CASE REPORT
No el compound he e ozygous mu a ion in SACS gene
leads o a milde au osomal ecessi e spas ic a axia o
Cha le oix-Saguenay, ARSACS, in a Finnish amily
Johanna Palmio
1
, Mikko K€
a pp€
a
2
, Pe e Baumann
3
, Sini Pen il€
a
1
, Jukka Moilanen
4
& Bja ne Udd
1,5,6
1
Depa men o Neu ology, Neu omuscula Resea ch Cen e , Tampe e Uni e si y and Uni e si y Hospi al, Tampe e, Finland
2
Depa men o Neu ology, Oulu Uni e si y Hospi al and Uni e si y o Oulu, Oulu, Finland
3
Depa men o Neu ology, Lapland Cen al Hospi al, Ro aniemi, Finland
4
Depa men o Clinical Gene ics and Medical Resea ch Cen e Oulu, Oulu Uni e si y Hospi al and Uni e si y o Oulu, Oulu, Finland
5
Folkh€
alsan Ins i u e o Gene ics and he Depa men o Medical Gene ics, Haa man Ins i u e, Uni e si y o Helsinki, Helsinki, Finland
6
Depa men o Neu ology, Vaasa Cen al Hospi al, Vaasa, Finland
Co espondence
Johanna Palmio, Depa men o Neu ology,
Neu omuscula Resea ch Cen e , Tampe e
Uni e si y Hospi al and Uni e si y o
Tampe e, Tampe e, FIN-33014, Finland. Tel:
+358-3-3116111; Fax: +358-3-35516164;
E-mail: [email p o ec ed]
Funding In o ma ion
No sou ces o unding we e decla ed o his
s udy.
Recei ed: 7 Ma ch 2016; Re ised: 31 Augus
2016; Accep ed: 20 Sep embe 2016
Clinical Case Repo s 2016; 4(12):
1151–1156
doi: 10.1002/cc 3.722
Key Clinical Message
Au osomal ecessi e spas ic a axia o Cha le oix-Saguenay is a a e diso de
ou side Quebec causing childhood-onse ce ebella a axia, pe iphe al neu opa-
hy, and py amidal ac signs. A Finnish amily wi h milde o m o ARSACS
was ound o ha bo h ee mu a ions, p.E1100K, p.N1489S, and p.M1359T, in
SACS gene. The mu a ions seg ega ed wi h he disease.
Keywo ds
Au osomal ecessi e, SACS gene, spas ic a axia.
In oduc ion
ARSACS is a ecessi e neu odegene a i e disease causing
childhood-onse ce ebella a axia, pe iphe al neu opa hy,
and py amidal ac signs [1]. I was i s desc ibed in he
Cha le oix-Saguenay-Lac-Sain -Jean egion o Quebec
whe e he es ima ion o equency o ca ie s is 1 o 22
[2]. The disease-causing gene, SACS, encodes a la ge p o-
ein sacsin ha is exp essed in b ain mo o sys ems and
in a ious o he issues [3]. Mo e han 100 mu a ions in
SACS ha e been iden i ied wo ldwide [4–6]. The p o ein’s
unc ion is s ill la gely unknown, al hough i s ole in he
egula ion o mi ochond ial physiology has been p oposed
[7, 8]. Recen unc ional and molecula analyses o mi o-
chond ial ac i i y in ib oblas s ob ained om ARSACS
pa ien s sugges ed in ol emen o oxida i e s ess and
mi ochond ial dys unc ion in he pa hogenesis o he
disease [9, 10].
The i s symp oms a e ypically balance p oblems
be o e he age o 5 yea s in mos cases, ollowed by
spas ici y and axonal-demyelina ing senso imo o pe iph-
e al neu opa hy in hei eens. The p og ession is slow;
pa ien s become wheelchai -bound app oxima ely in
hei 4 h decade [11]. Addi ional ea u es include hype -
myelina ed e inal ibe s, u ge incon inence, and e ec ile
dys unc ion. Ce ebella e mis a ophy and linea hypo-
in ensi ies in he pons a e ypical ea ly indings [12,
13]. No all pa ien s display he classic iad; occasional
a ypical and la e-onse o ms o ARSACS ha e been
epo ed, and ecen ly, SACS mu a ions ha e been iden-
i ied in a ew pa ien s wi h nonp og essi e congeni al
a axia [9, 14].
We epo he e he i s Finnish ARSACS amily wi h
compound he e ozygous mu a ion in SACS ha causes
he classic iad pheno ype, al hough wi h la e onse and
slowe p og ession han in mos epo ed cases.
ª2016 The Au ho s. Clinical Case Repo s published by John Wiley & Sons L d.
This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion-NonComme cial-NoDe i s License, which pe mi s use and
dis ibu ion in any medium, p o ided he o iginal wo k is p ope ly ci ed, he use is non-comme cial and no modi ica ions o adap a ions a e made.
1151
Me hods
The pa ien s
A Finnish amily wi h ou a ec ed siblings was examined
and ollowed up o mo e han 30 yea s. The clinical symp-
oms we e classi ied as spas ic a axia, al hough wo b o he s
we e i s diagnosed wi h Cha co –Ma ie–Too h (CMT) dis-
ease due o dis al weakness and elec ophysiology indings.
Two o he siblings and he pa en s we e heal hy (Fig. 1A).
The pa ien s we e egula ly examined by neu ologis s and
in es iga ed by ne e conduc ion eloci ies (NCV), elec-
omyog am (EMG), b ain imaging and he p oband also by
su al ne e biopsy and wo muscle biopsies. Two pa ien s
unde wen oph halmic examina ions. None o he pa ien s
had in ellec ual p oblems, isual symp oms, o epilepsy.
Gene ic e alua ion
DNA was ex ac ed om leukocy es by s anda d me hods.
The DNA sample o he p oband was used o en ich-
men o a sequencing lib a y by NimbleGen SeqCap EZ
Human Exome 2.0. Pai ed-end sequencing (100 bp) was
pe o med using Illumina HiSeq 2000 sequence wi h a
sequencing dep h o 30X. Sequence eads we e aligned o
he human e e ence genome (UCSC hg19) using he
Bu ows–Wheele aligne [15]. Va ian calling was made
wi h Genome Analysis Toolki . The da a we e isualized
wi h In eg a i e Genomics Viewe [16]. F om he
sequencing da a o u he analysis we e selec ed all he
exons and exon–in on bo de s o he ollowing genes
known o be associa ed wi h ecessi e a axia: FXN,TTPA,
C10o 72,APTX,SETX,SYNE1,ADCK3,TDP1,SIL1,
POLG,ATM,MRE11A,SACS,PHYH, and PEX7. DNA
samples o he o he siblings ( h ee a ec ed, wo una -
ec ed) we e used o s udy he seg ega ion o he a ian s
de ec ed in he p oband by Sange sequencing.
The s udy was app o ed by he IRB o Tampe e Uni e -
si y Hospi al. All pa icipan s p o ided app op ia e consen .
Resul s
Family desc ip ion
The p oband (II:2), a-63-yea -old emale, p esen ed wi h
p og essi e a axic gai s a ing a age 25 (Table 1). She had,
howe e , expe ienced mild p oblems wi h balance since he
eens. The i s examina ion a age 30 ound mild dysa h ia,
mild ho izon al nys agmus, and sligh in en ion emo in
he limbs. Achilles and b achio adialis e lexes we e absen ,
bu Babinski sign was p esen . Dis al muscles in he lowe
limbs we e a ophic, and gai was spas ic a axic. Spas ici y,
a axia, and p oblems wi h balance s eadily p og essed and
led o wheelchai con inemen a age 43.
Elec ophysiological s udies showed dec eased senso y
and mo o NCVs. A age 30, muscle and su al ne e
biopsies we e pe o med wi h no mal his ology. Fi e yea s
la e , a new muscle biopsy showed mild neu ogenic
c.3298G>A p.E1100K c.4076T>C p.M1359T c.4466A>G p.N1489S
Con ol
Paen II-2
*DNA a ailable I:1 I:2
II:1* II:2* II:3* II:4* II:5* II:6*
c.[3298G>A;4466A>G]
p.[E1100K;N1489S]
/
c.4076T>C p.M1359T
c.[3298G>A;4466A>G]
p.[E1100K;N1489S]
/
c.4076T>C p.M1359T
c.[3298G>A;4466A>G]
p.[E1100K;N1489S]
/
c.4076T>C p.M1359T
c.[3298G>A;4466A>G]
p.[E1100K;N1489S]
/
c.4076T>C p.M1359T
c.[3298G>A;4466A>G]
p.[E1100K;N1489S]
/
w
w
/
w
(A)
(B)
Figu e 1. Pedig ee o he amily (A) and elec ophe og ams om Sange sequencing (B).
1152 ª2016 The Au ho s. Clinical Case Repo s published by John Wiley & Sons L d.
ARSACS in a Finnish amily J. Palmio e al.
indings: sca e ed angula and a ophic ibe s, and ibe -
ype g ouping. Gene ic analyses a ha ime excluded
CMT1A and spinoce ebella a axia SCA1.
He b o he (II:1) had been mo e ho oughly in es i-
ga ed a age 26 due o muscle weakness and p oblems
wi h balance s a ing a school age. On elec ophysiology,
NCVs we e dec eased leading o a diagnosis o CMT.
Howe e , spas ici y soon became e iden , as did p og es-
si e a axia o all limbs. He became wheelchai -bound a
age 39 and, a ha ime, ma ked spas ic pa apa esis and
a ophy in all limbs we e no ed. He died 25 yea s la e o
pneumonia. Pa ien II:4 expe ienced lowe limb weakness
and balance p oblems since age 6. He was la e diagnosed
wi h spinoce ebella a axia and polyneu opa hy. A age
36, he had no mal s eng h in he uppe limbs bu gene -
alized weakness in he lowe limb muscles. Gai was a axic
wi h uns eady balance; he became wheelchai -dependen
a age 33. A he mos ecen examina ion (age 59), he
s eng h and coo dina ion in he uppe limbs we e s ill
wi hin no mal ange, al hough lowe limbs, eye mo e-
men s, and speech we e se e ely a axic. Spas ici y was
ma ked in he lowe limbs. The younges o he siblings
(II:6) p esen ed wi h dis al lowe limb weakness and
a axic gai a he age o 18. The p og ession o he disease
has been slow; a age 54, he e we e ma ked weakness in
he lowe limbs and mode a e a axia in he uppe limbs.
Se e e spas ici y in he lowe limbs led o in a hecal
baclo en ea men , bu she is s ill ambulan wi h a walke
and uses a wheelchai occasionally.
In addi ion, all a ec ed siblings had dysa h ic speech,
saccadic eye mo emen and nys agmus, pes ca us, and
hamme oes. Dis al a e lexia was e iden in wo pa ien s,
all e lexes we e absen in one pa ien , and Babinski sign
p esen in wo and a loss o ib a ion sense in h ee. One
pa ien had symp oms indica i e o neu ogenic bladde .
Oph halmic examina ion e ealed hickening o he e i-
nal ne e ibe laye in one pa ien , and he o he had
no mal indings (Fig. 2A).
The p oband had no mal indings on b ain imaging a
age 35. She did no unde go u he imaging s udies. In
pa ien II:6, MRI was pe o med a age 43 (Fig. 2B),
showing ce ebella a ophy ha had sligh ly p og essed in
i e yea s. Co ical a ophy was p esen in on al and
pa ie al lobes as well as ypical linea hypo-in ensi ies in
he pons. Mo e ad anced changes we e e iden in II:4 a
age 59 (Fig. 2C) and in II:1 a age 41.
Molecula gene ics
Exome sequencing o pa ien II:2 e ealed h ee a e
he e ozygous mu a ions in SACS. All h ee mu a ions we e
con i med by Sange sequencing (Fig. 1B). O he mu a-
ions, c4466A>G p.N1489S has a low equency (0.0046) in
no mal popula ion, whe eas he o he wo a e no el. Sange
sequencing analysis o he o he siblings indica ed ha
mu a ion combina ion c.[3298G>A;4466A>G]; [4076T>C]
p.[E1100K;N1489S]; [M1359T] seg ega ed wi h he disease
(Fig. 1A).
Discussion
ARSACS is inc easingly ecognized wo ldwide and consid-
e ed o be one o he mos equen ypes o spas ic a axia
a e F ied eich a axia and a axia elangiec asia [5, 9].
Table 1. Clinical cha ac e is ics o he amily.
Pa Age/sex
Age o
onse
Clinical symp oms
a p esen a ion
Ce ebella
a axia Spas ici y Polyneu opa hy
Muscle
weakness/
a ophy Ambula ion B ain CT/MRI
II:1 65*/M 10 Lowe limb
weakness
and spas ici y
Yes Yes,
ma ked
Senso imo o
demyelina ing
Ma ked spas ic
pa apa esis and
a ophy in all
limbs
WCB since
age 39
CT: Co ical
a ophy in
ce eb um,
ce ebellum,
b ain s em
II:2 63/F (15) 25 Poo balance
since eens;
a axic gai
since age 25
Yes. Gai , UL
and LL l.a.
Yes, LL Senso imo o
demyelina ing
Dis al lowe
legs, hands
WCB since
age 45
CT: no mal a
age 35
II:4 59/M 6 Dis al lowe limb
weakness
Yes. Gai , LL,
speech
Yes, LL
se e e
Senso imo o
demyelina ing
LL weakness WCB since
age 33
MRI: Co ical
a ophy
II:6 54/F 18 Dis al lowe
limb
weakness,
a axic gai
Yes. LL:
ma ked
UL:
mode a e
Yes Senso imo o
demyelina ing
Ma ked
weakness
in LL
Walke , WCh
when needed
since age 52
MRI: Co ical
a ophy in
ce eb um,
ce ebellum
*Age a dea h; UL, uppe limbs; LL, lowe limbs; WCB, wheelchai bound; WCh, wheelchai .
ª2016 The Au ho s. Clinical Case Repo s published by John Wiley & Sons L d. 1153
J. Palmio e al.ARSACS in a Finnish amily
Ne e heless, ou amily is he i s ARSACS amily
iden i ied in Finland.
The pa ien s ha bo ing wo ounde mu a ions iden i-
ied in Quebec ha e mani es ed wi h he uni o m p esen-
a ion o uns eadiness and a axia in ea ly childhood,
ollowed by spas ici y du ing childhood and neu opa hy
du ing he eens [1–3]. In o he popula ions wi h di e -
en pa hogenic mu a ions, he pheno ype is s ill qui e
cons an , al hough occasional la e onse and a ypical
o ms ha e been iden i ied [4–9, 14]. The age o onse
and he p esen ing symp oms as well as he a e o p o-
g ession a ied in ou amily. P oblems wi h gai s a ed
in adolescence in wo siblings, whe eas ano he wo had
lowe limb weakness since ea ly school yea s, leading o
he ini ial diagnosis o CMT. The inal diagnosis based on
clinical symp oms and indings was he e o e challenging
and, in ac , ea ly on one clinical gene icis dismissed
ARSACS as a possible cause o he amily’s disease in his
consul a ion.
Re inal ne e ibe laye hype myelina ion and ce ebel-
la e mis a ophy as well as hypo-in ensi ies in he pons
a e conside ed he ea ly hallma ks o he disease, and
oge he wi h ypical clinical ea u es, hey could help in
eaching accu a e diagnosis ea ly [12, 13, 17]. In one sib-
ling, he e was a inding o hype myelina ion in e ina,
and in ano he , hypo-in ensi ies we e p esen in he pons
in addi ion o ce ebella a ophy, hus comple ing he
clinical pheno ype.
(A)
(B)
(C)
Figu e 2. Imaging indings o he pa ien s. Funduscopic indings o pa ien II:4 (A). The e is hickening o he myelina ed laye s o e ina (a ow).
Pa ien II:2 unde wen b ain imaging a age 43 (B). The e is ce ebella a ophy, and i has sligh ly p og essed since he las imaging i e yea s
p e iously (no shown). Co ical a ophy is seen in on al and pa ie al lobes and linea hypo-in ensi y in he pons (a ow). B ain MRI o pa ien II:4
(C) shows mo e ad anced co ical a ophy o ce eb um and ce ebellum.
1154 ª2016 The Au ho s. Clinical Case Repo s published by John Wiley & Sons L d.
ARSACS in a Finnish amily J. Palmio e al.
We iden i ied h ee mu a ions in SACS seg ega ing in
he amily. None o hese we e p e iously epo ed in
ARSACS, bu based on seg ega ion analysis, he no el
p.M1359T mu a ion is a disease-causing allele. Two o he
mu a ions p.E1100K and p.N1489S a e on he same allele,
and i canno be concluded which one is disease causing,
bu he allele as such is ecessi ely pa hogenic. Acco ding
o he equency in no mal popula ion and mu a ion p e-
dic ion p og am, Mu a ionTas e [18], p.E1100K is mo e
likely pa hogenic, bu wi hou u he unc ional s udies,
his canno be de e mined. O he amino acids mu a ed
in ou pa ien s (p.E1100, p.M1359, and p.N1489),
p.N1489 is loca ed in he second SRR domain o sacsin
p o ein, whe eas he o he wo a e loca ed ou side he
desc ibed domains. A leas wo missense mu a ions,
p.D168Y and p.R2703C, known o be loca ed in SRR
domain ha e been iden i ied o cause spas ic a axia o
Cha le oix-Saguenay disease pheno ype [4, 19]. O hese,
p.D168Y has been epo ed o ab oga e he abili y o he
sacsin p o ein o hyd olyze ATP [20]. Howe e , because
i is unce ain whe he p.N1489S is pa hogenic o no , i s
impac on p o ein unc ion is di icul o p edic .
The classic iad, ce ebella a axia, pe iphe al neu opa-
hy, and py amidal ac signs, was e iden in ou amily
and compa ible wi h ARSACS, al hough disease onse was
la e and p og ession was slowe han in mos epo ed
cases. Many o he p e iously epo ed ARSACS mu a-
ions ha e been nonsense o ameshi s which may be a
hin o geno ype–pheno ype aspec s ega ding se e i y,
al hough no clea geno ype–pheno ype co ela ions ha e
been ound [6, 9]. Anyway, i is impo an o ecognize
he ypical symp oms and o complemen he iad wi h
he mo e speci ic indings in he pons and e ina o each
ea ly and accu a e diagnosis.
Acknowledgmen s
The e a e no acknowledgemen s o be epo ed.
Con lic o In e es
None decla ed.
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1156 ª2016 The Au ho s. Clinical Case Repo s published by John Wiley & Sons L d.
ARSACS in a Finnish amily J. Palmio e al.