Neu ología
37
(2022)
257—262
NEUROLOGÍA
www.else ie .es/neu ologia
ORIGINAL
ARTICLE
Au osomal
ecessi e
spinoce ebella
a axia
SCAR8/ARCA1:
fi s
amilies
de ec ed
in
Spain夽
M.
A iasa,∗,
P.
Mi b,
M.
Fe nández-Ma a ubiac,
J.
A pac,
R.
Ga cía-Ramosc,
P.
Blanco-A iasd,
B.
Quin anse, ,
M.J.
Sob idoe,
aSe icio
de
Neu ología,
Complexo
Hospi ala io
de
San iago
de
Compos ela,
San iago
de
Compos ela,
La
Co u˜
na,
Spain
bSe icio
de
Neu ología,
Hospi al
Vi gen
del
Rocío,
Se illa,
Spain
cSe icio
de
Neu ología,
Hospi al
Clínico
San
Ca los,
Mad id,
Spain
dFundación
Pública
Galega
de
Medicina
Xenómica,
San iago
de
Compos ela,
La
Co u˜
na,
Spain
eG upo
de
Neu ogené ica,
Ins i u o
de
In es igación
Sani a ia
de
San iago
(IDIS)-Complexo
Hospi ala io
Uni e si a io,
San iago
de
Compos ela,
La
Co u˜
na,
Spain
Cen o
de
In es igación
Biomédica
en
Red
de
En e medades
Ra as
(CIBERER),
Ins i u o
de
Salud
Ca los
III,
Mad id,
Spain
Recei ed
28
Decembe
2018;
accep ed
16
Janua y
2019
A ailable
online
10
Ap il
2021
KEYWORDS
A axia;
Au osomal
ecessi e
inhe i ance;
SYNE1;
ARCA1;
SCAR8;
Sequencing;
Gene
panel
Abs ac
In oduc ion:
Au osomal
ecessi e
spinoce ebella
a axia
ype
8
(ARCA1/SCAR8)
is
caused
by
mu a ions
o
he
SYNE1
gene.
The
disease
was
ini ially
desc ibed
in
amilies
om
Quebec
(Canada)
wi h
a
pheno ype
o
pu e
ce ebella
synd ome,
bu
in
ecen
yea s
has
been
epo ed
wi h
a
mo e
a iable
clinical
pheno ype
in
o he
coun ies.
Cases
ha e
ecen ly
been
desc ibed
o
muscula
dys ophy,
a h og yposis,
and
ca diomyopa hy
due
o
SYNE1
mu a ions.
Objec i e:
To
desc ibe
clinical
and
molecula
findings
om
4
pa ien s
(3
men
and
one
woman)
diagnosed
wi h
ARCA1/SCAR8
om
3
Spanish
amilies
om
di e en
egions.
Ma e ial
and
me hods:
We
desc ibe
he
clinical,
pa aclinical,
and
gene ic
esul s
om
4
pa ien s
diagnosed
wi h
ARCA1/SCAR8
a
di e en
Spanish
neu ology
depa men s.
Resul s:
Onse
occu ed
in
he
hi d
o
ou h
decade
o
li e
in
all
pa ien s.
A e
15
yea s
o
p og ession,
3
pa ien s
p esen ed
pu e
ce ebella
synd ome,
simila
o
he
Canadian
pa ien s;
he
ou h
pa ien ,
wi h
o e
30
yea s’
p og ession,
p esen ed
e ical
gaze
palsy,
py ami-
dal
signs,
and
mode a e
cogni i e
impai men .
In
all
pa ien s,
MRI
s udies
showed
ce ebella
a ophy.
The
gene ic
s udy
e ealed
dis inc
pa hogenic
SYNE1
mu a ions
in
each
amily.
夽Please
ci e
his
a icle
as:
A ias
M,
Mi
P,
Fe nández-Ma a ubia
M,
A pa
J,
Ga cía-Ramos
R,
Blanco-A ias
P,
e
al.
He edoa axia
ce ebelosa
ecesi a
ARCA1/SCAR8:
p ime as
amilias
de ec adas
en
Espa˜
na.
Neu ología.
2022;37:257—262.
∗Co esponding
au ho .
E-mail
add ess:
[email p o ec ed]
(M.
A ias).
2173-5808/©
2019
Sociedad
Espa˜
nola
de
Neu olog´
ıa.
Published
by
Else ie
Espa˜
na,
S.L.U.
This
is
an
open
access
a icle
unde
he
CC
BY-NC-ND
license
(h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
M.
A ias,
P.
Mi ,
M.
Fe nández-Ma a ubia
e
al.
Conclusions:
ARCA1/SCAR8
can
be
ound
wo ldwide
and
may
be
caused
by
many
dis inc
mu a-
ions
in
he
SYNE1
gene.
The
disease
may
mani es
wi h
a
complex
pheno ype
o
a ying
se e i y.
©
2019
Sociedad
Espa˜
nola
de
Neu olog´
ıa.
Published
by
Else ie
Espa˜
na,
S.L.U.
This
is
an
open
access
a icle
unde
he
CC
BY-NC-ND
license
(h p://c ea i ecommons.o g/licenses/by-nc-nd/
4.0/).
PALABRAS
CLAVE
A axia;
He encia
au osómica
ecesi a;
SYNE1;
ARCA1;
SCAR8;
Secuenciación;
Panel
de
genes
He edoa axia
ce ebelosa
ecesi a
ARCA1/SCAR8:
p ime as
amilias
de ec adas
en
Espa˜
na
Resumen
In oducción:
La
ARCA1/SCAR8
es
un
he edoa axia
ecesi a
causada
po
mu aciones
en
el
gen
SYNE1,
que
ue
desc i a
inicialmen e
en
amilias
ancocanadienses
(Quebec)
con
un
sínd ome
ce ebeloso
pu o.
En
la
ac ualidad
se
desc ibe
cada
ez
más
es e
ipo
de
a axia
en
o as
pa es
del
mundo
y
con
un
eno ipo
muy
a iable.
Recien emen e
se
han
no ificado
casos
de
dis ofia
muscula ,
a og iposis
y
mioca diopa ía
po
mu aciones
de
es e
gen.
Obje i os:
Desc ibi
los
hallazgos
clínicos
y
molecula es
en
3
amilias
espa˜
nolas
de
di e en e
o igen
geog áfico,
las
p ime as
en
las
que
se
confi mó
el
diagnós ico
de
ARCA1/SCAR8
con
análisis
molecula .
Ma e ial
y
mé odos: E aluación
clínica,
p uebas
pa aclínicas
y
es udio
gené ico
en
4
pacien es
(3
a ones
y
una
muje ),
diagnos icados
en
dis in os
se icios
de
neu ología
espa˜
noles.
Resul ados:
Los
sín omas
ce ebelosos
comenza on
en
odos
los
casos
en
la
e ce a-cua a
décadas.
T as
15
a˜
nos
de
e olución,
3
pacien es
p esen aban
un
sínd ome
ce ebeloso
pu o
simila
a
la
desc ipción
o iginal,
mien as
que
un
pacien e
con
más
de
30
a˜
nos
de
e olución
p esen aba
ambién
pa álisis
de
mi ada
e ical,
a ec ación
pi amidal
y
mode ado
de e io o
cogni i o.
El
es udio
de
esonancia
magné ica
mos ó
en
odos
los
casos
a ofia
es ingida
al
ce ebelo.
La
secuenciación
de
SYNE1
pe mi ió
iden ifica
dis in as
a ian es
pa ogénicas
en
cada
amilia.
Conclusiones:
La
ARCA1/SCAR8
iene
una
dis ibución
mundial
con
una
g an
di e sidad
de
mu aciones
en
SYNE1.
Además
de
a axia
puede
da
luga
a
un
complejo
eno ipo
de
inicio
y
g a edad
muy
a iable.
©
2019
Sociedad
Espa˜
nola
de
Neu olog´
ıa.
Publicado
po
Else ie
Espa˜
na,
S.L.U.
Es e
es
un
a ´
ıculo
Open
Access
bajo
la
licencia
CC
BY-NC-ND
(h p://c ea i ecommons.o g/licenses/by-
nc-nd/4.0/).
In oduc ion
Au osomal
ecessi e
spinoce ebella
a axias
(ARCA
o
SCAR)
a e
a
b oad,
he e ogeneous
g oup
o
neu odegene a i e
diso de s.
They
can
mani es
as
pu e
o
complex
ce e-
bella
synd ome
and
may
be
associa ed
wi h
symp oms
including
in ellec ual
disabili y,
oculomo o
abno mali ies,
py amidal
and
ex apy amidal
symp oms,
and
pe iphe al
neu opa hy.1—3 Some
sub ypes
p esen
cha ac e is ic
lab-
o a o y
findings
ha
acili a e
diagnosis.1—3 The
mos
equen
au osomal
ecessi e
a axias
include
F ied eich
a axia
(FA),
a axia
elangiec asia,
a axia
wi h
i amin
E
deficiency,
abe alipop o einaemia,
a axia
wi h
oculomo o
ap axia
(AOA),
and
au osomal
ecessi e
spas ic
a axia
o
Cha le oix-Saguenay
(ARSACS);
all
o
hese
a e
associa ed
wi h
a
complex
pheno ype.1—3
Au osomal
ecessi e
ce ebella
a axia
ype
1
(ARCA1
o
SCAR8,
OMIM
#610743)
was
fi s
desc ibed
in
amilies
om
Beauce
and
Bas-S -Lau en
(Quebec,
Canada).
The
disease
is
caused
by
mu a ions
in
he
spec in
epea
con aining
nuclea
en elope
1
(SYNE1)
gene,
loca ed
on
ch omosome
6.4,5 The
gene
includes
146
exons
and
encodes
a
gian
p o ein
comp ising
8797
amino
acids,
known
as
nuclea
en elope
spec in
epea
p o ein
1
(nesp in
1).
The
p o-
ein
is
exp essed
in
Pu kinje
cells,
he
oli a y
bodies,
and
in
myocy es;
i
has
4
domains
(one
p esen ing
he
spec in-like
s uc u e
cha ac e is ic
o
memb ane-ancho ed
p o eins)
and
plays
an
impo an
ole
in
main aining
he
s uc u e
o
he
cell,
as
i
fixes
he
nuclea
lamina
o
he
cy oskele-
on
and
con ibu es
o
he
o ganisa ion
o
cy oplasmic
o ganelles.6—8
ARCA1
has
also
been
desc ibed
in
pa ien s
om
B azil,
Japan,
he
Uni ed
Kingdom,
Saudi
A abia,
and,
in
a
ecen
mul i-cen e
s udy
using
massi e
sequencing
ech-
niques,
in
amilies
om
F ance,
Ge many,
Belgium,
I aly,
and
Alge ia.
As
a
esul ,
i
is
now
conside ed
a
glob-
ally
dis ibu ed
he edi a y
a axia.
While
ARCA1
was
fi s
epo ed
o
be
associa ed
wi h
a
pu e
ce ebella
synd ome,
mo e
ecen
s udies
ha e
con ibu ed
o
he
knowledge
o
i s
pheno ype,
and
i
is
now
known
ha
he
disease
can
p esen
a
a
wide
ange
o
ages
as
a
mul isys-
emic
disease
wi h
signs
o
uppe
and
lowe
mo o
neu on
in ol emen ,
musculoskele al
in ol emen ,
and
cogni i e
impai men .9
258
Neu ología
37
(2022)
257—262
Table
1
Clinical
da a
and
SYNE1
mu a ions.
Family/pa ien
Sex
Age
o
onse /cu en
age
Symp oms
SYNE1
a ian s
de ec eda
1/
1
M
27/40
P edominan ly
appendicula
pu e
ce ebella
synd ome
1)
c.13045C>T;
p.R4349*
2)
c.25114C>T;
p.R8372*
1/
2
W
22/35
P edominan ly
axial
pu e
ce ebella
synd ome
1)
c.13045C>T;
p.R4349*
2)
c.25114C>T;
p.R8372*
2/
3
M
33/47
P edominan ly
axial
pu e
ce ebella
synd ome
1)
c.17099
c.17100del;
p.I5700T s**11
2)
c.4555C>T;
p.Q1519*
3/
4W
35/72
Ce ebella -plus
synd ome
(dysphagia,
conjuga e
e ical
gaze
palsy;
py amidal
signs)
1)
c.16177.2A>G
2)
c.16177.2A>G
M:
man;
W:
woman.
aHGVS
nomencla u e,
NM
033071.3
used
as
e e ence.
This
s udy
p esen s
a
compa a i e
desc ip ion
o
he
phe-
no ype
o
he
disease
in
he
fi s
3
Spanish
amilies
diagnosed
wi h
ARCA1.
Pa ien s
and
me hods
Fou
pa ien s
wi h
ce ebella
a axia
we e
a ended
a
he
neu ology
depa men s
o
Complexo
Hospi ala io
Uni e -
si a io
de
San iago
de
Compos ela
(La
Co u˜
na),
Hospi al
Clínico
San
Ca los
(Mad id),
and
Hospi al
Uni e si a io
Vi gen
del
Rocío
(Se ille).
In
all
cases,
he
ollowing
es s
we e
pe o med
be o e
defini i e
diagnosis
o
ARCA1:
(a)
blood
analysis
(comple e
blood
coun ;
sys ema ic
biochemis y;
o al
p o ein
es ;
lipid
p ofile;
i amins
E,
B9,
and
B12;
alpha- e op o ein;
ce uloplasmin;
coppe ;
lac ic,
py u ic,
and
phy anic
acid;
choles anol;
chi o iosidase;
CCL18
[PARC];
and
an
an i-
body
panel
including
ANA,
an i-Ro,
an i-La,
an i- hy oid,
an i-gliadin,
and
an i-GAD
an ibodies)
and
u ine
analysis
(elemen s
and
sedimen ,
coppe );
(b)
neu ophysiological
s udies
(mul imodal
e oked
po en ials,
mo o
and
senso y
ne e
conduc ion
eloci y);
(c)
oph halmological
examina-
ion;
(d)
neu oimaging
s udies
wi h
b ain
and
spinal
co d
MRI,
and
in
one
case
b ain 18F-deoxiglucose
posi on
emis-
sion
omog aphy
(18FDG-PET);
and
(e)
gene ic
s udies
(FA,
AOA1,
AOA2,
SCA1-7,
SCA17,
NPC1,
and
NPC2).
Defini i e
diagnosis
was
eached
by
s udying
he
SYNE1
gene
using
nex
gene a ion
sequencing
echniques
(a axia
panel)
ollowed
by
Sange
sequencing
o
confi m
he
mu a-
ions
iden ified.
Resul s
Labo a o y
analyses
(in ended
o
ule
ou
a axias
wi h
bioma ke s
o
suscep ible
o
disease-modi ying
ea men ),
oph halmological
examina ion,
neu ophysiological
s udies,
and
p e ious
gene ic
s udies
all
yielded
no mal
o
nega i e
esul s.
Table
1
summa ises
he
main
clinical
da a
and
he
pa hogenic
SYNE1
a ian s
de ec ed
(NM
033071.3)
in
4
pa ien s
om
3
di e en
amilies.
The
pa ien s
a e
desc ibed
below.
Family
1:
pa ien s
1
and
2
The
pa ien s
we e
siblings,
a
man
o
40
yea s
o
age
and
a
woman
o
35,
bo n
o
heal hy,
non-consanguineous
pa -
en s,
in
Galicia,
Spain.
The e
we e
no
known
cases
o
simila
condi ions
o
o he
ela ed
neu ological
symp oms
in
he
amily.
In
bo h
pa ien s,
disease
onse
occu ed
in
he
hi d
decade
o
li e;
ini ial
symp oms
we e
ins abili y
and
dysa h ia,
ollowed
by
slowly
p og essing
loss
o
limb
coo dina ion.
A e
mo e
han
12
yea s
o
p og ession,
hey
we e
able
o
walk
unsuppo ed.
The
sis e
ecei ed
ea -
men
o
mode a e
anxie y
and
dep ession.
Bo h
pa ien s
p esen ed
dysa h ia
wi h
scanning
speech,
pe sis en
bidi-
ec ional
ho izon al
gaze-e oked
nys agmus,
appendicula
a axia,
and,
o
a
g ea e
ex en ,
uncal
a axia,
p e en ing
andem
gai .
Tendon
eflexes
we e
p ese ed
and
plan-
a
eflexes
we e
flexo .
In
bo h
cases,
b ain
MRI
de ec ed
ma ked
di use
a ophy
o
he
ce ebellum,
wi h
he
b ain-
s em
and
ce eb al
whi e
ma e
being
una ec ed
(Fig.
1).
The
gene ic
s udy
iden ified
a ian s
c.13045>T;
p.R4349*
(exon
77)
and
c.25114C>T;
p.R8372*
(exon
140)
in
bo h
sib-
lings;
he
fi s
a ian
was
inhe i ed
om
hei
a he
and
he
second
om
hei
mo he .
Bo h
a ian s
a e
p edic ed
o
cause
p ema u e
s op
codons,
esul ing
in
a
unca ed
p o ein.
To
da e,
hese
a ian s
ha e
no
been
desc ibed
in
o he
pa ien s
in
he
li e a u e;
hei
equency
in
he
gnomAD
da abase
is
ex emely
low
(0.00005-0.000008).
Family
2:
pa ien
3
The
pa ien
was
a
47-yea -old
man
bo n
o
non-
consanguineous
pa en s
in
Andalusia,
Spain.
Disease
onse
259
M.
A ias,
P.
Mi ,
M.
Fe nández-Ma a ubia
e
al.
Figu e
1
Sagi al
T1-weigh ed
and
axial
T2-weigh ed
MRI
sequences
om
pa ien
1,
e ealing
di use
a ophy
o
he
ce ebellum,
no mal
mo phology
o
he
b ains em,
and
no
whi e
ma e
lesions.
occu ed
a
he
age
o
34
yea s,
wi h
impai ed
speech
p o-
duc ion;
mon hs
la e ,
he
expe ienced
di ficul y
descending
s ai s,
and
subsequen ly
p esen ed
ins abili y
while
walk-
ing
and
iding
a
bicycle.
A
he
age
o
40
yea s,
he
began
o
lose
coo dina ion
in
he
uppe
limbs.
He
did
no
p esen
diplopia,
dysphagia,
o
cogni i e
impai men .
The
pa ien ’s
b o he
had
de eloped
simila
symp oms
in
he
hi d
decade
o
li e,
and
commi ed
suicide
sho ly
he ea e .
A
pa e -
nal
fi s
cousin,
a
woman
o
50
yea s
o
age,
also
p esen ed
a axia,
bu
i
was
no
possible
o
examine
he .
Examina ion
o
he
pa ien
e ealed
dysa h ia
wi h
scanning
speech,
mild
ocula
mo emen
anomaly
in
he
o m
o
hype me -
ic
saccades,
appendicula
a axia,
and,
o
a
g ea e
ex en ,
uncal
a axia,
which
p e en ed
andem
gai .
MRI
e ealed
di use
ce ebella
a ophy.
The
gene ic
s udy
e ealed
2
unca ing
SYNE1
a ian s,
which
we e
classed
as
p obably
pa hogenic:
c.17099
c.17100del;
p.I5700T s*11
(exon
90),
a
dele ion
causing
a
ame
shi ,
and
c.4555C>T;
p.Q1519*
(exon
35),
which
causes
a
p ema u e
s op
codon.
Bo h
a ian s
we e
ound
in
ans.
Nei he
has
p e iously
been
desc ibed
ei he
as
a
mu a ion
o
as
a
polymo phism
in
he
popula ion
da abases
consul ed
(dbSNP,
gnomAD,
1000G).
Family
3:
pa ien
4
The
pa ien
was
a
72-yea -old
woman
whose
pa en s
we e
fi s
cousins,
bo n
in
Andalusia,
Spain.
She
p esen ed
di -
ficul y
walking,
which
had
p og essed
since
he
age
o
35
yea s.
She
was
he
younges
o
6
siblings,
and
he
only
one
o
p esen
a axia.
The
ini ial
symp om
was
gai
ins abili y,
ollowed
by
dysa h ia
and
subsequen ly
loss
o
limb
coo -
dina ion.
Mo e
ecen ly,
she
epo ed
u ina y
incon inence
and
mild
memo y
complain s.
Examina ion
e ealed
mixed
dysa h ia
(spas ic
and
ce ebella ),
sup anuclea
e ical
gaze
palsy,
bidi ec ional
ho izon al
nys agmus,
hypome ic
ho izon al
saccades,
dysme ia
and
dysdiadochokinesia
in
all
4
limbs,
mode a e
spas ici y,
and
endon
hype eflexia
in
he
lowe
limbs,
wi h
ankle
clonus
and
bila e al
Babinski
sign.
A
he
ime
o
examina ion,
she
was
unable
o
s and
o
walk,
and
used
a
wheelchai .
The
neu opsychological
examina ion
showed
defici s
in
lea ning
and
e bal
memo y
consolida ion
and
mode a e
impai men
o
isuospa ial
unc ion;
she
did
no
mee
diagnos ic
c i e ia
o
demen ia.
The
gene ic
s udy
e ealed
ha
he
pa ien
was
homozy-
gous
o
a
p e iously
desc ibed
pa hogenic
SYNE1
a ian
(c.16177-2A>G),
loca ed
in
in on
84,
a ec ing
a
splice
accep o
si e;
he
a ian
is
p edic ed
o
cause
he
loss
o
exon
85,
dis up ing
he
no mal
ma u a ion
o
he
mRNA.
We
also
de ec ed
a
missense
a ian
o
unce ain
significance:
c.9736C>G;
p.Q3246E,
egis e ed
as
s149901087
on
he
dbSNP151
da abase,
wi h
a
popula ion
equency
o
0.02%-
0.06%.
Th ee
o
7
bioin o ma ic
analysis
sys ems
p edic ed
ha
he
a ian
may
be
dele e ious.
As
we
would
expec ,
all
he
pa ien ’s
daugh e s
we e
he e ozygous
ca ie s
o
bo h
a ian s.
S uc u al
neu oimaging
e ealed
di use
a ophy
o
he
ce ebellum.
We
also
pe o med
a
b ain 18FDG-PET
s udy,
which
showed
di use
ce ebella
hypome abolism
wi h
no
me abolic
al e a ions
in
o he
b ain
egions.
260
Neu ología
37
(2022)
257—262
Discussion
To
ou
knowledge,
hese
a e
he
fi s
4
cases
o
ARCA1/SCAR8
in
Spanish
pa ien s.
In
all
cases,
he
disease
ini ially
p e-
sen ed
wi h
uncal
a axia
and/o
dysa h ia
in
he
hi d
o
ou h
decade
o
li e.
Th ee
pa ien s,
wi h
disease
p og es-
sion
imes
o
a ound
15
yea s,
p esen ed
slowly
p og essi e
pu e
ce ebella
synd omes,
wi h
pance ebella
a ophy
on
MRI
s udies
and
no
e idence
o
polyneu opa hy
in
neu o-
physiological
s udies.
The
ou h
pa ien ,
a
woman
wi h
a
gai
diso de
o
o e
35
yea s’
p og ession,
p esen ed
py a-
midal
ac
in ol emen ,
sup anuclea
oculomo o
palsy,
and
mode a e
cogni i e
impai men ,
in
addi ion
o
he
ce ebella
synd ome.
One
in e es ing
finding
was
ha
he
b ain 18FDG-PET
s udy
pe o med
in
his
pa ien
e ealed
hypome abolism
in
he
ce ebellum
only.
In
o he
wo ds,
in
he
fi s
2
decades
o
p og ession,
ou
pa ien s’
clini-
cal
symp oms
o e lap
wi h
hose
desc ibed
in
pa ien s
om
Quebec,4,5 whe e
his
o m
o
a axia
was
fi s
desc ibed,
and
whe e
i
cons i u es
he
hi d
leading
cause
o
au osomal
ecessi e
a axia,
a e
ARSACS
and
FA.10
In
2013,
a
Japanese
s udy
epo ed
he
fi s
cases
no
o igina ing
in
Canada.11 One
pa ien
p esen ed
onse
du -
ing
childhood,
wi h
mo o
neu on
disease
associa ed
wi h
a axia,
and
2
p esen ed
simila
symp oms
o
he
F ench-
Canadian
pa ien s.
I
should
be
no ed
ha
in
Japan,
SCA36
(a
dominan
he edi a y
a axia
caused
by
an
in onic
expan-
sion
in
NOP56)
p esen s
wi h
mo e
ex ensi e
mo o
neu on
in ol emen
han
ha
obse ed
in
he
‘‘Cos a
da
Mo e’’
SCA36
a axia
desc ibed
in
Spain.12,13 In
he
same
yea ,
2
cases
o
ARCA1
we e
diagnosed
in
pa ien s
om
B azil
and
F ance,
who
p esen ed
mu a ions
no
desc ibed
in
he
am-
ilies
om
Quebec.14
A
s udy
conduc ed
in
he
Uni ed
Kingdom
included
196
cases
o
spo adic
o
au osomal
ecessi e
a axia
and
iden-
ified
SYNE1
mu a ions
in
4
pa ien s
om
3
amilies
( om
Tu key,
S i
Lanka,
and
he
Uni ed
Kingdom).15 Th ee
pa ien s
p esen ed
pu e
ce ebella
synd ome,
whe eas
he
pa ien
o
Tu kish
o igin
p esen ed
ma ked
py amidal
ac
in ol e-
men .
The
au ho s
analyse
and
desc ibe
all
he
mu a ions
epo ed
a
he
ime
o
hei
s udy,
and
pos ula e
ha
g ea e
p oximi y
o
he
mu a ions
o
he
3end
o
he
gene
is
associa ed
wi h
g ea e
p edisposi ion
o
mo o
neu on
in ol emen .15 Howe e ,
we
did
no
obse e
mo o
neu on
signs
in
ou
pa ien s
om
amily
1,
who
p esen ed
a
mu a-
ion
in
exon
140.
In
2016,
an
ex ensi e
mul i-cen e
s udy
(including
cen es
om
a ious
Eu opean
coun ies
and
Alge-
ia)
was
published,
which
included
434
index
pa ien s
wi h
he
mos
p e alen
o ms
o
SCA
and
FA.9Exome
sequenc-
ing
de ec ed
23
pa ien s
(5%)
om
un ela ed
amilies,
in
whom
hey
iden ified
35
pa hogenic
a ian s
(34
no
p e i-
ously
desc ibed).
The
clinical
pheno ypes
epo ed
in
ha
s udy
consis ed
o
pu e
ce ebella
synd ome
in
19%
o
cases
and
complex
o ms
in
he
emaining
pa ien s.
The
au ho s
obse ed
mo o
neu on
disease
in
58%
o
pa ien s,
in ellec ual
de elopmen
diso de
in
10%,
and
espi a o y
dys unc ion
seconda y
o
b ains em
in ol emen
in
3
cases.
The
mean
age
o
onse
was
22
yea s
( ange,
6-40),
lowe
han
ha
obse ed
in
ou
pa ien s
and
in
Canadian
s udies.
The
au ho s
conclude
ha
ARCA1
should
be
conside ed
a
equen
cause
o
au osomal
ecessi e
a axia.9We
should
unde sco e
he
ac
ha
none
o
he
Spanish
pa ien s
desc ibed
in
his
s udy
ca ied
any
o
he
mu a ions
epo ed
in
p e ious
publica ions.
Mo e
ecen ly,
he
spec um
o
mani es a ions
asso-
cia ed
wi h
SYNE1
mu a ions
has
con inued
o
expand.
Gi en
he
in ense
ce ebella
a ophy
obse ed,
he
ce e-
bella
hypoplasia
and
in ellec ual
disabili y
in
some
o
hese
pa ien s
a e
pa icula ly
in e es ing,
as
hey
sugges
a
pheno ypic
spec um
anging
om
neona al
mani es a-
ions
o
adul
onse .16 In
a
amily
om
Saudi
A abia
wi h
ARCA1,
MRI
showed
lesions
sugges i e
o
mul iple
scle o-
sis,
bu
wi hou
oligoclonal
bands
in
he
ce eb ospinal
fluid
and
wi h
no mal
isual
e oked
po en ials.17 A
new
amily
has
been
desc ibed
in
Japan
ha
does
no
p esen
associ-
a ed
mo o
neu on
disease.18 He e ozygous
SYNE1
mu a ions
ha e
been
epo ed
in
se e al
cases
esembling
Eme y-
D ei uss
muscula
dys ophy,
a h og yposis,
and
dila ed
ca diomyopa hy.19,20
In
conclusion,
ARCA1
seems
o
be
eme ging
as
one
o
he
mos
p e alen
o ms
o
au osomal
ecessi e
a axia.
SYNE1
mu a ions
a e
one
o
he
mos
equen
causes
o
pu e
ce ebella
synd ome
wi h
onse
in
young
adul s,
whe he
spo adic
o
wi h
suspec ed
au osomal
ecessi e
inhe i ance.
Suspicion
should
be
e en
s onge
in
he
e en
o
neu oimag-
ing
findings
o
ma ked
pance ebella
a ophy
and
absence
o
polyneu opa hy
o
biochemical
ma ke s
o
o he
ypes
o
ARCA.
Howe e ,
gi en
he
clinical
o e lap
be ween
ARCA1
and
many
o he
en i ies,
we
conside
massi e
sequencing
(a axia
panel
o
whole-exome
sequencing)
o
be
he
mos
sui able
diagnos ic
app oach
in
he
majo i y
o
pa ien s.
Conflic s
o
in e es
The
au ho s
ha e
no
conflic s
o
in e es
o
decla e.
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