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In a amilial Va iabili y in A axia-Telangiec asia: A Case Repo o Th ee Siblings wi h
Iden ical ATM Mu a ions
Elmakhzen Bad eddine * and EL ALAMI Anass
Medical Gene ics and Onco-Gene ics Labo a o y, Hospi al Uni e si y Hassan II, Fez, Mo occo.
Wo ld Jou nal o Ad anced Resea ch and Re iews, 2025, 27(02), 1807-1811
Publica ion his o y: Recei ed on 16 July 2025; e ised on 24 Augus 2025; accep ed on 26 Augus 2025
A icle DOI: h ps://doi.o g/10.30574/wja .2025.27.2.3077
Abs ac
A axia- elangiec asia (A-T) is a a e, au osomal ecessi e neu odegene a i e diso de caused by pa hogenic a ian s in
he ATM (a axia- elangiec asia mu a ed) gene, loca ed on ch omosome 11q22–23. The ATM p o ein is a
se ine/ h eonine kinase essen ial o he de ec ion o DNA double-s and b eaks and ac i a ion o cell-cycle
checkpoin s. Classic A-T ypically mani es s in ea ly childhood wi h p og essi e ce ebella a axia, oculocu aneous
elangiec asias, immunode iciency, adiosensi i i y, and a high p edisposi ion o malignancy.[1]
We desc ibe a non-consanguineous amily wi h h ee siblings a ec ed by a axia- elangiec asia (A-T) due o iden ical
compound he e ozygous pa hogenic a ian s in he ATM gene: c.72+2T>C (splice dono mu a ion) and c.6100C>T (p.
A g2034Te , nonsense mu a ion). Despi e sha ing he same geno ype, he siblings exhibi ed ma ked a iabili y in age
o onse and clinical p og ession, anging om ea ly-childhood gai ins abili y o la e-onse eg ession o p e iously
no mal mo o skills. All a ec ed siblings had ele a ed se um alpha- e op o ein (AFP) and ce ebella signs, bu di e ed
in he iming o elangiec asia appea ance and se e i y o mo o impai men . This epo highligh s he ole o gene ic
backg ound and possible modi ie ac o s in he pheno ypic exp ession o A-T.
Keywo ds: A axia-Telangiec asia; ATM Gene; Alpha-Fe op o ein; In a amilial Va iabili y; Ce ebella A ophy;
Telangiec asia
1. In oduc ion
A axia- elangiec asia (A-T; OMIM #208900) is an au osomal ecessi e neu odegene a i e diso de caused by biallelic
pa hogenic a ian s in he ATM (a axia- elangiec asia mu a ed) gene loca ed on ch omosome 11q22.3. The ATM p o ein
is a se ine/ h eonine kinase c i ical o he de ec ion and epai o DNA double-s and b eaks, main enance o genomic
s abili y, and egula ion o cell cycle checkpoin s [1].
The classic pheno ype usually p esen s be ween ages 1 and 4 yea s wi h p og essi e ce ebella a axia, ollowed by
oculocu aneous elangiec asias, immunode iciency, inc eased suscep ibili y o malignancy, and adia ion sensi i i y
[1,2]. Labo a o y ea u es include ele a ed AFP le els a e age wo and ch omosomal ins abili y. Acco ding o Gene
Re iews, geno ype–pheno ype co ela ion is impe ec , and conside able a iabili y exis s—e en among indi iduals
wi h iden ical mu a ions—due o en i onmen al, epigene ic, o modi ie gene e ec s [1].
We epo a amily wi h h ee compound he e ozygous siblings ha bo ing he ATM a ian s c.72+2T>C and c.6100C>T,
exhibi ing subs an ial a iabili y in symp om onse and p og ession.
Wo ld Jou nal o Ad anced Resea ch and Re iews, 2025, 27(02), 1807-1811
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2. Case epo
The amily unde in es iga ion o igina es om a u al egion in Mo occo whe e bo h pa en s we e bo n and aised;
howe e , he e is no known consanguini y. The couple is heal hy, wi h no neu ological o immunological symp oms, bu
bo h we e ound o be he e ozygous ca ie s o dis inc pa hogenic a ian s in he ATM gene. The a he ca ies he
c.72+2T>C splice si e a ian , while he mo he ca ies he c.6100C>T nonsense a ian (p.A g2034Te ). They ha e i e
child en, h ee o whom a e a ec ed by a axia- elangiec asia, each inhe i ing bo h a ian s in ans, esul ing in
compound he e ozygosi y.
The i s a ec ed child, a boy, was bo n a e an uncomplica ed p egnancy and no mal deli e y. His ea ly psychomo o
de elopmen was age-app op ia e, and he eached all mo o and speech miles ones wi hou delay. F om ea ly
childhood, he expe ienced ecu en episodes o abdominal pain, which we e ini ially conside ed unc ional. A he age
o i e, his pa en s no iced p og essi e speech di icul ies, a waddling gai , and equen imbalance. These symp oms
g adually wo sened, leading o signi ican gai ins abili y. Neu ological examina ion e ealed a ce ebella synd ome
wi h dysa h ia, uncal a axia, dysme ia, and gai dis u bance. Labo a o y analysis demons a ed ele a ed AFP le els,
a inding cha ac e is ic o A-T. B ain compu ed omog aphy (CT) showed ma ked e mian ce ebella a ophy along wi h
mild co ical–subco ical a ophy, consis en wi h he neu ological p esen a ion.
The second a ec ed child, a gi l, is cu en ly i e yea s old. She p esen ed wi h gai ins abili y om ea ly childhood,
which p og essed g adually. By he age o i e, ocula elangiec asias we e e iden on oph halmological examina ion.
Like he b o he , she had ele a ed AFP le els. Neu ological e alua ion con i med ce ebella in ol emen , and
oculomo o abno mali ies, including abno mal saccadic mo emen s, we e obse ed. He disease cou se was mo e apid
in he appea ance o elangiec asias compa ed wi h he olde b o he .
The younges a ec ed child, a boy, is h ee yea s old. He began showing signs o gai imbalance du ing oddle hood, bu
his mo o impai men emains milde han ha o his olde siblings a compa able ages. Telangiec asias ha e no ye
been de ec ed on clinical examina ion. Ne e heless, AFP le els a e ele a ed, indica ing a biochemical ma ke o disease
e en in his ea ly s age. His neu ological symp oms a e cu en ly limi ed o mild ce ebella signs, wi h p ese ed speech
and no signi ican dysa h ia.
2.1. Gene ic Tes ing
Molecula analysis was ini ia ed wi h whole-exome sequencing in he i s a ec ed child, which iden i ied wo
pa hogenic a ian s in he ATM gene: c.72+2T>C, a splice dono si e a ian p edic ed o esul in abe an mRNA
p ocessing, and c.6100C>T (p. A g2034Te ), a nonsense a ian leading o p ema u e p o ein unca ion. Bo h a ian
we e epo ed in cle e da abase as pa hogenic in nume ous cases. These indings es ablished a diagnosis o a axia-
elangiec asia (Figu e 1).
Subsequen Sange sequencing was pe o med o a ge ed a ian analysis in he es o he amily, con i ming ha all
h ee a ec ed siblings we e compound he e ozygo es o he same wo ATM a ian s, inhe i ed in ans om hei
ca ie pa en s.
Wo ld Jou nal o Ad anced Resea ch and Re iews, 2025, 27(02), 1807-1811
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Figu e 1 Elec ophe og ams depic ing he gene ic p o iles o indi iduals in he amily
A: He e ozygous Va ian C.72+2T>C (Splice Dono Mu a ion), B: He e ozygous Va ian C.6100C>T (P. A g2034Te )
3. Discussion
This amily illus a es se e al impo an aspec s o ATM- ela ed disease: compound he e ozygosi y o wo clea ly
pa hogenic a ian s, he classical neu ological and labo a o y ea u es o A-T, and s iking in a amilial pheno ypic
a iabili y.
The c.72+2T>C mu a ion a ec s he in a ian +2 posi ion o he dono splice si e in in on 4, p edic ed o esul in exon
skipping o c yp ic splice si e usage, p oducing a ameshi and p ema u e e mina ion. The c.6100C>T a ian
in oduces a p ema u e s op codon a posi ion A g2034, p edic ed o igge nonsense-media ed decay. Bo h alleles a e
loss-o - unc ion mu a ions ypically associa ed wi h comple e loss o ATM kinase ac i i y, co ela ing wi h classic ea ly-
onse A-T.[3]
Se e al published epo s desc ibe pa ien s ca ying ei he c.72+2T>C o c.6100C>T in compound he e ozygosi y wi h
ano he unca ing ATM a ian . Sando al e al., Po u alski e al., and Taylo e al. consis en ly epo onse o gai
ins abili y be ween ages 1–3 yea s, ea ly elangiec asia appea ance, apid neu ological decline, and equen
immunode iciency [2,3,4]. Cases wi h he exac combina ion o c.72+2T>C and p. A g2034Te ha e been linked o se e e
pheno ypes, o en wi h wheelchai dependence be o e adolescence and ma ked ce ebella a ophy [5].
In con as , ou amily showed delayed onse in wo siblings (5 yea s), milde ea ly cou se in he younges (onse a 3
yea s wi h p ese ed speech and no elangiec asia), and a iable p og ession a es. Telangiec asia appea ed only in he
middle child by age 5, whe eas he eldes had ma ked e mian ce ebella a ophy wi hou ocula in ol emen a he
same age, and he younges emains wi hou elangiec asia. AFP ele a ion was uni e sal and p esen e en in he
younges child, as epo ed in >95% o A-T cases.[1]
Pheno ypic a iabili y in A-T despi e iden ical geno ypes is well ecognized [23†sou ce]. Possible explana ions include
di e ences in en i onmen al exposu es, modi ying genes, s ochas ic de elopmen al ac o s, and epigene ic in luences.
Sando al e al. (1999) [4] and Po u alski e al. (2014) [5] bo h epo ed in a amilial di e ences in age a onse and
se e i y, e en among pa ien s wi h he same unca ing ATM a ian s. This a iabili y complica es p ognosis and
highligh s he need o indi idualized clinical su eillance (Table 1).
Wo ld Jou nal o Ad anced Resea ch and Re iews, 2025, 27(02), 1807-1811
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All h ee siblings had ma kedly ele a ed AFP, consis en wi h >95% p e alence in A-T [6], and neu oimaging e ealed
ce ebella a ophy, p edominan ly e mian, in he eldes p oband. The middle child displayed oph halmologic signs o
elangiec asia, a hallma k ea u e, while he younges p esen ed p ima ily wi h gai ins abili y. None had ye de eloped
immunode iciency- ela ed in ec ions se e e enough o equi e hospi al admission, bu mild ecu en espi a o y
in ec ions we e no ed, wa an ing immunological ollow-up.[7]
F om a managemen pe spec i e, ea ly ecogni ion o A-T enables an icipa o y guidance, including immunologic
moni o ing, pulmona y ca e, a oidance o ionizing adia ion exposu e, and malignancy su eillance [23†sou ce]. Gi en
he inc eased li e ime cance isk e en o he e ozygous ATM mu a ion ca ie s [24†sou ce], gene ic counseling o
ex ended amily membe s is essen ial. [8,9]
This epo adds o he body o e idence on in a amilial clinical he e ogenei y in A-T and ein o ces he impo ance o
comp ehensi e amily-based gene ic e alua ion. Unde s anding he mechanisms behind a iable exp essi i y in
iden ical ATM geno ypes emains an impo an esea ch goal, wi h implica ions o p ognosis, counseling, and a ge ed
he apy de elopmen .
Table 1 Compa ison o Clinical Fea u es Be ween Repo ed Pa ien s wi h ATM c.72+2T>C and/o p. A g2034Te
Mu a ions and he P esen Family
Fea u e
Li e a u e [5,6,9] (same o simila
a ian )
You Family
Geno ype
c.72+2T>C + unca ing mu a ion
(including p. A g2034Te in some
epo s)
c.72+2T>C + c.6100C>T (p. A g2034Te )
Onse age
Mos ly 1–3 yea s (gai ins abili y)
3 yea s (younges ), 5 yea s (middle, elde )
Neu ological
cou se
Rapid p og ession o se e e a axia; ea ly
wheelchai use
Slowe in younges ; elde child had no mal
de elopmen un il age 5 be o e eg ession
Telangiec asia
onse
O en be o e 6 yea s
P esen in middle child a 5 yea s; absen in
younges
AFP ele a ion
Almos uni e sal a e age 2
P esen in all h ee siblings (including younges )
Ce ebella a ophy
Ea ly and p og essi e
Eldes : ma ked e mian a ophy; o he s: clinical
signs wi hou imaging ye
Immunode iciency
Common; ecu en in ec ions
Mild ecu en in ec ions, no se e e
immunode iciency documen ed ye
4. Conclusion
We desc ibe h ee siblings wi h iden ical compound he e ozygous ATM mu a ions bu ma kedly di e en ages o onse
and p og ession. Compa ed o published cases, ou pa ien s exhibi ed delayed onse and slowe de e io a ion. This case
emphasizes he he e ogenei y o A-T, he impo ance o AFP and gene ic es ing in ea ly diagnosis, and he need o
indi idualized su eillance.
Compliance wi h e hical s anda ds
Acknowledgmen s
We hank he amily o hei pa icipa ion.
Disclosu e o con lic o in e es
The au ho s decla e no con lic s o in e es .
Wo ld Jou nal o Ad anced Resea ch and Re iews, 2025, 27(02), 1807-1811
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S a emen o e hical app o al
The p esen esea ch wo k does no con ain any s udies pe o med on animals o human expe imen a ion by he
au ho s.
S a emen o in o med consen
In o med consen was ob ained om all indi idual pa icipan s included in he s udy.
Re e ences
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