ORIGINAL COMMUNICATION

New findings in the ataxia of Charlevoix–Saguenay

Jose Gazulla • Isabel Benavente • Ana Carmen Vela • Miguel Angel Marın •

Luis Emilio Pablo • Alessandra Tessa • Marıa Rosario Barrena • Filippo Maria Santorelli •

Claudia Nesti • Pedro Modrego • Marıa Tintore • Jose Berciano

Received: 5 August 2011 / Revised: 28 September 2011 / Accepted: 29 September 2011 / Published online: 13 October 2011

� Springer-Verlag 2011

Abstract The aim of the study was to enhance our under-

standing of the pathogenesis of the ataxia of Charlevoix–

Saguenay, based on the findings presented herein. Five

patients with a molecular diagnosis of this disease underwent

clinical, radiological, ophthalmologic and electrophysio-

logical examinations. Five novel mutations, which included

nonsense and missense variants, were identified, with these

resulting in milder phenotypes. In addition to the usual

manifestations, a straight dorsal spine was found in every

case, and imaging techniques showed loss of the dorsal ky-

phosis. Cranial MRI demonstrated hypointense linear stria-

tions at the pons. Tensor diffusion MRI sequences revealed

that these striations corresponded with hyperplastic ponto-

cerebellar fibres, and tractographic sequences showed

interrupted pyramidal tracts at the pons. Ocular coherence

tomography demonstrated abnormal thickness of the nerve

fibre layer. Electrophysiological studies showed nerve con-

duction abnormalities compatible with a dysmyelinating

neuropathy, with signs of chronic denervation in distal

muscles. The authors suggest that the hyperplastic ponto-

cerebellar fibres compress the pyramidal tracts at the pons,

and that the amount of retinal fibres traversing the optic discs

is enlarged. These facts point to the contribution of an

abnormal developmental mechanism in the ataxia of Char-

levoix–Saguenay. Accordingly, spasticity would be medi-

ated by compression of the pyramidal tracts, neuromuscular

symptoms by secondary axonal degeneration superimposed

on the peripheral myelinopathy, while the cause of the pro-

gressive ataxia remains speculative. The distinctive aspect of

the dorsal spine could be of help in the clinical diagnosis.

J. Gazulla � P. Modrego

Service of Neurology, Hospital Universitario Miguel Servet,

Avenida Isabel la Catolica, 1-3, 50009 Zaragoza, Spain

J. Gazulla (&)

Luis Vives 6, esc dcha, 78 B, 50006 Zaragoza, Spain

e-mail: josegazulla@gmail.com

I. Benavente

Service of Clinical Neurophysiology, Hospital San Jorge,

Avenida Martınez de Velasco, s/n. 22004 Huesca, Spain

A. C. Vela � M. A. Marın

Service of Radiology, Hospital Universitario Miguel Servet,

Zaragoza, Spain

L. E. Pablo

Service of Ophthalmology, Hospital Universitario

Miguel Servet, Zaragoza, Spain

A. Tessa � F. M. Santorelli � C. Nesti

Molecular Medicine and Neurogenetics, IRCCS Fondazione

Stella Maris. Vial del Tirreno, 331, Calambrone, Pisa, Italy

M. R. Barrena

Service of Radiology, Clınica Montecanal,

Franz Schubert, 2, 50012 Zaragoza, Spain

M. Tintore

Nucleic Acid Chemistry Group,

Chemistry and Molecular Pharmacology Programme, Institute

for Research in Biomedicine of Barcelona,

Baldiri Reixac, 10, 08028 Barcelona, Spain

J. Berciano

Department of Neurology, University Hospital Marques de

Valdecilla, University of Cantabria and Centro de Investigacion

Biomedica en Red de Enfermedades Neurodegenerativas,

Avenida de Valdecilla, 25, 39008 Santander, Spain

123

J Neurol (2012) 259:869–878

DOI 10.1007/s00415-011-6269-5

Keywords ARSACS � Peripheral and central

myelinopathy � Pontocerebellar fibre hyperplasia � Retinal

nerve fibre hyperplasia � Straight dorsal spine

Introduction

The autosomal recessive spastic ataxia of Charlevoix–

Saguenay (ARSACS) is a disease caused by mutations in

the SACS gene, located on chromosome 13q12.12 [39].

Believed at first to be restricted to Canada, ARSACS has

been diagnosed in various countries afterwards, and the

two initial founder mutations identified in the province of

Quebec have increased to more than 70, coming from

around the world [11, 25, 28].

In this article, the authors present five patients with a

molecular diagnosis of ARSACS, together with the results

of clinical, radiological, ophthalmologic, electrophysio-

logical and genetic examinations. On the basis of the

findings obtained in these studies, a pathogenic hypothesis

is proposed, different from the neurodegenerative genesis

attributed to this disease.

Patients and methods

Five patients, in whom a diagnosis of ARSACS was sus-

pected, underwent the following procedures:

1. A complete clinical evaluation.

2. An imaging study comprising cranial CT and MRI

examinations. Spinal X-ray and MRI scans were done

in two patients.

3. An ophthalmologic survey, consisting of visual acuity

and field tests, stereophotographs of the optic discs,

and retinal nerve fibre layer (RNFL) assessment by

monochromatic photography and ocular coherence

tomography (OCT).

4. An electrophysiological study that included motor and

sensory nerve conduction studies; F wave latencies and

blink reflexes. Concentric needle electromyography of

proximal and distal muscles was also performed.

Somatosensory, auditory, electroretinogram and visu-

ally evoked potentials were recorded, as well as

sympathetic skin responses.

5. A molecular study, in which total DNA was purified

from peripheral blood. The coding exons and flanking

introns of SACS were amplified by polymerase chain

reaction, purified and bidirectionally sequenced using

oligonucleotide primers [12]. The presence of

large-scale gene deletions in SACS was ruled out by

multiple ligation-dependent probe amplification and

quantitative-PCR protocols, described elsewhere [38].

Segregation of mutations with the disease was ana-

lyzed in close relatives, whenever possible. New

mutations were also ruled out in over 300 ethnically-

matched control chromosomes.

This study was approved by the local ethics committee.

Every patient gave informed consent for its realization,

according to the Declaration of Helsinki.

Results

Clinical findings

The series comprised four women and one man, aged

37–57 years. Every patient displayed pes cavus and ham-

mertoes. In addition, a straight dorsal spine, a posterior flat

rib cage with protruding scapulae, together with normal

muscle strength in the scapular girdle, were also found

(Fig. 1).

Fig. 1 a, b Note straight dorsal spine, flat posterior rib cage and

protruding scapulae in two patients. Absence of dorsal kyphosis and

lack of bone and soft tissue abnormalities in X-ray (c) and MRI

(d) scans. Spinal cord atrophy is evident in image D

870 J Neurol (2012) 259:869–878

123

Patients 1 and 2 experienced a late progression of dis-

ease (at 42 and 31 years of age, respectively), after dis-

playing abnormal gait since infancy. On the opposite,

patients 3, 4 and 5 suffered progression since disease onset.

Severe spasticity was present in the hips and knees. The

patellar reflexes were always preserved, while the achilles

and brachioradialis were abolished; only patient 2 had

spared distal tendon reflexes. Extensor plantar responses

were found in every instance.

Mild distal weakness was present in the upper limbs. In

the lower limbs, it was mild in patients 1 and 2, and

moderate in the others. Vibration sense was diminished in

the lower limbs in patients 1 and 2, and absent in the

remaining. Gait was limited to a few steps with bilateral

support; only patient 2 retained independent ambulation.

Dysmetria was moderate in patients 1 and 2, and severe

in the others. Gaze evoked nystagmus and non-smooth

ocular pursuit were present in every case. Mild dystonic

posturing of the hands was observed in patient 4.

Radiological findings

T1-weighted sagittal midline cranial MRI scans revealed

atrophy of the superior cerebellar vermis, upper cervical

cord and cerebral cortex, while the brainstem appeared to

be of normal size. Proton density, T2 and fluid-attenuation

inversion recovery (FLAIR) axial sequences demonstrated

paramedial, bilateral and parallel linear hypointensities in

the basis and tegmentum of the pons, together with thick

middle cerebellar peduncles.

Single-voxel spectroscopic analyses of the pons, using

1.5 and 3 Tesla machines, verified a mild elevation of the

choline/creatine ratio, characteristic of normal white mat-

ter. Diffusion tensor colour encoded MRI maps demon-

strated: (1) an occupation of the pontine basis and

tegmentum by pontocerebellar fibres; (2) thin and abnor-

mally placed pyramidal tracts at the pons; (3) abnormally

thick middle cerebellar peduncles; and (4) normal medial

lemnisci (Fig. 2).

Diffusion tensor tractographies showed that the pyra-

midal tracts were interrupted at the pons, although the

pyramids showed a normal size and location at the

medulla. An extremely large amount of pontocerebellar

fibres was detected, which compressed the pyramidal tracts

and gave place to unusually thick middle cerebellar pe-

duncles (Fig. 3).

X-ray films revealed a straight spine, an absence of the

dorsal kyphosis and a lack of bone abnormalities in the

tested patients (Fig. 1c). Dorsal spine MRI scans confirmed

these findings, without disclosing soft tissue anomalies

(Fig. 1d).

Ophthalmological findings

Normal visual acuities and mild peripheral campimetric

non-specific defects were found in every case. Monochro-

matic photographies showed increased visibility of the

RNFL, while OCT demonstrated an increased thickness of

this layer, which ranged from 125–220 lm.

Electrodiagnostic findings

The results are presented in Tables 1, 2 and 3. Every tested

nerve showed abnormalities of motor and sensory con-

duction that fell into the demyelinating range. The ampli-

tudes of the motor and sensory potentials were low,

although associated with significant increases in the tem-

poral dispersions of action potentials on distal and proxi-

mal stimulation, even in the lower limbs.

Minimal F wave latencies and F wave latency chron-

odispersions were prolonged. So were the blink reflex

latencies. Sympathetic skin responses were normal, as

reported previously [16].

Electromyography revealed signs of chronic denervation

in distal muscles, though not so in proximal ones; the

recruitment pattern was reduced in every tested muscle.

Somatosensory, brainstem auditory and visual evoked

responses showed increased latencies and prolonged cen-

tral conduction times, which doubled normal values on

occasion.

Molecular findings

Patient 1 exhibited the hemizygous mutation c.13405G [C/p.A4469P, which replaces alanine 4469 for proline in the

functionally relevant HEPN domain [4]. The other allele,

inherited from her mother, harboured a large genomic

deletion (D) that encompassed SACS, as described else-

where [38].

Patient 2 harboured a c.1894C [ T substitution

(p.R632 W) on the paternal allele, and a c.12973C [ T

variant (p.R4325X) on the maternal one. The p.R632 W

mutation affects a highly conserved residue in sacsin,

whereas p.R4325X predicts premature protein truncation.

Patients 3 and 4 were sibs and harboured the nonsense

mutation c.832C [ T/p.Q278X in compound heterozy-

gosity with c.9670C [ T/p.R3224X on the paternal allele;

both variants predict sacsin truncation at positions 278 and

3,224, respectively.

Patient 5, an offspring of consanguineous parents,

demonstrated the homozygous mutation c.3198T [A/p.C1066X, which predicts early sacsin truncation. Each

parent carried the mutation in heterozygous form.

J Neurol (2012) 259:869–878 871

123

Discussion

ARSACS usually presents with early onset lower-limb

spasticity, cerebellar ataxia, peripheral neuropathy, and

skeletal and retinal anomalies [7, 8, 10, 31], in spite of

cases with incomplete clinical expression [34] or late onset

[5]. Although the resulting clinical picture is easily rec-

ognizable, some aspects of the disease need to be defined

better, as will be considered below.

In addition to the well-known skeletal abnormalities of

pes cavus and hammertoes [8], an alteration of the dorsal

kyphosis was observed in every patient presented herein.

The dorsal spine appeared straight, and the posterior rib

cage flat; and despite an absence of muscle weakness, the

superior angles of the scapulae stuck out from the thoracic

wall, exhibiting the peculiar appearance shown in Fig. 1.

X-ray and MRI scans showed loss of the physiological

dorsal kyphosis, without bone or soft tissue anomalies. As

scoliosis is the spinal abnormality most frequently associ-

ated with spinocerebellar degenerations, the observed

straight spine could represent a skeletal anomaly charac-

teristic of ARSACS.

Dystonia has occasionally been reported in ARSACS

[39], and abnormal posturing of the hands was noted in

patient 4, which did not cause any motor handicap. Thus,

dystonia seems to be infrequent and mild in this disease.

MRI scans showed atrophy of the cerebellum, cerebral

cortex and spinal cord. A pontine hypointense linear stri-

ation was found in every patient; this finding has been

claimed as unique to ARSACS [23].

In an effort to determine the nature of the hypointense

striation, spectroscopy and diffusion tensor MRI sequences

were performed. Although a spectroscopic analysis gave

normal results, diffusion tensor maps showed that the

hypointense striation corresponded with pontocerebellar

fibres, and that the pyramidal tracts were thin and out of

their normal location.

Tractographic MRI sequences showed that the pyrami-

dal tracts were interrupted by an abnormally large number

of pontocerebellar fibres, which gave the basis pontis a

bulky appearance and constituted thick middle cerebellar

peduncles.

Tensor diffusion MRI has been used to assess some

degenerative ataxias, and atrophy of the nervous structures

Fig. 2 Diffusion tensor colour

MRI maps of the pontine

structures (blue, craniocaudal

fibres; green, anteroposterior

fibres; red, latero-lateral fibres).

a, c Normal configuration of the

pons in a control subject:

pyramidal tracts, medial

lemnisci and superior cerebellar

peduncles (blue),

pontocerebellar fibres (red), and

middle cerebellar peduncles

(green). b, d In an ARSACS

patient, small and laterally

placed pyramidal tracts;

occupation of the basis and

tegmentum pontis by

pontocerebellar fibres, and thick

middle cerebellar peduncles

872 J Neurol (2012) 259:869–878

123

was found in every case [22, 37, 43]. Thus, the increased

amount of pontocerebellar fibres detected in our patients

does not suggest a degenerative origin, but would be more

evocative of a developmental one. In this case, the

pontocerebellar fibres would compress the pyramidal tracts

at the pons since the embryonic period, causing spasticity

from a very early age, as reported [7–10]. Although the

corticospinal tracts were reported to be small at the pons in

ARSACS, and the pontine nuclei, preserved, the ponto-

cerebellar fibres were not detailed [7, 9, 10]. Therefore, a

review of the pathological findings should be carried out in

this disease, in order to confirm the proposed hypothesis.

Most of the pontocerebellar fibres use glutamate as a

neurotransmitter [26]. Taking into account the increased

Fig. 3 Diffusion tensor

tractographies. a, c, e Normal

control appearance of the

pyramidal tracts, medial

lemnisci and middle cerebellar

peduncles. b, d, f Images from

ARSACS patients. b Note

interruption of the pyramidal

tracts at the pons. d Increased

number of fibres in the middle

cerebellar peduncles. f Greatly

increased amount of

pontocerebellar fibres,

thickened middle cerebellar

peduncles and normal

appearance of the descending

pyramidal tracts

J Neurol (2012) 259:869–878 873

123

amount of pontocerebellar fibres found in the images pre-

sented herein, it is plausible that glutamate excitotoxicity

could bring about neuronal death in the cerebellar cortex [2,

21, 32]. This phenomenon could be responsible for the cer-

ebellar atrophy evident on MRI scans, and for the progres-

sive ataxia associated with ARSACS, of more tardive

appearance than spasticity [7–10]. Damage to the spinocer-

ebellar tracts and the proprioceptive pathways could con-

tribute to the genesis of the ataxia, as well.

Although two spasticity-lacking phenotypes of ARS-

ACS have been described, these have been attributed to the

presence of severe muscle hypotonia, not to an absence of

Table 1 Nerve conduction studies

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5

Median nerve

MDL (n \ 4 ms)a 7.2 6 5.5 8.1 5.1

MCV (n [ 52 m/s) 33.1 34.9 39.8 30.3 41.2

D CMAP amplitude (n [ 7 mV) 0.7 2.7 2.9 2.4 6.6

D CMAP duration (n \ 9 ms) 16.1 12.4 8 10.8 5.8

P-D CMAP dispersion (n \ 130%) 95 106 107 98 110

D SCV (n \ 50 m/s) 25 34.9 31.2 Absent 32.9

SNAP amplitude (n [ 11 lV) 2.1 2.9 0.6 – 0.5

D SNAP duration (n \ 1.4 ms) 9.3 2.7 12 – 4.9

P-D CSNAP dispersion (n \ 120%) 143 159 – – –

Ulnar nerve

MDL (n \ 3.1 ms) 3.5 3.9 4.2 7 3.2

MCV (n [ 57 m/s) 36.1 32 38.2 44.9 34.9

D CMAP amplitude (n [ 7 mV) 1.7 5.5 5.2 2.9 7

D CMAP duration (n \ 9 ms) 14.3 14.6 7.2 7.6 6.1

P-D CMAP dispersion (\ 130%) 135 109 139 152 104

SCV (n [ 54 m/s) 35.7 37.7 34.6 Absent 36.7

SNAP amplitude (n [ 5 lV) 2 1.8 1 – 1,6

SNAP duration (n \ 1.6 ms) 6.2 2.7 5.3 – 2.9

P-D CSNAP dispersion (\ 120%) 134 – 123 – –

Peroneal nerve

MDL (n \ 5 ms) 7.6 12.6 5.8 (TA) Absent 6,9

MCV ([ 44 m/s) 21.2 22.4 21.3 – 28

D CMAP amplitude (n [ 3 mV) 0.2 0.5 0.3 – 1.2

D CMAP duration (n \ 9 ms) 6.3 8.6 15 – 5.1

P–D CMAP dispersion (n \ 130%) 104.8 115 106 – 181

SCV (n [ 40 m/s) 33.3 Absent Absent Absent Absent

Tibial nerve

MDL (n \ 5.1 ms) 9.3 8.3 Absent 10.2 Absent

MCV m/s (n [ 43 m/s) 22.4 30.8 – 22.8 –

D CMAP amplitude (n [ 4 mV) 0.2 0.2 – 0.1 –

D CMAP duration (\ 9 ms) 11.9 6.5 – 2.6 –

P–D CMAP dispersion (\ 130%) 106 350 – 122 –

Blink reflex

R1 (n \ 13 ms) 11 13 12,8 12.2 NP

R2 (n \ 41 ms) 57 50.5 49.8 77.5 NP

R2 c (n \ 44 ms) 62.7 55.4 55 81.5 NP

CMAP compound muscle action potential, CSNAP compound sensory nerve action potential, CV conduction velocity, D distal, MDL motor distal

latency, MCV motor conduction velocity, NP not performed, P proximal, P–D proximal–distal, SCV sensory conduction velocity, SNAP sensory

nerve action potenial, TA tibialis anterior, VLA very low amplitudea Normal values in brackets

874 J Neurol (2012) 259:869–878

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spasticity along the disease course. Besides, bilateral Ba-

binski signs were found in these patients, which disclosed

the presence of a pyramidal syndrome [33, 34].

An increased visibility of the retinal nerve fibres, which

embedded vessels in the peripapillary region, was reported

in the original description of ARSACS [8]. Colour

Table 2 Electromyographic findings

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5

Triceps brachii

Spontaneous activity None None None None None

Duration N N N N N

Amplitude N N N N N

Recruitment Discrete N N N N

First dorsal interosseous

Spontaneous activity None None None PW (2 ?) None

Duration 1? N 2? 2? 2?

Amplitude 1? N 2? 2? 2?

Recruitment Reduced N Reduced Reduced Reduced

Rectus femoris – –

Spontaneous activity None None None None None

Duration N N N N N

Amplitude N N N N N

Recruitment Discrete Reduced Reduced Reduced Reduced

Tibialis anterior

Spontaneous activity N None None Fib ? None

Duration 2? 2? 2? 2? 2?

Amplitude 2? 2? 2? 2? 2?

Recruitment Reduced Discrete Reduced Discrete Discrete

Gastrocnemius

Spontaneous activity N Fib 2? Fib 3? Fib 2? None

Duration 1? 1? 1? N 2?

Amplitude 1? 1? 2? N 2?

Recruitment Reduced Discrete Discrete Reduced Discrete

Fib fibrillation potentials, N normal, PW positive waves

Table 3 Evoked potentials

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5

Median nerve sensory evoked potentials

EP latency (ms)a 12.8 Absent 10.4 Absent Absent

N13 Latency (\14.8 ms) 16.4 14.2 16.25 14 Absent

N20 Latency (\21 ms) 27 25.9 Absent 30 25

CCT (\6.8 ms) 10.6 11.7 – 15.55 –

Tibial nerve sensory evoked potentials (PF)

P40 latency (\41.7 ms) Absent 37 Absent 38 Absent

Brainstem auditory evoked potentials

V latency (\6.5 ms) 6.4 6.84 6.76 7.6 7.15

I–V interval (\4.7 ms) 5.1 5.42 5.26 5.76 5.56

Visual evoked potentials

P100 latency (\114 ms) 144 111 133.2 132 139

RCT (\55.4 ms) 77.4 48.3 65.7 64.5 NP

CCT central conduction time, EP Erb’s point, NP not performed PF popliteal fossa, RCT retino-cortical timea Normal values in brackets

J Neurol (2012) 259:869–878 875

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stereophotographs and monochromatic photographs

showed enhanced visibility of the RNFL in every patient

presented here, while OCT demonstrated an increase in

average thickness of the RNFL, which ranged from 125 to

220 lm, as compared with a mean of 96 ± 7 lm in heal-

thy volunteers [17, 29]. Increased thickness of the RNFL

has also been described by other authors, with the use of

OCT [13, 41]; an enlarged amount of nervous fibres

probably accounts for these findings.

Visual acuity was normal herein, and only mild and

peripheral visual defects were found. These results rule out

the possibility of deposition of myelin in the retina,

because myelin, being opaque to light, would have caused

severe loss of visual acuity, as well as significant campi-

metric defects.

The issue of the peripheral nerve participation in

ARSACS has not been definitely established. It has been

claimed to be a myelinopathy [31], an axonopathy [12, 14],

or a disease bearing similarity with the intermediate forms

of Charcot–Marie–Tooth neuropathy [6, 16].

Our electroneurographic findings (Table 1) showed that,

when action potentials were found, the majority of motor

and sensory nerves disclosed abnormalities of conduction

that fell into the demyelinating range. Distal motor laten-

cies were prolonged, and minimum F wave latencies and

chronodispersions, increased. A noteworthy finding was an

increase in the distal, and also in proximal–distal, temporal

dispersions of the action potentials, which was found in

most of the motor and sensory nerves that could be tested.

This result indicates that fast and intermediate myelinated

fibres did not exhibit uniform nerve conduction velocities,

and means that the damage to the myelin sheath had a

multifocal distribution [35, 36].

A multifocal pattern of involvement has been found in

anomalies of myelin metabolism and diseases of Schwann

cells, in addition to dysimmune demyelinating neuropa-

thies [20]. It is known that Schwann cells exert influence on

axonal properties, and that changes induced by abnormal

myelin may cause axonal degeneration at distal regions

[18, 24]. In this survey, electromyographic signs of chronic

denervation were found in distal muscles of the limbs,

though not so in proximal ones (Table 2).

Systematic studies of evoked potentials have seldom

been performed in ARSACS. The results in Table 3 show

abnormalities in the somatosensory, auditory and visually

evoked responses. When these could be obtained, increased

latencies and conduction times were found, pointing to

abnormal conduction in the central pathways [6], except for

normal visual evoked responses in patient 2, which have

been previously described in ARSACS [16].

To summarize, the electrophysiological findings were

consistent with a peripheral and central myelinopathy, as

demonstrated by the slow conduction velocities and

increased temporal dispersion of action potentials in the

peripheral nerves, and the prolongation of latencies and

central conduction times in the evoked responses. A

superimposed peripheral axonal involvement was also

present, as mentioned above. These results are in line with

those reported previously, which proposed that the neu-

ropathy in ARSACS was caused by a developmental defect

of myelination, to which a degenerative process of

peripheral axons was added [31]. Therefore, it seems cer-

tain that sacsin must exert some influence on central and

peripheral myelin, although its presence in the peripheral

nervous system has not been examined yet.

ARSACS is caused by recessive mutations in the SACS

gene, located on chromosome 13q12.12 [39]. It has one

large exon with an open reading frame of 11.487 nucleo-

tides [15], eight newly identified 50 smaller exons [27], and

at least a non-coding one [40]. The nine exons consist of

over 15.000 bp and encode sacsin, a 4.579 amino acid

protein [39, 40]. This contains an N-terminus ubiquitin-like

(UbL) domain (amino acids 1–124), able to interact with

the proteasome [30], a J domain (which is the defining

feature of the Hsp40 family of Hsp70 co-chaperones)

between amino acids 4322–4370, and a C-terminus HEPN

domain involved in nucleotide binding, between residues

4,451 and 4,567 [4]. Sacsin also contains an N-terminus

recurring arrangement of three adjacent 360 amino acid

domains, which has been termed ‘‘sacsin repeating region’’.

This kind of repeating regions are usually placed in pro-

teins that contain a C-terminus J domain [3].

SACS mRNA has been detected by in situ hybridization

in all areas of the human brain, especially in the cerebral

cortex, hippocampus and cerebellum, and also in pancreas,

connective tissue and skeletal muscle [15].

The mutations in SACS presented in this work are novel,

except for p.R4325X [1, 42], and were not detected in over

400 Mediterranean control chromosomes. The affected

residues are conserved during evolution, and very likely

make these new variants disease-causative. Although

functional analyses were not possible, in silico predictions

using the HumVar-trained PolyPhen2 v2.0, anticipated that

the new changes were probably pathogenic [11]. Although

it has not been possible to establish a precise genotype–

phenotype correlation in ARSACS [5], it seems clear that

in this observation, patients who harboured missense

mutations on one allele displayed milder phenotypes than

those who bore nonsense ones. Unfortunately, the number

of patients presented herein is too short to draw a definite

correlation.

In conclusion, ARSACS has not demonstrated the

behaviour of a degenerative disorder, defined by cell loss

and tissue atrophy. Instead, the presence of abnormal

amounts of pontocerebellar and retinal fibres would rather

suggest a disorder of development in its genesis. As would

876 J Neurol (2012) 259:869–878

123

the electrophysiological records, indicative of a dysmyeli-

nating process. Phenomena derived from these factors

could cause spasticity (compression of the pyramidal

tracts), ataxia (cerebellar atrophy and spinocerebellar tract

dysmyelination), and progression of the neuromuscular

manifestations (secondary axonal degeneration). The

hypothesis that diseases of development may aggravate

after birth, as proposed in this article, has been considered

previously [19]. The possibility that ARSACS could be a

storage disease has also been taken into account, although

extensive metabolic screening did not uncover anomalies

[23].

Consequently, the evolution of symptoms in ARSACS is

not uniform [9]. Spasticity is present from very early in life

and does not seem to worsen. Visual field defects, probably

secondary to a disproportionate number of retinal fibres

traversing the optic disk, are not symptomatic. In contrast,

clinical deterioration is due to an increasing involvement of

the cerebellum and peripheral nervous system, which

causes ataxia and weakness.

The role played by sacsin in the manifestations of

ARSACS remains to be established; however, it seems

apparent that nonsense mutations with a loss of function

are associated with more severe progressive symptoms.

Our pathogenetic proposal needs confirmation by means

of studies that corroborate the results presented in this

article, while the relevance of the molecular findings awaits

further functional tests.

Finally, the distinctive aspect of the straight dorsal spine

could be an aid in the clinical diagnosis of ARSACS.

Acknowledgments The authors wish to thank Drs. Jorge Artal, Jose

Luis Capablo, Manuel Gracia-Naya and Pilar Larrode for referral of

patients; Dr. Elena Garcıa, for help with the ophthalmological part of

this article, and Mr. Juan Luis Fuentes, for the ophthalmologic pho-

tographs. We also thank Ms. Stephanie Lyon, for linguistic assess-

ment. This work is dedicated to the memory of Paloma Agueras

(1958–2009).This work was supported by grants of the Italian Min-

istry of Health (Ricerca Corrente, RC-FSM-02/2010) and of the

European Union for EUROSPA (E-RARE grant IT0807), to FMS;

and by a grant of the Centro de Investigacion Biomedica en Red de

Enfermedades Neurodegenerativas and Fondo de Investigaciones

Sanitarias (PI07/132E to JB).

Conflict of interest The authors declare that they have no conflict

of interest.

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