographical distribution and numbers of ARSACS families with *SACS* gene mutations in Japan. We could not find apparent regional accumulation of ARSACS families in Japan. Table 1 lists the previously identified SACS gene mutations that we could confirm in the 17 Japanese ARSACS families. The mutations were unique ones for each family except for one missense mutation (W3248R) found in two unrelated families.

Fig. 1. Regional distribution of ARSACS families in Japan.

ARSACS families show a nationwide distribution in Japan. The numbers in circles are the numbers of families identified in the regions.


Table 1. Previously identified *SACS* gene mutations in Japanese patients.

#### **3. Genetics**

156 Spinocerebellar Ataxia

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

*SACS* gene identification has enabled us to find ARSACS patients worldwide outside Quebec: Tunisia (El Euch-Fayache et al., 2003) in 2003, Italy (Criscuolo et al., 2004; Grieco et al., 2004)in 2004, Japan (Ogawa et al., 2004) in 2004, and Turkey (Richter et al., 2004) in 2004. More cases were then reported in Spain (Criscuolo et al., 2005), France (Anheim et al., 2008), Belgium (Ouyang et al., 2008), the Netherlands (Vermeer et al., 2008), Germany (Gerwig et al., 2010), Maritime Canada (Guernsey et al., 2010), and Morocco and eastern Europe (Baets et al., 2010). In eastern France, ARSACS was identified in two index patients among 102 autosomal recessive cerebellar ataxia (ARCA) ones (Anheim et al., 2008), meanwhile among 43 Dutch ARCA patients, 16 with mutations in the *SACS* gene were identified (Vermeer et al., 2008). In Japan, 17 Japanese ARSACS families have been discovered on SACS gene analysis so far (Ogawa et al., 2004; Hara et al., 2005; Shimazaki et al., 2005; Yamamoto et al., 2005; Ouyang et al., 2006; Yamamoto et al., 2006; Okawa et al., 2006; Hara et al., 2007; Takado et al., 2007; Shimazaki et al., 2007; Kamada et al., 2008; Tsugawa et al., 2009; Haga et al., 2011; Miyatake et al., 2011; Komure et al., 2006). ARSACS might be the second most frequent ARCA next to ataxia with oculomotor apraxia 1 (AOA1) in Japan. Figure 1 shows the geographical distribution and numbers of ARSACS families with *SACS* gene mutations in Japan. We could not find apparent regional accumulation of ARSACS families in Japan. Table 1 lists the previously identified SACS gene mutations that we could confirm in the 17 Japanese ARSACS families. The mutations were unique ones for each family except for one

1941-1985 period (De Braekeleer et al., 1993).

missense mutation (W3248R) found in two unrelated families.

Fig. 1. Regional distribution of ARSACS families in Japan.

**2.2 Non-Quebec** 

#### **3.1 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-

Autosomal Recessive Spastic Ataxia of Charlevoix-

**3.2 Normal sacsin function** 

**3.3 Pathogenesis of ARSACS** 

**4. Clinical phenotypes** 

**4.1 Original Quebec phenotype** 

disease.

al., 2008; Terracciano et al., 2009; McMillan et al., 2009).

GTP, but it does not have GTPase activity (Kozlov et al., 2011).

Saguenay (ARSACS): Clinical, Radiological and Epidemiological Aspects 159

large deletions of the whole *SACS* gene and adjacent genes have been reported (Breckpot et

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 (Anderson, Siller, and 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

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

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

MAR-2011). The *SACS* gene comprises ten exons with a 13,737 bp ORF encoding 4579 amino acids (Figure 2A).

The *SACS* gene is predicted to encode a 520-kDa multidomain protein, sacsin. The region near the C-terminus exhibits sequence similarity to the J-domain (DnaJ motif) of heat shock protein (HSP) 40 proteins (Parfitt et al., 2009), and the higher eukaryote and prokaryote nucleotide-binding (HEPN) domain (Grynberg, Erlandsen, and Godzik, 2003) (Figure 2B). A ubiquitin-like domain was identified at the N-terminus of sacsin (Parfitt et al., 2009)(Figure 2B). A sacsin repeating region (SRR) is present in triplicate at the N-terminus of sacsin (Anderson, Siller, and Barral, 2010). A xeroderma pigmentosum complementation group Cbinding (XPCB) domain (Kamionka and Feigon, 2004) upstream of the DnaJ domain is also predicted.

Fig. 2. Primary structure of the *SACS* gene (A) and domain organization of the sacsin protein (B). UBL: ubiquitin-like domain; SRR: sacsin repeating region; XPCB: XPC-binding domain; DnaJ: DnaJ motif (adopted from (Kozlov et al., 2011)).

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).

#### **3.2 Normal sacsin function**

158 Spinocerebellar Ataxia

MAR-2011). The *SACS* gene comprises ten exons with a 13,737 bp ORF encoding 4579 amino

The *SACS* gene is predicted to encode a 520-kDa multidomain protein, sacsin. The region near the C-terminus exhibits sequence similarity to the J-domain (DnaJ motif) of heat shock protein (HSP) 40 proteins (Parfitt et al., 2009), and the higher eukaryote and prokaryote nucleotide-binding (HEPN) domain (Grynberg, Erlandsen, and Godzik, 2003) (Figure 2B). A ubiquitin-like domain was identified at the N-terminus of sacsin (Parfitt et al., 2009)(Figure 2B). A sacsin repeating region (SRR) is present in triplicate at the N-terminus of sacsin (Anderson, Siller, and Barral, 2010). A xeroderma pigmentosum complementation group Cbinding (XPCB) domain (Kamionka and Feigon, 2004) upstream of the DnaJ domain is also

Fig. 2. Primary structure of the *SACS* gene (A) and domain organization of the sacsin protein (B). UBL: ubiquitin-like domain; SRR: sacsin repeating region; XPCB: XPC-binding

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

domain; DnaJ: DnaJ motif (adopted from (Kozlov et al., 2011)).

acids (Figure 2A).

predicted.

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 (Anderson, Siller, and 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).

#### **3.3 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.

#### **4. 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

Autosomal Recessive Spastic Ataxia of Charlevoix-

influence the intellectual impairment.

patients examined (Bouchard, 1991).

**4.3 Ophthalmologic findings** 

bearing relation to the disease.

(Meijer et al., 2004), and SPG30 (Klebe et al., 2006).

Miyatake et al., 2011).

Saguenay (ARSACS): Clinical, Radiological and Epidemiological Aspects 161

cases of early-onset cerebellar ataxia without spasticity. After that, several reports on spasticity-lacking ARSACS patients were published (Hara et al., 2007; Baets et al., 2010;

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

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

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

Although increased visibility of myelinated retinal nerve fibers is a hallmark of ARSACS in Quebec patients (Bouchard, 1991), there have been a considerable number of non-Quebec patients without this characteristic sign for ARSACS (El Euch-Fayache et al., 2003; Grieco et al., 2004; Criscuolo et al., 2004; Richter et al., 2004; Hara et al., 2005; Yamamoto et al., 2005; Ouyang et al., 2006; Okawa et al., 2006; Yamamoto et al., 2006; Hara et al., 2007; Baets et al., 2010). Thus, retinal hypermyelination is a variable feature in non-Quebec patients. It is, however, very useful for suspecting a diagnosis of ARSACS, especially in an unusual phenotype without spasticity (Shimazaki et al., 2005). In a case without retinal hypermyelination, ARSACS resembles conditions referred to as early onset cerebellar ataxia with retained tendon reflexes (EOCA) (Chio et al., 1993), Friedreich ataxia with retained reflexes (De Castro et al., 1999), and several clinical descriptions of hereditary spastic paraplegia such as SPG7 (Wilkinson et al., 2004), SPG21 (Simpson et al., 2003), SPG27

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

any clinical or electrophysiologic signs of peripheral neuropathy (Baets et al., 2010).

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.

#### **4.2 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 (Shimazaki et al., 2005). 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 (Shimazaki et al., 2005). 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 (Hara et al., 2007; 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).

#### **4.3 Ophthalmologic findings**

160 Spinocerebellar Ataxia

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

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.,

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

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 (Shimazaki et al., 2005). 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 (Shimazaki et al., 2005). 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

prominent myelinated fibers radiating from the disc on the retina.

**4.2 Non-Quebec atypical phenotypes** 

2010).

Quebec patients.

Although increased visibility of myelinated retinal nerve fibers is a hallmark of ARSACS in Quebec patients (Bouchard, 1991), there have been a considerable number of non-Quebec patients without this characteristic sign for ARSACS (El Euch-Fayache et al., 2003; Grieco et al., 2004; Criscuolo et al., 2004; Richter et al., 2004; Hara et al., 2005; Yamamoto et al., 2005; Ouyang et al., 2006; Okawa et al., 2006; Yamamoto et al., 2006; Hara et al., 2007; Baets et al., 2010). Thus, retinal hypermyelination is a variable feature in non-Quebec patients. It is, however, very useful for suspecting a diagnosis of ARSACS, especially in an unusual phenotype without spasticity (Shimazaki et al., 2005). In a case without retinal hypermyelination, ARSACS resembles conditions referred to as early onset cerebellar ataxia with retained tendon reflexes (EOCA) (Chio et al., 1993), Friedreich ataxia with retained reflexes (De Castro et al., 1999), and several clinical descriptions of hereditary spastic paraplegia such as SPG7 (Wilkinson et al., 2004), SPG21 (Simpson et al., 2003), SPG27 (Meijer et al., 2004), and SPG30 (Klebe et al., 2006).

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.

Autosomal Recessive Spastic Ataxia of Charlevoix-

Age at exam, gender

> Cerebellar ataxia

Retinal myelinated fibers

Peripheral neuropathy

Mental impairment

Amino acid substitutions

> Superior cerebellar vermian atrophy

Pontine linear hypointensity (T2)

MCP hypointensity (T2)

> Medulla oblongata atrophy

Upper cervical cord atrophy

Superior cerebellar CBF decrease

Saguenay (ARSACS): Clinical, Radiological and Epidemiological Aspects 163

Case 1 2 3 4 5 6

Age at onset 6 6 3 8 7 3

Hyperreflexia + + + - - - Leg spasticity + + + - - - Babinski sign + + + + + +

47, F 43, M 46, M 37, M 33, M 57, F

++ + ++ + ++ ++

+ + + + + +

+ + + + + +

NE +(WAIS-R) +(WAIS-R) NE +(WAIS-R) +(MMSE)

W3248R W3248R W3248R F1054S F1054S D1996fsX1999

+ + + + + +

+ + + + + +

+ + + + + +



+- NE +- + + +

Table 2. Clinical, genetic and MRI findings in the ARSACS patients. NE: not examined;

MCP: Middle cerebellar peduncle; CBF: cerebral blood flow in SPECT.

#### **5. Neuroradiology**

#### **5.1 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 (Shimazaki et al., 2012). 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.

#### **5.2 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 (Shimazaki et al., 2012). 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).

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

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

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

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

The hypointensity in the pons and middle cerebellar peduncle might be specific findings for ARSACS cases even in non-Quebec ones with clinical heterogeneity (Shimazaki et al., 2012). 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

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 (Shimazaki et al., 2012). Upper cervical atrophy is not a constant feature of ARSACS. In thirteen Belgium cases, cervical spinal cord atrophy

**5. Neuroradiology 5.1 Brain MRI findings** 

and middle cerebellar peduncles (Figure 3, A-1).

abnormal MCP signal is not specific for Japanese patients.

was observed on MRI in only one case (Baets et al., 2010).

al., 2010).

paraplegias.

cases.

**5.2 Spinal MRI findings** 


Table 2. Clinical, genetic and MRI findings in the ARSACS patients. NE: not examined; MCP: Middle cerebellar peduncle; CBF: cerebral blood flow in SPECT.

Autosomal Recessive Spastic Ataxia of Charlevoix-

**5.3 SPECT findings** 

different feature from in ARSACS.

analyses of cases 4, 5, and 6.

**6. Neuropathology** 

hemisphere.

Saguenay (ARSACS): Clinical, Radiological and Epidemiological Aspects 165

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

Fig. 4. 123I-IMP SPECT with three-dimensional stereotactic surface projection (3D-SSP)

The results showed decreased blood flow in the superior cerebellar vermis and cerebellar

**6.1 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.

Fig. 3. Representative brain MRI findings in two ARSACS patients. T2-weighted and FLAIR images of patient 3 (A-2a, 2b, 4a, and 4b) and patient 2 (B-1, 2a, 2b, 4a, and 4b) showed hypointensity in the pons (arrowheads) and bilateral middle cerebellar peduncles (arrows). Sagittal sections (A-3 and B-3) revealed superior cerebellar vermian atrophy in all patients. A T2\* image of patient 3 (A-1) disclosed no remarkable low intensity in the pontine tegmentum or cerebellar peduncles (Shimazaki et al., 2012).

#### **5.3 SPECT findings**

164 Spinocerebellar Ataxia

Fig. 3. Representative brain MRI findings in two ARSACS patients. T2-weighted and FLAIR images of patient 3 (A-2a, 2b, 4a, and 4b) and patient 2 (B-1, 2a, 2b, 4a, and 4b) showed hypointensity in the pons (arrowheads) and bilateral middle cerebellar peduncles (arrows). Sagittal sections (A-3 and B-3) revealed superior cerebellar vermian atrophy in all patients. A T2\* image of patient 3 (A-1) disclosed no remarkable low intensity in the pontine

tegmentum or cerebellar peduncles (Shimazaki et al., 2012).

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.

Fig. 4. 123I-IMP SPECT with three-dimensional stereotactic surface projection (3D-SSP) analyses of cases 4, 5, and 6.

The results showed decreased blood flow in the superior cerebellar vermis and cerebellar hemisphere.

#### **6. Neuropathology**

#### **6.1 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.

Autosomal Recessive Spastic Ataxia of Charlevoix-

Culture, Sports, Science and Technology in Japan.

print], ISSN 1089-8638

ISSN 0028-3940

(Sep 2010), pp. 1181-1188, ISSN 0028-3878

and Langlois, 1999).

**10. References** 

**9. Acknowledgements** 

Saguenay (ARSACS): Clinical, Radiological and Epidemiological Aspects 167

spastic gait with evolving pes cavus (Bouchard et al., 2007). 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

This work was supported by Grants-in Aid from the Research Committee for Ataxic Diseases (Y.T. and H.S.), the Ministry of Health, Labour and Welfare of Japan. This work was also supported by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases (Y.T.), and the Ministry of Health, Labor and Welfare of Japan, and supported by a Grant-in-Aid for Scientific Research (C) (23591253 to H.S.) from The Ministry of Education,

Anderson, J. F., E. Siller, and J. M. Barral. (2010). The sacsin repeating region (SRR): a novel

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Bouchard, J. P. (1991). Ressesive spastic ataxia of Charlevoix-Saguenay. In *Hereditary* 

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*Neuropathies and Spinocerebellar Atrophies. Handbook of Clinical Neurology*, edited by J.

#### **6.2 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.

Muscle biopsy disclosed typical and obvious neurogenic atrophy, i.e., grouped atrophy in the studied patients (Bouchard, 1991; El Euch-Fayache et al., 2003).

#### **7. Neurophysiology**

#### **7.1 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 (Shimazaki et al., 2005). 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 (Shimazaki et al., 2005)), 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).

#### **7.2 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.

#### **8. 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 spastic gait with evolving pes cavus (Bouchard et al., 2007). 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).

#### **9. Acknowledgements**

166 Spinocerebellar Ataxia

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

Muscle biopsy disclosed typical and obvious neurogenic atrophy, i.e., grouped atrophy in

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 (Shimazaki et al., 2005). 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 (Shimazaki et al., 2005)), 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.,

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

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

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

**6.2 Nerve and muscle biopsy** 

**7. Neurophysiology** 

2003).

**7.1 Peripheral nerve conduction studies** 

**7.2 Motor and sensory evoked potentials** 

pathway involvement (Bouchard, 1991).

**8. Therapy and management** 

blink reflex was observed in Friedreich' ataxia patients.

axonal neuropathy associated with demyelinating features.

the studied patients (Bouchard, 1991; El Euch-Fayache et al., 2003).

This work was supported by Grants-in Aid from the Research Committee for Ataxic Diseases (Y.T. and H.S.), the Ministry of Health, Labour and Welfare of Japan. This work was also supported by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases (Y.T.), and the Ministry of Health, Labor and Welfare of Japan, and supported by a Grant-in-Aid for Scientific Research (C) (23591253 to H.S.) from The Ministry of Education, Culture, Sports, Science and Technology in Japan.

#### **10. References**


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**9** 

*Spain* 

**Neurochemistry and Neuropharmacology** 

*1Department of Neurology, Hospital Universitario Miguel Servet, Zaragoza,* 

José Gazulla1, Cristina Andrea Hermoso-Contreras2 and María Tintoré3

*3Nucleic Acid Chemistry Group, Chemistry and Molecular Pharmacology Programme,* 

The aim of this work has been to review the neurochemical alterations described in the cerebellar ataxias, and to enumerate the attempts made at their pharmacological treatment. As will be shown, little use has been made of the neurochemical information available, and

The predominant (though not exclusive) reference to degenerative ataxias is due to the fact that the specificity of the affected cell populations should allow anticipation of more or less specific neurochemical alterations. This information could be used to look for therapeutic strategies, given the absence of curative treatments for the majority of ataxic disorders. This review covers only the pharmacologic attempts performed to treat ataxic symptoms, and is not exhaustive in terms of nosology, genetics or congenital errors of metabolism. The neurochemical basis of some non-degenerative ataxias that demonstrate favourable responses to pharmacological treatment are also reviewed. An outline of the physiological neurotransmission in the cerebellum opens this chapter

The cerebellum is made up of four pairs of nuclei located in the deep white matter that covers the fourth ventricle, and is surrounded by a superficial layer of grey matter. The

In the cortex of the cerebellum, there are several types of inhibitory interneurons that utilize -aminobutyric acid (GABA) as neurotransmitter. These are Golgi cells (that coexpress

Purkinje cells are also GABAergic; they are the only ones whose axons exit the cortex of the cerebellum, projecting towards the cerebellar and vestibular nuclei. They use taurine as an

cerebellar cortex has a very uniform cellular structure and great cell density.

GABA with glycine), stellate cells, basket cells and Lugaro cells.

**1. Introduction** 

(Table 1).

osmotic regulator.

the therapeutic trials have been far from successful.

**2. Neurotransmission in the cerebellum** 

**of the Cerebellar Ataxias** 

*2School of Medicine, University of Zaragoza, Zaragoza,* 

*Institute for Research in Biomedicine of Barcelona, Barcelona,* 

