Molecula Gene ics and Me abolism Repo s 26 (2021) 100690
A ailable online 15 Decembe 2020
2214-4269/© 2020 The Au ho s. Published by Else ie Inc. 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/).
Sho Communica ion
Leigh synd ome associa ed wi h TRMU gene mu a ions
Júlia Sala-Co omina
a
, Lucía Doughe y-de Miguel
a
, Ja ie de las He as
b
,
Amaia Lasa-A anzas i
c
, Elena Ga cia-A umi
c
,
d
,
e
, Lidia Ca e˜
no
d
,
e
, Jose An onio A anz
,
Cla a Ca nice
, Ma ía Unce a-Su´
a ez
g
, Angel Sanchez-Mon a˜
nez
h
, Lau a Go
e
,
i
,
F ede ic To
e
,
i
, Mi eia del To o
a
,
e
,
*
a
Pedia ic Neu ology Depa men , Vall d’Heb on Uni e si y Hospi al, Uni e si a Au ´
onoma de Ba celona, Spain
b
Di ision o Pedia ic Me abolism, C uces Uni e si y Hospi al, Bioc uces-Bizkaia Heal h Resea ch Ins i u e, CIBER-ER; Uni e si y o he Basque Coun y (UPV/EHU),
Spain
c
Depa men o Clinical and Molecula Gene ics, Vall d’Heb on Uni e si y Hospi al, Uni e si a Au ´
onoma de Ba celona, Spain
d
Resea ch G oup on Neu omuscula and Mi ochond ial Diso de s, Vall d’Heb on Ins i u de Rece ca (VHIR), Vall d’Heb on Hospi al Uni e si a i, Ba celona, Spain
e
Cen o de In es igaci´
on Biom´
edica en Red de En e medades Ra as (CIBERER), Ins i u o de Salud Ca los III, Ba celona, Spain
Me abolic Labo a o y, Vall d’Heb on Uni e si y Hospi al, Uni e si a Au ´
onoma de Ba celona, Spain
g
Biochemis y Labo a o y (Me abolism A ea), C uces Uni e si y Hospi al, Bioc uces-Bizkaia Heal h Resea ch Ins i u e, CIBER-ER, Uni e si y o he Basque Coun y
(UPV/EHU), Spain
h
Pedia ic Neu o adiology Depa men , Vall d’Heb on Uni e si y Hospi al, Uni e si a Au ´
onoma de Ba celona, Spain
i
Inbo n E o s o Me abolism, Biochemis y and Molecula Gene ics Depa men , Hospi al Clínic, IDIBAPS, Facul y o Medicine and Heal h Science-Uni e si y o
Ba celona, In e nal Medicine Se ice-Hospi al Clínic o Ba celona, Spain
ARTICLE INFO
Keywo ds:
TRMU
Acu e li e ailu e
Leigh synd ome
Mi ochond ial disease
ABSTRACT
RNA 5-me hylaminome hyl-2- hiou idyla e me hyl ans e ase (TRMU) de iciency causes an ea ly onse po en-
ially e e sible acu e li e ailu e, so a epo ed in less han 30 pa ien s. We desc ibe wo new un ela ed
pa ien s wi h an acu e li e ailu e and a neu oimaging compa ible wi h Leigh synd ome (LS) due o TRMU
de iciency, a combina ion no p e iously epo ed. Ou epo enla ges he pheno ypical spec um o TRMU
disease.
1. In oduc ion
TRMU is a nuclea gene ha encodes he mi ochond ial-speci ic
RNA-modi ying enzyme: 5-me hylaminome hyl-2- hiou idyla e me h-
yl ans e ase. TRMU pa hogenic a ian s we e i s epo ed as a mod-
i ie in pa ien s wi h senso ineu al dea ness ca ying homoplasmic
m.1555G >A a ian in he mi ochond ial gene MTRNR1 (OMIM
*561000) [1]. In 2009, pa hogenic a ian s in TRMU gene we e
desc ibed as esponsible o acu e li e ailu e in he i s mon hs o age
(OMIM #613070) [2]. Pa ien s who su i ed his li e- h ea ening pe iod
ully eco e ed and had a no mal de elopmen wi hou ecu ence. To
ou knowledge, 26 pa ien s wi h TRMU pa hogenic a ian s ha e been
published. Since he i s desc ip ion o e e sible hepa ic ailu e, only a
ew o he pheno ypes wi h ex a-hepa ic mani es a ions ha e been e-
po ed. Leigh synd ome (LS), ea u ed by hype lac acidemia and sym-
me ical lesions in b ains em, basal ganglia and o he b ain s uc u es, is
he mos common pedia ic p esen a ion o mi ochond ial disease [3].
We p esen wo ecen ly diagnosed pa ien s wi h acu e li e ailu e
caused by TRMU pa hogenic a ian s associa ed o LS, a pheno ypic
combina ion no p e iously epo ed.
2. Case epo s
We ex ensi ely sea ched he li e a u e o pa ien s wi h TRMU
molecula ly con i med disease and clinical desc ip ion. Supplemen a y
Table 1 summa izes clinical, labo a o y, adiological and gene ic da a
desc ibed in TRMU pa ien s in p e iously published pa ien s (n =26)
and we added ou wo pa ien s (Pa ien 1 is P27, Pa ien 2 is P28).
Pa ien 1, a gi l, was he second child o non-consanguineous pa -
en s. She was bo n a e m a e an une en ul p egnancy. He psycho-
mo o de elopmen and g ow h pa ame e s (weigh , leng h and head
ci cum e ence a +0.2 SD) we e no mal un il he age o 3 mon hs, when
she p esen ed a apid de e io a ion and ailu e o h i e. She su e ed
p og essi e gene alized hypo onia, luc ua ing le el o consciousness,
* Co esponding au ho a : Pedia ic Neu ology Depa men , Vall d’Heb on Uni e si y Hospi al, Passeig de la Vall d’Heb on, 119-129, Ba celona 08035, Spain.
E-mail add ess: [email p o ec ed] (M. del To o).
Con en s lis s a ailable a ScienceDi ec
Molecula Gene ics and Me abolism Repo s
jou nal homepage: www.else ie .com/loca e/ymgm
h ps://doi.o g/10.1016/j.ymgm .2020.100690
Recei ed 15 Sep embe 2020; Recei ed in e ised o m 19 No embe 2020; Accep ed 24 No embe 2020
Molecula Gene ics and Me abolism Repo s 26 (2021) 100690
2
dec eased in ake, weigh -loss (−2 SD) and p og essi e hepa omegaly.
Labo a o y indings showed acu e li e ailu e, me abolic acidosis and
pe sis en high lac a e in blood, u ine and CSF. B ain MRI showed acu e
and symme ical lesions o pon inus ac s, uppe ce ebella peduncles,
basal nuclei and whi e ma e , wi h es ic ion on DWI and a lac a e peak
on MRS (See Fig. 1A-D). Abdominal ul asound showed an inc eased size
and echogenici y o he li e , wi hou any o he pa hological indings.
Echoca diog aphy, EEG and oph halmologic examina ions we e no mal.
The espi a o y chain complex ac i i ies in muscle biopsy we e
dec eased excep o no mal CII, and inc eased ci a e syn hase ac i i y.
Muscle biopsy indings sugges ed mi ochond ial myopa hy (see suppl
able). Lac ic acidosis co ec ion and supplemen a ion wi h ca ni ine,
bio ine and hiamine was ini ia ed wi h ansien clinical and
biochemical imp o emen . A e wo mon hs he pa ien was eadmi ed
o PICU wi h se e e hepa ic ailu e, coagulopa hy, ubulopa hy and
lac ic acidosis, e ac o y o all ea men s and she died a he age o 6
mon hs.
Mi ochond ial DNA sequencing was no mal. Clinical whole exome
sequencing (T uSigh One®, Illumina, San Diego) demons a ed wo
mu a ions in ans in TRMU gene: c.160_161delTG:p.Cys54* (non-p e-
iously epo ed, bu likely pa hogenic acco ding o ACMG c i e ia since
i c ea es an s op codon) and c.680G >C:p.A g227Th (p e iously
desc ibed in [4]). Pa en s we e ca ie s o hese a ian s.
Pa ien 2, a boy, was he i s child o non-consanguineous pa en s.
A e a non-complica ed p egnancy, he was bo n a e m wi h low bi h-
weigh (−2.7 SD). Du ing he i s 12 h o li e he p esen ed gene alized
hypo onia wi h se e e lac ic acidosis, p og essi e ele a ion o
ansaminases and coagulopa hy. B ain MRI showed T2 hype in ense
sup a and in a en o ial lesions a ec ing bila e al halami, sub halamic
nuclei and b ains em and a lac a e peak on MRS (See Fig. 1E-O). Fu he
me abolic in es iga ions showed high lac a e/py u a e a io, impo an
ele a ion o in e media e me aboli es o K ebs cycle in u ine, and
hype alaninemia. Unde he suspicion o a mi ochond ial diso de ,
ea men wi h coenzyme Q, ibo la in, hiamine and bio in we e
ini ia ed wi h no clinical imp o emen . He showed a e ac o y hype -
lac acidaemia (15–20 mmol/L) and died a he age o 25 days om a
mul iple o gan ailu e. The espi a o y chain complexes ac i i ies we e
measu ed in muscle and, excep o CII, all o hem and also ci a e
syn hase ac i i y we e dec eased. When analyzing hei a io, mos o
hem became no malized, so no signi ican al e a ions we e de ec ed.
The low ac i i y o all complexes and also o ci a e syn hase, could
indica e a low numbe o mi ochond ia in he muscle. Mi ochond ial
DNA sequencing was no mal. Exome Sequencing showed wo pa ho-
genic a ian s in TRMU: c.2 T >A: p.Me 1? ( epo ed in [2]) and
c.491delT: p.Leu164P o sTe 22 (non-p e iously epo ed, bu also
pa hogenic acco ding o ACMG ules due o ameshi change gene -
a ing p ema u e s op codon). Mos ele an indings in pa ien ’s nec-
opsy we e: massi e hepa ic s ea osis, inc ease in hea hickness a he
expense o g oups o acuola ed and g anula cy oplasm myocy es,
among which conse ed myocy es we e iden i ied, and se e e spongi-
o ic acuoliza ion in halamus, midb ain, unk and ocal ce ebellum.
In summa y, bo h pa ien s p esen ed an ea ly onse Leigh synd ome
and an acu e li e ailu e wi h p og ession o mul io ganic ailu e and
a al ou come due o TRMU a ian s, and can no be explained by o he
Fig. 1. MRI o pa ien 1 (P27 in he supplemen a y able) showed symme ical lesions o pon inus ac s, uppe ce ebella peduncles, basal nuclei and whi e ma e
wi h es ic ion in DWI (A-D). MRI o pa ien 2 (P28 in he suppl able) showed an inc eased lac a e peak in he MRS (E), sup a and in a en o ial lesions a ec ing
bila e al halami, sub halamic nuclei and b ains em in DWI (F-J) and T2 (K-O).
J. Sala-Co omina e al.
Molecula Gene ics and Me abolism Repo s 26 (2021) 100690
3
gene ic indings in he whole exome-sequencing.
3. Discussion
We epo wo ecen ly diagnosed un ela ed pa ien s wi h TRMU
pa hogenic a ian s, associa ing LS and acu e li e ailu e, a combina-
ion no p e iously epo ed.
Classical p esen a ion o TRMU pa hogenic a ian s has been
desc ibed o da e in 26 pa ien s wi h acu e li e ailu e as he main
pheno ype, some o which sha e o he clinical indings (Supplemen a y
able) [2,5–12]. Almos all (24/26) epo ed pa ien s su e ed om he-
pa ic ailu e. One (P18) had a myopa hic pheno ype (p osis, a igabili y,
bulba in ol emen wi h eeding and espi a o y di icul ies a onse
wi h comple e eco e y) and ano he (P20) a a al hea ailu e in his
i s mon h o li e. O he ex ahepa ic mani es a ions include a a iable
ange o symp oms: e e sible dila ed ca diomyopa hy and neph-
omegaly (P4), bulba in ol emen wi h eeding di icul ies (P18,P19),
some deg ee o hypo onia (P15, P17, P18), hypo hy oidism, mac ocy ic
anemia and mic ocephaly (P21, P22), ich hyosis (P24), e c. Long- e m
ou come a ies om comple e eco e y (19/26) o dea h due o li e ,
hea o mul io ganic ailu e (7/26). When su i ing he acu e phase,
mos pa ien s ha e a no mal de elopmen and comple e eco e y.
Howe e , long e m ollow-up da a a e no a ailable o all o hese
pa ien s. Rega ding biochemical indings, all pa ien s showed inc eased
se um lac a e le el (3.2–40.0 mmol/L), wi h a iable ange o lac a e in
CSF ( om no mal, o 3.9 mmol/L). Abno mal li e unc ion was p esen
in all pa ien s (a ailable da a om 24/26) wi h a iable deg ees o
ansaminase ele a ion, coagulopa hy, choles asis o ele a ed al a-
e op o ein. Li e biopsies (9/23) showed signs o mild o se e e he-
pa ic in ol emen in biopsies aken se e al mon hs a e onse : onco-
cy ic changes in he hepa ocy es, ocal s ea osis and ocal ballooning o
cy oplasm, mic onodula ci hosis, canalicula choles asis o pa en
signs o ib osis, i egula ci hosis wi h nodula ion and mac o esicula
s ea osis. No no mal hepa ic biopsies we e epo ed. Analysis o espi-
a o y chain enzyme ac i i ies demons a ed a combined espi a o y
chain complex de iciency in mos o he cases wi h a ailable da a (11/
26). B ain MRI was pe o med in 17/26 pa ien s. All excep h ee we e
no mal. P16 had a lac a e peak in MRI wi h no lesions, P15 had myeli-
na ion delay wi h no mal MRS and P19 had a e e sible T2 high signal in
igh halamus wi h lac a e peak in MRS.
Ou pa ien s a e simila o he ones epo ed in li e a u e in e ms o
li e ailu e and abno mal labo a o y indings. In con as , ou pa ien s
p esen ed a neu ological clinical onse consis ed o an acu e encepha-
lopa hy and de elopmen al eg ession (P1) and se e e hypo onia om
bi h (P2). All wo displayed symme ical and bila e al lesions in MRI
a ec ing di e en b ain s uc u es consis en wi h LS, wi h a lac a e
peak on MRS. Pos mo em s udy in P2 demons a ed massi e hepa ic
s ea osis, also seen in li e biopsies o p e ious pa ien s and spongio ic
acuoliza ion in halamus, midb ain, unk and ocal ce ebellum as seen
in LS [3]. In e es ingly, his nec opsy showed ca diac a ec ion, despi e
he pa ien no ha ing p esen ed e iden ca diological symp oms. Only
wo p e ious pa ien s (P4, P20) we e men ioned o ha e ca diological
in ol emen .
Clinical p esen a ion o Leigh synd ome a ies depending on he age
o onse [13]. In ypical in an ile onse , ini ial nonspeci ic mani es a-
ions can be seen: omi ing, hypo onia, ailu e o h i e o de elop-
men al delay, o en wi h acu e wo sening o p e ious clinical s a e a e
a clinical e en such as in ec ion. On he o he hand, li e in ol emen i
is a e y unusual clinical mani es a ion. Bila e al symme ical lesions
wi hin he b ains em, basal ganglia and less equen whi e ma e , T2-
W in MRI cha ac e ize he disease wi h ele a ed lac a e in MRS [14].
Bo h clinical and neu oimaging ea u es occu ed in ou wo pa ien s.
Pa hogenic a ian s in o e 75 genes (nuclea and mi ochond ial DNA),
ha e been associa ed o Leigh synd ome [14], despi e wha , hal o he
cases emain wi hou a gene ic diagnosis [13]. De ec s o nuclea DNA
genes a e he main cause o Leigh synd ome, wi h only 25% o all cases
caused by m DNA pa hogenic a ian s. Bo h isola ed and mul iple
complex de iciencies can be ound, being hese las ones mainly caused
by mu a ions in mo e han 150 p o eins implica ed in mi ochond ial
ansla ion, including TRMU [15]. Axial and/o pe iphe al hypo onia
was desc ibed in ou pa ien s (P15, P16, P18 and P19), P25 had seizu e-
like episodes and mild de elopmen al delay has been epo ed in P24
and P26. Al hough neu ological in ol emen has been desc ibed in some
pa ien s, none o hem had b ain lesions compa ible wi h Leigh
synd ome.
TRMU encodes a p o ein ha pa icipa es in he modi ica ion o
mi ochond ial RNAs. Speci ically, i is esponsible o he 2- hiola ion
o he nucleo ide a he wobble posi ion o he RNA-Lys, RNA-Glu,
and -RNA-Gln [2]. Many o he genes ela ed o mi ochond ial ans-
la ion a e iden i ied o cause Leigh synd ome [13,14]. Simila pa ho-
genic mechanisms could be sha ed be ween hese genes o explain Leigh
synd ome in ou pa ien s, bu u he in es iga ions a e needed o un-
de s and why only a ew pa ien s wi h TRMU pa hogenic a ian s
de eloped his pheno ype.
Al hough mos o he epo ed pa ien s (19/26) expe ienced a pa ial
o o al eco e y a e he acu e phase, all o ou pa ien s died du ing he
i s mon hs o li e. They p esen ed se e e neu ological in ol emen and
inally died om mul io ganic ailu e.
A possible explana ion o cla i y a geno ype-pheno ype co ela ion
has been p oposed [2]: pa ien s ca ying wo missense a ian s (excep
hose occu ing in i s me hionine) seem o ha e be e p ognosis han
when, nonsense, ameshi o splicing a ian s a e p esen . Bo h pa-
ien s ca ied nonsense and ameshi a ian s espec i ely, in com-
pound he e ozygosi y wi h known missense pa hogenic a ian s. On he
o he hand, i s desc ip ions o TRMU de ec s sugges ed inc easing
cys eine a ailabili y in la e in ancy as a possible explana ion o clinical
eco e y [2]. Pa ien 2 had an abno mal bi h weigh , which may induce
hinking ha cys eine de iciency in ma e nal and neona al nu i ion
could also be a po en ial con ibu o o a se e e pheno ype. Howe e ,
pa ien 1 had no mal weigh be o e clinical de e io a ion a 3 mon hs
old. The e o e, we conclude ha nei he molecula indings no
ma e nal/neona al nu i ion seem eason enough o explain he clinical
he e ogenei y o he diso de .
To conclude, TRMU gene sequencing should be conside ed in pa-
ien s wi h Leigh synd ome, especially when li e in ol emen is p e-
sen , and also in pa ien s wi h o he mi ochond ial pheno ypes as
p og essi e ailu e o h i e, mild-mode a e psychomo o delay, mild
li e in ol emen and me abolic acidosis wi h hype lac acidemia.
Fu he pa ien epo s and mo e in es iga ions a e needed o explain
his pheno ypical a iabili y e en hough ca ying same pa hogenic
a ian s. Ou epo enla ges he pheno ypical spec um o TRMU
disease.
Funding
This wo k was pa ially suppo ed by he Spanish Ins i u o de Salud
Ca los III, Fondo de In es igaciones Sani a ias and co ounded wi h
ERDF unds (G an No. FIS PI15/01428, PI19/01772).
Au ho s a emen
All pe sons who mee au ho ship c i e ia a e lis ed as au ho s, and all
au ho s ce i y ha hey ha e pa icipa ed su icien ly in he wo k o
ake public esponsibili y o he con en , including pa icipa ion in he
concep , design, analysis, w i ing, o e ision o he manusc ip .
Fu he mo e, each au ho ce i ies ha his ma e ial o simila ma e ial
has no been and will no be submi ed o o published in any o he
publica ion be o e his submission.
Au ho ship con ibu ions
Speci ic au ho con ibu ions a e lis ed below.
J. Sala-Co omina e al.
Molecula Gene ics and Me abolism Repo s 26 (2021) 100690
4
•Júlia Sala-Co omina: Concep ualiza ion, me hodology, isualiza ion,
w i ing – o iginal d a .
•Lucía Doughe y-de Miguel: Concep ualiza ion, me hodology, isu-
aliza ion, w i ing – o iginal d a .
•Ja ie de las He as: Concep ualiza ion, me hodology, w i ing.
•Amaia Lasa-A anzas i: Me hodology, da a cu a ion and e iew.
•Elena Ga cia-A umi: Me hodology, supe ision, w i ing e iew.
•Lidia Ca e˜
no: Me hodology, da a cu a ion
•Jose An onio A anz:.Me hodology, da a cu a ion.
•Cla a Ca nice : Me hodology, da a cu a ion.
•Ma ía Unce a-Su´
a ez: Me hodology, da a cu a ion.
•Angel Sanchez-Mon a˜
nez: Me hodology, w i ing e iew. and edi ing.
•Lau a Go : Me hodology, da a cu a ion, w i ing e iew.
•F ede ic To : Me hodology, w i ing e iew.
•Mi eia del To o: Concep ualiza ion, me hodology, supe ision,
w i ing e iew and edi ing.
Acknowledgmen s
The Cen o de In es igaci´
on Biom´
edica en Red de En e medades
Ra as (CIBERER), is an ini ia i e o he Ins i u o de Salud Ca los III
(Minis e io de Ciencia e Inno aci´
on, Spain). This s udy was suppo ed by
he Ag`
encia de Ges i´
o d’Aju s Uni e si a is i de Rece ca (AGAUR) (2014:
SGR 393) and he CERCA P og amme/Gene ali a de Ca alunya. The
p esen s udy was suppo ed by he Depa men de Salu , Gene ali a de
Ca alunya (URDCAT p ojec , SLT002/16/00174).
All pe sons who ha e made subs an ial con ibu ions o he wo k
epo ed in he manusc ip (e.g., echnical help, w i ing and edi ing
assis ance, gene al suppo ), bu who do no mee he c i e ia o
au ho ship, a e named in he Acknowledgemen s and ha e gi en us hei
w i en pe mission o be named. I we ha e no included an Acknowl-
edgemen s, hen ha indica es ha we ha e no ecei ed subs an ial
con ibu ions om non-au ho s.
Appendix A. Supplemen a y da a
Supplemen a y da a o his a icle can be ound online a h ps://doi.
o g/10.1016/j.ymgm .2020.100690.
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