Ci a ion: Fe nandez-Pombo, A.;
Diaz-Lopez, E.J.; Cas o, A.I.;
Sanchez-Iglesias, S.; Cobelo-Gomez,
S.; P ado-Mo aña, T.; A aujo-Vila , D.
Clinical Spec um o
LMNA-Associa ed Type 2 Familial
Pa ial Lipodys ophy: A Sys ema ic
Re iew. Cells 2023,12, 725. h ps://
doi.o g/10.3390/cells12050725
Academic Edi o : Thomas Decha
Recei ed: 31 Janua y 2023
Re ised: 16 Feb ua y 2023
Accep ed: 17 Feb ua y 2023
Published: 24 Feb ua y 2023
Copy igh : © 2023 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
cells
Sys ema ic Re iew
Clinical Spec um o LMNA-Associa ed Type 2 Familial Pa ial
Lipodys ophy: A Sys ema ic Re iew
An ia Fe nandez-Pombo 1,2 , E e a do Josue Diaz-Lopez 1,2 , Ana I. Cas o 2,3, So ia Sanchez-Iglesias 1,
Sil ia Cobelo-Gomez 1, Te esa P ado-Mo aña 1,2 and Da id A aujo-Vila 1,2,*
1UETeM-Molecula Pa hology G oup, Depa men o Psychia y, Radiology, Public Heal h, Nu sing and
Medicine, IDIS-CIMUS, Uni e si y o San iago de Compos ela, 15706 San iago de Compos ela, Spain
2Di ision o Endoc inology and Nu i ion, Uni e si y Clinical Hospi al o San iago de Compos ela,
15706 San iago de Compos ela, Spain
3CIBER Fisiopa ología de la Obesidad y la Nu ición (CIBERobn), 28029 Mad id, Spain
*Co espondence: [email p o ec ed]; Tel.: +34-981-951-611
Abs ac :
Type 2 amilial pa ial lipodys ophy (FPLD2) is a laminopa hic lipodys ophy due o
pa hogenic a ian s in he LMNA gene. I s a i y implies ha i is no well-known. The aim o his
e iew was o explo e he published da a ega ding he clinical cha ac e isa ion o his synd ome in
o de o be e desc ibe FPLD2. Fo his pu pose, a sys ema ic e iew h ough a sea ch on PubMed
un il Decembe 2022 was conduc ed and he e e ences o he e ie ed a icles we e also sc eened.
A o al o 113 a icles we e included. FPLD2 is cha ac e ised by he loss o a s a ing a ound
pube y in women, a ec ing limbs and unk, and i s accumula ion in he ace, neck and abdominal
isce a. This adipose issue dys unc ion condi ions he de elopmen o me abolic complica ions
associa ed wi h insulin esis ance, such as diabe es, dyslipidaemia, a y li e disease, ca dio ascula
disease, and ep oduc i e diso de s. Howe e , a g ea deg ee o pheno ypical a iabili y has been
desc ibed. The apeu ic app oaches a e di ec ed owa ds he associa ed como bidi ies, and ecen
ea men modali ies ha e been explo ed. A comp ehensi e compa ison be ween FPLD2 and o he
FPLD sub ypes can also be ound in he p esen e iew. This e iew aimed o con ibu e owa ds
augmen ing knowledge o he na u al his o y o FPLD2 by b inging oge he he main clinical esea ch
in his ield.
Keywo ds: LMNA; Dunnigan disease; ype 2 amilial pa ial lipodys ophy; laminopa hies; FPLD2
1. In oduc ion
The LMNA gene codi ies o lamin A/C, which is an in e media e ilamen p o ein
p esen in he nuclea lamina and an impo an de e minan o nuclea and cellula a -
chi ec u e. The co ec p ocessing o he A- ype lamins is essen ial o he p e en ion o
se e al diso de s [
1
]. In his ega d, p elamin A is a nesyla ed, me hyla ed and p ocessed
by zinc me allop o ease o o m he ma u e lamin A (Figu e 1).
Thus, he e a e a numbe o diseases caused by pa hogenic a ian s in he LMNA
gene ( amilial pa ial lipodys ophy ype 2 [FPLD2] o Dunnigan disease, Hu chinson-
Gil o d p oge ia synd ome, mandibuloac al dysplasia ype A, Eme y D ei uss muscula
dys ophy, Limb-Gi dle muscula dys ophy o a ypical p oge oid synd ome, among
o he s) o o he genes ha in luence his lamin p ocessing (such as ZMPSTE24 gene
a ian s in mandibuloac al dysplasia ype B o in es ic i e de mopa hy ype 1) o in
genes ha in luence i s p ope unc ioning on ch oma in (such as BANF1 gene a ian s in
Nés o -Guille mo p oge ia synd ome). These diso de s a e known as laminopa hies, which
mainly a ec mesenchymal issues (muscle, adipose issue and bone), al hough some a ec
he ne ous sys em (Figu e 1) [1–3].
Cells 2023,12, 725. h ps://doi.o g/10.3390/cells12050725 h ps://www.mdpi.com/jou nal/cells
Cells 2023,12, 725 2 o 23
Cells 2023, 12, x FOR PEER REVIEW 2 o 22
mainly a ec mesenchymal issues (muscle, adipose issue and bone), al hough some a -
ec he ne ous sys em (Figu e 1) [1–3].
Figu e 1. Lamin A p ocessing pa hway and laminopa hies a ec ing mesenchymal issues. P elamin
A is a nesyla ed, me hyla ed and p ocessed by ZMPSTE24, gi ing ise o he ma u e lamin A. Al-
e a ions in his lamin A p ocessing pa hway a e esponsible o se e al diso de s known as lam-
inopa hies, which mainly a ec mesenchymal issues. In his igu e, laminopa hies a e dis ibu ed
acco ding o he mos cha ac e is ically a ec ed mesenchymal issue (adipose issue in he case o
ype 2 amilial pa ial lipodys ophy). MSC: mesenchymal s em cell.
FPLD2 also belongs o a bigge amily o FPLD synd omes ha include a se o Men-
delian diso de s due o a ian s in di e en genes ela ed o adipogenesis and lipogenesis
and which sha e subcu aneous a loss om he limbs and glu eal egion, in addi ion o
he a iable egional accumula ion o excess a [4–6]. Due o adipose issue dys unc ion,
ec opic a accumula ion and, consequen ly, insulin esis ance, hey also sha e se e al
me abolic abno mali ies and como bidi ies. Howe e , he e is a g ea deg ee o pheno yp-
ical a iabili y be ween he di e en FPLD diso de s. To da e, se en sub ypes and ano he
ou unclassi ied a ian s o FPLD ha e been desc ibed, wi h FPLD2 and FPLD1 being he
mos equen [7].
The ex eme a i y o lipodys ophy synd omes such as FPLD2 implies ha hey a e
no well-known. In ac , he knowledge we cu en ly ha e abou he clinical cha ac e isa-
ion o his disease, he associa ed como bidi ies and i s na u al cou se is mainly based on
s udies limi ed o small samples. In addi ion, among he mos ascina ing ai s o his
Figu e 1.
Lamin A p ocessing pa hway and laminopa hies a ec ing mesenchymal issues. P elamin
A is a nesyla ed, me hyla ed and p ocessed by ZMPSTE24, gi ing ise o he ma u e lamin A.
Al e a ions in his lamin A p ocessing pa hway a e esponsible o se e al diso de s known as
laminopa hies, which mainly a ec mesenchymal issues. In his igu e, laminopa hies a e dis ibu ed
acco ding o he mos cha ac e is ically a ec ed mesenchymal issue (adipose issue in he case o
ype 2 amilial pa ial lipodys ophy). MSC: mesenchymal s em cell.
FPLD2 also belongs o a bigge amily o FPLD synd omes ha include a se o
Mendelian diso de s due o a ian s in di e en genes ela ed o adipogenesis and li-
pogenesis and which sha e subcu aneous a loss om he limbs and glu eal egion, in
addi ion o he a iable egional accumula ion o excess a [
4
–
6
]. Due o adipose issue
dys unc ion, ec opic a accumula ion and, consequen ly, insulin esis ance, hey also sha e
se e al me abolic abno mali ies and como bidi ies. Howe e , he e is a g ea deg ee o
pheno ypical a iabili y be ween he di e en FPLD diso de s. To da e, se en sub ypes and
ano he ou unclassi ied a ian s o FPLD ha e been desc ibed, wi h FPLD2 and FPLD1
being he mos equen [7].
The ex eme a i y o lipodys ophy synd omes such as FPLD2 implies ha hey a e no
well-known. In ac , he knowledge we cu en ly ha e abou he clinical cha ac e isa ion o
his disease, he associa ed como bidi ies and i s na u al cou se is mainly based on s udies
limi ed o small samples. In addi ion, among he mos ascina ing ai s o his diso de ,
as in he es o laminopa hies, a e i s complex geno ype-pheno ype associa ions and i s
clinical he e ogenei y [2].
Thus, his e iew aimed o collec and summa ise he published da a ega ding he
classical and a ypical clinical ea u es o Dunnigan disease and i s associa ed como bidi ies,
Cells 2023,12, 725 3 o 23
as well as he di e en ial diagnosis wi h o he FPLD sub ypes, in o de o con ibu e o he
unde s anding o his diso de .
2. Ma e ials and Me hods
2.1. Sea ch S a egy
To show he cu en knowledge abou he clinical cha ac e is ics, o gan abno mali-
ies and associa ed como bidi ies o FPLD2, a sys ema ic e iew based on he P e e ed
Repo ing I ems o Sys ema ic Re iews and Me a-Analyses (PRISMA) p o ocol was con-
duc ed [
8
]. The p o ocol o his sys ema ic e iew is also published in he Open Science
Fo um egis ies and can be accessed using he ollowing: h ps://os .io/d453h (accessed
on 15 Feb ua y 2023). Fo his pu pose, a sea ch on PubMed was pe o med using he
e ms “Dunnigan” OR “ amilial pa ial lipodys ophy” OR “FPLD”. The da abase was
sea ched up o Decembe 2022, wi hou a ime limi a ion and wi hou language es ic ions.
The e e ences o he e ie ed a icles we e also sc eened o iden i y addi ional s udies and
expand ou sea ch (Figu e 2).
Cells 2023, 12, x FOR PEER REVIEW 3 o 22
diso de , as in he es o laminopa hies, a e i s complex geno ype-pheno ype associa ions
and i s clinical he e ogenei y [2].
Thus, his e iew aimed o collec and summa ise he published da a ega ding he
classical and a ypical clinical ea u es o Dunnigan disease and i s associa ed como bidi-
ies, as well as he di e en ial diagnosis wi h o he FPLD sub ypes, in o de o con ibu e
o he unde s anding o his diso de .
2. Ma e ials and Me hods
2.1. Sea ch S a egy
To show he cu en knowledge abou he clinical cha ac e is ics, o gan abno mali-
ies and associa ed como bidi ies o FPLD2, a sys ema ic e iew based on he P e e ed
Repo ing I ems o Sys ema ic Re iews and Me a-Analyses (PRISMA) p o ocol was con-
duc ed [8]. The p o ocol o his sys ema ic e iew is also published in he Open Science
Fo um egis ies and can be accessed using he ollowing: h ps://os .io/d453h (accessed
on 15 Feb ua y 2023). Fo his pu pose, a sea ch on PubMed was pe o med using he
e ms “Dunnigan” OR “ amilial pa ial lipodys ophy” OR “FPLD”. The da abase was
sea ched up o Decembe 2022, wi hou a ime limi a ion and wi hou language e-
s ic ions. The e e ences o he e ie ed a icles we e also sc eened o iden i y addi ional
s udies and expand ou sea ch (Figu e 2).
Figu e 2. Sea ch s a egy and low diag am o a icles.
Figu e 2. Sea ch s a egy and low diag am o a icles.
2.2. S udy Selec ion
A o al o 788 a icles we e iden i ied h ough his da abase sea ch. S udies ha epo
clinical and/o biochemical da a on pa ien s wi h FPLD2 we e eligible o inclusion in he
cu en e iew. The main exclusion c i e ia we e (a) a icles no ul illing he opic o in e es
o his e iew; (b) e iew a icles, me a-analyses, indi idual case epo s, edi o ials o
commen s; and (c) s udies no conduc ed on humans. Two au ho s independen ly e iewed
he abs ac s o he e ie ed a icles, applying he p e iously-men ioned inclusion and
Cells 2023,12, 725 4 o 23
exclusion c i e ia and, subsequen ly e iewed he ull ex o he s udies o de e mine hei
inal inclusion.
2.3. Iden i ica ion and Inclusion o S udies
F om he 788 a icles ini ially ound, 454 we e excluded aking in o accoun ha hey
did no ul il he opic o in e es o his e iew, wo we e excluded because hey we e
published e a a and 66 we e excluded because hey we e ocused on o he FPLD sub ypes
o laminopa hies, o he han Dunnigan disease. Du ing he sc eening and eligibili y
p ocesses, 79 e iew a icles o me a-analyses, 71 indi idual case epo s, eigh le e s o he
edi o and one commen we e also excluded. In addi ion, a o al o 6 s udies we e inally
included a e he sc eening o he e e ences o he ini ial pool o e ie ed a icles. Thus,
inally, 113 a icles we e included in he cu en e iew. The low diag am ega ding he
esea ch s a egy can be seen in Figu e 2.
3. Resul s
3.1. P e alence
Since he i s epo o Dunnigan disease in 1974 [
9
], se e al cases ha e been de-
sc ibed o e he yea s. Al hough i is di icul o speak o p e alence in a a e diso de , in
2017, aking in o accoun da abase and li e a u e sea ches, a p e alence o 1.7–2.8 cases
pe million was de e mined o pa ial lipodys ophy (bo h FPLD and acqui ed pa ial
lipodys ophy) [10].
Wi h he aim o e alua ing he p e alence o missense a ian s in he LMNA gene
exclusi ely, a DNA sequencing da a ex ac ion was pe o med om 60,706 un ela ed
indi iduals in he Exome Agg ega ion Conso ium (ExAC) da abase. Allele equencies
anged om 1-pe -100,000 o 1-pe -1,000 and we e p ima ily he e ozygous (only wo we e
homozygous [p.S625C and p.R644C]) [11].
In a mo e ecen analysis, looking o clinical and molecula lipodys ophy diagnos ic
codes, also using he ExAC da abase, a pa hogenic a ian ca ie p e alence o au osomal
dominan FPLD o ~1 in 7588 indi iduals was es ima ed. Wha is mo e s iking is ha
addi ional pa hogenic a ian s in he LMNA gene (such as he p.R482Q a ian associa ed
wi h FPLD2) we e also ound in pa ien s wi h me abolic abno mali ies in he lipodys ophy
spec um, bu wi hou a clinical diagnosis [
12
]. This only con i ms ha lipodys ophy
synd omes such as Dunnigan disease a e unde diagnosed and unde es ima ed condi ions,
poo ly unde s ood by physicians ou side he specialis ea men cen e se ing.
Thus, he e is de ini ely g ea di icul y in making a ealis ic es ima e o a speci ic
subg oup o a e and he e ogeneous diseases, and only la ge and p olonged egis ies will
make i possible o p esen a mo e objec i e pic u e o he eal da a.
3.2. Clinical Cha ac e is ics
As o mos FPLD sub ypes (excep o ypes 5, 6 and hose associa ed wi h PCYT1A
and MFN2 genes), he epo ed ansmission o FPLD2 suppo s an au osomal dominan
mode o inhe i ance [
13
–
15
]. Howe e , his diso de can ac ually be conside ed a co-
dominan disease, aking in o accoun ha homozygous cases ha e also been desc ibed [
16
].
I is classically cha ac e ised by he loss o a om he unk, bu ocks and uppe and
lowe limbs, in addi ion o a accumula ion in he ace, neck and sup acla icula ossae,
gi ing a Cushingoid appea ance [
13
,
15
,
17
,
18
] (Figu e 3). In his sense,
in i o
mo pho-
unc ional assessmen o a depo s in he neck a ea o FPLD2 pa ien s by PET/CT analysis
exhibi ed he absence o b own adipose issue ac i i y, he e o e showing ha ailu e in
adipose issue b owning may be a con ibu o o disease [
19
]. T unk lipoa ophy also
con ibu es o he appea ance o labial hype ophy [15]. Lipomas a e likewise a common
cha ac e is ic o hese pa ien s, wi h a epo ed p e alence o 20%, e en in lipoa ophic
a eas [
20
]. Along wi h his abno mal a dis ibu ion, muscula hype ophy and myalgias
a e also ecu en ea u es in hese pa ien s [13,21–23].
Cells 2023,12, 725 5 o 23
Cells 2023, 12, x FOR PEER REVIEW 5 o 22
unc ional assessmen o a depo s in he neck a ea o FPLD2 pa ien s by PET/CT analysis
exhibi ed he absence o b own adipose issue ac i i y, he e o e showing ha ailu e in
adipose issue b owning may be a con ibu o o disease [19]. T unk lipoa ophy also con-
ibu es o he appea ance o labial hype ophy [15]. Lipomas a e likewise a common
cha ac e is ic o hese pa ien s, wi h a epo ed p e alence o 20%, e en in lipoa ophic
a eas [20]. Along wi h his abno mal a dis ibu ion, muscula hype ophy and myalgias
a e also ecu en ea u es in hese pa ien s [13,21–23].
Figu e 3. Clinical ea u es o Dunnigan disease. While he e is a loss o adipose issue om he unk,
bu ocks and limbs, a excess in he ace and neck and muscle hype ophy is e iden in women
wi h FPLD2; in men, his cha ac e is ic pheno ype is no so appa en .
O he cha ac e is ic ea u es o hese pa ien s a e he p esence o e y p ominen pe-
iphe al eins due o he lack o subcu aneous a [24], he p esence o signs o insulin
esis ance such as acan hosis nig icans and ac ocho dons [16,25,26], as well as signs o
hype and ogenism in a ec ed women, such as hi su ism [13,23].
Al hough he onse o he pheno ype has been desc ibed in some cases in childhood,
wi h o he signs and como bidi ies occu ing la e in li e [27], in mos cases, in his speci ic
FPLD sub ype, lipodys ophy usually appea s p og essi ely a ound pube y in women,
and la e in men [13,14,23,28].
Pa ien s some imes admi o ha ing se e al di icul ies coming o e ms wi h hei
appea ance, ela ing o physical discom o and psychological dis ess, especially in he
case o women, which may lead hem o conside he possibili y o unde going cosme ic
su ge y [14].
Clinical esea ch has also e ealed ha he exp ession and se e i y o he pheno ype
may be ma kedly dependen on sex, wi h women being mo e a ec ed. On he con a y,
in men, he clinical diagnosis o FPLD can be mo e p oblema ic, aking in o accoun he
less-appa en lipodys ophy pheno ype in mos cases and i s la e onse (Figu e 3), lead-
ing o delays in he diagnosis [13,26]. In ac , men a e usually diagnosed a e hei emale
ela i es.
Figu e 3.
Clinical ea u es o Dunnigan disease. While he e is a loss o adipose issue om he unk,
bu ocks and limbs, a excess in he ace and neck and muscle hype ophy is e iden in women wi h
FPLD2; in men, his cha ac e is ic pheno ype is no so appa en .
O he cha ac e is ic ea u es o hese pa ien s a e he p esence o e y p ominen
pe iphe al eins due o he lack o subcu aneous a [
24
], he p esence o signs o insulin
esis ance such as acan hosis nig icans and ac ocho dons [
16
,
25
,
26
], as well as signs o
hype and ogenism in a ec ed women, such as hi su ism [13,23].
Al hough he onse o he pheno ype has been desc ibed in some cases in childhood,
wi h o he signs and como bidi ies occu ing la e in li e [
27
], in mos cases, in his speci ic
FPLD sub ype, lipodys ophy usually appea s p og essi ely a ound pube y in women,
and la e in men [13,14,23,28].
Pa ien s some imes admi o ha ing se e al di icul ies coming o e ms wi h hei
appea ance, ela ing o physical discom o and psychological dis ess, especially in he
case o women, which may lead hem o conside he possibili y o unde going cosme ic
su ge y [14].
Clinical esea ch has also e ealed ha he exp ession and se e i y o he pheno ype
may be ma kedly dependen on sex, wi h women being mo e a ec ed. On he con a y,
in men, he clinical diagnosis o FPLD can be mo e p oblema ic, aking in o accoun
he less-appa en lipodys ophy pheno ype in mos cases and i s la e onse (Figu e 3),
leading o delays in he diagnosis [
13
,
26
]. In ac , men a e usually diagnosed a e hei
emale ela i es.
When compa ing he e ozygous and homozygous pa ien s, mo e se e e lipoa ophy
was also ound in he la e . Thus, in a ecen s udy conduc ed on 65 pa ien s ca ying he
monoallelic LMNA p.(Th 655Asn s*49) a ian and 13 ca ying he same biallelic a ian ,
while 54% o he e ozygous subjec s we e diagnosed du ing amily sc eening, 69% o
homozygous pa ien s we e diagnosed due o medical complica ions, all o hem p esen ing
ob ious clinical ea u es o lipodys ophy [
16
]. In his sense, compound he e ozygosi y
in he LMNA gene was also ound o be associa ed wi h a ela i ely mo e se e e FPLD2
pheno ype [29].
I has also been epo ed ha mos FPLD2 pa ien s wi h he p e iously desc ibed
classic pheno ype a e hose who ha bou he e ozygous missense a ian s a ec ing a ginine
a codon 482 in exon 8 o he LMNA gene, while hose p esen ing wi h o he LMNA a ian s
a e conside ed o ha e a ypical FPLD2. Thus, pa ien s wi h he p.(R644C), he p.(R582H) o
Cells 2023,12, 725 6 o 23
he p.(R582C) a ian s in exon 11, pa ien s wi h he p.(T528M) a ian in exon 9, pa ien s
wi h he p.(D47N) a ian in exon 1, o e en pa ien s wi h he p.(R471G) a ian in exon 8
o he LMNA gene, we e shown, in p e ious s udies, o ha e a milde pheno ype, wi h less
se e e loss o a , occu ing a an olde age in some cases. In con as , o he cases wi h he
p.(R349W) a ian in exon 6 showed a mo e ema kable a loss, e en in he ace [
5
,
30
–
36
].
O he dis inc i e ea u es ound in subjec s wi h non-codon 482 FPLD2 we e he absence o
p ominen labia majo a, he lack o acan hosis nig icans and hi su ism [
5
] and he p esence
o equen muscle signs such as myalgias o weakness [
37
]. In addi ion, o he cases o
FPLD2 wi h o he he e ozygous pa hogenic a ian s, such as p.(R541P) o p.(K486E), we e
epo ed o ha e a mo e complex pheno ype ha may mo e closely esemble gene alised
lipodys ophy [
38
]. This clinical he e ogenei y sugges s he possible in luence o o he
ac o s, such as en i onmen , which migh induce epigene ic changes o he p esence o
single nucleo ide polymo phisms in LMNA ha could modula e he clinical exp essi i y o
his diso de .
3.3. Body Composi ion
Th oughou he li e a u e, he body composi ion o pa ien s wi h FPLD2 has mainly
been e alua ed h ough dual-ene gy X- ay abso p iome y (DXA) (Figu e 4) o magne ic es-
onance imaging (MRI), al hough some isola ed s udies ha e used bioelec ical impedance
analysis (BIA) o his pu pose. These body composi ion echniques ha e been shown
o help diagnosis by e ealing e en subclinical changes in a deposi ion sugges i e o
lipodys ophy [
37
,
39
]. Th ough hese echniques, he p e iously men ioned clinical ind-
ings o he nea - o al absence o adipose issue in he limbs and uncal a ea (wi hou
educ ion in in aabdominal and in a ho acic a ), along wi h an excess o adipose issue in
he ace, neck, chin, axillae, and labia majo a ha e been con i med [
4
,
30
,
40
–
42
]. In addi ion,
using he Dixon me hod o MRI, no only was quan i ied a li e obse ed o be high
in FPLD2 subjec s, bu panc ea ic a was also g ea e in his popula ion. Fu he mo e, a
posi i e ela ionship was demons a ed be ween hese speci ic a con en s and me abolic
pa ame e s such as glyca ed haemoglobin (HbA1c) o iglyce ides [41,43].
Al hough compu ed omog aphy and MRI emain he e e ence s anda ds o as-
sessing isce al adipose issue (VAT) and subcu aneous abdominal adipose issue (SAT)
dis ibu ion, hese a e expensi e and limi ed echniques wi h ce ain ope a i e con aindi-
ca ions. Thus, he de e mina ion o possible co ela ions be ween MRI da a o uncal
adiposi y and simple clinical measu es, such as BIA-de i ed da a in FPLD women, could
be o use in he assessmen o body composi ion in hese subjec s. In his sense, a signi ican
co ela ion be ween mid- high a pe cen age by MRI and BIA has been obse ed [
44
],
and he measu emen o o al a pe cen age mos s ongly co ela ed wi h bo h VAT and
SAT [45].
Fu he mo e, in line wi h p e iously desc ibed clinical indings, women wi h a ypical
FPLD showed less se e e loss o adipose issue, e alua ed ia MRI, om he limbs and
unk, and pa icula ly om he glu eal egion and p oximal highs han women wi h
ypical FPLD [
5
,
33
]. Despi e his loss o a , pe ia icula adipose issue was ound o be
p ese ed in he lowe limbs o pa ien s wi h Dunnigan disease [
46
]. In addi ion, se e al
s udies compa ed he body composi ion o FPLD2 subjec s wi h o he FPLD sub ypes,
such as ha associa ed wi h pa hogenic a ian s in he PPARG gene. In hese s udies,
pa ien s wi h FPLD3 showed highe limb a , wi h p ese ed uncal a mass and inc eased
skin old hickness in he high, cal , iceps, and biceps, along wi h highe le els o lep in
han FPLD2 subjec s [
36
,
47
–
49
]. Al hough FPLD3 pa ien s a e, he e o e, conside ed o
ha e milde lipodys ophy, i has been obse ed ha hey de elop mo e se e e me abolic
complica ions [
47
], sugges ing ha he se e i y o hese me abolic dis u bances may no
only be associa ed wi h he ex en o a loss.
Cells 2023,12, 725 7 o 23
Cells 2023, 12, x FOR PEER REVIEW 7 o 22
Figu e 4. Compa a i e body composi ion de e mined by Dual-Ene gy X- ay Abso p iome y. Com-
pa a i e, colou -mapped, o al body composi ion scans ia whole-body Dual-Ene gy X- ay Abso p-
iome y o pa ien s wi h FPLD2, FPLD3 and non-lipodys ophic subjec s. G een ep esen s an a ea
o low-le el % a (0–25%), yellow an a ea o medium-le el % a (25–60%), and ed an a ea o high-
le el % a (60–100%); (A) Less-p onounced a loss can be obse ed in he woman wi h PPARG-
associa ed FPLD in compa ison wi h he women wi h FPLD2. Di e ences can be seen e en when
compa ing di e en a ian s wi hin exon 8 o he LMNA gene; (B) Di e ences in he dis ibu ion o
adipose issue a e less e iden in men wi h FPLD2 when compa ed wi h age and BMI-ma ched
heal hy o obese con ols.
Al hough compu ed omog aphy and MRI emain he e e ence s anda ds o as-
sessing isce al adipose issue (VAT) and subcu aneous abdominal adipose issue (SAT)
dis ibu ion, hese a e expensi e and limi ed echniques wi h ce ain ope a i e con ain-
dica ions. Thus, he de e mina ion o possible co ela ions be ween MRI da a o uncal
adiposi y and simple clinical measu es, such as BIA-de i ed da a in FPLD women, could
be o use in he assessmen o body composi ion in hese subjec s. In his sense, a signi i-
can co ela ion be ween mid- high a pe cen age by MRI and BIA has been obse ed
[44], and he measu emen o o al a pe cen age mos s ongly co ela ed wi h bo h VAT
and SAT [45].
Fu he mo e, in line wi h p e iously desc ibed clinical indings, women wi h a ypi-
cal FPLD showed less se e e loss o adipose issue, e alua ed ia MRI, om he limbs and
unk, and pa icula ly om he glu eal egion and p oximal highs han women wi h
ypical FPLD [5,33]. Despi e his loss o a , pe ia icula adipose issue was ound o be
p ese ed in he lowe limbs o pa ien s wi h Dunnigan disease [46]. In addi ion, se e al
s udies compa ed he body composi ion o FPLD2 subjec s wi h o he FPLD sub ypes,
such as ha associa ed wi h pa hogenic a ian s in he PPARG gene. In hese s udies, pa-
ien s wi h FPLD3 showed highe limb a , wi h p ese ed uncal a mass and inc eased
skin old hickness in he high, cal , iceps, and biceps, along wi h highe le els o lep in
Figu e 4.
Compa a i e body composi ion de e mined by Dual-Ene gy X- ay Abso p iome y. Com-
pa a i e, colou -mapped, o al body composi ion scans ia whole-body Dual-Ene gy X- ay Abso p-
iome y o pa ien s wi h FPLD2, FPLD3 and non-lipodys ophic subjec s. G een ep esen s an a ea o
low-le el % a (0–25%), yellow an a ea o medium-le el % a (25–60%), and ed an a ea o high-le el
% a (60–100%); (
A
) Less-p onounced a loss can be obse ed in he woman wi h PPARG-associa ed
FPLD in compa ison wi h he women wi h FPLD2. Di e ences can be seen e en when compa ing
di e en a ian s wi hin exon 8 o he LMNA gene; (
B
) Di e ences in he dis ibu ion o adipose
issue a e less e iden in men wi h FPLD2 when compa ed wi h age and BMI-ma ched heal hy o
obese con ols.
On he o he hand, se e al adipose issue cu -o s and indexes ha e been p oposed
in he li e a u e o help guide he diagnosis o Dunnigan disease. Thus, lowe -limb a
measu ed by DXA in emale child en wi h FPLD2 was ini ially ound o be below o equal
o he 1s pe cen ile o NHANES [
28
]. In a subsequen s udy, i was also de e mined
ha lowe -limb a pe cen age below he 1s pe cen ile acco ding o DXA may di ec he
diagnosis o FPLD2 in women (wi h a speci ici y o 0.995 and a sensi i i y o 1.0), especially
i he e a e concomi an me abolic complica ions, and, he e o e, gene ic es ing should
be ca ied ou in hese cases [
50
]. Fa Mass Ra io (FMR), de ined as he a io be ween he
unk and lowe -limb a mass h ough DXA, was likewise p oposed. I showed a g ea e
alue o FPLD2 subjec s in compa ison wi h con ols as well as imp o ed accu acy o
e alua ing hese pa ien s wi h a cu -o poin o 1.2 [
51
]. Ano he index p oposed as an
objec i e measu emen capable o de e mining a excess in hese pa ien s was he body
adiposi y index (BAI), calcula ed as (hip ci cum e ence/heigh 1.5)-18. Thus, BAI was ound
o be lowe in FPLD2 in compa ison wi h age and BMI-ma ched heal hy indi iduals and
Cells 2023,12, 725 8 o 23
p esen ed a mo e signi ican co ela ion wi h pa ame e s such as o al a pe cen age and
a mass, as well as wi h lep in le els, han BMI [52].
DXA may p o ide no only quan i a i e bu also quali a i e in o ma ion. In his sense,
a me hod was ecen ly desc ibed which may be use ul in he diagnosis o lipodys ophy
synd omes such as FPLD2 h ough he econs uc ion o DXA images using a colou -coded
ep esen a ion ha highligh s only adipose issue (“ a shadows”). This me hod was
able o di e en ia e FPLD om con ol subjec s wi h 85% sensi i i y and 96% speci ici y.
In addi ion, he iden i ica ion o he “Dunnigan sign” (hype ophy o mons pubis a
su ounded by subcu aneous lipoa ophy) is also help ul in ecognising subjec s wi h
FLPD2, which can easily be acknowledged by his speci ic me hod [53].
As a as skele al muscle is conce ned, in compa ison wi h heal hy women ma ched
o age and BMI, pa ien s wi h FPLD2 showed g ea e olume in he high, cal and psoas
muscles, as well as inc eased a m and leg muscle masses when measu ed ia DXA. In addi-
ion, insulin sensi i i y was shown o be nega i ely co ela ed o cal muscle olume [
54
].
Howe e , in a ecen s udy, despi e his inc eased muscula i y, FPLD2 subjec s did no
demons a e inc eased muscle s eng h and e en showed ea lie a igue on ches -p ess
exe cise. Fu he mo e, he inc ease in skele al muscle was ound o be likely due o e-
duced muscle p o ein deg ada ion a he han o g ea e p o ein syn hesis, wi h impai ed
mi ochond ial unc ion playing a ele an ole in his dys unc ion [55].
On he o he hand, bone can also be assessed h ough body composi ion echniques
such as DXA. Laminopa hies such as Hu chinson-Gil o d p oge ia synd ome, mandibu-
loac al dysplasia, LMNA-associa ed a ypical p oge oid synd ome, Nés o -Guille mo p oge-
ia synd ome, es ic i e de mopa hy o le hal oe al akinesia a e cha ac e ised by bone
al e a ions, sugges ing ha lamin A/C could play an impo an ole in he pa hogeny o he
loss o bone mass ela ed o ageing [
56
–
59
]. Howe e , in he case o FPLD2, no di e ences
in bone mine al densi y e alua ed ia DXA we e ound compa ed o non-lipodys ophic
obese women o women wi h FPLD1 [
60
]. Ne e heless, in ano he s udy, se e al pa-
ien s wi h FPLD showed non-speci ic degene a i e adiog aphic abno mali ies such as
os eoa h i is o calci ic endoni is and/o os eochond osis [61].
3.4. Como bidi ies and O gan Abno mali ies
Mos lipodys ophy synd omes such as FPLD2 a e cha ac e ised by he p esence o
insulin esis ance and, consequen ly, by a a iable deg ee o me abolic dys unc ion, wi h
diabe es, dyslipidaemia, a y li e disease, ca dio ascula disease, and ep oduc i e dys-
unc ion. In ac , i is known ha pa ien s wi h di e en FPLD sub ypes wi h simila uncal
mass o subjec s wi h non-FPLD obesi y ha e wo se me abolic p o iles [
62
]. In addi ion o
se e al clinical cha ac e is ics, Table 1shows he main epo ed como bidi ies o FPLD2
as well as speci ic di e en ial ea u es and como bidi ies o o he FPLD synd omes o
hei di e en ial diagnosis, aking in o accoun he g ea simila i ies o hese lipodys ophy
synd omes [63–87].
I has been epo ed ha como bidi ies in Dunnigan disease de elop a e age 10,
which is why i has been p oposed ha while clinical e iew and die e ic suppo a e
bene icial o child en wi h his diso de , o mal sc eening o o gan abno mali ies be o e
he age o 10 may no be o bene i . Howe e , his ecommenda ion has o be aken wi h
cau ion conside ing he an icipa ion phenomenon ecen ly desc ibed o his popula ion,
wi h he occu ence o me abolic complica ions such as diabe es and hype iglyce idaemia
a an ea lie age ac oss gene a ions [28,88,89].
Cells 2023,12, 725 9 o 23
Table 1.
Clinical cha ac e is ics o FPLD2 and i s di e en ial diagnosis wi h o he amilial pa ial
lipodys ophy synd omes.
FPLD2 Main Cha ac e is ics
[4–6,13–128]
Di e en ial Cha ac e is ics o o he FPLD
Synd omes
[63–87]
Gene LMNA
Unknown (FPLD1), PPARG (FPLD3), PLIN1
(FPLD4), CIDEC (FPLD5), LIPE (FPLD6), CAV1
(FPLD7), AKT2,PCYT1A,ADRA2A,MFN2.
Inhe i ance
AD (homozygous cases ha e also been desc ibed).
AR in FPLD5, FPLD6, PCYT1A- and
MFN2- ela ed FPLD
Onse o pheno ype Pube y in women, la e in men. - Bi h (FPLD7)
- Childhood-adul hood (o he FPLD).
Abno mal a dis ibu ion
- Loss o a in he limbs, unk and glu eal
egion.
- Accumula ion o a in he ace, neck, chin,
axillae, in e scapula a ea, labia majo a and
abdominal isce a.
- Less appa en in men.
- A ypical FPLD2 (non-codon 482 FPLD2):
milde pheno ype.
- FPLD1: accumula ion o abdominal a .
- FPLD3: less se e e loss o a .
- FPLD7: loss o a in he ace and uppe
body.
Clinical ea u es
- Subcu aneous lipomas.
- Muscula hype ophy, mialgias.
- Phlebomegaly.
- Signs o insulin esis ance (acan hosis
nig icans, ac ocho dons).
- Hype and ogenism.
- Hype ophy o mons pubis, “Dunnigan
sign”.
- FPLD1: KöB index > 3.477.
- FPLD3: less p ominen muscula u e, no
phlebomegaly.
- FPLD6: mul iple lipoma osis.
- FPLD7: congeni al ca a ac s, p oge oid
ea u es.
-PCYT1A- ela ed FPLD: sho s a u e,
muscula a ophy.
-MFN2- ela ed FPLD: lipoma ous masses.
Analy ical pa ame e s
- Lowe plasma lep in and adiponec in le els
han con ols, wi h no s anda dised cu -o s.
- Gene ally inc eased TNF-α, IL-1β, IL-6 and
IL-10 le els.
-MFN2- ela ed FPLD: e y low lep in
le els.
- FPLD6: ele a ed c ea ine kinase le els.
Main como bidi ies
- Insulin esis ance.
- Type 2 diabe es melli us.
- Dyslipidaemia (high iglyce ide le els, low
HDL choles e ol).
- Acu e panc ea i is.
- Hype ension.
-
Ca dio ascula disease (ca diac hype ophy,
a io en icula conduc ion de ec s, hea
ailu e, ea ly a he oscle osis, a hy hmias).
- Li e disease (NAFLD, NASH).
- Fe ili y p oblems.
- PCOS.
-
Renal disease (p o einu ia and p og ession o
enal ailu e).
- An icipa ion phenomenon (diabe es,
hype iglyce idaemia).
- FPLD3: ea lie and mo e se e e
me abolic complica ions. Ea ly
hype ension.
- FPLD6: au o- luo escen d usen-like
e inal deposi s. Muscula dys ophy in
some pa ien s.
-MFN2- ela ed FPLD: pe iphe al axonal
neu opa hy.
In o de o demons a e a comp ehensi e compa ison be ween FPLD2 and o he FPLD sub ypes, e e ences
[63–87]
, ela ed o FPLD sub ypes o he han Dunnigan disease, ha e been added in addi ion o he e ie ed
a icles om he da abase sea ch and e e ence sc eening. AD: au osomal dominan ; AR: au osomal ecessi e;
NAFLD: non-alcoholic a y li e disease; NASH: non-alcoholic s ea ohepa i is; PCOS: polycys ic o a y synd ome.
Cells 2023,12, 725 16 o 23
Da a A ailabili y S a emen :
No new da a we e c ea ed o analysed in his s udy. Da a sha ing is
no applicable o his a icle.
Acknowledgmen s: We a e indeb ed o he pa ien s o his s udy o hei collabo a ion.
Con lic s o In e es :
D.A.-V. has ecei ed hono a ia as scien i ic ad iso om Am y Pha ma. The
es o he au ho s decla e no con lic o in e es .
Re e ences
1.
B oe s, J.L.; Ramaeke s, F.C.; Bonne, G.; Yaou, R.B.; Hu chison, C.J. Nuclea lamins: Laminopa hies and hei ole in p ema u e
ageing. Physiol. Re . 2006,86, 967–1008. [C ossRe ] [PubMed]
2.
Guillín-Ama elle, C.; Fe nández-Pombo, A.; Sánchez-Iglesias, S.; A aújo-Vila , D. Lipodys ophic laminopa hies: Diagnos ic clues.
Nucleus 2018,9, 249–260. [C ossRe ] [PubMed]
3.
Cabanillas, R.; Cadiñanos, J.; Villamey ide, J.A.; Pé ez, M.; Longo, J.; Richa d, J.M.; Ál a ez, R.; Du án, N.S.; Illán, R.; González,
D.J.; e al. Nés o -Guille mo p oge ia synd ome: A no el p ema u e aging condi ion wi h ea ly onse and ch onic de elopmen
caused by BANF1 mu a ions. Am. J. Med. Gene . A 2011,155A, 2617–2625. [C ossRe ] [PubMed]
4.
Ga g, A.; Peshock, R.M.; Fleckens ein, J.L. Adipose issue dis ibu ion pa e n in pa ien s wi h amilial pa ial lipodys ophy
(Dunnigan a ie y). J. Clin. Endoc inol. Me ab. 1999,84, 170–174. [PubMed]
5.
Ga g, A. Gende di e ences in he p e alence o me abolic complica ions in amilial pa ial lipodys ophy (Dunnigan a ie y).
J. Clin. Endoc inol. Me ab. 2000,85, 1776–1782.
6.
Ga g, A.; Vinai hee han, M.; Wea he all, P.T.; Bowcock, A.M. Pheno ypic he e ogenei y in pa ien s wi h amilial pa ial lipodys-
ophy (dunnigan a ie y) ela ed o he si e o missense mu a ions in lamin a/c gene. J. Clin. Endoc inol. Me ab.
2001
,86, 59–65.
7.
Fe nández-Pombo, A.; Sánchez-Iglesias, S.; Cobelo-Gómez, S.; He mida-Ameijei as, Á.; A aújo-Vila , D. Familial pa ial lipodys-
ophy synd omes. P esse Med. 2021,50, 104071. [C ossRe ]
8.
Page, M.J.; McKenzie, J.E.; Bossuy , P.M.; Bou on, I.; Ho mann, T.C.; Mul ow, C.D.; Shamsee , L.; Te zla , J.M.; Akl, E.A.;
B ennan, S.E.; e al. The PRISMA 2020 s a emen : An upda ed guideline o epo ing sys ema ic e iews. BMJ
2021
,372, n71.
[C ossRe ]
9.
Dunnigan, M.G.; Coch ane, M.A.; Kelly, A.; Sco , J.W. Familial lipoa ophic diabe es wi h dominan ansmission. A new
synd ome. Q J. Med. 1974,43, 33–48.
10.
Chique e, E.; O al, E.A.; Ga g, A.; A aújo-Vila , D.; Dhankha , P. Es ima ing he p e alence o gene alized and pa ial lipodys o-
phy: Findings and challenges. Diabe es Me ab. Synd . Obes. 2017,10, 375–383. [C ossRe ]
11.
Flo wick, A.; Dha ma aj, T.; Ju gens, J.; Valle, D.; Wilson, K.L. LMNA Sequences o 60,706 Un ela ed Indi iduals Re eal 132
No el Missense Va ian s in A-Type Lamins and Sugges a Link be ween Va ian p.G602S and Type 2 Diabe es. F on . Gene .
2017
,
8, 79. [C ossRe ]
12.
Gonzaga-Jau egui, C.; Ge, W.; S aples, J.; Van Hou , C.; Yada , A.; Colonie, R.; Leade , J.B.; Ki chne , H.L.; Mu ay, M.F.; Reid, J.G.;
e al. Geisinge -Regene on Disco EHR collabo a ion. Clinical and Molecula P e alence o Lipodys ophy in an Unasce ained
La ge Clinical Ca e Coho . Diabe es 2020,69, 249–258. [C ossRe ]
13.
Vigou oux, C.; Mag é, J.; Van yghem, M.C.; Bou u , C.; Lascols, O.; Shackle on, S.; Lloyd, D.J.; Gue ci, B.; Pado a, G.; Valensi, P.;
e al. Lamin A/C gene: Sex-de e mined exp ession o mu a ions in Dunnigan- ype amilial pa ial lipodys ophy and absence o
coding mu a ions in congeni al and acqui ed gene alized lipoa ophy. Diabe es 2000,49, 1958–1962. [C ossRe ]
14.
Jackson, S.N.; Howle , T.A.; McNally, P.G.; O’Rahilly, S.; T emba h, R.C. Dunnigan-Kobbe ling synd ome: An au osomal
dominan o m o pa ial lipodys ophy. QJM 1997,90, 27–36. [C ossRe ]
15.
Köbbe ling, J.; Dunnigan, M.G. Familial pa ial lipodys ophy: Two ypes o an X linked dominan synd ome, le hal in he
hemizygous s a e. J. Med. Gene . 1986,23, 120–127. [C ossRe ]
16.
T eibe , G.; Flaus Fu maniuk, A.; Guilleux, A.; Medjane, S.; Bon an i, O.; Schneebeli, S.; Be na d, C.; Le-Moullec, N.; Baki i, F.;
Pholsena, M.; e al. A ecu en amilial pa ial lipodys ophy due o a monoallelic o biallelic LMNA ounde a ian highligh s
he mul i ace ed ca diac mani es a ions o me abolic laminopa hies. Eu . J. Endoc inol. 2021,185, 453–462. [C ossRe ]
17.
D ac, H.; Madej-Pila czyk, A.; Gospoda czyk-Szo , K.; Gaweł, M.; Kwieci´nski, H.; Hausmanowa-Pe usewicz, I. Familial pa ial
lipodys ophy associa ed wi h he he e ozygous LMNA mu a ion 1445G>A (A g482Gln) in a Polish amily. Neu ol. Neu ochi . Pol.
2010,44, 291–296. [C ossRe ] [PubMed]
18.
Da idson, M.B.; Young, R.T. Me abolic s udies in amilial pa ial lipodys ophy o he lowe unk and ex emi ies. Diabe ologia
1975,11, 561–568. [C ossRe ] [PubMed]
19.
Pelleg ini, C.; Columba o, M.; Schena, E.; P encipe, S.; And enacci, D.; Iozzo, P.; Angela Guzza di, M.; Capanni, C.; Ma ioli, E.;
Loi, M.; e al. Al e ed adipocy e di e en ia ion and unbalanced au ophagy in ype 2 Familial Pa ial Lipodys ophy: An
in i o
and in i o s udy o adipose issue b owning. Exp. Mol. Med. 2019,51, 1–17. [C ossRe ] [PubMed]
20.
A aújo-Vila , D.; Vic o ia, B.; González-Méndez, B.; Ba ei o, F.; Fe nández-Rod íguez, B.; Ce eijo, R.; Gallego-Escu edo, J.M.;
Villa oya, F.; Pañeda-Menéndez, A. His ological and molecula ea u es o lipoma ous and nonlipoma ous adipose issue in
amilial pa ial lipodys ophy caused by LMNA mu a ions. Clin. Endoc inol. 2012,76, 816–824. [C ossRe ]
Cells 2023,12, 725 17 o 23
21.
Spule , S.; Kalbhenn, T.; Zabojszcza, J.; an Landeghem, F.; Lud ke, A.; Wenzel, K.; Koehnlein, M.; Schuelke, M.; Ludemann, L.;
Schmid , H.H. Muscle and ne e pa hology in Dunnigan amilial pa ial lipodys ophy. Neu ology
2007
,68, 677–683. [C ossRe ]
[PubMed]
22.
Akinci, G.; Topaloglu, H.; Demi , T.; Danyeli, A.E.; Talim, B.; Keskin, F.E.; Kadioglu, P.; Talip, E.; Al ay, C.; Yaylali, G.F.; e al.
Clinical spec a o neu omuscula mani es a ions in pa ien s wi h lipodys ophy: A mul icen e s udy. Neu omuscul. Diso d.
2017
,
27, 923–930. [C ossRe ] [PubMed]
23.
Van yghem, M.C.; Pigny, P.; Mau age, C.A.; Rouaix-Eme y, N.; S ojko ic, T.; Cuisse , J.M.; Millai e, A.; Lascols, O.; Ve me sch, P.;
Wemeau, J.L.; e al. Pa ien s wi h amilial pa ial lipodys ophy o he Dunnigan ype due o a LMNA R482W mu a ion show
muscula and ca diac abno mali ies. J. Clin. Endoc inol. Me ab. 2004,89, 5337–5346. [C ossRe ] [PubMed]
24.
Bu n, J.; Ba ai se , M. Pa ial lipoa ophy wi h insulin esis an diabe es and hype lipidaemia (Dunnigan synd ome). J. Med.
Gene . 1986,23, 128–130. [C ossRe ]
25.
Mo el, C.F.; Thomas, M.A.; Cao, H.; O’Neil, C.H.; Picke ing, J.G.; Foulkes, W.D.; Hegele, R.A. A LMNA splicing mu a ion in wo
sis e s wi h se e e Dunnigan- ype amilial pa ial lipodys ophy ype 2. J. Clin. Endoc inol. Me ab.
2006
,91, 2689–2695. [C ossRe ]
26.
Vaidya, R.A.; Vaidya, A.D.B.; Talwalka , S.C.; Meh alia, S.D.; Sh ingi, M.S.; Pandey, S.N.; Shah, S.J.; Godse, C.; Joshi, J.V.; She h, J.;
e al. Clinical, endoc ine and me abolic s udies in he kind ed o amilial pa ial lipodys ophy–a synd ome o insulin esis ance.
J. Assoc. Physicians India 2002,50, 773–776.
27.
Schmid , H.H.; Genschel, J.; Baie , P.; Schmid , M.; Ockenga, J.; Tie ge, U.J.; P ops ing, M.; Bu ne , C.; Manns, M.P.; Lochs, H.;
e al. Dyslipemia in amilial pa ial lipodys ophy caused by an R482W mu a ion in he LMNA gene. J. Clin. Endoc inol. Me ab.
2001,86, 2289–2295. [C ossRe ]
28.
Pa ni, N.; Li, X.; Adams-Hue , B.; Vasandani, C.; Gomez-Diaz, R.A.; Ga g, A. Regional Body Fa Changes and Me abolic
Complica ions in Child en Wi h Dunnigan Lipodys ophy-Causing LMNA Va ian s. J. Clin. Endoc inol. Me ab.
2019
,104,
1099–1108. [C ossRe ]
29.
Hegele, R.A.; Cao, H.; Ande son, C.M.; H amiak, I.M. He e ogenei y o nuclea lamin A mu a ions in Dunnigan- ype amilial
pa ial lipodys ophy. J. Clin. Endoc inol. Me ab. 2000,85, 3431–3435.
30.
Resende, A.T.P.; Ma ins, C.S.; Bueno, A.C.; Mo ei a, A.C.; Foss-F ei as, M.C.; de Cas o, M. Pheno ypic di e si y and glucoco i-
coid sensi i i y in pa ien s wi h amilial pa ial lipodys ophy ype 2. Clin. Endoc inol. 2019,91, 94–103. [C ossRe ]
31.
So kina, E.L.; Kalashniko a, M.F.; Melnichenko, G.A.; Tyulpako , A.N. [Familial pa ial lipodys ophy (Dunnigan synd ome) due
o LMNA gene mu a ion: The i s desc ip ion o i s clinical case in Russia]. Te A kh 2015,87, 83–87. [C ossRe ]
32.
A aújo-Vila , D.; Fe nández-Pombo, A.; Vic o ia, B.; Mosque a-O guei a, A.; Cobelo-Gómez, S.; Cas o-Pais, A.; He mida-
Ameijei as, A.; Loidi, L.; Sanchez-Iglesias, S. Va iable Exp essi i y and Allelic He e ogenei y in Type 2 Familial Pa ial Lipodys-
ophy: The p.(Th 528Me ) LMNA Va ian . J. Clin. Med. 2021,10, 1497. [C ossRe ]
33.
Mo y, P.B.; C ispim, F.; F ei e, M.B.; Salles, J.E.; Valé io, C.M.; Godoy-Ma os, A.F.; Dib, S.A. Pheno ypic di e si y in pa ien s wi h
lipodys ophy associa ed wi h LMNA mu a ions. Eu . J. Endoc inol. 2012,167, 423–431. [C ossRe ]
34.
Mon eneg o, R.M., J .; Cos a-Rique o, A.D.; Fe nandes, V.O.; Mon eneg o, A.P.D.R.; de San ana, L.S.; Jo ge, A.A.L.; Ka bage,
L.B.A.S.; Aguia , L.B.; Ca alho, F.H.C.; Teles, M.G.; e al. Homozygous and He e ozygous Nuclea Lamin A p.R582C Mu a ion:
Di e en Lipodys ophic Pheno ypes in he Same Kind ed. F on . Endoc inol. 2018,9, 458. [C ossRe ]
35.
Muschke, P.; Kölsch, U.; Jakubiczka, S.; Wieland, I.; B une, T.; Wieacke , P. The he e ozygous LMNA mu a ion p.R471G causes a
a iable pheno ype wi h ea u es o wo ypes o amilial pa ial lipodys ophy. Am. J. Med. Gene . A.
2007
,143A, 2810–2814.
[PubMed]
36.
Akinci, B.; Onay, H.; Demi , T.; Sa as-E de e, ¸S.; Gen, R.; Simsi , I.Y.; Keskin, F.E.; E ü k, M.S.; Uzum, A.K.; Yaylali, G.F.; e al.
Clinical p esen a ions, me abolic abno mali ies and end-o gan complica ions in pa ien s wi h amilial pa ial lipodys ophy.
Me abolism 2017,72, 109–119. [C ossRe ] [PubMed]
37.
Decaudain, A.; Van yghem, M.C.; Gue ci, B.; Héca , A.C.; Auclai , M.; Reznik, Y.; Na bonne, H.; Ducluzeau, P.H.; Donadille, B.;
Lebbe, C.; e al. New me abolic pheno ypes in laminopa hies: LMNA mu a ions in pa ien s wi h se e e me abolic synd ome.
J. Clin. Endoc inol. Me ab. 2007,92, 4835–4844. [C ossRe ] [PubMed]
38.
de And ade, N.X.S.; Adiyaman, S.C.; Yuksel, B.D.; Fe a i, C.T.; Eldin, A.J.; Saydam, B.O.; Al ay, C.; Sha ma, P.; Bha e, N.; Li le,
A.; e al. Unusual p esen a ions o LMNA-associa ed lipodys ophy wi h complex pheno ypes and gene alized a loss: When he
gene ic diagnosis unco e s no el ea u es. AACE Clin. Case Rep. 2020,6, e79–e85. [C ossRe ]
39.
McLaughlin, P.D.; Ryan, J.; Hodne , P.A.; O’Hallo an, D.; Mahe , M.M. Quan i a i e whole-body MRI in amilial pa ial
lipodys ophy ype 2: Changes in adipose issue dis ibu ion coincide wi h biochemical imp o emen . AJR Am. J. Roen genol.
2012,199, W602–W606. [C ossRe ]
40.
Mon ei o, L.Z.; Foss-F ei as, M.C.; Júnio Mon eneg o, R.M.; Foss, M.C. Body a dis ibu ion in women wi h amilial pa ial
lipodys ophy caused by mu a ion in he lamin A/C gene. Indian J. Endoc inol. Me ab. 2012,16, 136–138. [C ossRe ]
41.
Godoy-Ma os, A.F.; Vale io, C.M.; Mo ei a, R.O.; Momesso, D.P.; Bi encou , L.K. Panc ea ic a deposi ion is inc eased and
ela ed o be a-cell unc ion in women wi h amilial pa ial lipodys ophy. Diabe ol. Me ab. Synd .
2018
,10, 71. [C ossRe ]
[PubMed]
42.
Bensmaïne, F.; Benoma , K.; Espia d, S.; Vahe, C.; Le Mapihan, K.; Lion, G.; Lemdani, M.; Chaza d, E.; E ns , O.; Vigou oux, C.;
e al. I isin le els in LMNA-associa ed pa ial lipodys ophies. Diabe es Me ab. 2019,45, 67–75. [C ossRe ]
Cells 2023,12, 725 18 o 23
43.
Ajluni, N.; Me al, R.; Neide , A.H.; B ady, G.F.; Bu as, E.; McKenna, B.; DiPaola, F.; Chene e , T.L.; Ho owi z, J.F.;
Buggs-Sax on, C.
; e al. Spec um o disease associa ed wi h pa ial lipodys ophy: Lessons om a ial coho . Clin. Endoc inol.
2017,86, 698–707. [C ossRe ] [PubMed]
44.
Al-A a , S.A.; Pollex, R.L.; Robinson, J.F.; A Miskie, B.; Walca ius, R.; Li le, C.H.; Ru , B.K.; Hegele, R.A. Quan i a i e and
quali a i e di e ences in subcu aneous adipose issue s o es ac oss lipodys ophy ypes shown by magne ic esonance imaging.
BMC. Med. Imaging 2007,7, 3. [C ossRe ] [PubMed]
45.
Joy, T.; Kennedy, B.A.; Al-A a , S.; Ru , B.K.; Hegele, R.A. P edic ing abdominal adipose issue among women wi h amilial
pa ial lipodys ophy. Me abolism 2009,58, 828–834. [C ossRe ] [PubMed]
46.
Al ay, C.; Secil, M.; Demi , T.; A ik, T.; Akinci, G.; Ku bay, N.O.; Temeloglu, E.K.; Simsi , I.Y.; Ozisik, S.; Demi , L.; e al.
De e mining esidual adipose issue cha ac e is ics wi h MRI in pa ien s wi h a ious sub ypes o lipodys ophy. Diagn. In e .
Radiol. 2017,23, 428–434. [C ossRe ]
47.
Vasandani, C.; Li, X.; Sekizka des, H.; B own, R.J.; Ga g, A. Pheno ypic Di e ences Among Familial Pa ial Lipodys ophy Due o
LMNA o PPARG Va ian s. J. Endoc . Soc. 2022,6, b ac155. [C ossRe ]
48.
Al-A a , S.A.; Pollex, R.L.; Robinson, J.F.; A Miskie, B.; Walca ius, R.; Ru , B.K.; Hegele, R.A. Semi-au oma ed segmen a ion and
quan i ica ion o adipose issue in cal and high by MRI: A p elimina y s udy in pa ien s wi h monogenic me abolic synd ome.
BMC. Med. Imaging 2006,6, 11. [C ossRe ]
49.
Demi , T.; Onay, H.; Sa age, D.B.; Temeloglu, E.; Uzum, A.K.; Kadioglu, P.; Al ay, C.; Ozen, S.; Demi , L.; Ca da , U.; e al. Familial
pa ial lipodys ophy linked o a no el pe oxisome p oli e a o ac i a o ecep o -
γ
(PPARG) mu a ion, H449L: A compa ison o
people wi h his mu a ion and hose wi h classic codon 482 Lamin A/C (LMNA) mu a ions. Diabe . Med.
2016
,33, 1445–1450.
[C ossRe ]
50.
Vasandani, C.; Li, X.; Sekizka des, H.; Adams-Hue , B.; B own, R.J.; Ga g, A. Diagnos ic Value o An h opome ic Measu emen s
o Familial Pa ial Lipodys ophy, Dunnigan Va ie y. J. Clin. Endoc inol. Me ab. 2020,105, 2132–2141. [C ossRe ]
51.
Vale io, C.M.; Zajden e g, L.; de Oli ei a, J.E.; Mo y, P.B.; Moyses, R.S.; Godoy-Ma os, A.F. Body composi ion s udy by dual-
ene gy x- ay abso p iome y in amilial pa ial lipodys ophy: Finding new ools o an objec i e e alua ion. Diabe ol. Me ab.
Synd . 2012,4, 40. [C ossRe ] [PubMed]
52.
Godoy-Ma os, A.F.; Mo ei a, R.O.; Vale io, C.M.; Mo y, P.B.; Moises, R.S. A new me hod o body a e alua ion, body adiposi y
index, is use ul in women wi h amilial pa ial lipodys ophy. Obesi y 2012,20, 440–443. [C ossRe ] [PubMed]
53.
Me al, R.; Ryan, B.J.; Maland ino, N.; Jalal, A.; Neide , A.H.; Muniyappa, R.; Akıncı, B.; Ho owi z, J.F.; B own, R.J.; O al, E.A.
“Fa Shadows” F om DXA o he Quali a i e Assessmen o Lipodys ophy: When a Pic u e Is Wo h a Thousand Numbe s.
Diabe es Ca e 2018,41, 2255–2258. [C ossRe ] [PubMed]
54.
Ji, H.; Wea he all, P.; Adams-Hue , B.; Ga g, A. Inc eased skele al muscle olume in women wi h amilial pa ial lipodys ophy,
Dunnigan a ie y. J. Clin. Endoc inol. Me ab. 2013,98, E1410–E1413. [C ossRe ]
55.
Simha, V.; Lanza, I.R.; Dasa i, S.; Klaus, K.A.; Le B asseu , N.; Vucko ic, I.; Lau en i, M.C.; Cobelli, C.; Po , J.D.; Nai , K.S.
Impai ed Muscle Mi ochond ial Func ion in Familial Pa ial Lipodys ophy. J. Clin. Endoc inol. Me ab.
2022
,107, 346–362.
[C ossRe ]
56.
Hennekam, R.C. Hu chinson-Gil o d p oge ia synd ome: Re iew o he pheno ype. Am. J. Med. Gene . A.
2006
,140, 2603–2624.
[C ossRe ]
57.
Kosho, T.; Takahashi, J.; Momose, T.; Nakamu a, A.; Saku ai, A.; Wada, T.; Yoshida, K.; Wakui, K.; Suzuki, T.; Kasuga, K.; e al.
Mandibuloac al dysplasia and a no el LMNA mu a ion in a woman wi h se e e p og essi e skele al changes. Am. J. Med. Gene .
A. 2007,143A, 2598–2603. [C ossRe ]
58.
Cunningham, V.J.; D’Apice, M.R.; Lica a, N.; No elli, G.; Cundy, T. Skele al pheno ype o mandibuloac al dysplasia associa ed
wi h mu a ions in ZMPSTE24. Bone 2010,47, 591–597. [C ossRe ]
59.
Mo egi, S.; Yokoyama, Y.; Uchiyama, A.; Ogino, S.; Takeuchi, Y.; Yamada, K.; Ha o i, T.; Hashizume, H.; Ishikawa, Y.;
Go o, M.
;
e al. Fi s Japanese case o a ypical p oge oid synd ome/a ypical We ne synd ome wi h he e ozygous LMNA mu a ion.
J. De ma ol. 2014,41, 1047–1052. [C ossRe ]
60.
Fe nandez-Pombo, A.; Ossandon-O e o, J.A.; Guillín-Ama elle, C.; Sánchez-Iglesias, S.; Cas o, A.I.; González-Méndez, B.;
Rod íguez-Ga cía, S.; Rod iguez-Cañe e, L.; Casanue a, F.F.; A aújo-Vila , D. Bone mine al densi y in amilial pa ial lipodys o-
phy. Clin. Endoc inol. 2018,88, 44–50. [C ossRe ]
61.
Teboul-Co é, S.; Rey-Jou in, C.; Miquel, A.; Va ie , C.; Capeau, J.; Robe , J.-J.; Pham, T.; Lascols, O.; Be enbaum, F.; La edo, J.-D.;
e al. Bone imaging indings in gene ic and acqui ed lipodys ophic synd omes: An imaging s udy o 24 cases. Skele al. Radiol.
2016,45, 1495–1506. [C ossRe ] [PubMed]
62.
Koo, E.; Foss-F ei as, M.C.; Me al, R.; Oze , M.; Eldin, A.J.; Akinci, B.; Mille , N.; Ro hbe g, A.E.; O al, E.A. The Me abolic
Equi alen BMI in Pa ien s wi h Familial Pa ial Lipodys ophy (FPLD) Compa ed wi h Those wi h Se e e Obesi y. Obesi y
2021
,
29, 274–278. [C ossRe ]
63.
Guillín-Ama elle, C.; Sánchez-Iglesias, S.; Cas o-Pais, A.; Rod iguez-Cañe e, L.; O dóñez-Mayán, L.; Pazos, M.;
González-Méndez, B.
;
Rod íguez-Ga cía, S.; Casanue a, F.F.; Fe nández-Ma miesse, A.; e al. Type 1 amilial pa ial lipodys ophy: Unde s anding he
Köbbe ling synd ome. Endoc ine 2016,54, 411–421. [C ossRe ] [PubMed]
64.
He bs , K.L.; Tannock, L.R.; Deeb, S.S.; Pu nell, J.Q.; B unzell, J.D.; Chai , A. Köbbe ling ype o amilial pa ial lipodys ophy: An
unde ecognized synd ome. Diabe es Ca e 2003,26, 1819–1824. [C ossRe ] [PubMed]
Cells 2023,12, 725 19 o 23
65.
Al-Shali, K.; Cao, H.; Knoe s, N.; He mus, A.R.; Tack, C.J.; Hegele, R.A. A single-base mu a ion in he pe oxisome p oli e a o -
ac i a ed ecep o gamma4 p omo e associa ed wi h al e ed
in i o
exp ession and pa ial lipodys ophy. J. Clin. Endoc inol.
Me ab. 2004,89, 5655–5660. [C ossRe ]
66.
Hegele, R.A.; U , E.; Ransom, T.P.; Cao, H. A ameshi mu a ion in pe oxisome-p oli e a o -ac i a ed ecep o -gamma in amilial
pa ial lipodys ophy sub ype 3 (FPLD3; MIM 604367). Clin. Gene . 2006,70, 360–362. [C ossRe ]
67.
F ancis, G.A.; Li, G.; Casey, R.; Wang, J.; Cao, H.; Le , T.; Hegele, R.A. Pe oxisomal p oli e a o ac i a ed ecep o -gamma
de iciency in a Canadian kind ed wi h amilial pa ial lipodys ophy ype 3 (FPLD3). BMC Med. Gene . 2006,7, 3. [C ossRe ]
68.
Auclai , M.; Vigou oux, C.; Bocca a, F.; Capel, E.; Vige al, C.; Gue ci, B.; Lascols, O.; Capeau, J.; Ca on-Deba le, M. Pe oxisome
p oli e a o -ac i a ed ecep o -
γ
mu a ions esponsible o lipodys ophy wi h se e e hype ension ac i a e he cellula enin-
angio ensin sys em. A e ioscle . Th omb. Vasc. Biol. 2013,33, 829–838. [C ossRe ]
69.
Semple, R.K.; Cha e jee, V.K.; O’Rahilly, S. PPAR gamma and human me abolic disease. J. Clin. In es ig.
2006
,116, 581–589.
[C ossRe ]
70.
Gando a, S.; Le Dou , C.; Bo omley, W.; Ce e a, P.; Gi al, P.; Reznik, Y.; Cha pen ie , G.; Auclai , M.; Delépine, M.; Ba oso, I.;
e al. Pe ilipin de iciency and au osomal dominan pa ial lipodys ophy. N. Engl. J. Med. 2011,364, 740–748. [C ossRe ]
71.
Kozusko, K.; Tsang, V.; Bo omley, W.; Cho, Y.H.; Gando a, S.; Mimmack, M.L.; Lim, K.; Isaac, I.; Pa el, S.; Saudek, V.; e al. Clinical
and molecula cha ac e iza ion o a no el PLIN1 ameshi mu a ion iden i ied in pa ien s wi h amilial pa ial lipodys ophy.
Diabe es 2015,64, 299–310. [C ossRe ] [PubMed]
72.
La e , T.W.; Pa el, K.A.; Colclough, K.; Cu an, J.; Dale, J.; Da is, N.; Sa age, D.B.; Flanagan, S.E.; Ella d, S.; Ha e sley, A.T.; e al.
PLIN1 Haploinsu iciency Is No Associa ed Wi h Lipodys ophy. J. Clin. Endoc inol. Me ab.
2018
,103, 3225–3230. [C ossRe ]
[PubMed]
73.
Jé u, I.; Van yghem, M.C.; Bismu h, E.; Ce e a, P.; Ba aud, S.; PLIN1-S udy G oup; Auclai , M.; Va ie , C.; Lascols, O.; Sa age,
D.B.; e al. Diagnos ic Challenge in PLIN1-Associa ed Familial Pa ial Lipodys ophy. J. Clin. Endoc inol. Me ab.
2019
,104,
6025–6032. [C ossRe ] [PubMed]
74.
Rubio-Cabezas, O.; Pu i, V.; Mu ano, I.; Saudek, V.; Semple, R.K.; Dash, S.; Hyden, C.S.S.; Bo omley, W.; Vigou oux, C.; Mag é, J.;
e al. Pa ial lipodys ophy and insulin esis an diabe es in a pa ien wi h a homozygous nonsense mu a ion in CIDEC. EMBO
Mol. Med. 2009,1, 280–287. [C ossRe ] [PubMed]
75.
Fa han, S.M.; Robinson, J.F.; McIn y e, A.D.; Ma osu, M.G.; Ticca, A.F.; Loddo, S.; Ca boni, N.; B anca i, F.; Hegele, R.A. A no el
LIPE nonsense mu a ion ound using exome sequencing in siblings wi h la e-onse amilial pa ial lipodys ophy. Can. J. Ca diol.
2014,30, 1649–1654. [C ossRe ] [PubMed]
76.
Ca boni, N.; B anca i, F.; Cocco, E.; Solla, E.; D’Apice, M.R.; Ma eddu, A.; McIn y e, A.; Fadda, E.; Mu a, M.; La anzi, G.; e al. A
pa ial lipodys ophy associa ed wi h muscula dys ophy o unknown gene ic o igin. Muscle Ne e
2014
,49, 928–930. [C ossRe ]
77.
Zolo o , S.; Xing, C.; Mahamid, R.; Shala a, A.; Sheikh-Ahmad, M.; Ga g, A. Homozygous LIPE mu a ion in siblings wi h mul iple
symme ic lipoma osis, pa ial lipodys ophy, and myopa hy. Am. J. Med. Gene . A. 2017,173, 190–194. [C ossRe ]
78.
Sollie , C.; Capel, E.; Aguilhon, C.; Smi no , V.; Auclai , M.; Douilla d, C.; Ladsous, M.; De oo -Dhellemmes, S.; Go wood, J.;
B aud, L.; e al. LIPE- ela ed lipodys ophic synd ome: Clinical ea u es and disease modeling using adipose s em cells. Eu . J.
Endoc inol. 2021,184, 155–168. [C ossRe ]
79.
Be ge , J.R.; O al, E.A.; Taylo , S.I. Familial lipodys ophy associa ed wi h neu odegene a ion and congeni al ca a ac s. Neu ology
2002,58, 43–47. [C ossRe ]
80.
Ga g, A.; Ki che , M.; Del Campo, M.; Ama o, R.S.; Aga wal, A.K.; Uni e si y o Washing on Cen e o Mendelian Genomics.
Whole exome sequencing iden i ies de no o he e ozygous CAV1 mu a ions associa ed wi h a no el neona al onse lipodys ophy
synd ome. Am. J. Med. Gene . A. 2015,167A, 1796–1806. [PubMed]
81.
Shea in, A.L.; Monks, B.R.; Seale, P.; Bi nbaum, M.J. Lack o AKT in adipocy es causes se e e lipodys ophy. Mol. Me ab.
2016
,
5, 472–479. [C ossRe ] [PubMed]
82.
Geo ge, S.; Roch o d, J.J.; Wol um, C.; G ay, S.L.; Schinne , S.; Wilson, J.C.; Soos, M.A.; Mu ga oyd, P.R.; Williams, R.M.;
Ace ini, C.L.; e al. A amily wi h se e e insulin esis ance and diabe es due o a mu a ion in AKT2. Science
2004
,304, 1325–1328.
[C ossRe ] [PubMed]
83.
Payne, F.; Lim, K.; Gi ousse, A.; B own, R.J.; Ko y, N.; Robbins, A.; Xue, Y.; Sleigh, A.; Coch an, E.; Adams, C.; e al. Mu a ions
dis up ing he Kennedy phospha idylcholine pa hway in humans wi h congeni al lipodys ophy and a y li e disease. P oc.
Na l. Acad. Sci. USA 2014,111, 8901–8906. [C ossRe ]
84.
Ga g, A.; Sankella, S.; Xing, C.; Aga wal, A.K. Whole-exome sequencing iden i ies ADRA2A mu a ion in a ypical amilial pa ial
lipodys ophy. JCI Insigh 2016,1, e86870. [C ossRe ]
85.
Rocha, N.; Bulge , D.A.; F on ini, A.; Ti he adge, H.; G ibshol , S.B.; Knox, R.; Page, M.; Ha is, J.; Payne, F.; Adams, C.; e al.
Human biallelic MFN2 mu a ions induce mi ochond ial dys unc ion, uppe body adipose hype plasia, and supp ession o lep in
exp ession. Eli e 2017,6, e23813. [C ossRe ]
86.
Sawye , S.L.; Cheuk-Him Ng, A.; Innes, A.M.; Wagne , J.D.; Dymen , D.A.; Te eaul , M.; Conso ium, C.R.C.; Majewski, J.;
Boyco , K.M.; Sc ea on, R.A.; e al. Homozygous mu a ions in MFN2 cause mul iple symme ic lipoma osis associa ed wi h
neu opa hy. Hum. Mol. Gene . 2015,24, 5109–5114. [C ossRe ]
87.
Capel, E.; Va ie , C.; Ce e a, P.; S ojko ic, T.; Disse, E.; Co e eau, A.-S.; Auclai , M.; Ve pon , M.-C.; Mosbah, H.; Gou dy, P.; e al.
MFN2-associa ed lipoma osis: Clinical spec um and impac on adipose issue. J. Clin. Lipidol. 2018,12, 1420–1435. [C ossRe ]
Cells 2023,12, 725 20 o 23
88.
Zhong, Z.X.; Ha is, J.; Wilbe , E.; Go man, S.; Sa age, D.B.; O’Rahilly, S.; S ea s, A.; Williams, R.M. Desc ibing he na u al his o y
o clinical, biochemical and adiological ou comes o child en wi h amilial pa ial lipodys ophy ype 2 (FPLD2) om he Uni ed
Kingdom: A e ospec i e case se ies. Clin. Endoc inol. 2022,97, 755–762. [C ossRe ]
89.
Je u, I.; Va ie , C.; Van yghem, M.C.; Lascols, O.; Vigou oux, C. LMNA-associa ed pa ial lipodys ophy: An icipa ion o me abolic
complica ions. J. Med. Gene . 2017,54, 413–416. [C ossRe ]
90.
Wong, S.P.; Huda, M.; English, P.; Ba gio a, A.; Wilding, J.P.; Co all, R.; Pinkney, J.H. Adipokines and he insulin esis ance
synd ome in amilial pa ial lipodys ophy caused by a mu a ion in lamin A/C. Diabe ologia 2005,48, 2641–2649. [C ossRe ]
91.
Hegele, R.A.; Cao, H.; Hu , M.W.; Ande son, C.M. LMNA R482Q mu a ion in pa ial lipodys ophy associa ed wi h educed
plasma lep in concen a ion. J. Clin. Endoc inol. Me ab. 2000,85, 3089–3093.
92.
Hegele, R.A.; K aw, M.E.; Ban, M.R.; Miskie, B.A.; Hu , M.W.; Cao, H. Ele a ed se um C- eac i e p o ein and ee a y
acids among nondiabe ic ca ie s o missense mu a ions in he gene encoding lamin A/C (LMNA) wi h pa ial lipodys ophy.
A e ioscle . Th omb. Vasc. Biol. 2003,23, 111–116. [C ossRe ]
93.
Haque, W.A.; Shimomu a, I.; Ma suzawa, Y.; Ga g, A. Se um adiponec in and lep in le els in pa ien s wi h lipodys ophies.
J. Clin. Endoc inol. Me ab. 2002,87, 2395. [C ossRe ]
94.
T eibe , G.; Guilleux, A.; Huynh, K.; Bon an i, O.; Flaus–Fu maniuk, A.; Cou e , D.; Melle , N.; Be na d, C.; Le-Moullec, N.; Do ay,
B.; e al. Lipoa ophic diabe es in amilial pa ial lipodys ophy ype 2: F om insulin esis ance o diabe es. Diabe es Me ab.
2022
,
49, 101409. [C ossRe ]
95.
Foss-F ei as, M.C.; Fe az, R.C.; Mon ei o, L.Z.; Gomes, P.M.; Iwaku a, R.; de F ei as, L.C.C.; Foss, M.C. Endoplasmic e iculum
s ess ac i a ion in adipose issue induces me abolic synd ome in indi iduals wi h amilial pa ial lipodys ophy o he Dunnigan
ype. Diabe ol. Me ab. Synd . 2018,10, 6. [C ossRe ] [PubMed]
96.
Godoy-Ma os, A.F.; Mo ei a, R.O.; MacDowell, R.; Bende , I.; Mo y, P.B.; Moises, R.S. Se um e inol binding p o ein 4 in pa ien s
wi h amilial pa ial lipodys ophy. Clin. Biochem. 2009,42, 1183–1186. [C ossRe ] [PubMed]
97.
Boschmann, M.; Engeli, S.; Mo o, C.; Lued ke, A.; Adams, F.; Go zelniak, K.; Rahn, G.; Mähle , A.; Dobbe s ein, K.; K uge , A.;
e al. LMNA mu a ions, skele al muscle lipid me abolism, and insulin esis ance. J. Clin. Endoc inol. Me ab.
2010
,95, 1634–1643.
[C ossRe ] [PubMed]
98.
A aujo-Vila , D.; La anzi, G.; Gonzalez-Mendez, B.; Cos a-F ei as, A.T.; P ie o, D.; Columba o, M.; Ma ioli, E.;
Vic o ia, B.;
Ma inez-Sanchez, N.; Ramazano a, A.; e al. Si e-dependen di e ences in bo h p elamin A and adipogenic genes in subcu a-
neous adipose issue o pa ien s wi h ype 2 amilial pa ial lipodys ophy. J. Med. Gene . 2009,46, 40–48. [C ossRe ]
99.
UU sich, M.J.; Fukui, R.T.; Gal ão, M.S.; Ma condes, J.A.; San omau o, A.T.; Sil a, M.E.; Rocha, D.M.; Wajchenbe g, B.L. Insulin
esis ance in limb and unk pa ial lipodys ophy ( ype 2 Köbbe ling-Dunnigan synd ome). Me abolism
1997
,46, 159–163.
[C ossRe ]
100.
A aújo-Vila , D.; Loidi, L.; Domínguez, F.; Cabezas-Ce a o, J. Pheno ypic gende di e ences in subjec s wi h amilial pa ial
lipodys ophy (Dunnigan a ie y) due o a nuclea lamin A/C R482W mu a ion. Ho m. Me ab. Res. 2003,35, 29–35. [C ossRe ]
101.
Haque, W.A.; O al, E.A.; Die z, K.; Bowcock, A.M.; Aga wal, A.K.; Ga g, A. Risk ac o s o diabe es in amilial pa ial
lipodys ophy, Dunnigan a ie y. Diabe es Ca e 2003,26, 1350–1355. [C ossRe ]
102.
Cao, H.; Hegele, R.A. Nuclea lamin A/C R482Q mu a ion in canadian kind eds wi h Dunnigan- ype amilial pa ial lipodys o-
phy. Hum. Mol. Gene . 2000,9, 109–112. [C ossRe ]
103.
Caldas, D.; Sil a Júnio , W.S.; Simone i, J.P.; Cos a, E.V.; Fa ias, M.L. Biochemical, ho monal and gene ic e alua ion o he amilies
o wo B azilian pa ien s wi h ype 2 amilial pa ial lipodys ophy. A q. B as. Endoc inol. Me abol.
2013
,57, 583–593. [C ossRe ]
[PubMed]
104.
Laza e, J.; Wang, J.; McIn y e, A.D.; Hegele, R.A. P e alence o se e e hype iglyce idemia and panc ea i is in amilial pa ial
lipodys ophy ype 2. J. Clin. Lipidol. 2021,15, 653–657. [C ossRe ]
105.
Lud ke, A.; Genschel, J.; B aban , G.; Baudi z, J.; Taupi z, M.; Koch, M.; We mke, W.; Wo man, H.J.; Schmid , H.H.-J. Hepa ic
s ea osis in Dunnigan- ype amilial pa ial lipodys ophy. Am. J. Gas oen e ol. 2005,100, 2218–2224. [C ossRe ]
106.
Speckman, R.A.; Ga g, A.; Du, F.; Benne , L.; Veile, R.; A ioglu, E.; Taylo , S.I.; Lo e , M.; Bowcock, A.M. Mu a ional and
haplo ype analyses o amilies wi h amilial pa ial lipodys ophy (Dunnigan a ie y) e eal ecu en missense mu a ions in he
globula C- e minal domain o lamin A/C. Am. J. Hum. Gene . 2000,66, 1192–1198. [C ossRe ]
107.
Ku bay, N.O.; Yu ekli, B.S.; Onay, H.; Al ay, C.T.; A ik, T.; Hekimsoy, Z.; Saygili, F.; Akinci, B. A case o amilial pa ial
lipodys ophy caused by a no el lamin A/C (LMNA) mu a ion in exon 1 (D47N). Eu . J. In e n. Med.
2016
,29, 37–39. [C ossRe ]
108.
Haque, W.A.; Vui ch, F.; Ga g, A. Pos -mo em indings in amilial pa ial lipodys ophy, Dunnigan a ie y. Diabe es Med.
2002
,
19, 1022–1025. [C ossRe ] [PubMed]
109. Nab dalik, K.; S ózik, A.; Minkina-P˛ed as, M.; Ja osz-Chobo , P.; Młyna ski, W.; G zeszczak, W.; Gump ech , J. Dunnigan- ype
amilial pa ial lipodys ophy associa ed wi h he he e ozygous R482W mu a ion in LMNA gene—Case s udy o h ee women
om one amily. Endok ynol. Pol. 2013,64, 306–311. [C ossRe ] [PubMed]
110.
A aújo-Vila , D.; Sánchez-Iglesias, S.; Cas o, A.; Cobelo-Gómez, S.; He mida-Ameijei as, A.; Rod íguez-Ca ne o, G.; Casanue a,
F.; Fe nández-Pombo, A. Va iable Exp essi i y in Type 2 Familial Pa ial Lipodys ophy Rela ed o R482 and N466 Va ian s in he
LMNA Gene. J. Clin. Med. 2021,10, 1259. [C ossRe ]
Cells 2023,12, 725 21 o 23
111.
A aújo-Vila , D.; Lado-Abeal, J.; Palos-Paz, F.; La anzi, G.; Bandín, M.A.; Bellido, D.; Domínguez-Ge pe, L.; Cal o, C.; Pé ez, O.;
Ramazano a, A.; e al. A no el pheno ypic exp ession associa ed wi h a new mu a ion in LMNA gene, cha ac e ized by pa ial
lipodys ophy, insulin esis ance, ao ic s enosis and hype ophic ca diomyopa hy. Clin. Endoc inol.
2008
,69, 61–68. [C ossRe ]
112.
Ga g, A.; Speckman, R.A.; Bowcock, A.M. Mul isys em dys ophy synd ome due o no el missense mu a ions in he amino-
e minal head and alpha-helical od domains o he lamin A/C gene. Am. J. Med. 2002,112, 549–555. [C ossRe ]
113.
Sub amanyam, L.; Simha, V.; Ga g, A. O e lapping synd ome wi h amilial pa ial lipodys ophy, Dunnigan a ie y and
ca diomyopa hy due o amino- e minal he e ozygous missense lamin A/C mu a ions. Clin. Gene .
2010
,78, 66–73. [C ossRe ]
[PubMed]
114.
Bidaul , G.; Ga cia, M.; Van yghem, M.-C.; Ducluzeau, P.-H.; Mo ichon, R.; Thiyaga ajah, K.; Mo i z, S.; Capeau, J.;
Vigou oux, C
.;
Bé ézia , V. Lipodys ophy-linked LMNA p.R482W mu a ion induces clinical ea ly a he oscle osis and
in i o
endo helial
dys unc ion. A e ioscle . Th omb. Vasc. Biol. 2013,33, 2162–2171. [C ossRe ]
115.
Hegele, R.A. P ema u e a he oscle osis associa ed wi h monogenic insulin esis ance. Ci cula ion
2001
,103, 2225–2229. [C ossRe ]
116.
We e ings, A.A.; an Rijsingen, I.A.; Plomp, A.S.; Zwinde man, A.H.; Lekanne Dep ez, R.H.; Mannens, M.M.; an den Be gh Wee -
man, M.A.; an de Wal, A.C.; Pin o-Sie sma, S.J. A no el lamin A/C mu a ion in a Du ch amily wi h p ema u e a he oscle osis.
A he oscle osis 2013,229, 169–173. [C ossRe ] [PubMed]
117.
Eldin, A.J.; Akinci, B.; da Rocha, A.M.; Me al, R.; Simsi , I.Y.; Adiyaman, S.C.; Ozpeli , E.; Bha e, N.; Gen, R.; Yu ekli, B.; e al.
Ca diac pheno ype in amilial pa ial lipodys ophy. Clin. Endoc inol. 2021,94, 1043–1053. [C ossRe ]
118.
Godoy-Ma os, A.F.; Valé io, C.M.; B agança, J.B.; Oli ei a Rde, A.; Zagu y, R.L.; Lus osa Rde, P.; Cama go, G.C.;
Nascimen o, C.A.
;
Mo ei a, R.O. E alua ion o epica dial adipose issue in amilial pa ial lipodys ophy. Diabe ol. Me ab. Synd .
2015
,7, 29.
[C ossRe ]
119.
Kwapich, M.; Lac oix, D.; Espia d, S.; Ninni, S.; B igadeau, F.; Kouakam, C.; Deg oo e, P.; Lau en , J.M.; Ti eau, V.; Jannin, A.; e al.
Diameno d–AEDNL Wo king G oup. Ca diome abolic assessmen o lamin A/C gene mu a ion ca ie s: A pheno ype-geno ype
co ela ion. Diabe es Me ab. 2019,45, 382–389. [C ossRe ] [PubMed]
120.
And e, P.; Schneebeli, S.; Vigou oux, C.; Lascols, O.; Schaa , M.; Che alie , P. Me abolic and ca diac pheno ype cha ac e iza ion in
37 a ypical Dunnigan pa ien s wi h non a nesyla ed mu a ed p elamin A. Am. Hea J. 2015,169, 587–593. [C ossRe ]
121.
Van yghem, M.C.; Vincen -Desplanques, D.; De ance-Fai e, F.; Capeau, J.; Fe mon, C.; Vala , A.S.; Lascols, O.; Heca , A.C.;
Pigny, P.; Deleme , B.; e al. Fe ili y and obs e ical complica ions in women wi h LMNA- ela ed amilial pa ial lipodys ophy.
J. Clin. Endoc inol. Me ab. 2008,93, 2223–2229. [C ossRe ] [PubMed]
122.
Gambine i, A.; Semple, R.K.; Fo lani, G.; Genghini, S.; G assi, I.; Hyden, C.S.S.; Pago o, U.; O’Rahilly, S.; Pasquali, R. Monogenic
polycys ic o a y synd ome due o a mu a ion in he lamin A/C gene is sensi i e o hiazolidinediones bu no o me o min. Eu .
J. Endoc inol. 2008,159, 347–353. [C ossRe ]
123.
Joy, T.R.; Hegele, R.A. P e alence o ep oduc i e abno mali ies among women wi h amilial pa ial lipodys ophy. Endoc . P ac .
2008,14, 1126–1132. [C ossRe ]
124. Hegele, R.A. Lessons om human mu a ions in PPARgamma. In . J. Obes. 2005,29 (Suppl. S1), S31–S35. [C ossRe ]
125.
Akinci, B.; Unlu, S.M.; Celik, A.; Simsi , I.Y.; Sen, S.; Nu , B.; Keskin, F.E.; Saydam, B.O.; Ozdemi , N.K.; Yu ekli, B.S.; e al. Renal
complica ions o lipodys ophy: A close look a he na u al his o y o kidney disease. Clin. Endoc inol.
2018
,89, 65–75. [C ossRe ]
[PubMed]
126.
Thong, K.M.; Xu, Y.; Cook, J.; Takou, A.; Wagne , B.; Kawa , B.; Ong, A.C. Coseg ega ion o ocal segmen al glome uloscle osis in
a amily wi h amilial pa ial lipodys ophy due o a mu a ion in LMNA. Neph on. Clin. P ac . 2013,124, 31–37. [C ossRe ]
127.
Rankin, J.; Aue -G umbach, M.; Bagg, W.; Colclough, K.; Duong, N.T.; Fen on-May, J.; Ha e sley, A.; Hudson, J.; Ja dine, P.;
Josi o a, D.; e al. Ex eme pheno ypic di e si y and nonpene ance in amilies wi h he LMNA gene mu a ion R644C. Am. J. Med.
Gene . A. 2008,146A, 1530–1542. [C ossRe ] [PubMed]
128.
Lado-Abeal, J.; Cal o, R.M.; Vic o ia, B.; Cas o, I.; Ob egon, M.J.; A aujo-Vila , D. Regional dec ease o subcu aneous adipose
issue in pa ien s wi h ype 2 amilial pa ial lipodys ophy is associa ed wi h changes in hy oid ho mone me abolism. Thy oid
2010,20, 419–424. [C ossRe ]
129.
Yousse , S.J.; Macielak, R.J.; Schimmen i, L.A.; Cha zopoulos, K.; P ice, D.L. Hypopha yngeal Squamous Cell Ca cinoma in Sis e s
wi h LMNA Associa ed Familial Pa ial Lipodys ophy: A Case Repo and Re iew o he Li e a u e. Ann. O ol. Rhinol. La yngol.
2020,129, 1243–1246. [C ossRe ]
130.
Akinci, B.; A O al, E.; Neide , A.; Rus, D.; Cheng, W.Y.; Thompson-Leduc, P.; Cheung, H.C.; B ad , P.; De F ei as, M.C.F.;
Mon eneg o, R.M.; e al. Como bidi ies and Su i al in Pa ien s Wi h Lipodys ophy: An In e na ional Cha Re iew S udy.
J. Clin. Endoc inol. Me ab. 2019,104, 5120–5135. [C ossRe ] [PubMed]
131.
Cook, K.; Ali, O.; Akinci, B.; de F ei as, M.C.F.; Mon eneg o, R.M.; Fe nandes, V.O.; Gup a, D.; Lou, K.-J.; Tu le, E.; A O al, E.; e al.
E ec o Lep in The apy on Su i al in Gene alized and Pa ial Lipodys ophy: A Ma ched Coho Analysis. J. Clin. Endoc inol.
Me ab. 2021,106, e2953–e2967. [C ossRe ] [PubMed]
Cells 2023,12, 725 22 o 23
132.
Mon ei o, L.; Foss-F ei as, M.C.; Na a o, A.; Pe ei a, F.; Coeli, F.; Ca neseca, E.; Junio , R.M.; Foss, M. E alua ion o Die a y
In ake, Leisu e-Time Physical Ac i i y, and Me abolic P o ile in Women wi h Mu a ion in he LMNA Gene. J. Am. Coll. Nu .
2017,36, 248–252. [C ossRe ]
133.
B own, R.J.; A aujo-Vila , D.; Cheung, P.T.; Dunge , D.; Ga g, A.; Jack, M.; Mungai, L.; O al, E.A.; Pa ni, N.; Ro he , K.I.; e al. The
Diagnosis and Managemen o Lipodys ophy Synd omes: A Mul i-Socie y P ac ice Guideline. J. Clin. Endoc inol. Me ab.
2016
,
101, 4500–4511. [C ossRe ]
134.
Lued ke, A.; Boschmann, M.; Colpe, C.; Engeli, S.; Adams, F.; Bi ken eld, A.L.; Hau e, S.; Rahn, G.; Lu , F.C.; Schmid , H.H.; e al.
Thiazolidinedione esponse in amilial lipodys ophy pa ien s wi h LMNA mu a ions: A case se ies. Ho m. Me ab. Res.
2012
,
44, 306–311. [C ossRe ] [PubMed]
135.
Vale io, C.M.; de Almeida, J.S.; Mo ei a, R.O.; Aguia , L.B.S.; Siciliano, P.O.; Ca alho, D.P.; Godoy-Ma os, A.F. Dipep idyl
pep idase-4 le els a e inc eased and pa ially ela ed o body a dis ibu ion in pa ien s wi h amilial pa ial lipodys ophy ype
2. Diabe ol. Me ab. Synd . 2017,9, 26. [C ossRe ]
136.
O al, E.A.; Ga g, A.; Tami, J.; Huang, E.A.; O’Dea, L.S.L.; Schmid , H.; Tiulpako , A.; Me ens, A.; Alexande , V.J.; Wa s, L.;
e al. Assessmen o e icacy and sa e y o olaneso sen o ea men o me abolic complica ions in pa ien s wi h amilial pa ial
lipodys ophy: Resul s o he BROADEN s udy: Volaneso sen in FPLD; The BROADEN S udy. J. Clin. Lipidol.
2022
,16, 833–849.
[C ossRe ] [PubMed]
137.
Foss-F ei as, M.C.; Akinci, B.; Neide , A.; Ba le , V.J.; Hu h, E.; Ka wa owska-P okopczuk, E.; O al, E.A. Selec i e a ge ing o
angiopoie in-like 3 (ANGPTL3) wi h upano sen o he ea men o pa ien s wi h amilial pa ial lipodys ophy (FPLD): Resul s
o a p oo -o -concep s udy. Lipids Heal h Dis. 2021,20, 174. [C ossRe ]
138.
Pa k, J.Y.; Ja o , E.D.; Coch an, E.K.; DePaoli, A.M.; Go den, P. Long- e m e icacy o lep in eplacemen in pa ien s wi h
Dunnigan- ype amilial pa ial lipodys ophy. Me abolism 2007,56, 508–516. [C ossRe ]
139.
Mosbah, H.; Van yghem, M.C.; Nobécou , E.; And eelli, F.; A chambeaud, F.; Bismu h, E.; B ie , C.; Ca igny, M.;
Che alie , B.
;
Donadille, B.; e al. The apeu ic indica ions and me abolic e ec s o me elep in in pa ien s wi h lipodys ophy synd omes:
Real-li e expe ience om a na ional e e ence ne wo k. Diabe es Obes. Me ab. 2022,24, 1565–1577. [C ossRe ]
140.
Simha, V.; Sub amanyam, L.; Szczepaniak, L.; Qui ne , C.; Adams-Hue , B.; Snell, P.; Ga g, A. Compa ison o e icacy and sa e y
o lep in eplacemen he apy in mode a ely and se e ely hypolep inemic pa ien s wi h amilial pa ial lipodys ophy o he
Dunnigan a ie y. J. Clin. Endoc inol. Me ab. 2012,97, 785–792. [C ossRe ]
141.
O al, E.A.; Go den, P.; Coch an, E.; A aújo-Vila , D.; Sa age, D.B.; Long, A.; Fine, G.; Salina di, T.; B own, R.J. Long- e m
e ec i eness and sa e y o me elep in in he ea men o pa ien s wi h pa ial lipodys ophy. Endoc ine
2019
,64, 500–511.
[C ossRe ] [PubMed]
142.
Va ie , C.; Fe i a, S.; Boudou, P.; Tchankou, C.; De ille, L.; Ri eline, J.; Young, J.; Ma hi on, L.; T a e , F.; Mo in, D.; e al. One-yea
me elep in imp o es insulin sec e ion in pa ien s wi h diabe es linked o gene ic lipodys ophic synd omes. Diabe es Obes. Me ab.
2016,18, 693–697. [C ossRe ]
143.
Ja o , E.D.; Ghany, M.G.; Coch an, E.K.; O al, E.A.; DePaoli, A.M.; P emkuma , A.; Kleine , D.E.; Go den, P. Lep in e e ses
nonalcoholic s ea ohepa i is in pa ien s wi h se e e lipodys ophy. Hepa ology 2005,41, 753–760. [C ossRe ]
144.
Miehle, K.; S um oll, M.; Fasshaue , M.; Hie l, T. Facial so issue olume dec eases du ing me elep in ea men in pa ien s
wi h pa ial and gene alized lipodys ophy. Endoc ine 2017. 58, 262–266. [C ossRe ]
145.
Me al, R.; Maland ino, N.; Wal e , M.; Neide , A.H.; Muniyappa, R.; O al, E.A.; B own, R.J. Endogenous Lep in Concen a ions
Poo ly P edic Me elep in Response in Pa ien s Wi h Pa ial Lipodys ophy. J. Clin. Endoc inol. Me ab.
2022
,107, e1739–e1751.
[C ossRe ]
146.
Sekizka des, H.; Coch an, E.; Maland ino, N.; Ga g, A.; B own, R.J. E icacy o Me elep in T ea men in Familial Pa ial
Lipodys ophy Due o PPARG s LMNA Pa hogenic Va ian s. J. Clin. Endoc inol. Me ab.
2019
,104, 3068–3076. [C ossRe ]
[PubMed]
147.
Oldenbu g, A.; B iand, N.; Sø ensen, A.L.; Cahyani, I.; Shah, A.; Moskaug, J.Ø.; Collas, P. A lipodys ophy-causing lamin A
mu an al e s con o ma ion and epigene ic egula ion o he an i-adipogenic MIR335 locus. J. Cell Biol.
2017
,216, 2731–2743.
[C ossRe ]
148.
Vad o , N.; Duband-Goule , I.; Cabe , E.; A anda, W.; Ba a eau, A.; Vica , P.; Ge bal, F.; B iand, N.; Vigou oux, C.;
Oldenbu g, A.R.
; e al. The p.R482W subs i u ion in A- ype lamins de egula es SREBP1 ac i i y in Dunnigan- ype amilial pa ial
lipodys ophy. Hum. Mol. Gene . 2015,24, 2096–2109. [C ossRe ]
149.
Kuo, F.-C.; Ne ille, M.J.; Saba a nam, R.; Wesolowska-Ande sen, A.; Phillips, D.; Wi emans, L.B.; an Dam, A.D.; Loh, N.Y.;
Todo ˇce i´c, M.; Den on, N.; e al. HOTAIR in e ac s wi h PRC2 complex egula ing he egional p eadipocy e ansc ip ome and
human a dis ibu ion. Cell Rep. 2022,40, 111136. [C ossRe ]
150.
A aújo-Vila , D.; Fe nández-Pombo, A.; Rod íguez-Ca ne o, G.; Ma ínez-Olmos, M.; Can ón, A.; Villa -Taibo, R.;
He mida-Ameijei as, Á.;
San ama ía-Nie o, A.; Díaz-O ega, C.; Ma ínez-Rey, C.; e al. LipoDDx: A mobile applica ion
o iden i ica ion o a e lipodys ophy synd omes. O phane J. Ra e Dis. 2020,15, 81. [C ossRe ] [PubMed]
Cells 2023,12, 725 23 o 23
151.
da Cunha Olega io, N.B.; da Cunha Ne o, J.S.; Ba bosa, P.C.S.; Pinhei o, P.R.; Landim, P.L.A.; Mon eneg o, A.P.D.R.;
Fe nandes, V.O.
; de Albuque que, V.H.C.; Dua e, J.B.F.; da C uz Pai a Lima, G.E.; e al. Iden i ying congeni al gene alized
lipodys ophy using deep lea ning-DEEPLIPO. Sci. Rep. 2023,13, 2176. [C ossRe ] [PubMed]
152.
on Schnu bein, J.; Adams, C.; Akinci, B.; Cecca ini, G.; D’Apice, M.R.; Gambine i, A.; Hennekam, R.C.M.; Je u, I.;
La anzi, G.
;
Miehle, K.; e al. Eu opean lipodys ophy egis y: Backg ound and s uc u e. O phane J. Ra e Dis.
2020
,15, 17. [C ossRe ]
[PubMed]
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